Paracetamol

De la Wikipedia,
enciclopedia liber
Paracetamolul (sau
paraacetilaminofenol,
acetaminofen) este un
derivat de para-
aminofenol din clasa
analidelor, cu aciune
analgezic i antipiretic.
Aciunea sa
antiinflamatoare este
practic inexistent, dar
acest lucru nu nseamn
c nu poate fi folosit n
durerile cauzate de
inflamaii.
Cuprins
1 Istoric
2 Sinteza chimic
3 Farmacologie
o 3.1
Farmacoci
netic
3.1
.1
M
etabolism i eliminare
4 Utilizare terapeutic
o 4.1 Indicaii terapeutice
o 4.2 Ci de administrare
o 4.3 Efecte adverse
o 4.4 Interaciuni
o 4.5 Contraindicaii
5 Toxicitate
o 5.1 Mecanismul celular al toxicitii
o 5.2 Intoxicaia
o 5.3 Tratamentul intoxicaiei
o 5.4 Produse farmaceutice
6 Legturi externe
7 Bibliografie

Paracetamol (Acetaminofen, para-acetil-amino-fenol)
4-(Acetilamino)fenol
CAS
103-90-2
cod ATC
N02BE01
Formul molecular brut C
8
H
9
NO
2

Mas molecular 151.17
Disponibilitate biologic aproape de 100% dup administrarea oral
Metabolism hepatic
Timp de njumtire 1 pn la 4 ore
Excreie renal
Ci de administrare oral, rectal
Doza minim letal mai mare de 8 g (la adultul sntos)
Proprieti fizice
Punct de topire 169 C
Densitate 1.263 g/cm
Solubilitate n ap
1.4 g/100 ml (la 20 C)
(solubil i n ali solveni polari)
Istoric
A fost sintetizat n 1873 prin reducerea p-nitrofenolului n mediu de acid acetic. Acetanilida
(antifebrina) fusese deja descoperit n 1866, iar fenacetina n 1877 i se foloseau ca antipiretice
i analgezice. Eventualele proprieti terapeutice ale paracetamolului au fost ignorate la data
descoperirii sale. n 1893 paracetamolul a fost decelat n urina pacienilor crora li se
administrase fenacetin, iar n 1899 n cea a pacienilor care luaser acetanilid. n ambele cazuri
a fost considerat un metabolit neimportant din punct de vedere farmacologic al acestor
medicamente. n 1946, Bernard Brodie i Julius Axelrod cercetau legturile cauzale dintre
analgezicele de tipul fenacetinei i acetanilidei i methemoblobinemie. Ei au descoperit c de
fapt efectul analgezic al acetanilidei se datora metabolitului su, paracetamolul, i c la
administrarea acestuia methemoglobinemia este mult redus ca inciden i amploare.
Sinteza chimic
O variant de sintez o reprezint acetilarea para-amino-fenolului cu anhidrid acetic:


p-amino-femol + anhidrid acetic p-acetil-amino-femol + acid acetic
Acetilarea se poate realiza i cu acid acetic, ns are un randament mult mai mic, din cauza apei
care rezult din reacie.
Farmacologie
Paracetamolul are o excelent biodisponibilitate dup administrarea oral, i din acest motiv
administraraea sa pe cale parenteral este extrem de rar folosit. Pe scurt, proprietile sale
terapeutice se explic prin inhibarea sintezei prostaglandinelor. Aceasta determin efectul
analgezic (prin blocarea formrii de prostaglandine E2 n sistemul nervos central i periferic) i
pe cel antipiretic (la nivelul centrului termoreglrii din hipotalamus. Sinteza prostaglandinelor
este rezultatul aciunii ciclooxigenazei, care este inhibat indirect de paracetamol.
Farmacocinetic


Model tridimensional al moleculei de paracetamol: Negru - Carbon; Alb - Hidrogen; Rou - Oxigen; Albastru - Azot
Se absoarbe rapid i aproape complet din tubul digestiv, concentraia plasmatic maxim
aprnd la 40-60 de minute dup ingestie. La maxim 4 ore absorbia este maxim. Difuzeaz n
toate esuturile, trecnd inclusiv de bariera hematoencefalic. Timpul de njumtire este de 1-3
ore, dar crete pn la 5 ore la nou-nscui i la pacienii cu insuficien hepatic sau renal. La
dozele terapeutice de 0,5-2 g legarea de proteinele plasmatice este de maxim 25% i minim 10%.
La dozele toxice sau n cazul insuficienei hepatice ajunge pn la 50%.
Metabolism i eliminare
80-90% este metabolizat n ficat prin conjugare, rezultnd glucurono- (cea mai mare parte) i
sulfoconjugai, excretai apoi n urin. 2% pn la 4% se elimin sub form neschimbat n
urin, iar o mic fraciune ia calea citocromului P450 din mitocondriile hepatice, fiind sursa unui
metabolit foarte toxic, care este rapid inactivat prin conjugare cu glutation. Acest metabolit este
apoi conjugat a doua oar cu cistein i acid mercapturic i eliminat renal. Aceast oxidare cu 2
electroni a acetaminofenului la N acetilbenzosemichinonimin, de ctre PHS implic probabil
formarea unui produs de oxidare cu un electron, Nacetil-benyosemichinonimin, radical liber,
ambii metabolii fiind impliaci n toxicitatea renal.Exist controverse n legtur cu identitatea
acestui metabolit intermediar. O serie de dovezi experimentale sugereaz c ar fi N-
acetilimidoquinona. n afar de aceste ci de inactivare, n ficat paracetamolul mai sufer i
conjugare cu cistein i deacetilare (rezultnd para-aminofenol).Dup cum se observ activarea
n prezena citocromuli P450 conduce la hepatotoxicitate, iar activarea de ctre PHS duce la
nefrotoxicitate, asta deoarece n zona medular renal are nivele joase de Cit P450, dar nivele
nalte de PHS.


Biotransformarea paracetamolului
Utilizare terapeutic
Indicaii terapeutice
Este utilizat n mod curent pentru tratamentul simptomatic al afeciunilor care implic
durere de intensitate slab sau moderat:
o cefalee
o nevralgii dentare
o dureri chirurgicale
o artralgii nereumatismale
o entorse, fracturi, luxaii
o dismenoree
Eficiena maxim a paracetamolului se obine n cazul durerilor slabe de origine non-visceral.
Ca antipiretic n hipertermiile de natur infecioas. Efectul antipiretic este proporional
cu temperatura: paracetamolul este complet ineficient n scderea temperaturii normale
Ci de administrare
Per os (oral)
Rectal
intravenos, pentru durerea postoperatorie
Efecte adverse
Manifestri alergice urticariene
Agranulocitoz sau granulocitopenie
Anemie
Trombocitopenie
Dup doze toxice sau utilizare cronic: hepatotoxicitate cu necroz hepatic generalizat
i ireversibil
Poate aprea dependena psihic de paracetamol, dar dezvoltarea toleranei i a
dependenei fizice nu a fost semnalat.
Interaciuni
Alcoolul i barbituricele pot potena hepatotoxicitatea, dar numai la doze mari
Modific rezultatul dozrii acidului uric n ser
Modific rezultatul dozrii glucozei n ser (doar pentru metoda glucozo-oxidazei)
Poate scadea tranzitoriu transaminazele, timpul de protrombin i bilirubina.
Efectul su hepatotoxic este potenat de cofein.
Contraindicaii
Hipersensibilitate la paracetamol
Se impune pruden n cazul insuficienei hepatice sau renale i n hepatite
Alcoolism
Toxicitate
Mecanismul celular al toxicitii
n caz de supradozare cile de inactivare prin sulfo- i glucurono-conjugare se satureaz i astfel
se recurge la calea n mod normal minoritar, a citocromului P450 (oxidare). Metabolitul
intermediar, foarte toxic datorit gradului mare de reactivitate, despre care se crede c este N-
acetilimidoquinona, este rapid conjugat cu glutation. Gluationul poate deveni destul de repede
insuficient n intoxicaiile masive, i astfel N-acetilimidoquinona liber difuzeaz n citoplasma
hepatocitelor, ajungnd s reacioneze ireversibil cu glicoproteinele membranare. Sunt afectate i
endomembranele, rezultnd practic eliberarea aa-numitelor componenete "microsomale".
Acesta este mecanisml de toxicitate al paracetamolului, dar i al altor compui care epuizeaz
rezervele hepatocelulare de glutation. Se ajunge la citoliz, cu necroz hepatic generalizat i
implicit insuficien hepatic. Majoritatea datelor experimentale indic faptul c depleia de
glutation la care apare citoliza este de circa 70%. Semnele unei intoxicaii apar la doze foarte
variate, ncepnd cu 5-8 g. n cazul indivizilor tarai sau al copiilor dozele periculoase pot fi mult
mai mici.
Intoxicaia
Fiier:Paracetamol.gif
Relaia dintre riscul de toxicitate hepatic manifest, timp i concentraia plasmatic a paracetamolului. Se observ
c pragul de alert este o concentraie de 150 de g/ml la 4 ore, i certitudinea afectrii ireversibile a ficatului apare
n cazul unei concentraii de 200 g/ml la 4 ore
Dup 1-3 ore de la ingestia unei doze mai mari de 5-8 g apar primele semne care constau n:
Grea
Vrsturi
Anorexie
Dureri abdominale
n intoxicaiile cu doze mult mai mari, acestea sunt nlocuite sau nsoite de:
Agitaie, delir
Stupoare, obnubilare sau com
Hipotermie moderat
Dispnee
Hipotensiune arterial i tahicardie mergnd pn la oc
Tratamentul intoxicaiei
Antidotul pentru intoxicaia cu paracetamol este N-acetilcisteina. Aceasta trebuie administrat
ct de repede posibil, n paralel cu diferite msuri de tratament simptomatic, i cu monitorizarea
funciilor vitale.
Este important de menionat faptul c o intoxicaie cu paracetamol are o perioad de evoluie
critic de pn la 72 de ore, n care pot s apar sau nu primele semne ale citolizei, manifestate
bochimic prin creterea marcat a transaminazelor i clinic prin semnele unei insuficiene
hepatice fulminante.
Paracetamolul este foarte toxic pentru cini, pisici i alte mamifere. Pentru aceste animale, doze
foarte mici pot da intoxicaii grave, letale. Din acest motiv paracetamolul este evitat de terapia
veterinar.
Produse farmaceutice
Paracetamol, (cpr filmate), Efferalgan, (cpr ef, sirop, supozitoare), Panadol (cpr, sirop),
Prefalgan (flac. injectabile i.v.) Se poate asocia cu codeina ptr potentarea efectelor (Napodoren)
sau cu tramadol (Zaldiar).
Legturi externe
en Pharmweb.net: O istorie a paracetamolului
en Cteva elemente de chimie a paracetamolului
en Julius Axelrod
en TheMedicine.NET: Paracetamol
ro Cofeina poteneaz efectele hepatotoxice ale acetaminofenului
Bibliografie
Matthew J. Ellenhorn, Seth Schonwald, Gary Ordog, Jonathan Wasserberger:
Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning (Medical
Toxicology), 2nd edition, 1997
Lester M., Md. Haddad, Michael W. Shannon, j Winchester, Judy Fletcher Editor),
Lames P. Winchester: Clinical Management of Poisoning and Drug Overdose
Roman Vlaicu, Emilia Macavei, Ioan Murean: Practica urgenelor medicale, vol. 1,
1979



Paracetamol (/prsitml/ or /prstml/), acetaminophen
i
/sitmnfn/, or
APAP, chemically named N-acetyl-p-aminophenol, is a widely used over-the-counter analgesic
(pain reliever) and antipyretic (fever reducer).
[4][5]
Paracetamol is the International
Nonproprietary Name (INN), Australian Approved Name (AAN) and British Approved Name
(BAN), while acetaminophen is the United States Adopted Name (USAN) and Japanese Adopted
Name (JAN).
[6][7][8]

Paracetamol is classified as a mild analgesic. It is commonly used for the relief of headaches and
other minor aches and pains and is a major ingredient in numerous cold and flu remedies. In
combination with opioid analgesics, paracetamol can also be used in the management of more
severe pain such as post-surgical pain and providing palliative care in advanced cancer
patients.
[9]
Though paracetamol is used to treat inflammatory pain, it is not generally classified as
an NSAID because it exhibits only weak anti-inflammatory activity.
While generally safe for use at recommended doses even small overdoses can be fatal. Compared
to other over-the-counter pain relievers, paracetamol is significantly more toxic in overdose but
may be less toxic when used chronically at recommended doses.
[10]
Paracetamol is the active
metabolite of phenacetin and acetanilide, two once popular as an analgesic and antipyretic in its
own right.
[11][12]
However, unlike phenacetin, acetanilide and their combinations, paracetamol is
not considered carcinogenic at therapeutic doses.
[13]

The words acetaminophen (used in the United States,
[7]
Canada,
[7]
Japan)
[6]
and paracetamol
(used elsewhere) both come from a chemical name for the compound: para-acetylaminophenol
and para-acetylaminophenol. In some contexts, it is simply abbreviated as APAP, for acetyl-
para-aminophenol. It is on the World Health Organization's List of Essential Medicines, a list of
the most important medication needed in a basic health system.
[14]

Contents
1 Medical uses
o 1.1 Fever
o 1.2 Pain
2 Adverse effects
o 2.1 Liver damage
o 2.2 Cancer
o 2.3 Skin reactions
o 2.4 Asthma
o 2.5 Other factors
o 2.6 Overdose
o 2.7 Pregnancy
3 Mechanism of action
4 Structure and reactivity
5 Synthesis
6 Metabolism
7 Reactions
8 History
9 Available forms
10 Veterinary use
o 10.1 Cats
o 10.2 Dogs
o 10.3 Snakes
11 Controversy
12 Classification
13 References
14 External links
Medical uses
Fever
Paracetamol is approved for reducing fever in people of all ages.
[15]
The World Health
Organization (WHO) recommends that paracetamol only be used to treat fever in children if their
temperature is greater than 38.5 C (101.3 F).
[16]
The efficacy of paracetamol by itself in
children with fevers has been questioned
[17]
and a meta-analysis showed that it is less effective
than ibuprofen.
[18]

Pain
Paracetamol is used for the relief of pains associated with many parts of the body. It has
analgesic properties comparable to those of aspirin, while its anti-inflammatory effects are
weaker. It is better tolerated than aspirin in patients in whom excessive gastric acid secretion or
prolongation of bleeding time may be a concern. Available without a prescription since 1959,
[19]

it has since become a common household drug.
[20]

Paracetamol has a relatively little anti-inflammatory activity, unlike other common analgesics
such as the NSAIDs aspirin and ibuprofen, but ibuprofen and paracetamol have similar effects in
the treatment of headache. Paracetamol can relieve pain in mild arthritis, but has no effect on the
underlying inflammation, redness, and swelling of the joint.
[21]

Regarding comparative efficacy, studies show conflicting results when compared to NSAIDs. A
randomised controlled trial of chronic pain from osteoarthritis in adults found similar benefit
from paracetamol and ibuprofen.
[22][23]

The efficacy of paracetamol when used in combination with weak opioids (such as codeine) was
assessed in data studies in 1996 and 2009,
[24][25]
which found improved efficacy for
approximately 50% of patients but increases in the number of patients experiencing adverse
effects. Combination drugs of paracetamol and strong opioids like morphine reduce the amount
of opioid needed and improve analgesic effect.
[26]

A randomised controlled trial of acute musculoskeletal pain in children found that the standard
over-the-counter dose of ibuprofen gives greater pain relief than the standard dose of
paracetamol.
[27]

Adverse effects
In recommended doses and for a limited course of treatment, the side effects of paracetamol are
mild to non-existent.
[28]
However some risks and adverse correlations have been identified:
Liver damage
Acute overdoses of paracetamol can cause potentially fatal liver damage. According to the US
Food and Drug Administration, "Acetaminophen can cause serious liver damage if more than
directed is used."
[29]
and in 2011 the FDA required manufacturers to update labels of all
prescription combination acetaminophen products to warn of the potential risk for severe liver
injury
[30]
and launched a public education program to help consumers avoid overdose.
[31]

[32]
The
risk may be heightened by chronic alcohol abuse. Paracetamol toxicity is the foremost cause of
acute liver failure in the Western world, and accounts for most drug overdoses in the United
States, the United Kingdom, Australia and New Zealand.
[33][34][35][36]
According to the FDA, in
the United States there were "56,000 emergency room visits, 26,000 hospitalizations, and 458
deaths per year related to acetaminophen-associated overdoses during the 1990s. Within these
estimates, unintentional acetaminophen overdose accounted for nearly 25 percent of the
emergency department visits, 10 percent of the hospitalizations, and 25 percent of the deaths."
[37]

Paracetamol is metabolised by the liver and is hepatotoxic; side effects are multiplied when
combined with alcoholic drinks, and very likely in chronic alcoholics or patients with liver
damage.
[28][38]
Some studies have suggested the possibility of a moderately increased risk of
upper gastrointestinal complications such as stomach bleeding when high doses are taken
chronically.
[39]
Kidney damage is seen in rare cases, most commonly in overdose.
[40]
The Food
and Drug Administration has warned doctors against prescribing paracetamol/narcotic
combinations whose dosages exceed 325 mg of paracetamol due to hepatoxicity risks of greater
magnitude than the therapeutic benefits conferred.
[41]

Cancer
Chronic users of paracetamol may have a higher risk of developing blood cancer.
[42]

Skin reactions
On August 2, 2013, the U.S. Food and Drug Administration (FDA) issued a new warning about
paracetamol. It stated that the drug could cause rare, and possibly fatal, skin reactions, such as
StevensJohnson syndrome and toxic epidermal necrolysis. Prescription-strength products will
be required to carry a warning label about skin reactions, and the FDA has urged manufacturers
to do the same with over-the-counter products.
[43]

Asthma
There is an association between paracetamol use and asthma but it is unclear if it has a role in
causing asthma.
[44]

As of 2014, the American Academy of Pediatrics and the National Institute for Health and
Clinical Excellence (NICE) continue to recommend paracetamol for pain and discomfort in
children,
[45][46][47][48][49][50]
but some experts have recommended that paracetamol use by children
with asthma, or at risk for asthma, should be avoided.
[51][52]

Other factors
In contrast to aspirin, paracetamol is not an antithrombotic, and thus may be used in patients
where coagulation is a concern, and it does not cause gastric irritation.
[53]
However, paracetamol
does not help reduce inflammation, while aspirin does.
[54]
Compared to ibuprofenwhose side
effects may include diarrhea, vomiting and abdominal painparacetamol has fewer adverse
gastrointestinal effects.
[55]

Unlike aspirin, paracetamol is generally considered safe for children, as it is not associated with
a risk of Reye's syndrome in children with viral illnesses.
[56]

Paracetamol when taken recreationally with opioids may cause hearing loss.
[57][better source needed]

Overdose
Main article: Paracetamol toxicity
Untreated paracetamol overdose results in a lengthy, painful illness. Signs and symptoms of
paracetamol toxicity may initially be absent or non-specific symptoms. The first symptoms of
overdose usually begin several hours after ingestion, with nausea, vomiting, sweating, and pain
as acute liver failure starts.
[58]
People who take overdoses of paracetamol do not lose
consciousness, although most people who attempt suicide with paracetamol wrongly believe that
they will be rendered unconscious by the drug.
[59]
The process of dying from an overdose usually
takes three to five days.
Paracetamol hepatotoxicity is, by far, the most common cause of acute liver failure in both the
United States and the United Kingdom.
[36][60]
Paracetamol overdose results in more calls to
poison control centers in the US than overdose of any other pharmacological substance.
[61]

Toxicity of paracetamol is believed to be due to its quinone metabolite.
[62]

Untreated overdose can lead to liver failure and death within days. Treatment is aimed at
removing the paracetamol from the body and replacing glutathione.
[62]
Activated charcoal can be
used to decrease absorption of paracetamol if the patient presents for treatment soon after the
overdose. While the antidote, acetylcysteine, (also called N-acetylcysteine or NAC) acts as a
precursor for glutathione, helping the body regenerate enough to prevent or at least decrease the
possible damage to the liver, a liver transplant is often required if damage to the liver becomes
severe.
[33][63]
NAC was usually given following a treatment nomogram (one for patients with risk
factors, and one for those without) but the use of the nomogram is no longer recommended as
evidence to support the use of risk factors was poor and inconsistent, and many of the risk factors
are imprecise and difficult to determine with sufficient certainty in clinical practice.
[64]
NAC also
helps in neutralizing the imidoquinone metabolite of paracetamol.
[62]
Renal failure is also a
possible side effect.
There were tablets available until 2004 (brand-name in the UK Paradote) that combined
paracetamol with an antidote (methionine), to protect the liver in case of an overdose. One
theoretical, but rarely if ever used, option in the United States is to request a compounding
pharmacy to make a similar drug mix for at-risk patients.
In June 2009, a U.S. Food and Drug Administration (FDA) advisory committee recommended
that new restrictions should be placed on paracetamol usage in the United States to help protect
people from the potential toxic effects. The maximum dosage at any given time would be
decreased from 1000 mg to 650 mg, while combinations of paracetamol and narcotic analgesics
would be prohibited. Committee members were particularly concerned by the fact that the
present maximum dosages of paracetamol had been shown to produce alterations in hepatic
function.
[65]

In January 2011, the FDA asked manufacturers of prescription combination products containing
paracetamol to limit the amount of paracetamol to no more than 325 mg per tablet or capsule and
began requiring manufacturers to update the labels of all prescription combination paracetamol
products to warn of the potential risk of severe liver damage.
[66][67][68][69]
Manufacturers had three
years to limit the amount of paracetamol in their prescription drug products to 325 mg per dosage
unit.
[67][69]
In November 2011, the Medicines and Healthcare products Regulatory Agency
revised UK dosing of liquid paracetamol for children.
[70]

Pregnancy
Experimental studies in animals and cohort studies in humans indicate no detectable increase in
congenital malformations associated with paracetamol use during pregnancy.
[71]
Additionally,
paracetamol does not affect the closure of the fetal ductus arteriosus as NSAIDs can.
[72]

However, paracetamol use by mother during pregnancy is associated with an increased risk of
childhood asthma.
[73]

Mechanism of action


AM404 Metabolite of paracetamol


Anandamide Endogenous cannabinoid
To date, the mechanism of action of paracetamol is not completely understood. The main
mechanism proposed is the inhibition of cyclooxygenase (COX), and recent findings suggest that
it is highly selective for COX-2.
[74]
Because of its selectivity for COX-2 it does not significantly
inhibit the production of the pro-clotting thromboxanes.
[74]
While it has analgesic and antipyretic
properties comparable to those of aspirin or other NSAIDs, its peripheral anti-inflammatory
activity is usually limited by several factors, one of which is the high level of peroxides present
in inflammatory lesions. However, in some circumstances, even peripheral anti-inflammatory
activity comparable to NSAIDs can be observed.
An article
[75]
in Nature Communications from researchers in London, UK and Lund, Sweden in
November 2011 has found a hint to the analgesic mechanism of paracetamol, being that the
metabolites of paracetamol e.g. NAPQI, act on TRPA1-receptors in the spinal cord to suppress
the signal transduction from the superficial layers of the dorsal horn, to alleviate pain.
This conclusion has been contested in a new hypothesis paper
[76]
on how paracetamol might act.
The author concedes that NAPQI is the active metabolite but that this reactive compound should
react not only with the thiol in TRPA1 but also with any other suitably available nucleophile that
it happens to encounter. It is suggested that thiol groups in cysteine proteases, e.g. the proteases
that take part in the processing of procytokines, such as those generating IL-1 and IL-6, might
be the targets giving rise to overall analgesic effects.
The COX family of enzymes are responsible for the metabolism of arachidonic acid to
prostaglandin H
2
, an unstable molecule that is, in turn, converted to numerous other pro-
inflammatory compounds. Classical anti-inflammatories such as the NSAIDs block this step.
Only when appropriately oxidised is the COX enzyme highly active.
[77][78]
Paracetamol reduces
the oxidised form of the COX enzyme, preventing it from forming pro-inflammatory
chemicals.
[79][80]
This leads to a reduced amount of prostaglandin E2 in the CNS, thus lowering
the hypothalamic set-point in the thermoregulatory centre.
Aspirin is known to inhibit the cyclooxygenase (COX) family of enzymes and, because
paracetamol's action is partially similar to aspirin's,
[clarification needed]
much research has focused on
whether paracetamol also inhibits COX. It is now clear that paracetamol acts via at least two
pathways.
[79][81][82][83]

The exact mechanisms by which COX is inhibited in various circumstances are still a subject of
discussion. Because of differences in the activity of paracetamol, aspirin, and other NSAIDs, it
has been postulated that further COX variants may exist. One theory holds that paracetamol
works by inhibiting the COX-3 isoforma COX-1 splice variantof the COX family of
enzymes.
[74]
When expressed in dogs, this enzyme shares a strong similarity to the other COX
enzymes, produces pro-inflammatory chemicals, and is selectively inhibited by paracetamol.
[84]

However, some research has suggested that, in humans and mice, the COX-3 enzyme is without
inflammatory action and paracetamol's blockage of it is not significant in its functioning in
humans.
[74][82]

Another possibility is that paracetamol blocks cyclooxygenase (as in aspirin), but that, in an
inflammatory environment where the concentration of peroxides is high, the high oxidation state
of paracetamol prevents its actions. This idea would mean that paracetamol has no direct effect at
the site of inflammation, but instead acts in the CNS where the environment is not oxidative, to
reduce temperature, etc.
[84]

Paracetamol also modulates the endogenous cannabinoid system.
[85]
Paracetamol is metabolised
to AM404, a compound with several actions; what is most important is that it inhibits the
reuptake of the endogenous cannabinoid/vanilloid anandamide by neurons. Anandamide
reuptake lowers synaptic levels of anandamide and results in more activation of the main pain
receptor (nociceptor) of the body, the TRPV1 (older name: vanilloid receptor). By inhibiting
anandamide reuptake, levels in the synapse remain high and are able to desensitise the TRPV1
receptor much like capsaicin. Furthermore, AM404 inhibits sodium channels, as do the
anesthetics lidocaine and procaine.
[86]
Both of these actions by themselves have been shown to
reduce pain, and are a possible mechanism for paracetamol. However, it has been demonstrated
that, when cannabinoid receptors are blocked with synthetic antagonists, paracetamol's analgesic
effects are prevented, suggesting its pain-relieving action involves the endogenous cannabinoid
system.
[87]
Spinal TRPA1 receptors have also been demonstrated to mediate antinociceptive
effects of paracetamol and 9-tetrahydrocannabinol in mice.
[88]

Increase of social behavior in mice dosed with paracetamol (which corresponds to a reduction of
social rejection response in humans) does not appear to be due to cannabinoid receptor type 1
activity. It may result from serotonin receptor agonism.
[89]

Structure and reactivity


Paracetamol molecule polar surface area


Paracetamol Electron Map Electrostatic surface area
Paracetamol consists of a benzene ring core, substituted by one hydroxyl group and the nitrogen
atom of an amide group in the para (1,4) pattern.
[90]
The amide group is acetamide (ethanamide).
It is an extensively conjugated system, as the lone pair on the hydroxyl oxygen, the benzene pi
cloud, the nitrogen lone pair, the p orbital on the carbonyl carbon, and the lone pair on the
carbonyl oxygen are all conjugated. The presence of two activating groups also make the
benzene ring highly reactive toward electrophilic aromatic substitution. As the substituents are
ortho, para-directing and para with respect to each other, all positions on the ring are more or
less equally activated. The conjugation also greatly reduces the basicity of the oxygens and the
nitrogen, while making the hydroxyl acidic through delocalisation of charge developed on the
phenoxide anion.
Synthesis
In a small-scale laboratory, paracetamol is prepared by a three-reaction sequence. First, nitration
of phenol with sodium nitrate gives a mixture of two isomers, from which the wanted 4-
nitrophenol (bp ~93 C) can easily be separated by steam distillation. In this electrophilic
aromatic substitution reaction, the phenol oxygen is strongly activating, thus the reaction requires
only mild conditions as compared to nitration of benzene itself. The nitro group is then reduced
to an amine, giving 4-aminophenol. This reaction can be accomplished using sodium
borohydride. Finally, the amine is acetylated with acetic anhydride.
[91]
The industrial process is
analogous, but hydrogenation is used instead of the sodium borohydride reduction.
[92][93]


An alternative industrial synthesis developed by HoechstCelanese involves direct acylation of
phenol with acetic anhydride catalyzed by HF, conversion of the ketone to a ketoxime with
hydroxylamine, followed by the acid-catalyzed Beckmann rearrangement to give the
amide.
[93][94]


Demand for paracetamol in the United States was estimated at 3035 thousand tonnes per year in
1997, equal to the demand from the rest of the world.
[95]

Metabolism


Main pathways of paracetamol metabolism (click to enlarge). Pathways shown in blue and
purple lead to non-toxic metabolites; the pathway in red leads to toxic NAPQI.
Paracetamol is metabolised primarily in the liver, into toxic and non-toxic products. Three
metabolic pathways are notable:
[62]

Glucuronidation is believed to account for 40% to two-thirds of the metabolism of
paracetamol.
[96]

Sulfation (sulfate conjugation) may account for 2040%.
[96]

N-hydroxylation and dehydration, then GSH conjugation, accounts for less than 15%.
The hepatic cytochrome P450 enzyme system metabolises paracetamol, forming a minor
yet significant alkylating metabolite known as NAPQI (N-acetyl-p-benzoquinone
imine)(also known as N-acetylimidoquinone).
[62][97]
NAPQI is then irreversibly
conjugated with the sulfhydryl groups of glutathione.
[97]

All three pathways yield final products that are inactive, non-toxic, and eventually excreted by
the kidneys. In the third pathway, however, the intermediate product NAPQI is toxic. NAPQI is
primarily responsible for the toxic effects of paracetamol; this constitutes an example of
toxication.
Production of NAPQI is due primarily to two isoenzymes of cytochrome P450: CYP2E1 and
CYP1A2. The P450 gene is highly polymorphic, however, and individual differences in
paracetamol toxicity are believed due to a third isoenzyme, CYP2D6. Genetic polymorphisms in
CYP2D6 may contribute to significantly different rates of production of NAPQI. Furthermore,
individuals can be classified as "extensive", "ultrarapid", "intermediate" and "poor" metabolisers
(producers of NAPQI), depending on their levels of CYP2D6 expression. Although CYP2D6
metabolises paracetamol into NAPQI to a lesser extent than other P450 enzymes, its activity may
contribute to paracetamol toxicity in extensive and ultrarapid metabolisers, and when
paracetamol is taken at very large doses.
[98]
At usual doses, NAPQI is quickly detoxified by
conjugation with glutathione.
[62][97]
Following overdose, and possibly also in extensive and
ultrarapid metabolisers, this detoxification pathway becomes saturated, and, as a consequence,
NAPQI accumulates causing liver and renal toxicity.
[62]

Reactions
4-Aminophenol may be obtained by the amide hydrolysis of paracetamol. 4-Aminophenol
prepared this way, and related to the commercially available Metol, has been used as a developer
in photography by hobbyists.
[99]
This reaction is also used to determine paracetamol in urine
samples: After hydrolysis with hydrochloric acid, 4-aminophenol reacts in ammonia solution
with a phenol derivate, e.g. salicylic acid, to form an indophenol dye under oxidization by air.
[100]

History


Julius Axelrod (pictured) and Bernard Brodie demonstrated that acetanilide and phenacetin are
both metabolised to paracetamol, which is a better tolerated analgesic.
Acetanilide was the first aniline derivative serendipitously found to possess analgesic as well as
antipyretic properties, and was quickly introduced into medical practice under the name of
Antifebrin by A. Cahn and P. Hepp in 1886.
[101]
But its unacceptable toxic effects, the most
alarming being cyanosis due to methemoglobinemia, prompted the search for less toxic aniline
derivatives.
[81]
Harmon Northrop Morse had already synthesised paracetamol at Johns Hopkins
University via the reduction of p-nitrophenol with tin in glacial acetic acid in 1877,
[102][103]
but it
was not until 1887 that clinical pharmacologist Joseph von Mering tried paracetamol on
patients.
[81]
In 1893, von Mering published a paper reporting on the clinical results of
paracetamol with phenacetin, another aniline derivative.
[104]
Von Mering claimed that, unlike
phenacetin, paracetamol had a slight tendency to produce methemoglobinemia. Paracetamol was
then quickly discarded in favor of phenacetin. The sales of phenacetin established Bayer as a
leading pharmaceutical company.
[105]
Overshadowed in part by aspirin, introduced into medicine
by Heinrich Dreser in 1899, phenacetin was popular for many decades, particularly in widely
advertised over-the-counter "headache mixtures", usually containing phenacetin, an aminopyrine
derivative of aspirin, caffeine, and sometimes a barbiturate.
[81]

Von Mering's claims remained essentially unchallenged for half a century, until two teams of
researchers from the United States analyzed the metabolism of acetanilide and paracetamol.
[105]

In 1947 David Lester and Leon Greenberg found strong evidence that paracetamol was a major
metabolite of acetanilide in human blood, and in a subsequent study they reported that large
doses of paracetamol given to albino rats did not cause methemoglobinemia.
[106]
In three papers
published in the September 1948 issue of the Journal of Pharmacology and Experimental
Therapeutics, Bernard Brodie, Julius Axelrod and Frederick Flinn confirmed using more specific
methods that paracetamol was the major metabolite of acetanilide in human blood, and
established that it was just as efficacious an analgesic as its precursor.
[107][108][109]
They also
suggested that methemoglobinemia is produced in humans mainly by another metabolite,
phenylhydroxylamine. A follow-up paper by Brodie and Axelrod in 1949 established that
phenacetin was also metabolised to paracetamol.
[110]
This led to a "rediscovery" of
paracetamol.
[81]
It has been suggested that contamination of paracetamol with 4-aminophenol,
the substance von Mering synthesised it from, may be the cause for his spurious findings.
[105]

Paracetamol was first marketed in the United States in 1950 under the name Triagesic, a
combination of paracetamol, aspirin, and caffeine.
[103]
Reports in 1951 of three users stricken
with the blood disease agranulocytosis led to its removal from the marketplace, and it took
several years until it became clear that the disease was unconnected.
[103]
Paracetamol was
marketed in 1953 by Sterling-Winthrop Co. as Panadol, available only by prescription, and
promoted as preferable to aspirin since it was safe for children and people with ulcers.
[103][105][111]

In 1955, paracetamol was marketed as Children's Tylenol Elixir by McNeil Laboratories.
[112]
In
1956, 500 mg tablets of paracetamol went on sale in the United Kingdom under the trade name
Panadol, produced by Frederick Stearns & Co, a subsidiary of Sterling Drug Inc. Panadol was
originally available only by prescription, for the relief of pain and fever, and was advertised as
being "gentle to the stomach," since other analgesic agents of the time contained aspirin, a
known stomach irritant. In 1963, paracetamol was added to the British Pharmacopoeia, and has
gained popularity since then as an analgesic agent with few side-effects and little interaction with
other pharmaceutical agents.
[103]
Concerns about paracetamol's safety delayed its widespread
acceptance until the 1970s, but in the 1980s paracetamol sales exceeded those of aspirin in many
countries, including the United Kingdom. This was accompanied by the commercial demise of
phenacetin, blamed as the cause of analgesic nephropathy and hematological toxicity.
[81]

The U.S. patent on paracetamol has long expired, and generic versions of the drug are widely
available under the Drug Price Competition and Patent Term Restoration Act of 1984, although
certain Tylenol preparations were protected until 2007. U.S. patent 6,126,967 filed September 3,
1998 was granted for "Extended release acetaminophen particles".
[113]

Available forms
See also: List of paracetamol brand names

Tylenol 500 mg capsules

Panadol 500 mg tablets

For comparison: The pure drug is a white crystalline powder.
Paracetamol is available in a tablet, capsule, liquid suspension, suppository, intravenous,
intramuscular and Effervescent form. The common adult dose is 500 mg to 1000 mg. The
recommended maximum daily dose, for adults, is 4000 mg. In recommended doses, paracetamol
is generally safe for children and infants, as well as for adults,
[114]
although rare cases of acute
liver injury have been linked to amounts lower than 2500 mg per day.
[115]

In some formulations, paracetamol is combined with the opioid codeine, sometimes referred to
as co-codamol (BAN). In the U.S., this combination is available only by prescription, while the
lowest-strength preparation is over-the-counter in Canada, and, in other countries, other strengths
may be available over the counter.
[citation needed]
Paracetamol is also combined with other opioids
such as dihydrocodeine, referred to as co-dydramol (BAN), oxycodone or hydrocodone. Another
very commonly used analgesic combination includes paracetamol in combination with
propoxyphene napsylate. A combination of paracetamol, codeine, and the calmative doxylamine
succinate is also available. The efficacy of paracetamol/codeine combinations have been
questioned by recent research.
[26]

Paracetamol is commonly used in multi-ingredient preparations for migraine headache, typically
including butalbital and paracetamol with or without caffeine, and sometimes containing
codeine.
Paracetamol is sometimes combined with phenylephrine hydrochloride.
[116]
Sometimes a third
active ingredient, such as ascorbic acid,
[116][117]
caffeine,
[118][119]
chlorpheniramine maleate,
[120]
or
guaifenesin.
[121][122][123]
is added to this combination.
Veterinary use
Cats
Paracetamol is extremely toxic to cats, which lack the necessary glucuronyl transferase enzymes
to safely break it down. Initial symptoms include vomiting, salivation, and discolouration of the
tongue and gums.
Unlike an overdose in humans, liver damage is rarely the cause of death; instead, methemoglobin
formation and the production of Heinz bodies in red blood cells inhibit oxygen transport by the
blood, causing asphyxiation (methemoglobemia and hemolytic anemia).
[124]

Treatment with N-acetylcysteine,
[125]
methylene blue or both is sometimes effective after the
ingestion of small doses of paracetamol.
Dogs
Although paracetamol is believed to have no significant anti-inflammatory activity, it has been
reported as effective as aspirin in the treatment of musculoskeletal pain in dogs.
[126]

A paracetamol-codeine product (trade name Pardale-V)
[127]
licensed for use in dogs is available
on veterinary prescription in the UK.
[127]
It should be administered to dogs only on veterinary
advice and with extreme caution.
[127]

The main effect of toxicity in dogs is liver damage, GI ulceration has been
reported.
[125][128][129][130]
N-acetylcysteine treatment is efficacious in dogs when administered
within a 2 hours of paracetamol ingestion.
[125][126]

Snakes
Paracetamol is also lethal to snakes, and has been suggested as a chemical control program for
the invasive brown tree snake (Boiga irregularis) in Guam.
[131][132]
Doses of 80 mg are inserted
into dead mice scattered by helicopter.
[133]

Controversy
In September 2013 an episode of This American Life entitled "Use Only as Directed"
[134]

highlighted deaths from acetominophen overdose. This report was followed by two reports by
ProPublica
[135][136]
alleging that the "FDA has long been aware of studies showing the risks of
acetaminophen. So has the maker of Tylenol, McNeil Consumer Healthcare, a division of
Johnson & Johnson" and "McNeil, the maker of Tylenol, ... has repeatedly opposed safety
warnings, dosage restrictions and other measures meant to safeguard users of the drug.".
A report prepared by an internal FDA working group describes a history of FDA initiatives
designed to educate consumers about the risk of acetominophen overdose, and notes that one
challenge to the Agency has been "identifying the appropriate message about the relative safety
of acetaminophen, especially compared to other OTC pain relievers (e.g., aspirin and other
NSAIDs)". The report notes that "Chronic use of NSAIDs is also associated with significant
morbidity and mortality. NSAID gastrointestinal risk is substantial, with deaths and
hospitalization estimated in one publication as 3200 and 32,000 per year respectively. Possible
cardiovascular toxicity with chronic NSAID use has been a major discussion recently", finally
noting that "The goal of the educational efforts is not to decrease appropriate acetaminophen use
or encourage substitution of NSAID use, but rather to educate consumers so that they can avoid
unnecessary health risks."
[10]

Classification
Paracetamol is part of the class of drugs known as "aniline analgesics"; it is the only such drug
still in use today.
[81]
It is not considered an NSAID because it does not exhibit significant anti-
inflammatory activity (it is a weak COX inhibitor).
[137][138]
This is despite the evidence that
paracetamol and NSAIDs have some similar pharmacological activity.
[139]

References
1. Granberg RA, Rasmuson AC (1999). "Solubility of paracetamol in pure solvents".
Journal of Chemical & Engineering Data 44 (6): 139195. doi:10.1021/je990124v.
2. Karthikeyan, M.; Glen, R. C.; Bender, A. (2005). "General Melting Point Prediction
Based on a Diverse Compound Data Set and Artificial Neural Networks". Journal of
Chemical Information and Modeling 45 (3): 581590. doi:10.1021/ci0500132.
PMID 15921448. edit
3. "melting point data for paracetamol". Lxsrv7.oru.edu. Retrieved 2011-03-19.
4. Aghababian, Richard V. (22 October 2010). Essentials of Emergency Medicine. Jones &
Bartlett Publishers. p. 814. ISBN 978-1-4496-1846-9.
5. Ahmad, Jawad (17 October 2010). Hepatology and Transplant Hepatology: A Case
Based Approach. Springer. p. 194. ISBN 978-1-4419-7085-5.
6. International Nonproprietary Names (INN) for Pharmaceutical Substances: Lists 1-96 of
Proposed INN and lists 1-57 of Recommended INN, cumulative list N12. World Health
Organization. 2007. p. v. ISBN 9789240560253. Retrieved 20 January 2014.
7. Macintyre, Pamela; Rowbotham, David; Walker, Suellen (26 September 2008). Clinical
Pain Management Second Edition: Acute Pain. CRC Press. p. 85. ISBN 978-0-340-
94009-9.
8. TGA Approved Terminology for Medicines, Section 1 Chemical Substances (PDF).
Therapeutic Goods Administration, Department of Health and Ageing, Australian
Government. July 1999. p. 97.
9. Scottish Intercollegiate Guidelines Network (SIGN) (2008). "6.1 and 7.1.1". Guideline
106: Control of pain in adults with cancer. Scotland: National Health Service (NHS).
ISBN 9781905813384.
10. "www.fda.gov".
11. Graham, GG; Davies, MJ; Day, RO; Mohamudally, A; Scott, KF (June 2013). "The
modern pharmacology of paracetamol: therapeutic actions, mechanism of action,
metabolism, toxicity and recent pharmacological findings.". Inflammopharmacology 21
(3): 20132. doi:10.1007/s10787-013-0172-x. PMID 23719833.
12. Toussaint, K; Yang, XC; Zielinski, MA; Reigle, KL; Sacavage, SD; Nagar, S; Raffa, RB
(December 2010). "What do we (not) know about how paracetamol (acetaminophen)
works?" (PDF). Journal of Clinical Pharmacy and Therapeutics 35 (6): 61738.
doi:10.1111/j.1365-2710.2009.01143.x. PMID 21054454.
13. Bergman K, Mller L, Teigen SW (1996). "The genotoxicity and carcinogenicity of
paracetamol: a regulatory (re)view". Mutat Res 349 (2): 26388. doi:10.1016/0027-
5107(95)00185-9. PMID 8600357.
14. "WHO Model List of EssentialMedicines". World Health Organization. October 2013.
Retrieved 22 April 2014.
15. "Acetaminophen". The American Society of Health-System Pharmacists. Retrieved 3
April 2011.
16. "Baby paracetamol asthma concern". BBC News. September 19, 2008. Retrieved
September 19, 2008.
17. Meremikwu M, Oyo-Ita A (2002). "Paracetamol for treating fever in children". Cochrane
Database Syst Rev (2): CD003676. doi:10.1002/14651858.CD003676. PMID 12076499.
18. Perrott DA, Piira T, Goodenough B, Champion GD (2004). "Efficacy and safety of
acetaminophen vs ibuprofen for treating children's pain or fever: a meta-analysis". Arch
Pediatr Adolesc Med 158 (6): 5216. doi:10.1001/archpedi.158.6.521. PMID 15184213.
19. "Our Story". McNEIL-PPC, Inc. Retrieved March 8, 2014.
20. "Medication and Drugs". MedicineNet. 19962010. Retrieved April 22, 2010.
21. "Paracetamol". Arthritis Research UK. Retrieved October 16, 2013.
22. Bradley JD, Brandt KD, Katz BP, Kalasinski LA, Ryan SI (1991). "Comparison of an
anti-inflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen
in the treatment of patients with osteoarthritis of the knee". N. Engl. J. Med. 325 (2): 87
91. doi:10.1056/NEJM199107113250203. PMID 2052056.
23. Eccles, R. (2006). "Efficacy and safety of over-the-counter analgesics in the treatment of
common cold and flu". Journal of Clinical Pharmacy and Therapeutics 31 (4): 309319.
doi:10.1111/j.1365-2710.2006.00754.x. PMID 16882099. edit
24. Anton J M de Craen, Giuseppe Di Giulio, Angela J E M Lampe-Schoenmaeckers,
Alphons G H Kessels, Jos Kleijnen (1996). "Analgesic efficacy and safety of
paracetamol-codeine combinations versus paracetamol alone: a systematic review". BMJ
313 (7053): 321324. doi:10.1136/bmj.313.7053.321.
25. Laurence Toms, Sheena Derry, R Andrew Moore, Henry J McQuay (2009). "Single dose
oral paracetamol (acetaminophen) with codeine for postoperative pain in adults".
Cochrane Database of Systematic Reviews (1). doi:10.1002/14651858.CD001547.pub2.
26. Murnion B (2010). "Combination analgesics in adults". Australian Prescriber (33): 113
5.
27. Clark E, Plint AC, Correll R, Gaboury I, Passi B (2007). "A randomized, controlled trial
of acetaminophen, ibuprofen, and codeine for acute pain relief in children with
musculoskeletal trauma". Pediatrics 119 (3): 4607. doi:10.1542/peds.2006-1347.
PMID 17332198.
28. Hughes, John (2008). Pain Management: From Basics to Clinical Practice. Elsevier
Health Sciences. ISBN 9780443103360.
29. US FDA. Page Last Updated: January 16, 2014. Acetaminophen Information Page
accessed February 23, 2014
30. US FDA. January 13, 2011 FDA limits acetaminophen in prescription combination
products; requires liver toxicity warnings Page accessed February 23, 2014
31. US FDA. Page updated August 6, 2013 Acetaminophen Toxicity Page accessed February
23, 2014
32. US FDA Page updated November 19, 2013 Using Acetaminophen and Nonsteroidal
Anti-inflammatory Drugs Safely Page accessed February 23, 2014
33. Daly FF, Fountain JS, Murray L, Graudins A, Buckley NA (2008). "Guidelines for the
management of paracetamol poisoning in Australia and New Zealandexplanation and
elaboration. A consensus statement from clinical toxicologists consulting to the
Australasian poisons information centres". Med J Aust 188 (5): 296301.
PMID 18312195.
34. Khashab M, Tector AJ, Kwo PY (2007). "Epidemiology of acute liver failure". Curr
Gastroenterol Rep 9 (1): 6673. doi:10.1007/s11894-008-0023-x. PMID 17335680.
35. Hawkins LC, Edwards JN, Dargan PI (2007). "Impact of restricting paracetamol pack
sizes on paracetamol poisoning in the United Kingdom: a review of the literature". Drug
Saf 30 (6): 46579. doi:10.2165/00002018-200730060-00002. PMID 17536874.
36. Larson AM, Polson J, Fontana RJ, et al. (2005). "Acetaminophen-induced acute liver
failure: results of a United States multicenter, prospective study". Hepatology 42 (6):
136472. doi:10.1002/hep.20948. PMID 16317692.
37. US FDA Date Posted Jan 14, 2011. Prescription Drug Products Containing
Acetaminophen: Actions to Reduce Liver Injury from Unintentional Overdose Page
accessed February 23, 2014
38. Dukes, MNG; Jeffrey K Aronson (2000). Meyler's Side Effects of Drugs, Vol XIV.
Elsevier. ISBN 9780444500939.
39. Garca Rodrguez LA, Hernndez-Daz S (December 15, 2000). "The risk of upper
gastrointestinal complications associated with nonsteroidal anti-inflammatory drugs,
glucocorticoids, acetaminophen, and combinations of these agents". Arthritis Research &
Therapy 3 (2): 98101. doi:10.1186/ar146. PMC 128885. PMID 11178116.
40. "Painkillers 'cause kidney damage'". BBC News. November 23, 2003. Retrieved March
27, 2010.
41. "FDA: Acetaminophen doses over 325 mg might lead to liver damage". Cnn.com.
January 16, 2014. Retrieved 2014-02-18.
42. Roland B. Walter, Filippo Milano, Theodore M. Brasky and Emily White (2011). "Long-
Term Use of Acetaminophen, Aspirin, and Other Nonsteroidal Anti-Inflammatory Drugs
and Risk of Hematologic Malignancies: Results From the Prospective Vitamins and
Lifestyle (VITAL) Study". Journal of Clinical Oncology 29 (17): 242431.
doi:10.1200/JCO.2011.34.6346. PMC 3107756. PMID 21555699.
43. "Acetaminophen linked to rare fatal skin reactions, FDA says". Washington Post. August
2, 2013. Retrieved 3 August 2013.
44. Henderson, AJ; Shaheen, SO (Mar 2013). "Acetaminophen and asthma.". Paediatric
Respiratory Reviews 14 (1): 915; quiz 16. doi:10.1016/j.prrv.2012.04.004.
PMID 23347656.
45. "Feverish illness in children: Assessment and initial management in children younger
than 5 years". NICE clinical guidelines (CG160). UK National Institute for Health and
Care Excellence. May 2013. Retrieved 25 February 2014.
46. "Common over-the-counter medications". Healthychildren.org. American Academy of
Pediatrics. July 10, 2013. Retrieved February 23, 2014.
47. Heintze, K; Petersen, KU (Jun 2013). "The case of drug causation of childhood asthma:
antibiotics and paracetamol". European Journal of Clinical Pharmacology 69 (6): 1197
209. doi:10.1007/s00228-012-1463-7. PMID 23292157.
48. "Link between Calpol and asthma 'not proven'". NHS Choices (UK National Health
Service). September 16, 2013. Retrieved February 23, 2014.
49. Section on Clinical Pharmacology and Therapeutics; Committee on Drugs; Sullivan, JE;
Farrar, HC (Mar 2011). "Fever and antipyretic use in children". Pediatrics (American
Academy of Pediatrics) 127 (3): 5807. doi:10.1542/peds.2010-3852. PMID 21357332.
50. CHMP Pharmacovigilance Working Party (February 24, 2011). Pharmacovigilance
Working Party (PhVWP) February 2011 plenary meeting (Report). European Medicines
Agency & Heads of Medicines Agencies. pp. 67.
51. Martinez-Gimeno, A; Garca-Marcos, Luis (Apr 2013). "The association between
acetaminophen and asthma: should its pediatric use be banned?". Expert Review of
Respiratory Medicine 7 (2): 11322. doi:10.1586/ers.13.8. PMID 23547988.
52. McBride, JT (Dec 2011). "The association of acetaminophen and asthma prevalence and
severity.". Pediatrics 128 (6): 11815. doi:10.1542/peds.2011-1106. PMID 22065272.
53. Sarg, Michael; Ann D Gross, and Roberta Altman (2007). The Cancer Dictionary.
Infobase Publishing. ISBN 9780816064113.
54. Neuss,G (2007). Chemistry: Course Companion. Oxford University Press. ISBN 978-0-
19-915146-2.
55. Ebrahimi, Sedigheh; Soheil Ashkani Esfahani, Hamid Reza Ghaffarian, Mahsima
Khoshneviszade (2010). "Comparison of efficacy and safety of acetaminophen and
ibuprofen administration as single dose to reduce fever in children". Iranian Journal of
Pediatrics 20 (4): 500501.
56. Lesko SM, Mitchell AA (1999). "The safety of acetaminophen and ibuprofen among
children younger than two years old". Pediatrics 104 (4): e39.
doi:10.1542/peds.104.4.e39. PMID 10506264.
57. Yorgason, JG; Luxford, W; Kalinec, F (Dec 2011). "In vitro and in vivo models of drug
ototoxicity: studying the mechanisms of a clinical problem.". Expert opinion on drug
metabolism & toxicology 7 (12): 152134. doi:10.1517/17425255.2011.614231.
PMID 21999330.
58. Rumack B, Matthew H (1975). "Acetaminophen poisoning and toxicity". Pediatrics 55
(6): 87176. PMID 1134886.
59. "Paracetamol". University of Oxford Centre for Suicide Research. 25 March 2013.
Retrieved 20 April 2013.
60. Ryder SD, Beckingham IJ (2001). "ABC of diseases of liver, pancreas, and biliary
system. Other causes of parenchymal liver disease". BMJ 322 (7281): 29092.
doi:10.1136/bmj.322.7281.290. PMC 1119531. PMID 11157536.
61. Lee WM (2004). "Acetaminophen and the U. S. Acute Liver Failure Study Group:
lowering the risks of hepatic failure". Hepatology 40 (1): 69. doi:10.1002/hep.20293.
PMID 15239078.
62. Mehta, Sweety (August 25, 2012) Metabolism of Paracetamol (Acetaminophen),
Acetanilide and Phenacetin. pharmaxchange.info
63. "Highlights of Prescribing Information". Acetadote. Retrieved 2014-02-10.
64. "Paracetamol overdose: new guidance on treatment with intravenous acetylcysteine".
Drug Safety Update 6 (2): A1. September 2012.
65. "FDA May Restrict Acetaminophen". Webmd.com. 2009-07-01. Retrieved 2011-03-19.
66. "FDA limits acetaminophen in prescription combination products; requires liver toxicity
warnings" (Press release). U. S. Food and Drug Administration (FDA). January 13, 2011.
Retrieved January 13, 2011.
67. "FDA Drug Safety Communication: Prescription Acetaminophen Products to be Limited
to 325 mg Per Dosage Unit; Boxed Warning Will Highlight Potential for Severe Liver
Failure". U. S. Food and Drug Administration (FDA). January 13, 2011. Retrieved
January 13, 2011.
68. Matthew Perrone (January 13, 2011). "FDA orders lowering pain reliever in Vicodin".
The Boston Globe. Associated Press. Retrieved January 13, 2011.
69. Gardiner Harris (January 13, 2011). "F. D. A. Plans New Limits on Prescription
Painkillers". The New York Times. Retrieved January 13, 2011.
70. "Liquid paracetamol for children: Revised UK dosing instructions have been introduced".
Mhra.gov.uk. Retrieved 2014-02-18.
71. Scialli, AR; Ang, R; Breitmeyer, J; Royal, MA (Dec 2010). "A review of the literature on
the effects of acetaminophen on pregnancy outcome" (PDF). Reproductive Toxicology
(Elmsford, N.Y.) 30 (4): 495507. doi:10.1016/j.reprotox.2010.07.007. PMID 20659550.
72. Rudolph, AM (Feb 23, 1981). "Effects of aspirin and acetaminophen in pregnancy and in
the newborn". Archives of Internal Medicine 141 (3): 35863.
doi:10.1001/archinte.141.3.358. PMID 7469626.
73. Eyers, S; Weatherall, M; Jefferies, S; Beasley, R (Apr 2011). "Paracetamol in pregnancy
and the risk of wheezing in offspring: a systematic review and meta-analysis" (PDF).
Clinical and Experimental Allergy : Journal of the British Society for Allergy and
Clinical Immunology 41 (4): 4829. doi:10.1111/j.1365-2222.2010.03691.x.
PMID 21338428.
74. Hinz, B.; Cheremina, O.; Brune, K. (2008). "Acetaminophen (paracetamol) is a selective
cyclooxygenase-2 inhibitor in man.". The FASEB journal : official publication of the
Federation of American Societies for Experimental Biology 22 (2): 383390.
doi:10.1096/fj.07-8506com. PMID 17884974. edit
75. Andersson DA, Gentry C, Alenmyr L, Killander D, Lewis SE, Andersson A, Bucher B,
Galzi J-L, Sterner O, Bevan S, Hgesttt ED, Zygmunt PM (2011). "TRPA1 mediates
spinal antinociception induced by acetaminophen and the cannabinoid (9)-
tetrahydrocannabiorcol". Nat Commun 2: 551. doi:10.1038/ncomms1559.
PMID 22109525.
76. Claesson, A. "On the mechanism of paracetamol's analgesic activity and a note on related
NSAID pharmacology". SlideShare. Retrieved 1 March 2013.
77. Ohki S, Ogino N, Yamamoto S, Hayaishi O (1979). "Prostaglandin hydroperoxidase, an
integral part of prostaglandin endoperoxide synthetase from bovine vesicular gland
microsomes". J. Biol. Chem. 254 (3): 82936. PMID 104998.
78. Harvison PJ, Egan RW, Gale PH, Nelson SD (1986). "Acetaminophen as a cosubstrate
and inhibitor of prostaglandin H synthase". Adv. Exp. Med. Biol. Advances in
Experimental Medicine and Biology 197: 73947. doi:10.1007/978-1-4684-5134-4_68.
ISBN 978-1-4684-5136-8. PMID 3094341.
79. Aronoff DM, Oates JA, Boutaud O (2006). "New insights into the mechanism of action
of acetaminophen: Its clinical pharmacologic characteristics reflect its inhibition of the
two prostaglandin H2 synthases". Clin. Pharmacol. Ther. 79 (1): 919.
doi:10.1016/j.clpt.2005.09.009. PMID 16413237.
80. Roberts, L.J. II. & Marrow, J.D. "Analgesic-antipyretic and Antiinflammatory Agents
and Drugs Employed in the Treatment of Gout" in, "Goodman & Gilman's The
Pharmacological Basis of Therapeutics 10th Edition" by Hardman, J.G. & Limbird, L.E.
Published by McGraw Hill, 2001, pp.687731 ISBN 0071354697
81. Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S (2006). "Paracetamol:
new vistas of an old drug". CNS Drug Reviews 12 (34): 25075. doi:10.1111/j.1527-
3458.2006.00250.x. PMID 17227290.
82. Kis B, Snipes JA, Busija DW (2005). "Acetaminophen and the cyclooxygenase-3 puzzle:
sorting out facts, fictions, and uncertainties". J. Pharmacol. Exp. Ther. 315 (1): 17.
doi:10.1124/jpet.105.085431. PMID 15879007.
83. Graham GG, Scott KF (2005). "Mechanism of action of paracetamol". American journal
of therapeutics 12 (1): 4655. doi:10.1097/00045391-200501000-00008.
PMID 15662292.
84. Chandrasekharan NV, Dai H, Roos KL, et al. (2002). "COX-3, a cyclooxygenase-1
variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning,
structure, and expression". Proc. Natl. Acad. Sci. U.S.A. 99 (21): 1392631.
doi:10.1073/pnas.162468699. PMC 129799. PMID 12242329.
85. Hgesttt ED, Jnsson BA, Ermund A, et al. (2005). "Conversion of acetaminophen to
the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent
arachidonic acid conjugation in the nervous system". J. Biol. Chem. 280 (36): 3140512.
doi:10.1074/jbc.M501489200. PMID 15987694.
86. Kfalvi A (2008). "9. Alternative interacting sites and novel receptors for cannabinoid
ligands". Cannabinoids and the Brain. Springer-Verlag. pp. 131160. doi:10.1007/978-0-
387-74349-3_9. ISBN 978-0-387-74348-6.
87. Ottani A, Leone S, Sandrini M, Ferrari A, Bertolini A (2006). "The analgesic activity of
paracetamol is prevented by the blockade of cannabinoid CB1 receptors". Eur. J.
Pharmacol. 531 (13): 2801. doi:10.1016/j.ejphar.2005.12.015. PMID 16438952.
88. Andersson, David; Gentry, Clive; Alenmyr, Lisa; Killander, Dan; Lewis, Simon E;
Andersson, Anders; Bucher, Bernard; Galzi, Jean-Luc et al. (November 2011). "TRPA1
mediates spinal antinociception induced by acetaminophen and the cannabinoid 9-
tetrahydrocannabiorcol". Nature Communications 2 (2): 551. doi:10.1038/ncomms1559.
PMID 22109525.
89. Gould, G. G.; Seillier, A.; Weiss, G.; Giuffrida, A.; Burke, T. F.; Hensler, J. G.; Rock, C.;
Tristan, A.; McMahon, L. R.; Salazar, A.; O'Connor, J. C.; Satsangi, N.; Satsangi, R. K.;
Gu, T. T.; Treat, K.; Smolik, C.; Schultz, S. T. (2012). "Acetaminophen differentially
enhances social behavior and cortical cannabinoid levels in inbred mice". Progress in
Neuro-Psychopharmacology and Biological Psychiatry 38 (2): 260269.
doi:10.1016/j.pnpbp.2012.04.011. PMC 3389197. PMID 22542870. edit
90. Bales, JR; Nicholson JK, Sadler PJ (1985). "Two-dimensional proton nuclear magnetic
resonance "maps" of acetaminophen metabolites in human urine". Clinical Chemistry 31
(5): 757762. PMID 3987005.
91. Ellis, Frank (2002). Paracetamol: a curriculum resource. Cambridge: Royal Society of
Chemistry. ISBN 0-85404-375-6.
92. Anthony S. Travis (2007). "Manufacture and uses of the anilines: A vast array of
processes and products". In Zvi Rappoport. The chemistry of Anilines Part 1. Wiley.
p. 764. ISBN 978-0-470-87171-3.
93. Elmar Friderichs, Thomas Christoph, Helmut Buschmann (2005), "Analgesics and
Antipyretics", Ullmann's Encyclopedia of Industrial Chemistry, Weinheim: Wiley-VCH,
doi:10.1002/14356007.a02_269.pub2
94. US patent 4524217, Kenneth G. Davenport & Charles B. Hilton, "Process for producing
N-acyl-hydroxy aromatic amines", published 1985-06-18, assigned to Celanese
Corporation
95. "Paracetamol". IARC Monographs 73: 401.
96. Hendrickson, Robert G.; Kenneth E. Bizovi (2006). "Acetaminophen", in Nelson, Lewis
H.; Flomenbaum, Neal; Goldfrank, Lewis R. et al. Goldfrank's toxicologic emergencies,
p. 525, New York: McGraw-Hill. Retrieved on January 18, 2009 through Google Book
Search.
97. Borne, Ronald F. "Nonsteroidal Anti-inflammatory Drugs" in Principles of Medicinal
Chemistry, Fourth Edition. Eds. Foye, William O.; Lemke, Thomas L.; Williams, David
A. Published by Williams & Wilkins, 1995. p. 544545.
98. Dong, H; Haining, RL; Thummel, KE; Rettie, AE; Nelson, SD (2000). "Involvement of
human cytochrome P450 2D6 in the bioactivation of acetaminophen". Drug Metab
Dispos 28 (12): 1397400. PMID 11095574.
99. Henney, K; Dudley B (1939). Handbook of Photography. Whittlesey House. p. 324.
100. Novotny PE, Elser RC (1984). "Indophenol method for acetaminophen in serum
examined". Clin. Chem. 30 (6): 8846. PMID 6723045.
101. Cahn, A; Hepp P (1886). "Das Antifebrin, ein neues Fiebermittel". Centralbl.
Klin. Med. 7: 56164.
102. Morse HN (1878). "Ueber eine neue Darstellungsmethode der
Acetylamidophenole". Berichte der deutschen chemischen Gesellschaft (in German) 11
(1): 2323. doi:10.1002/cber.18780110151.
103. Milton Silverman, Mia Lydecker, Philip Randolph Lee (1992). Bad Medicine:
The Prescription Drug Industry in the Third World. Stanford University Press. pp. 8890.
ISBN 0804716692.
104. Von Mering J. (1893) Beitrage zur Kenntniss der Antipyretica. Ther Monatsch 7:
577587.
105. Sneader, Walter (2005). Drug Discovery: A History. Hoboken, N.J.: Wiley.
p. 439. ISBN 0471899801.
106. Lester D, Greenberg LA, Carroll RP (1947). "The metabolic fate of acetanilid and
other aniline derivatives: II. Major metabolites of acetanilid appearing in the blood". J.
Pharmacol. Exp. Ther. 90 (1): 6875. PMID 20241897.
107. Brodie, BB; Axelrod J (1948). "The estimation of acetanilide and its metabolic
products, aniline, N-acetyl p-aminophenol and p-aminophenol (free and total conjugated)
in biological fluids and tissues". J. Pharmacol. Exp. Ther. 94 (1): 2228.
PMID 18885610.
108. Brodie, BB; Axelrod J (1948). "The fate of acetanilide in man". J. Pharmacol.
Exp. Ther. 94 (1): 2938. PMID 18885611.
109. Flinn, Frederick B; Brodie BB (1948). "The effect on the pain threshold of N-
acetyl p-aminophenol, a product derived in the body from acetanilide". J. Pharmacol.
Exp. Ther. 94 (1): 7677. PMID 18885618.
110. Brodie BB, Axelrod J (1949). "The fate of acetophenetidin (phenacetin) in man
and methods for the estimation of acetophenitidin and its metabolites in biological
material". J Pharmacol Exp Ther 94 (1): 5867.
111. Landau, Ralph; Achilladelis, Basil; Scriabine, Alexander (1999). Pharmaceutical
Innovation: Revolutionizing Human Health. Chemical Heritage Foundation. pp. 248249.
ISBN 978-0-941901-21-5.
112. Rapoport, Alan (15 December 1991). Headache Relief. Touchstone. p. 97.
ISBN 978-0-671-74803-6.
113. US patent 6126967, "Extended release acetaminophen particles", issued October
03, 2000
114. "Acetaminophen." Physicians' Desk Reference, 63rd ed. Montvale, NJ: Thomson
PDR; 2009: 19151916.
115. "Acetaminophen Overdose and Liver InjuryBackground and Options for
Reducing Injury", Charles Ganley, MD, Gerald Dal Pan, MD, Bob Rappaport, MD, May
22, 2009, Retrieved July 8, 2010.
116. Atkinson, Hartley C.; Stanescu, Ioana; Anderson, Brian J. (2014). "Increased
Phenylephrine Plasma Levels with Administration of Acetaminophen". New England
Journal of Medicine 370 (12): 11711172. doi:10.1056/NEJMc1313942. ISSN 0028-
4793. PMID 24645960.
117. "Ascorbic acid/Phenylephrine/Paracetamol". NHS Choices. National Health
Service. Retrieved March 25, 2014.
118. "Phenylephrine/Caffeine/Paracetamol dual relief". NHS Choices. National Health
Service. Retrieved March 25, 2014.
119. "Beechams Decongestant Plus With Paracetamol". NHS Choices. National Health
Service. Retrieved March 25, 2014.
120. Senyuva, H.; Ozden, T. (2002). "Simultaneous High-Performance Liquid
Chromatographic Determination of Paracetamol, Phenylephrine HCl, and
Chlorpheniramine Maleate in Pharmaceutical Dosage Forms" (PDF). Journal of
Chromatographic Science 40 (2): 97100. doi:10.1093/chromsci/40.2.97. ISSN 0021-
9665. PMID 11881712.
121. Janin, A.; Monnet, J. (2014). "Bioavailability of paracetamol, phenylephrine
hydrochloride and guaifenesin in a fixed-combination syrup versus an oral reference
product". Journal of International Medical Research 42 (2): 347359.
doi:10.1177/0300060513503762. ISSN 0300-0605. PMID 24553480.
122. "Paracetamol phenylephrine hydrochloride guaifenesin". NPS MedicineWise.
National Prescribing Service (Australia). Retrieved March 25, 2014.
123. "Phenylephrine/Guaifenesin/Paracetamol". NHS Choices. National Health
Service. Retrieved March 25, 2014.
124. Allen AL (2003). "The diagnosis of acetaminophen toxicosis in a cat". Can Vet J
44 (6): 50910. PMC 340185. PMID 12839249.
125. Richardson, JA (2000). "Management of acetaminophen and ibuprofen toxicoses
in dogs and cats". J. Vet. Emerg. Crit. Care 10 (4): 28591. doi:10.1111/j.1476-
4431.2000.tb00013.x.
126. Maddison, Jill E.; Stephen W. Page, David Church (2002). Small Animal Clinical
Pharmacology. Elsevier Health Sciences. pp. 2601. ISBN 0702025739.
127. "Pardale-V Oral Tablets". NOAH Compendium of Data Sheets for Animal
Medicines. The National Office of Animal Health (NOAH). 11 November 2010.
Retrieved 20 January 2011.
128. Villar D, Buck WB, Gonzalez JM (1998). "Ibuprofen, aspirin and acetaminophen
toxicosis and treatment in dogs and cats". Vet Hum Toxicol 40 (3): 15662.
PMID 9610496.
129. Meadows, Irina; Gwaltney-Brant, Sharon (2006). "The 10 Most Common
Toxicoses in Dogs". Veterinary Medicine: 1428.
130. Dunayer, E (2004). "Ibuprofen toxicosis in dogs, cats, and ferrets". Veterinary
Medicine: 5806.
131. Johnston J, Savarie P, Primus T, Eisemann J, Hurley J, Kohler D (2002). "Risk
assessment of an acetaminophen baiting program for chemical control of brown tree
snakes on Guam: evaluation of baits, snake residues, and potential primary and secondary
hazards". Environ Sci Technol 36 (17): 382733. doi:10.1021/es015873n.
PMID 12322757.
132. Brad Lendon (2010-09-07). "Tylenol-loaded mice dropped from air to control
snakes". CNN. Retrieved 2010-09-07.
133. Sabrina Richards (2012-05-01). "It's Raining Mice". The Scientist.
134. "Use Only as Directed". This American Life. Episode 505. 20 September 2013.
Public Radio International. WBEZ. Retrieved 24 September 2013.
135. Gerth, Jeff; T. Christian Miller (20 September 2013). "Use Only as Directed".
ProPublica. Retrieved 24 September 2013.
136. Miller, T. Christian; Jeff Gerth (20 September 2013). "Dose of Confusion".
ProPublica. Retrieved 24 September 2013.
137. Viswanathan, A. N.; Feskanich, D.; Schernhammer, E. S.; Hankinson, S. E.
(2008). "Aspirin, NSAID, and Acetaminophen Use and the Risk of Endometrial Cancer".
Cancer Research 68 (7): 2507. doi:10.1158/0008-5472.CAN-07-6257. PMC 2857531.
PMID 18381460. edit
138. Altinoz, M. A.; Korkmaz, R. (2004). "NF-kappaB, macrophage migration
inhibitory factor and cyclooxygenase-inhibitions as likely mechanisms behind the
acetaminophen- and NSAID-prevention of the ovarian cancer". Neoplasma 51 (4): 239
247. PMID 15254653. edit
139. Byrant, Bronwen; Knights, Katleen; Salerno, Evelyn (2007). Pharmacology for
health professionals. Elsevier. p. 270. ISBN 9780729537872.


The drug acetaminophen is a pain reliever (an analgesic ) and a fever- reducing agent (an
antipyretic). It is found in over-the-counter medicines such as Tylenol and Excedrin. It is widely
used to treat both chronic and acute pain and is considered to have a pain-relieving potency
similar to that of other over-the-counter analgesics, such as aspirin and ibuprofen. Its chemical
name is 4-hydroxyacetanalide. Its chemical formula is C
8
H
9
NO
2
(see Figure 1).

Figure 1. Structure of acetaminophen.
Acetaminophen was used as a pain reliever as early as the late 1800s. It was approved for use by
the U.S. Food and Drug Administration in 1950, shortly after it was discovered that the closely
related drug paracetin was broken down in the body to acetaminophen, and that the beneficial
effects of paracetin were actually the effects of acetaminophen.
Acetaminophen works by inhibiting the synthesis of chemical messengers called prostaglandins,
which help to transmit pain signals and induce fever. The body produces prostaglandins in
response to an injury or illness. Acetaminophen reduces the pain by helping to block this
signaling. Acetaminophen stops some prostaglandin functions while not affecting others.
Prostaglandins are known to promote inflammation and swelling of many body tissues. Unlike
aspirin and ibuprofen, acetaminophen does not have anti-inflammatory action.
The differences in the actions of these drugs involve their tissue specificities. Aspirin and
ibuprofen act on a broad range of tissues. Acetaminophen inhibits prostaglandin synthesis more
specifically in the cells of the nervous system and is a much less effective inhibitor of this in
other tissues. This selectivity gives acetaminophen its analgesic and antipyretic effects without
acetaminophen's acting as an anti-inflammatory drug.
Acetaminophen is known to cause less stomach irritation than aspirin and ibuprofen, and it does
not inhibit platelet aggregation and blood clotting (as does aspirin).
When given in its therapeutic dose (500 mg every 46 hours), acetaminophen is a safe and
effective pain reliever. However, at higher doses it can be severely toxic to the liver, and even
fatal.
The drug itself is not toxic, but a toxic compound, N-acetyl- p -benzoquinonimine, is formed
from it as it is broken down by enzymes in the liver. In small amounts this compound can be
detoxified and excreted . But in large amounts it overwhelms the detoxification system and the
compound begins killing liver tissue. Overdose can be treated by giving the patient activated
charcoal, which absorbs the acetaminophen in the patient's stomach and intestines, and by
administering N -acetylcystine, a compound that can deactivate the toxic product of metabolism
.

Read more: http://www.chemistryexplained.com/A-Ar/Acetaminophen.html#ixzz2zcT0vqBA



Codeina, numit i metilmorfin, este un alcaloid natural din opiu. Concentraia sa n extractul
de opiu (meconat) variaz ntre 0,7% i 2,5%. Sinteza industrial a codeinei se face prin O-
metilarea morfinei. Are proprieti analgezice mult mai slabe dect morfina, dar este mai
avantajoas dect aceasta n privina aciunii antitusive i antidiareice.
Cuprins
1 Farmacologie
2 Utilizare medical
o 2.1 Ci de administrare
o 2.2 Indicaii
o 2.3 Contraindicaii
o 2.4 Efecte adverse
o 2.5 Interaciuni
3 Statut legal
4 Legturi externe
5 Bibliografie
Farmacologie
Dintre toi receptorii pentru opioide, codeina are cea mai mare afinitate pentru receptorii (miu),
subtipul
2
(responsabili de efectul antitusiv). Legarea la subtipul
1
, ceva mai slab, este
responsabil pentru efectele analgezice. Este metabolizat n ficat la 6-glucuronid-codein prin
conjugare cu acid glucuronic n proporie de 80%. Restul trece n norcodein (2%), morfin
(0,5%), 2-glucuronid-morfin (2%), 6-glucuronid-morfin (0.8%) i normorfin (2.5%).
Transformarea n morfin i implicit n 6-glucuronid-morfin, metabolitul cel mai activ, este o
reacie de O-dealchilare (O-demetilare) catalizat de enzima CYP2D6 a citocromului P450. La
un segment al populaiei albe de circa 6-10%, enzima CYP2D6 este fie prost tradus, fie
deficitar, astfel nct codeina este aproape lipsit de efecte analgezice. Tot acest fenomen st la
baza diminurii efectului analgezic al codeinei de ctre substane care inhib aceast enzim, ca
antidepresivele fluoxentin i citalopram. Exist i variaii genetice ale CYP2D6 care, prin
metabolizare intens, produc la doze "antitusive" de codein cantiti de 3-12 ori mai mari de
morfin. S-a raportat un caz care a prezentat oprire respiratorie din aceast cauz.
Utilizare medical
Ci de administrare
Cel mai frecvent se administreaz oral, sub form de sruri de codein: sulfat sau fosfat. Este
inclus n multe combinaii alturi de paracetamol, aspirin i alte antiinflamatoare
nonsteroidiene, deoarece n aceste asocieri componentele i poteneaz reciproc efectul
analgezic.
Indicaii
Tuse fr expectoraie. n prezent codeina se folosete doar la cazurile rebele i foarte
grave.
Diaree
Dureri moderate sau severe
Contraindicaii
Sensibilitate la codein sau la alte opiacee
Insuficien respiratorie
Insuficien hepatic, renal, cardiac
Nu se admnistreaz la sportivi, deoarece pozitiveaz testele de dopaj
Femei care alpteaz
La gravide se impune pruden, este mai bine s fie evitat
La copii sub 5 ani poate produce convulsii
Efecte adverse
Sedare
Grea, vrsturi
Constipaie
La doze mari sau la copii exist riscul de deprimare respiratorie, pn la stop respirator
Rezisten (diminuarea efectelor odat cu administrarea de doze din ce n ce mai mari pe
timp ndelungat). Dependena este posibil, ns riscul este mult mai mic dect la
morfin.
Interaciuni
efectul deprimant al codeinei este potenat de fenotiazine, antidepresive triciclice,
sedative hipnotice, alcool. Codeina poteneaz analgezicele, efectele codeinei sunt
sczute de caolin (scade absorbia)
modific testele de laborator: crete concentraiile serice ale LDH, amilazei, lipazei,
TGO, TGP
Statut legal
n Romnia: drog de mare risc (tabelul II din Legea nr 143/2000 privind combaterea
traficului si consumului ilicit de droguri)
Internaional: Lista galben a Single Convention on Narcotic Drugs:
http://www.incb.org/pdf/e/list/yellow.pdf.
Legturi externe
ro Legea nr 143/2000 privind combaterea traficului si consumului ilicit de droguri
en Codeina la www.drugs.com
Bibliografie
Matthew J. Ellenhorn, Seth Schonwald, Gary Ordog, Jonathan Wasserberger:
Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning (Medical
Toxicology), 2nd edition, 1997
Lester M., Md. Haddad, Michael W. Shannon, j Winchester, Judy Fletcher Editor),
Lames P. Winchester: Clinical Management of Poisoning and Drug Overdose


odeine or 3-methylmorphine (a naturally occurring methylated morphine) is an opiate used for
its analgesic, antitussive, antidiarrheal, antihypertensive, anxiolytic, antidepressant, sedative and
hypnotic properties. It is also used to suppress premature labor contractions, myocardial
infarction, and has many other potential and indicated uses. It is often sold as a salt in the form of
either codeine sulfate or codeine phosphate.
Codeine is the second-most predominant alkaloid in opium, at up to three percent. Although
codeine can be extracted from natural sources, a semi-synthetic process is the primary source of
codeine for pharmaceutical use. It is considered the prototype of the weak to midrange opioids
(tramadol, dextropropoxyphene, dihydrocodeine, hydrocodone, oxycodone).
It is on the World Health Organization's List of Essential Medicines, a list of the most important
medication needed in a basic health system.
[2]

Contents
1 Medical uses
o 1.1 Formulations
2 Adverse effects
o 2.1 Withdrawal and dependence
3 Pharmacokinetics
4 Relation to other opiates
5 History
6 Recreational use
o 6.1 Detection
7 Legal status
o 7.1 Australia
o 7.2 Denmark
o 7.3 France
o 7.4 Germany, Switzerland and Austria
o 7.5 Greece
o 7.6 Hong Kong
o 7.7 Iceland
o 7.8 India
o 7.9 Iran
o 7.10 Ireland
o 7.11 Italy
o 7.12 Japan
o 7.13 Maldives
o 7.14 Romania
o 7.15 Russia
o 7.16 Spain
o 7.17 Sri Lanka
o 7.18 United Arab Emirates
o 7.19 United Kingdom
o 7.20 United States
8 References
Medical uses
Codeine is used to treat mild to moderate pain and to relieve cough.
[3]
Codeine is also used to
treat diarrhea and diarrhea-predominant irritable bowel syndrome, although loperamide (which is
available OTC for milder diarrhea), diphenoxylate, paregoric or even laudanum (also known as
Tincture of Opium) are more frequently used to treat severe diarrhea.
[4]

Formulations
Codeine is marketed as both a single-ingredient drug and in combination preparations with
paracetamol (as co-codamol: e.g., brands Paracod, Panadeine, and the Tylenol-with-codeine
series, including Tylenol 3 and 1,2,4); with aspirin; (as co-codaprin); or with ibuprofen (as
Nurofen Plus). These combinations provide greater pain relief than either agent alone (drug
synergy).
Codeine is also commonly marketed in products containing codeine with other pain killers or
muscle relaxers, as well as codeine mixed with phenacetin (Emprazil With Codeine No. 1, 2, 3, 4
and 5), naproxen, indomethacin, diclofenac, and others, as well as more complex mixtures,
including such mixtures as aspirin + paracetamol + codeine caffeine antihistamines and other
agents, such as those mentioned above.
Codeine-only products can be obtained with a prescription as a time release tablet (e.g., Codeine
Contin 100 mg and Perduretas 50 mg). Codeine is also marketed in cough syrups with zero to a
half-dozen other active ingredients, and a linctus (e.g., Paveral) for all of the uses for which
codeine is indicated.
Injectable codeine is available for subcutaneous or intramuscular injection; intravenous injection
can cause a serious reaction that can progress to anaphylaxis. Codeine suppositories are also
marketed in some countries.
Adverse effects
Common adverse effects associated with the use of codeine include drowsiness and constipation.
Less common are itching, nausea, vomiting, dry mouth, miosis, orthostatic hypotension, urinary
retention, depression, and coughing. Rare adverse effects include anaphylaxis, seizure, acute
pancreatitis and respiratory depression.
[5]
As with all opiates, longer-term effects can vary but
can include diminished libido, apathy and memory loss. Some people may also have an allergic
reaction to codeine, such as the swelling of skin and rashes.
[6]

Codeine and morphine as well as opium were used for control of diabetes until relatively
recently
[citation needed]
, and still are in rare cases in some countries, and the hypoglycemic effect of
codeine, although usually weaker than that of morphine, diamorphine, or hydromorphone, can
lead to cravings for sugar.
Tolerance to many of the effects of codeine develops with prolonged use, including therapeutic
effects. The rate at which this occurs develops at different rates for different effects, with
tolerance to the constipation-inducing effects developing particularly slowly for instance.
A potentially serious adverse drug reaction, as with other opioids, is respiratory depression. This
depression is dose-related and is a mechanism for the potentially fatal consequences of overdose.
As codeine is metabolized to morphine, morphine can be passed through breast milk in
potentially lethal amounts, fatally depressing the respiration of a breastfed baby.
[7][8]
In August
2012, the Federal Drug Administration issued a warning about deaths in pediatric patients < 6
years old after ingesting "normal" doses of acetaminophen with codeine after tonsillectomy.
[9]

Some patients are very effective converters of codeine to its active form, morphine, resulting in
lethal blood levels. The FDA presently is recommending very cautious use of Codeine in young
tonsillectomy patients: use the drug in the lowest amount that can control the pain, use "as
needed" and not "around the clock", and seek immediate medical attention if a child on codeine
exhibits excessive sedation or abnormally noisy breathing.
Withdrawal and dependence
As with other opiate-based pain killers, chronic use of codeine can cause physical dependence.
When physical dependence has developed, withdrawal symptoms may occur if a person
suddenly stops the medication. Withdrawal symptoms include: drug craving, runny nose,
yawning, sweating, insomnia, weakness, stomach cramps, nausea, vomiting, diarrhea, muscle
spasms, chills, irritability, and pain. To minimize withdrawal symptoms, long-term users should
gradually reduce their codeine medication under the supervision of a healthcare professional.
[10]

Codeine is metabolized to codeine-6-glucuronide (C6G) by uridine diphosphate glucuronosyl
transferase UGT2B7, and, since only about 5% of codeine is metabolized by cytochrome P450
CYP2D6, the current evidence is that C6G is the primary active compound.
[11]
Claims about the
supposed "ceiling effect" of codeine doses are based on the assumption that high doses of
codeine saturate CYP2D6, preventing further conversion of codeine to morphine, however it is
now known that C6G is the main metabolite responsible for codeine's analgesia.
[12]

There is also no evidence that CYP2D6 inhibition is useful in treating codeine dependence,
[13]

though the metabolism of codeine to morphine (and hence further metabolism to glucuronide
morphine conjugates) does have an effect on the abuse potential of codeine.
[14]
However,
CYP2D6 has been implicated in the toxicity and death of neonates when codeine is administered
to lactating mothers, particularly those with increased 2D6 activity ("ultra-rapid"
metabolizers).
[15][16]

Pharmacokinetics
The conversion of codeine to morphine occurs in the liver and is catalysed by the cytochrome
P450 enzyme CYP2D6. CYP3A4 produces norcodeine and UGT2B7 conjugates codeine,
norcodeine, and morphine to the corresponding 3- and 6- glucuronides. Srinivasan, Wielbo and
Tebbett speculate that codeine-6-glucuronide is responsible for a large percentage of the
analgesia of codeine, and, thus, these patients should experience some analgesia.
[17]
Many of the
adverse effects will still be experienced in poor metabolizers. Conversely, 0.5-2% of the
population are "extensive metabolizers"; multiple copies of the gene for 2D6 produce high levels
of CYP2D6 and will metabolize drugs through that pathway more quickly than others.
Some medications are CYP2D6 inhibitors and reduce or even completely block the conversion
of codeine to morphine. The most well-known of these are two of the selective serotonin
reuptake inhibitors, paroxetine (Paxil) and fluoxetine (Prozac) as well as the antihistamine
diphenhydramine (Benadryl) and the antidepressant, bupropion (Wellbutrin, also known as
Zyban). Other drugs, such as rifampicin and dexamethasone, induce CYP450 isozymes and thus
increase the conversion rate.
CYP2D6 converts codeine into morphine, which then undergoes glucuronidation. Life-
threatening intoxication, including respiratory depression requiring intubation, can develop over
a matter of days in patients who have multiple functional alleles of CYP2D6, resulting in ultra-
rapid metabolism of opioids such as codeine into morphine.
[18][19][20]

Studies on codeine's analgesic effect are consistent with the idea that metabolism by CYP2D6 to
morphine is important, but some studies show no major differences between those who are poor
metabolizers and extensive metabolizers. Evidence supporting the hypothesis that ultrarapid
metabolizers may get greater analgesia from codeine due to increased morphine formation is
limited to case reports.
[21]

The active metabolites of codeine, notably morphine, exert their effects by binding to and
activating the -opioid receptor.
Relation to other opiates
Codeine has been used in the past as the starting material and prototype of a large class of mainly
mild to moderately strong opioids; such as hydrocodone (1920 in Germany), oxycodone (1916 in
Germany), dihydrocodeine (1908 in Germany), and its derivatives such as nicocodeine (1956 in
Austria).
[citation needed]
However, these opiates are no longer synthesized from codeine and are
usually synthesized from other opioid alkaloids; specifically thebaine.
[citation needed]
Other series of
codeine derivatives include isocodeine and its derivatives, which were developed in Germany
starting around 1920.
As an analgesic, codeine compares moderately to other opiates. Related to codeine in other ways
are codoxime, thebacon, codeine-N-oxide (genocodeine), related to the nitrogen morphine
derivatives as is codeine methobromide, and heterocodeine, which is a drug six times stronger
than morphine and 72 times stronger than codeine due to a small re-arrangement of the molecule,
viz. moving the methyl group from the 3 to the 6 position on the morphine carbon skeleton.
Drugs bearing resemblance to codeine in effects due to close structural relationship are variations
on the methyl groups at the 3 position including ethylmorphine a.k.a. codethyline (Dionine) and
benzylmorphine (Peronine). While having no narcotic effects of its own, the important opioid
precursor thebaine differs from codeine only slightly in structure. Pseudocodeine and some other
similar alkaloids not currently used in medicine are found in trace amounts in opium as well.
History
Codeine, or 3-methylmorphine, is an alkaloid found in the opium poppy, Papaver somniferum
var. album, a plant in the papaveraceae family. Opium poppy has been cultivated and utilized
throughout human history for a variety of medicinal (analgesic, anti-tussive and anti-diarrheal)
and hypnotic properties linked to the diversity of its active components, which include morphine,
codeine and papaverine.
Codeine is found in concentrations of 1.0 to 3.0 per cent in opium prepared by the latex method
from unripe pods of Papaver somniferum. The name codeine is derived from the Greek word
kodeia () for "poppy head". The relative proportion of codeine to morphine, the most
common opium alkaloid at 4 to 23 per cent, tends to be somewhat higher in the poppy straw
method of preparing opium alkaloids.
Until the beginning of the 19th century, raw opium was used in diverse preparations known as
laudanum (see Thomas de Quincey's "Confessions of an English Opium-Eater", 1821) and
paregoric elixirs, a number of which were popular in England since the beginning of the 18th
century; the original preparation seems to have been elaborated in Leiden, the Netherlands
around 1715 by a chemist named Lemort; in 1721 the London Pharmocopeia mentions an Elixir
Asthmaticum, replaced by the term Elixir Paregoricum ("pain soother") in 1746.
The progressive isolation of opium's several active components opened the path to improved
selectivity and safety of the opiates-based pharmacopeia.
Morphine had already been isolated in Germany by German pharmacist Friedrich Sertrner in
1804.
[22]
Codeine was first isolated decades later in 1832 in France by Pierre Robiquet, a French
chemist and pharmacist already famous for the discovery of alizarin, the most widespread red
dye, while working on refined morphine extraction processes. This paved the way for the
elaboration of a new generation of safer, codeine-based specific antitussive and antidiarrheal
formulations.
Codeine is currently the most widely used opiate in the world,
[23][24]
and is one of the most
commonly used drugs overall according to numerous reports by organizations including the
World Health Organization and its League of Nations predecessor agency. It is one of the most
effective orally administered opioid analgesics and has a wide safety margin. Its strength ranges
from 8 to 12 percent of morphine in most people; differences in metabolism can change this
figure as can other medications, depending on its route of administration.
While codeine can be directly extracted from opium, its original source, most codeine is
synthesized from the much more abundant morphine through the process of O-methylation.
[24][25]

By 1972, the effects of the War On Drugs had caused across-the-board shortages of illicit and
licit opiates because of a scarcity of natural opium, poppy straw, and other sources of opium
alkaloids, and the geopolitical situation was growing difficult for the United States. After a large
percentage of the opium and morphine in the US National Stockpile of Strategic & Critical
Materials was tapped in order to ease severe shortages of medicinal opiates the codeine-based
antitussives in particular in late 1973, researchers were tasked with finding a way to
synthesize codeine and its derivatives. They quickly succeeded using petroleum or coal tar and a
process developed at the United States' National Institutes of Health.
Numerous codeine salts have been prepared since the drug was discovered. The most commonly
used are the hydrochloride (freebase conversion ratio 0.805), phosphate (0.736), sulphate
(0.859), and citrate (0.842). Others include a salicylate NSAID, codeine salicylate (0.686), and at
least four codeine-based barbiturates, the cyclohexenylethylbarbiturate (0.559),
cyclopentenylallylbarbiturate (0.561), diallylbarbiturate (0.561), and diethylbarbiturate (0.619).
Recreational use
Codeine can be used as a recreational drug.
In some countries, cough syrups and tablets containing codeine are available without
prescription; some potential recreational users are reported to buy codeine from multiple
pharmacies so as not to arouse suspicion. In countries like Canada, in an effort to reduce
recreational use, all OTC purchases of codeine are electronically recorded, and any pharmacy
can access these records if desired. A heroin addict may use codeine to ward off the effects of a
withdrawal.
[26]

Codeine is also available in conjunction with the anti-nausea medication promethazine in the
form of a syrup. Brand named as Phenergan with Codeine or in generic form as promethazine
with codeine. Called 'syrup', 'lean', or 'purple drank', this medication is quickly becoming one of
the most commonly misused codeine preparations.
[27]
Rapper Pimp C, from the group UGK, died
from an overdose of this combination.
[28]

Codeine is also demethylated by reaction with pyridine to synthesize morphine, which can then
be acetylated to make heroin (diacetylmorphine). Pyridine is toxic and possibly carcinogenic, so
morphine produced in this manner (and potentially contaminated with pyridine) may be
particularly harmful.
[29]
Codeine can also be turned into -chlorocodide, which is used in the
clandestine synthesis of desomorphine (Permonid) (desomorphine attracted attention in 2010 in
Russia due to an upsurge in clandestine production, presumably due to its relatively simple
synthesis from codeine.
[citation needed]
The drug is easily made from codeine, iodine and red
phosphorus,
[30]
in a similar process to the manufacture of methamphetamine from
pseudoephedrine, but desomorphine made this way is highly impure and contaminated with
various toxic and corrosive byproducts.).
Detection
Codeine and/or its major metabolites may be quantitative in blood, plasma or urine to monitor
therapy, confirm a diagnosis of poisoning or assist in a medico-legal death investigation. Drug
abuse screening programs generally test urine, hair, sweat or saliva. Many commercial opiate
screening tests directed at morphine cross-react appreciably with codeine and its metabolites, but
chromatographic techniques can easily distinguish codeine from other opiates and opioids. It is
important to note that codeine usage results in significant amounts of morphine as an excretion
product. Furthermore, heroin contains codeine (or acetyl codeine) as an impurity and its use will
result in excretion of small amounts of codeine. Poppy seed foods represent yet another source of
low levels of codeine in one's biofluids. Blood or plasma codeine concentrations are typically in
the 50300 g/L range in persons taking the drug therapeutically, 7007000 g/L in chronic
users and 100010,000 g/L in cases of acute fatal over dosage.
[31][32][33]

Legal status
In Australia, Canada, New Zealand, Sweden, the United Kingdom, the United States and many
other countries, codeine is regulated under various narcotic control laws. In some countries it is
available without a medical prescription in combination preparations from licensed pharmacists
in doses up to 15mg.
Australia
In Australia, codeine preparations must be sold only at a pharmacy. Preparations will often be a
combination of paracetamol (500 mg), ibuprofen (200 mg) and doxylamine succinate (5 mg),
and the codeine content may range from 5 mg to 15 mg; preparations with in excess of 30 mg per
tablet are S4 (schedule 4, or Prescription Only) medications. The item is given over the counter,
no prescriptions, at the discretion of the Pharmacist. Most preparations are considered S3
(schedule 3, or Pharmacist Only) medications, meaning that they must be sold with the direct
involvement of a pharmacist. It must be labelled and usage history monitored by the Pharmacist
to help deter misuse and dependence. The exception to this rule is cold and flu preparations such
as "Codral". These preparations contain phenylephrine (5 mg), paracetamol(500 mg) and
codeine(9.5 mg).
[34]

Preparations containing pure codeine (e.g., codeine phosphate tablets or codeine phosphate
linctus) are available on prescription and are considered S8 (schedule 8, or Controlled Drug
(Possession without authority illegal)). Schedule 8 preparations are subject to the strictest
regulation of all medications available to consumers.
Denmark
In Denmark codeine is sold over the counter with max 9.6 mg in mixture.
[citation needed]
The item is
given over the counter, no prescriptions. The strongest available over the counter preparation
containing codeine has 9.6 mg (with aspirin, brand name Kodimagnyl); anything stronger
requires a prescription.
France
In France, most preparations containing codeine do not require a doctor's prescription. Example
products containing codeine include Nocodion (cough pills, and syrup), Codoliprane (codeine
with paracetamol), Prontalgine and Migralgine (codeine, paracetamol and caffeine).
[35]

Germany, Switzerland and Austria
Codeine is listed under the Betubungsmittelgesetz in Germany and the similarly named
narcotics and controlled substances law in Switzerland. In Austria, the drug is listed under the
Suchtmittelgesetz in categories corresponding to their classification under the Single Convention
on Narcotic Drugs. Dispensing of products containing codeine and similar drugs
(dihydrocodeine, nicocodeine, benzylmorphine, ethylmorphine etc.), in general, requires a
prescription order from a doctor or the discretion of the pharmacist.
Municipal and provincial regulations may impact availability, in particular in Austria and
Switzerland, which allows cities and provinces to regulate the selling of the least-regulated
schedule of the SMG/BtMG. Individual chemists' shops can opt out of providing them or
imposing volume, frequency, or single-purchase limitations and other things of the same store.
Plain codeine hydrochloride tablets (which in the USA would share CSA Schedule II with drugs
like morphine, cocaine, hydromorphone, and bezitramide) as well as other non-injectable forms
of codeine and its midrange derivatives can be dispensed in this way; the same goes for most
chemical classes of benzodiazepines, the majority of non-barbiturate sedative/hypnotics, and at
least a handful of barbiturates.
Title 76 of the Schengen treaty has made it possible for countries within the signatory states to
import and export drugs with various provisos, recording and ordering requirements, and various
other rules.
Greece
Codeine is classed as an illegal drug in Greece, and individuals possessing it could conceivably
be arrested, even if they were legitimately prescribed it in another country. It is sold only with a
doctor's prescription (Lonarid-N, Lonalgal).
[36]

Hong Kong
In Hong Kong, codeine is regulated under Laws of Hong Kong, Dangerous Drugs Ordinance,
Chapter 134, Schedule 1. It can be used legally only by health professionals and for university
research purposes. The substance can be given by pharmacists under a prescription. Anyone who
supplies the substance without prescription can be fined $10,000 (HKD). The maximum penalty
for trafficking or manufacturing the substance is a $5,000,000 (HKD) fine and life imprisonment.
Possession of the substance for consumption without license from the Department of Health is
illegal with a $1,000,000 (HKD) fine and/or 7 years of jail time.
However, codeine is available without prescription from licensed pharmacists in doses up to
0.1%
[37]:Schedule 1, Part IV, paragraph 23
(i.e. 5 mg/5ml)
[37]:Section 3, (1) (a)

Iceland
Preparations of paracetamol and codeine require a prescription in Iceland. These tablets are
known as Parkdn.
India
Codeine preparations require a prescription in India. A preparation of paracetamol and codeine is
available in India. Codeine is also present in various cough syrups as codeine phosphate.
Iran
Preparations of codeine in Iran normally comes with paracetamol, but can be purchased over-the-
counter. Iran's deputy health minister reported that codeine is Iran's best selling OTC medication.
The recreational use of codeine has also become widespread throughout Iran but authorities
continue to let codeine be purchased without permission from a doctor, although the pharmacist
may ask for the identification of the purchaser to verify they are 18 years or older to buy.
Ireland
In Ireland, new regulations came into effect on August 1, 2010
[38]
concerning codeine, due to
worries about the overuse of the drug. Codeine remains a semi non-prescriptive, over-the-counter
drug up to a limit of 12.8 mg per pill, but codeine products must be out of the view of the public
to facilitate the legislative requirement that these products are not accessible to the public for
self-selection.
[39]
In practice, this means customers must ask pharmacists for the product
containing codeine in name, and the pharmacist makes a judgement whether it is suitable for the
patient to be using codeine, and that patients are fully advised of the correct use of these
products. Products containing more than 12.8 mg codeine are available on prescription only.
[40]

Italy
Codeine tablets or preparations require a prescription in Italy. Preparations of paracetamol and
codeine are available in Italy as Co-Efferalgan and Tachidol.
Japan
Codeine and similar mid-level centrally acting agents in combination with non-opioid analgesics,
antihistamines, vitamins, inert GI agents like kaolin & pectin, mild laxatives, antacids, and herbal
preparations, can be purchased over the counter, with 10 mg being the ceiling for OTC
dispensing.
[citation needed]
This is also true of ethylmorphine and dihydrocodeine, and also
diphenoxylate, some weak relatives of the thiambutene opioid family.
[citation needed]

Maldives
The Maldives takes an infamously strict line on medicines, with many common drugs, notably
anything with containing codeine being banned unless you have a notarized and authenticated
doctor's prescription. Visitors breaking the rules, even inadvertently, have been deported or
imprisoned.
Romania
Codeine is not allowed without a medical prescription. Codeine is sold under the name Farmacod
and its concentration does not exceed 15 mg. There is a known combination of acetylsalicylic
acid, paracetamol and codeine phosphate hemihydrate named Aspaco that is allowed without a
medical prescription but its case is signed with an exclamation red symbol which means that
driving won't be allowed during treatment. There are no sanctions whether the drug is given
without a prescription.
Russia
According to ITAR-Tass and Austria Presse-Agentur, OTC availability of codeine products was
rescinded nationwide in 2012 because of the discovery of the Krokodil method of underground
desomorphine synthesis. Opponents of the move point out that codeine has not been available
OTC in 22 of Russia's oblasts for years and the demand will call forth its own supply, meaning
that only legitimate end users are negatively impacted (activist quoted in Pravda story on issue)
Spain
Codeine tablets or preparations require a prescription in Spain, although this is often not
enforced and many pharmacies will sell codeine products without the requirement of a
prescription.
[citation needed]

Sri Lanka
Codeine preparations are available as over the counter pharmacy medicines in Sri Lanka. The
most common preparation is Panadeine, which contains 500 mg of Paracetamol and 8 mg of
Codeine.
United Arab Emirates
The UAE takes an exceptionally strict line on medicines, with many common drugs, notably
anything with containing codeine being banned unless you have a notarized and authenticated
doctor's prescription. Visitors breaking the rules, even inadvertently, have been deported or
imprisoned. The US Embassy to the UAE maintains an unofficial list of what may not be
imported.
United Kingdom
In the United Kingdom, the sale and possession of codeine are restricted separately under law.
Neat codeine and higher-strength codeine formulations are generally prescription-only medicines
(POM) meaning that the sale of such products is restricted under the Medicines Act 1968.
Lower-strength products containing combinations of up to 12.8 mg of codeine per dosage unit,
combined with paracetamol, ibuprofen or aspirin are available behind the counter at pharmacies.
Codeine linctus of 15 mg per 5 ml is also available at some pharmacies, although a purchaser
would have to request it specifically from the pharmacist.
Under the Misuse of Drugs Act 1971 codeine is a Class B controlled substance or a Class A drug
when prepared for injection.
[41]
The possession of controlled substances without a prescription is
a criminal offence.
[42]
However, certain preparations of codeine are exempt from this restriction
under Schedule 5 of the Misuse of Drugs Regulations 2001. It is thus legal to possess codeine
without a prescription, provided that it is compounded with at least one other active or inactive
ingredient and that the dosage of each tablet, capsule, etc does not exceed 100 mg or 2.5%
concentration in the case of liquid preparations. The exemptions do not to apply to any
preparation of codeine designed for injection.
[43]

United States
Narcotic content number in the US names of codeine tablets and combination products like
Tylenol With Codeine No. 3, Emprin With Codeine No. 4, and pure codeine tablets are as
follows: No. 1 - 7 or 8 mg (1/8 grain), No. 2 - 15 or 16 mg (1/4 grain), No. 3 - 30 or 32 mg (1/2
grain), No. 4 - 60 or 64 mg (1 grain). The Canadian "Frosst 222"
[44]
series is identical to the
above list: "222" contains 8 mg codeine, "282" 15 mg, "292" 30 mg, and "293" 60 mg. This
system, which is also used at present in the trade names of some dihydrocodeine and
ethylmorphine products both in and outside of North America, was inaugurated with the Pure
Food and Drug Act of 1906 and related legislation and refined since.
Equivalent scales for labeling stronger opioids such as diacetylmorphine (heroin), morphine,
opium salts mixtures, and others were in common use in the past, and on occasion one can find
past references to brand names for hydrocodone (invented 1920, introduced in US 1943),
hydromorphone (invented 1924), oxycodone (invented 1916), paregoric and similar drugs
containing narcotic content numbers. For example. from circa 1900 to 1925, the most common
cough medicine was terpin hydrate With Heroin Elixir No. 2.
Contrary to the advertising matter of some pharmacies, 60 mg is No. 4, not No. 6, and tablets
with 45 mg of codeine are not No. 4 and would in all likelihood be classified as No. 3 under
that system. Whether the scale goes to No. 5 and higher is moot at this point, as in the United
States and Canada single-dose-unit concentrations of more than 64 mg are not manufactured.
The United States Controlled Substances Act of 1970 does place dosage unit strengths of 90 mg
of codeine and higher in Schedule II, even if mixed with another active ingredient.
Oral tablets, hypodermic tablets, liquid forms, and capsules of less common doses are available
in some cases the equivalent dihydrocodeine, dionine, benzylmorphine, and opium dosages were
previously available in North America (and in most cases still are in other countries, particularly
the 45 mg paracetamol/codeine and 50 and 100 mg single-ingredient codeine tablets).
In the United States, codeine is regulated by the Controlled Substances Act. Federal law dictates
that codeine be a Schedule II controlled substance when used in products for pain-relief that
contain codeine alone or more than 90 mg per dosage unit. Tablets of codeine in combination
with aspirin or acetaminophen (paracetamol/Tylenol) made for pain relief are listed as Schedule
III; and cough syrups are Schedule III or V, depending on formula. The acetaminophen/codeine
pain-relief elixir (trade name Tylenol Elixir with Codeine) is a Schedule IV controlled
substance.
[45]

Some states have chosen to classify Schedule V codeine preparations into a more restrictive
schedule in order to cut down the abuse of prescription codeine preparations. Minnesota, for
instance, has chosen to reclassify Schedule V codeine preparations (such as Cheratussin) as a
Schedule II controlled substance.
[46]

Preparations for cough or diarrhea containing small amounts of codeine in combination with two
or more other active ingredients are Schedule V in the US, and in some states may be dispensed
in amounts up to 4 fl. oz. per 48 hours (one or two states set the limit at 4 fl. oz. per 72 hours)
without a prescription. Schedule V specifically consigns the product to state and local regulation
beyond certain required record-keeping requirements (a dispensary log must be maintained for
two years in a ledger from which pages cannot easily be removed and/or are pre-numbered, and
the pharmacist must ask for photo identification) and also maintain controlled substances in the
closed system at the root of the rgime intended by the Controlled Substances Act of 1970; the
codeine in these products was a Schedule II substance when the company making the Schedule
V product acquired it for mixing up the end-product.
In locales where dilute codeine preparations are non-prescription, anywhere from very few to
perhaps a moderate percentage of pharmacists will sell these preparations without a prescription.
However, many states have their own laws that do require a prescription for Schedule V drugs.
The December 2008 issue of The Bulletin of the National Codeine OTC Lobby (Vol. XVIII, No.
4) listed 12 states with some kind of OTC access to codeine, noting that small independent
pharmacies are the most likely to have it. This situation is roughly equivalent to that in February
1991, when the aforementioned organisation undertook its first comprehensive study of Schedule
V and overall codeine, dihydrocodeine, ethylmorphine, and hydrocodone availability.
Other drugs that are present in Schedule V narcotic preparations like the codeine syrups are
ethylmorphine and dihydrocodeine. Paregoric and hydrocodone were transferred to Schedule III
from Schedule V even if the preparation contains two or more other active ingredients, and
diphenoxylate is usually covered by state prescription laws even though this relative of pethidine
is a Schedule V substance when adulterated with atropine to prevent abuse.
Around the world, codeine is, contingent on its concentration, a Schedule II and III drug under
the Single Convention on Narcotic Drugs.
[47]

References
1. Shen H, He MM, Liu H, et al (August 2007). "Comparative metabolic capabilities and
inhibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17". Drug Metab. Dispos.
35 (8): 1292300. doi:10.1124/dmd.107.015354. PMID 17470523.
2. "WHO Model List of EssentialMedicines". World Health Organization. October 2013.
Retrieved 22 April 2014.
3. "Codeine". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
4. Stefano Guandalini; Haleh Vaziri (November 8, 2010). Diarrhea: Diagnostic and
Therapeutic Advances. New York, USA: Humana Press. p. 452. ISBN 1-60761-182-1.
5. "Codeine - adverse effects". Medscape reference - Drugs, Diseases & Procedures.
WebMD LLC. Retrieved 27 Sep 2012.
6. Codeine Information from Drugs.com
7. CTV News, Codeine use while breastfeeding may be dangerous, Wed. Aug. 20 2008
8. Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ (August 2006). "Pharmacogenetics
of morphine poisoning in a breastfed neonate of a codeine-prescribed mother". Lancet
368 (9536): 704. doi:10.1016/S0140-6736(06)69255-6. PMID 16920476.
9. "FDA Drug Safety Communication: Codeine use in certain children after tonsillectomy
and/or adenoidectomy may lead to rare, but life-threatening adverse events or death".
Food and Drug Administration.
10. Alberta Health Services; AADAC (April 16, 2007). "The ABCs - Codeine and Other
Opioid Painkillers". Alberta Alcohol and Drug Abuse Commission. Retrieved Sep 12,
2008.
11. Armstrong SC, Cozza KL (2003). "Pharmacokinetic drug interactions of morphine,
codeine, and their derivatives: theory and clinical reality, Part II". Psychosomatics 44 (6):
51520. doi:10.1176/appi.psy.44.6.515. PMID 14597688.
12. Vree TB, van Dongen RT, Koopman-Kimenai PM (2000). "Codeine analgesia is due to
codeine-6-glucuronide, not morphine". Int. J. Clin. Practa. 54 (6): 3958.
PMID 11092114.
13. Fernandes LC, Kilicarslan T, Kaplan HL, Tyndale RF, Sellers EM, Romach MK (June
2002). "Treatment of codeine dependence with inhibitors of cytochrome P450 2D6". J
Clin Psychopharmacol 22 (3): 3269. doi:10.1097/00004714-200206000-00014.
PMID 12006904.
14. Kathiramalainathan K, Kaplan HL, Romach MK, et al. (2000). "Inhibition of cytochrome
P450 2D6 modifies codeine abuse liability". J Clin Psychopharmacol 20 (4): 43544.
doi:10.1097/00004714-200008000-00008. PMID 10917405.
15. Koren G, Cairns J, Chitayat D, Gaedigk A, Leeder SJ (2006). "Pharmacogenetics of
morphine poisoning in a breastfed neonate of a codeine-prescribed mother". Lancet 368
(9536): 704. doi:10.1016/S0140-6736(06)69255-6. PMID 16920476.
16. Willmann S, Edginton AN, Coboeken K, Ahr G, Lippert J (2009). "Risk to the Breast-
Fed Neonate From Codeine Treatment to the Mother: A Quantitative Mechanistic
Modeling Study". Clinical Pharmacology & Therapeutics 86 (6): 63443.
doi:10.1038/clpt.2009.151.
17. Srinivasan V, Wielbo D, Tebbett IR (1997). "Analgesic effects of codeine-6-glucuronide
after intravenous administration". European Journal of Pain 1 (3): 18590.
doi:10.1016/S1090-3801(97)90103-8. PMID 15102399.
18. Lurcott G (1998). "The effects of the genetic absence and inhibition of CYP2D6 on the
metabolism of codeine and its derivatives, hydrocodone and oxycodone". Anesth Prog 45
(4): 1546. PMC 2148980. PMID 10483388.
19. Gasche Y, Daali Y, Fathi M, et al. (December 2004). "Codeine intoxication associated
with ultrarapid CYP2D6 metabolism". N. Engl. J. Med. 351 (27): 282731.
doi:10.1056/NEJMoa041888. PMID 15625333.
20. Caraco Y (December 2004). "Genes and the response to drugs". N. Engl. J. Med. 351
(27): 28679. doi:10.1056/NEJMe048278. PMID 15625340.
21. Gardiner, S. J.; Begg, E. J. (2006). "Pharmacogenetics, Drug-Metabolizing Enzymes, and
Clinical Practice". Pharmacological Reviews 58 (3): 521590. doi:10.1124/pr.58.3.6.
PMID 16968950. edit
22. Andreas Luch (2009). Molecular, clinical and environmental toxicology. Springer. p. 20.
ISBN 3-7643-8335-6.
23. Opiates.com - Codeine
24. Science Daily (March 2010) - "Unlocking the Opium Poppy's Biggest Secret: Genes That
Make Codeine, Morphine"
25. Elmhurt College - Narcotic Analgesic Drugs
26. Boekhout van Solinge, Tim (1996). "7. La politique de soins des annes quatre-vingt-
dix". L'hrone, la cocane et le crack en France. Trafic, usage et politique (in French).
Amsterdam: CEDRO Centrum voor Drugsonderzoek, Universiteit van Amsterdam.
pp. 247262.
27. Leinwand, Donna (2006-10-18). "DEA warns of soft drink-cough syrup mix". USA
Today. Retrieved 2006-10-23.
28. "Pimp C's death caused by overdose and sleep condition - Houston Chronicle".
Chron.com. 2008-02-04. Retrieved 2014-01-12.
29. Hogshire, Jim (June 1999). Pills-A-Go-Go: A Fiendish Investigation into Pill Marketing,
Art, History & Consumption. Los Angeles: Feral House. pp. 216223. ISBN 978-0-
922915-53-8.
30. Savchuk, S. A.; Barsegyan, S. S.; Barsegyan, I. B.; Kolesov, G. M. (2011).
"Chromatographic study of expert and biological samples containing desomorphine".
Journal of Analytical Chemistry 63 (4): 36170. doi:10.1134/S1061934808040096.
31. Thevis M, Opfermann G, Schnzer W (2003). "Urinary concentrations of morphine and
codeine after consumption of poppy seeds". J. Anal. Toxicol. 27 (1): 536.
PMID 12587685.
32. Cone EJ, Welch P, Paul BD, Mitchell JM (1991). "Forensic drug testing for opiates, III.
Urinary excretion rates of morphine and codeine following codeine administration". J.
Anal. Toxicol. 15 (4): 1616. PMID 1943064.
33. Baselt, R. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster
City CA: Biomedical Publications. pp. 355360.
34. "Codeine crackdown comes into effect". ABC.net.au. Retrieved 2010-11-22.
35. "vital list of codein". vidal.com. Retrieved 2011-01-12.
36. "Pharmacies in Greece". About.com. Retrieved 2009-10-10.
37. Laws of Hong Kong, Dangerous Drugs Ordinance, Chapter 134
38. "Codeine regulations cause a few headaches". The Irish Times. 8 Aug 2010.
39. Office of The Attorney General, Regulation 5(1)(e) of the Regulation of Retail Pharmacy
Businesses Regulations 2008 (S.I. 488 of 2008)
40. Non-Prescription Medicinal Products Containing Codeine: Draft Guidance for
Pharmacists. Pharmaceutical Society of Ireland.
41. "Misuse of Drugs Act 1971". Legislation.gov.uk. Retrieved 2014-01-12.
42. "Misuse of Drugs Act 1971". Legislation.gov.uk. Retrieved 2014-01-12.
43. "The Misuse of Drugs Regulations 2001". Legislation.gov.uk. 2013-12-09. Retrieved
2014-01-12.
44. Business and History - Merck Frosst Canada Inc. | Western Libraries
45. Valeant Pharmaceuticals. "Prescribing Information for Capital with Codeine
(acetaminophen with codeine) showing Schedule V designation" (PDF). Retrieved 2011-
02-25.
46. "152.02 SCHEDULES OF CONTROLLED SUBSTANCES". State of Minnesota.
Retrieved 30 May 2013.
47. International Narcotics Control Board. "List of Narcotic Drugs under International
Control" (PDF). Retrieved 2006-05-24.


http://www.chemspider.com/Chemical-Structure.4447447.html
http://pubchem.ncbi.nlm.nih.gov/rest/chemical/codeine
This article is about the stimulant drug. For other uses, see Caffeine (disambiguation).
Caffeine


Systematic (IUPAC) name
1,3,7-Trimethyl-1H-purine-2,6(3H,7H)-dione
3,7-Dihydro-1,3,7-trimethyl-1H-purine-2,6-dione
Clinical data
AHFS/Drugs.com monograph
Pregnancy cat. C (US)
Legal status Unscheduled (AU) GSL (UK) OTC (US)
Dependence liability Moderate
Routes Oral, insufflation, enema
Pharmacokinetic data
Bioavailability 99%
Protein binding 17% to 36%
Metabolism demethylation by CYP1A2
Half-life 5 hours
Excretion urine (100%)
Identifiers
ATC code N06BC01
PubChem CID 2519
DrugBank DB00201
ChemSpider 2424


UNII 3G6A5W338E


KEGG D00528


ChEBI CHEBI:27732


ChEMBL CHEMBL113


PDB ligand ID CFF (PDBe, RCSB PDB)
Chemical data
Formula C
8
H
10
N
4
O
2


Mol. mass 194.19 g/mol
SMILES[show]
InChI[show]
Caffeine is a bitter, white crystalline xanthine alkaloid and a stimulant drug. Caffeine is found in
varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural
pesticide that paralyzes and kills certain insects feeding on the plants, as well as enhancing the
reward memory of pollinators. It is most commonly consumed by humans in infusions extracted
from the seed of the coffee plant and the leaves of the tea bush, as well as from various foods and
drinks containing products derived from the kola nut. Other sources include yerba mat, guarana
berries, guayusa, and the yaupon holly.
In humans, caffeine acts as a central nervous system stimulant, temporarily warding off
drowsiness and restoring alertness. It is the world's most widely consumed psychoactive drug,
but unlike many other psychoactive substances, it is legal and unregulated in nearly all parts of
the world. Beverages containing caffeine, such as coffee, tea, soft drinks, and energy drinks,
enjoy great popularity. In North America, 90% of adults consume caffeine daily.
[1]

Part of the reason caffeine is classified by the Food and Drug Administration as generally
recognized as safe is that toxic doses (over 10 grams for an average adult) are much higher than
typically used doses (less than 500 milligrams). Ordinary consumption has low health risks, even
when carried on for years there may be a modest protective effect against some diseases,
including Parkinson's disease,
[2][3]
heart disease,
[4]
and certain types of cancer. Some people
experience sleep disruption if they consume caffeine, especially during the evening hours, but
others show little disturbance and the effect of caffeine on sleep is highly variable.
Evidence of a risk to pregnancy is equivocal, with some authorities concluding that it is wise for
pregnant women to limit consumption to the equivalent of two cups of coffee per day or less.
[5][6]

Caffeine has pressor and mild diuretic effects when administered to people who are not used to
it, but regular users develop a tolerance to this effect, and studies have generally failed to support
the common notion that ordinary consumption contributes significantly to dehydration. With
heavy use, tolerance develops rapidly to autonomic effects such as elevated heart rate and muscle
twitching, but not to the cognitive or arousal effects of caffeine. The degree to which caffeine
can produce significant dependency and caffeine addiction remains a subject of controversy in
the medical literature.
Contents
1 Health effects
o 1.1 Stimulant effects
o 1.2 Physical effects
o 1.3 Psychological effects
o 1.4 Caffeine toxicity
o 1.5 Addiction and tolerance
o 1.6 Withdrawal
o 1.7 Other animals
o 1.8 Microbial remediation
2 Sources and consumption
3 Chemical properties and biosynthesis
4 Pharmacology
o 4.1 Mechanism of action
o 4.2 Metabolism
5 Detection in biological fluids
6 Decaffeination
7 History
o 7.1 Discovery
o 7.2 Legality
8 Religion
9 References
10 Bibliography
11 External links
Health effects
Main article: Health effects of caffeine


Health effects of caffeine
Stimulant effects
Caffeine is a central nervous system and metabolic stimulant,
[7]
and is used both recreationally
and medically to reduce physical fatigue and to restore alertness when drowsiness occurs. It
produces increased wakefulness, faster and clearer flow of thought, increased focus, and better
general body coordination.
[8]
The amount of caffeine needed to produce effects varies from
person to person, depending on body size and degree of tolerance. Effects begin less than an hour
after consumption, and a moderate dose usually wears off in about five hours.
[8]

Caffeine has a number of effects on sleep, but does not affect all people in the same way. It
improves performance during sleep deprivation but may lead to subsequent insomnia.
[9]
In shift
workers it leads to fewer mistakes caused by tiredness.
[10]
In athletics, moderate doses of caffeine
can improve sprint,
[11]
endurance,
[12]
and team sports performance,
[13]
but the improvements are
usually not very large. Interestingly, some evidence suggests that coffee does not produce the
ergogenic effects observed in other caffeine sources.
[14]
High doses of caffeine, however, can
impair athletic performance by interfering with coordination.
[15]
Evidence shows that, contrary to
common advice, caffeine may be helpful at high altitude.
[16]

Physical effects
Consumption of 10001500 mg per day is associated with a condition known as caffeinism.
[17]

Caffeinism usually combines caffeine dependency with a wide range of unpleasant physical and
mental conditions including nervousness, irritability, restlessness, insomnia, headaches, and heart
palpitations after caffeine use.
[18]

Coffee consumption is associated with a lower overall risk of cancer.
[19]
This is primarily due to
a decrease in the risks of hepatocellular and endometrial cancer, but it may also have a modest
effect on colorectal cancer.
[20]
There does not appear to be a significant protective effect against
other types of cancers, and heavy coffee consumption may increase the risk of bladder cancer.
[20]

Moderate coffee consumption may decrease the risk of cardiovascular disease,
[4]
and it may
somewhat reduce the risk of type 2 diabetes.
[21]
Drinking four or more cups of coffee per day
does not affect the risk of hypertension compared to drinking little or no coffee. However those
who drink 13 cups per day may be at a slightly increased risk.
[22]
Caffeine increases intraocular
pressure in those with glaucoma but does not appear to affect normal individuals.
[23]
It may
protect people from liver cirrhosis.
[24]
There is no evidence that coffee stunts a child's growth.
[25]

Caffeine may increase the effectiveness of some medications including ones used to treat
headaches.
[26]
Similarly, intravenous caffeine is often used in hospitals to provide temporary pain
relief for headaches caused by low cerebrospinal fluid pressure.
Caffeine consumption during pregnancy does not appear to increase the risk of congenital
malformations, miscarriage or growth retardation even when consumed in moderate to high
amounts.
[27]
However as the data supporting this conclusion is of poor quality some suggest
limiting caffeine consumption during pregnancy.
[28][29]
For example the UK Food Standards
Agency has recommended that pregnant women should limit their caffeine intake, out of
prudence, to less than 200 mg of caffeine a day the equivalent of two cups of instant coffee, or
one and a half to two cups of fresh coffee.
[30]
The American Congress of Obstetricians and
Gynecologists (ACOG) concluded in 2010 that caffeine consumption is safe up to 200 mg per
day in pregnant women.
[6]
Although the evidence that caffeine may be harmful during pregnancy
is equivocal, there is some evidence that the hormonal changes associated with pregnancy slow
the metabolic clearance of caffeine from the system, causing a given dose to have longer-lasting
effects (as long as 15 hours in the third trimester).
[31]

Caffeine is a weak bronchodilator. In clinical tests on adults with athsma, at fairly low doses
(5mg/kg of body weight), caffeine has been shown to provide a small improvement in lung
function, such that it needs to be controlled for in diagnostic tests.
[32]
Caffeine is the primary
treatment of the breathing disorders apnea of prematurity
[33]
and may also be effective in
preventing bronchopulmonary dysplasia in premature infants.
[34]
The only short-term risk
associated with caffeine citrate treatment is a temporary reduction in weight gain during the
therapy,
[35]
and longer term studies (18 to 21 months) have shown lasting benefits of treatment of
premature infants with caffeine.
[36]
While some authors have raised the possibility of subtle long-
term problems,
[37]
follow-up neurological data at 18 months and at five years after neonatal
caffeine treatment revealed the opposite; treatment appears to be neuroprotective, as caffeine-
treated children were significantly less likely to have cerebral palsy and had reduced rates of
language and cognitive delay.
[38][39]

When doses of caffeine equivalent to 23 cups of coffee are administered to people who have not
consumed caffeine during prior days, they produce a mild increase in urinary output.
[40]
Because
of this diuretic effect, some authorities have recommended that athletes or airline passengers
avoid caffeine to reduce the risk of dehydration.
[40]
Most people who consume caffeine, however,
ingest it daily. Regular users of caffeine have been shown to develop a strong tolerance to the
diuretic effect,
[40]
and studies have generally failed to support the notion that ordinary
consumption of caffeinated beverages contributes significantly to dehydration, even in
athletes.
[41][42]

Psychological effects
The US National Institutes of Health states: "[Too] much caffeine can make you restless,
anxious, and irritable. It may also keep you from sleeping well and cause headaches, abnormal
heart rhythms, or other problems. If you stop using caffeine, you could get withdrawal
symptoms. Some people are more sensitive to the effects of caffeine than others. They should
limit their use of caffeine. So should pregnant and nursing women.
[43]
"
Four caffeine-induced disorders are recognized by the American Psychiatric Association (APA)
including: caffeine intoxication, caffeine-induced sleep disorder, caffeine-induced anxiety
disorder and caffeine-related disorder not otherwise specified (NOS).
[44]
The DSM-IV defines a
person with caffeine-induced sleep disorder as an individual who regularly ingests high doses of
caffeine sufficient to induce a significant disturbance in his or her sleep, sufficiently severe to
warrant clinical attention.
[44]
As of 2010 the effect of caffeine on people with ADHD is not
known.
[45]
Some studies have however found a modest protective effect against Alzheimer
disease, but the evidence is inconclusive.
[46][47][48]

Caffeine can have negative effects on anxiety disorders.
[49]
A number of clinical studies have
shown a positive association between caffeine and anxiogenic effects and/or panic disorder.
[50][51]

At high doses, typically greater than 300 mg, caffeine can both cause and worsen anxiety
[52]
or,
rarely, trigger mania or psychosis. In moderate doses caffeine may reduce symptoms of
depression and lower suicide risk.
[45]
In moderate doses caffeine typically does not affect
learning or memory,
[53]
and can improve cognitive functions, especially in people who are
fatigued, possibly due to its effect on alertness.
[54]
For some people, anxiety can be very much
reduced by discontinuing caffeine use.
[55]

Caffeine toxicity


Primary symptoms of caffeine intoxication
[56]

Caffeine overdose can result in a state of central nervous system over-stimulation called caffeine
intoxication (DSM-IV 305.90).
[44]
This syndrome typically occurs only after ingestion of large
amounts of caffeine, well over the amounts found in typical caffeinated beverages and caffeine
tablets (e.g., more than 400500 mg at a time). The symptoms of caffeine intoxication are
comparable to the symptoms of overdoses of other stimulants: they may include restlessness,
fidgeting, anxiety, excitement, insomnia, flushing of the face, increased urination,
gastrointestinal disturbance, muscle twitching, a rambling flow of thought and speech,
irritability, irregular or rapid heart beat, and psychomotor agitation.
[56]
In cases of much larger
overdoses, mania, depression, lapses in judgment, disorientation, disinhibition, delusions,
hallucinations, or psychosis may occur, and rhabdomyolysis (breakdown of skeletal muscle
tissue) can be provoked.
[57][58]

Extreme overdose can result in death.
[59][60]
The median lethal dose (LD
50
) given orally is 192
milligrams per kilogram in rats. The LD
50
of caffeine in humans is dependent on individual
sensitivity, but is estimated to be about 150 to 200 milligrams per kilogram of body mass or
roughly 80 to 100 cups of coffee for an average adult.
[61]
Though achieving lethal dose of
caffeine would be difficult with regular coffee, it is easier to reach high doses with caffeine pills,
and the lethal dose can be lower in individuals whose ability to metabolize caffeine is impaired.
Chronic liver disease is one factor that can slow the metabolism of caffeine.
[62]
There has been a
reported death of a man who had liver cirrhosis overdosing on caffeinated mints.
[63][64][65]
Drugs
such as fluvoxamine or levofloxacin can have a similar effect by blocking the liver enzyme
responsible for the metabolism of caffeine, thus increasing the central effects and blood
concentrations of caffeine five-fold.
[58][59][60][66]
The exact cause of death in such cases is
uncertain, but may result from cardiac arrhythmia leading to cardiac arrest.
Treatment of severe caffeine intoxication is generally supportive, providing treatment of the
immediate symptoms, but if the patient has very high serum levels of caffeine then peritoneal
dialysis, hemodialysis, or hemofiltration may be required.
[56]

Addiction and tolerance
Main article: Caffeine addiction
With repetitive use, physical dependence or addiction may occur. Also, some effects of caffeine,
particularly the autonomic effects, decrease over time, a phenomenon known as a tolerance.
Tolerance develops quickly to some (but not all) effects of caffeine, especially among heavy
coffee and energy drink consumers.
[67]
Some coffee drinkers develop tolerance to its sleep-
disrupting effects, but others apparently do not.
[31]

Withdrawal
Withdrawal symptoms including headaches, irritability, inability to concentrate, drowsiness,
insomnia, and pain in the stomach, upper body, and joints may appear within 12 to 24 hours
after discontinuation of caffeine intake, peak at roughly 48 hours, and usually last from 2 to 9
days.
[68]
Withdrawal headaches are experienced by 52% of people who stopped consuming
caffeine for two days after an average of 235 mg caffeine per day prior to that.
[69]
In prolonged
caffeine drinkers, symptoms such as increased depression and anxiety, nausea, vomiting,
physical pains and intense desire for caffeine containing beverages are also reported. Peer
knowledge, support and interaction may aid withdrawal.
Caffeine withdrawal is categorized as a mental disorder in the DSM-5 (the 5th edition of the
Diagnostic and Statistical Manual published by the American Psychiatric Association).
[70]

Previous versions of the manual included "caffeine intoxication" but not caffeine withdrawal.
Other animals


Caffeine has a significant effect on spiders, which is illustrated here in the erratic construction of
their webs.
See also: Effect of psychoactive drugs on animals
While safe in humans, caffeine is considerably more toxic to various animals, such as dogs and
birds.
[71][72]
The increased toxicity of caffeine in some animals is at least partly due to a poorer
ability to metabolize the compound.
[73]
Caffeine also has a pronounced effect on mollusks,
various insects, and spiders.
[74]

Microbial remediation
Pseudomonas putida CBB5 can live on pure caffeine and has been observed to break caffeine
down into carbon dioxide and ammonia.
[75]

Sources and consumption
See also: Caffeinated drink
Caffeine Content in Select Food and
Drugs
[76][77][78][79][80]

Product Serving size
Caffeine
per
serving
(mg)
Caffeine
(mg/L)
Caffeine
tablet
1 tablet 100
Caffeine Content in Select Food and
Drugs
[76][77][78][79][80]

Product Serving size
Caffeine
per
serving
(mg)
Caffeine
(mg/L)
(regular-
strength)
Caffeine
tablet (extra-
strength)
1 tablet 200
Excedrin
tablet
1 tablet 65
Hershey's
Special Dark
(45% cacao
content)
1 bar (43 g or
1.5 oz)
31
Hershey's
Milk
Chocolate
(11% cacao
content)
1 bar (43 g or
1.5 oz)
10
Percolated
coffee
207 mL
(7.0 US fl oz)
80135 386652
Drip coffee
207 mL
(7.0 US fl oz)
115175 555845
Coffee,
decaffeinated
207 mL
(7.0 US fl oz)
515 2472
Coffee,
espresso
4460 mL
(1.5
2.0 US fl oz)
100
1,691
2,254
Tea black,
green, and
other
types,
steeped for 3
min.
177 millilitres
(6.0 US fl oz)
22
74
[79][80]

124416
Guayak
yerba mate
(loose leaf)
6 g (0.21 oz) 85
[81]
approx. 358
Coca-Cola
Classic
355 mL
(12.0 US fl oz)
34 96
Mountain
Dew
355 mL
(12.0 US fl oz)
54 154
Caffeine Content in Select Food and
Drugs
[76][77][78][79][80]

Product Serving size
Caffeine
per
serving
(mg)
Caffeine
(mg/L)
Pepsi Max
355 mL
(12.0 US fl oz)
69 194
Guaran
Antarctica
350 mL
(12 US fl oz)
30 100
Jolt Cola
695 mL
(23.5 US fl oz)
280 403
Red Bull
250 mL
(8.5 US fl oz)
80 320
Global consumption of caffeine has been estimated at 120,000 tonnes per year, making it the
world's most popular psychoactive substance. This amounts to one serving of a caffeinated
beverage for every person every day.
[82]

Caffeine is found in many plant species, where it acts as a natural pesticide, with high caffeine
levels being observed in seedlings still developing foliage but lacking mechanical protection;
[83]

caffeine paralyzes and kills certain insects feeding on the plant.
[84]
High caffeine levels have also
been found in the surrounding soil of coffee bean seedlings. Therefore, caffeine is understood to
have a natural function as both a natural pesticide and an inhibitor of seed germination of other
nearby coffee seedlings, thus giving it a better chance of survival.
[85]
Caffeine has also been
found to enhance the reward memory of honeybees, improving the reproductive success of the
plant.
[86]

Common sources of caffeine are coffee, tea, soft drinks and energy drinks, caffeine supplements,
and (to a lesser extent) chocolate derived from cocoa beans.
[87]
Less commonly used sources of
caffeine include the yerba mat, guarana and ilex guayusa plants,
[88]
which are sometimes used in
the preparation of teas and energy drinks. Two of caffeine's alternative names, mateine and
guaranine, are derived from the names of these plants.
[89]

The disparity in experience and effects between the various natural caffeine sources could be
because plant sources of caffeine also contain widely varying mixtures of other xanthine
alkaloids, including the cardiac stimulants theophylline and theobromine, and other substances
such as polyphenols that can form insoluble complexes with caffeine.
[90][clarification needed]

One of the world's primary sources of caffeine is the coffee "bean" (which is the seed of the
coffee plant), from which coffee is brewed. Caffeine content in coffee varies widely depending
on the type of coffee bean and the method of preparation used;
[91]
even beans within a given bush
can show variations in concentration. In general, one serving of coffee ranges from 80 to 100
milligrams, for a single shot (30 milliliters) of arabica-variety espresso, to approximately 100
125 milligrams for a cup (120 milliliters) of drip coffee.
[92][93]
Arabica coffee typically contains
half the caffeine of the robusta variety.
[91]

In general, dark-roast coffee has very slightly less caffeine than lighter roasts because the
roasting process reduces a small amount of the bean's caffeine content.
[92][93]

Tea contains more caffeine than coffee by dry weight. A typical serving, however, contains
much less, since tea is normally brewed much weaker. Also contributing to caffeine content are
growing conditions, processing techniques, and other variables. Thus, certain types of tea may
contain somewhat more caffeine than other teas.
[94]

Tea contains small amounts of theobromine and slightly higher levels of theophylline than
coffee. Preparation and many other factors have a significant impact on tea, and color is a very
poor indicator of caffeine content. Teas like the pale Japanese green tea, gyokuro, for example,
contain far more caffeine than much darker teas like lapsang souchong, which has very little.
[94]



No-Doz 100 mg caffeine tablets
Caffeine is also a common ingredient of soft drinks, such as cola, originally prepared from kola
nuts. Soft drinks typically contain about 10 to 50 milligrams of caffeine per serving. By contrast,
energy drinks, such as Red Bull, can start at 80 milligrams of caffeine per serving. The caffeine
in these drinks either originates from the ingredients used or is an additive derived from the
product of decaffeination or from chemical synthesis. Guarana, a prime ingredient of energy
drinks, contains large amounts of caffeine with small amounts of theobromine and theophylline
in a naturally occurring slow-release excipient.
[95]

Chocolate derived from cocoa beans contains a small amount of caffeine. The weak stimulant
effect of chocolate may be due to a combination of theobromine and theophylline, as well as
caffeine.
[96]
A typical 28-gram serving of a milk chocolate bar has about as much caffeine as a
cup of decaffeinated coffee, although dark chocolate has about the same caffeine as coffee by
weight. Some dark chocolate currently in production contains as much as 160 mg per 100 g
[77]

which is double the caffeine content of the highest caffeinated drip coffee by weight.
Various manufacturers market caffeine tablets, claiming that using caffeine of pharmaceutical
quality improves mental alertness. These effects have been borne out by research that shows
caffeine use (whether in tablet form or not) results in decreased fatigue and increased
attentiveness.
[8]

These tablets are commonly used by students studying for their exams and by people who work
or drive for long hours.
[97]
One U.S. company is also marketing dissolving caffeine strips as an
alternative to energy drinks.
[98]
Another unusual intake route is SpazzStick, a caffeinated lip
balm.
[99]
As of 2013, a number of innovative caffeinated products such as Alert Energy Caffeine
Gum, a Wrigley product, had been introduced in the United States, but were under scrutiny; after
announcement of an investigation by the FDA of the health effects of added caffeine in foods,
Alert Energy Caffeine Gum was voluntarily withdrawn from sale.
[100]

As of 2011, inhaled caffeine is a distribution method under scrutiny by some U.S. lawmakers.
[101]

Chemical properties and biosynthesis


Caffeine biosynthesis
[102]



Caffeine laboratory synthesis
[103][104]

Pure anhydrous caffeine is a white colorless powder with a melting point of 227228 C.
Caffeine is moderately soluble in water at room temperature (2 g/100 mL), but very soluble in
boiling water (66 g/100 mL).
[105]
It is also moderately soluble in ethanol (1.5 g/100 mL).
[105]
It is
weakly basic (pK
a
= ~0.6) requiring strong acid to protonate it.
[106]

Caffeine does not contain any stereogenic centers
[107]
and hence is classified as an achiral
molecule.
[108]

The xanthine core of caffeine contains two fused rings, a pyrimidinedione and imidazole. The
pyrimidinedione in turn contains two amide functional groups that exist predominately in a
zwitterionic resonance form where the nitrogen atoms are double bonded to their adjacent amide
carbons atoms. Hence all six of the atoms within the pyrimidinedione ring system are sp
2

hybridized and planar. Therefore the fused 5,6 ring core of caffeine contains a total of ten pi
electrons and hence according to Hckel's rule is aromatic.
[109]

Caffeine is synthesized in plants from the purine nucleotides AMP, GMP, and IMP. These in
turn are transformed into xanthosine and then theobromine, the latter being the penultimate
precursor of caffeine.
[110]
Being readily available as a byproduct of decaffeination, caffeine is not
usually synthesized chemically.
[111]
If desired, it may be synthesized from dimethylurea and
malonic acid.
[103][104][112]

Pharmacology
Inside the body caffeine acts through several mechanisms, but its most important effect is to
counteract a substance called adenosine that naturally circulates at high levels throughout the
body, and especially in the nervous system. In the brain, adenosine plays a generally protective
role, part of which is to reduce neural activity levels for example, there is some evidence that
adenosine helps to induce torpor in animals that seasonally hibernate.
[113]

Mechanism of action


Caffeine's primary mechanism of action is as an antagonist of adenosine receptors in the brain
Adenosine acts as an inhibitory neurotransmitter that suppresses activity in the central nervous
system. "Largely as a consequence of its blockade of adenosine receptors, caffeine also has
profound effects on most of the other major neurotransmitters, including dopamine,
acetylcholine, serotonin, and, in high doses, on norepinephrine",
[114]
and to a small extent
epinephrine, glutamate, and cortisol.
[citation needed]
At high doses, exceeding 500 milligrams,
caffeine inhibits GABA neurotransmission. GABA reduction explains why caffeine increases
anxiety, insomnia, rapid heart and respiration rate.
[citation needed]

Because caffeine is both water- and lipid-soluble, it readily crosses the bloodbrain barrier that
separates the bloodstream from the interior of the brain. Once in the brain, the principal mode of
action is as a nonselective antagonist of adenosine receptors (in other words, an agent that
reduces the effects of adenosine). The caffeine molecule is structurally similar to adenosine, and
is capable of binding to adenosine receptors on the surface of cells without activating them,
thereby acting as a competitive inhibitor.
[115]

Adenosine is found in every part of the body, because it plays a role in the fundamental
adenosine triphosphate (ATP) related energy producing mechanism and is also needed for RNA
synthesis, but it has additional functions in the brain. The evidence indicates that brain adenosine
acts to protect the brain by suppressing neural activity and by increasing blood flow via receptors
located on vascular smooth muscle.
[116]
Brain adenosine levels are increased by various types of
metabolic stress, including lack of oxygen and interruption of blood flow. There is evidence that
adenosine functions as a synaptically released neurotransmitter in some parts of the brain;
however, stress-related adenosine increases appear to be produced mainly by extracellular
metabolism of ATP. Unlike most neurotransmitters, adenosine does not seem to be packaged
into vesicles that are released in a voltage-controlled manner, but the possibility of such a
mechanism has not been fully ruled out.
[116]

Several classes of adenosine receptors have been described, with different anatomical
distributions. A
1
receptors are widely distributed, and act to inhibit calcium uptake. A
2A
receptors
are heavily concentrated in the basal ganglia, an area that plays a critical role in behavior control,
but can be found in other parts of the brain as well, in lower densities. There is evidence that A
2A

receptors interact with the dopamine system, which is involved in reward and arousal. (A
2A

receptors can also be found on arterial walls and blood cell membranes.)
[117]

Beyond its general neuroprotective effects, there are reasons to believe that adenosine may be
more specifically involved in control of the sleepwake cycle. Robert McCarley and his
colleagues have argued that accumulation of adenosine may be a primary cause of the sensation
of sleepiness that follows prolonged mental activity, and that the effects may be mediated both
by inhibition of wake-promoting neurons via A
1
receptors, and activation of sleep-promoting
neurons via indirect effects on A
2A
receptors.
[117]
More recent studies have provided additional
evidence for the importance of A
2A
, but not A
1
, receptors.
[118]

Caffeine, like other xanthines, also acts as a phosphodiesterase inhibitor.
[119]
As a competitive
nonselective phosphodiesterase inhibitor,
[120]
caffeine raises intracellular cAMP, activates protein
kinase A, inhibits TNF-alpha
[121][122]
and leukotriene
[123]
synthesis, and reduces inflammation and
innate immunity.
[123]

A number of potential mechanisms have been proposed for the athletic performance-enhancing
effects of caffeine.
[124]
In the classic, or metabolic theory, caffeine may increase fat utilization
and decrease glycogen utilization. Caffeine mobilizes free fatty acids from fat and/or
intramuscular triglycerides by increasing circulating epinephrine levels. The increased
availability of free fatty acids increases fat oxidation and spares muscle glycogen, thereby
enhancing endurance performance. In the nervous system, caffeine may reduce the perception of
effort by lowering the neuron activation threshold, making it easier to recruit the muscles for
exercise.
[125]

Caffeine metabolites
Metabolites of caffeine also contribute to caffeine's effects. Paraxanthine is responsible for an
increase in the lipolysis process, which releases glycerol and fatty acids into the blood to be used
as a source of fuel by the muscles. Theobromine is a vasodilator that increases the amount of
oxygen and nutrient flow to the brain and muscles. Theophylline acts as a smooth muscle
relaxant that chiefly affects bronchioles and acts as a chronotrope and inotrope that increases
heart rate and force of contraction.
[126]

Metabolism


Caffeine is metabolized in the liver into three primary metabolites: paraxanthine (84%),
theobromine (12%), and theophylline (4%)
Caffeine from coffee or other beverages is absorbed by the small intestine within 45 minutes of
ingestion and then distributed throughout all tissues of the body.
[127]
Peak blood concentration is
reached within 12 hours.
[128]
It is eliminated by first-order kinetics.
[129]
Caffeine can also be
absorbed rectally, evidenced by the formulation of suppositories of ergotamine tartrate and
caffeine (for the relief of migraine)
[130]
and chlorobutanol and caffeine (for the treatment of
hyperemesis).
[131]

The biological half-life of caffeine the time required for the body to eliminate one-half of the
total amount of caffeine varies widely among individuals according to such factors as age, liver
function, pregnancy, some concurrent medications, and the level of enzymes in the liver needed
for caffeine metabolism. It can also be significantly altered by drugs or hormonal states. In
healthy adults, caffeine's half-life has been measured with a range of results. Some measures get
4.9 hours,
[132]
and others are at around 6 hours.
[133]
Heavy cigarette smokers show a decrease in
half-life of 3050%,
[31]
oral contraceptives can double it,
[31]
and pregnancy can raise it even
more, to as much as 15 hours during the last trimester.
[31]
In newborn infants the half-life can be
80 hours or more; however it drops very rapidly with age, possibly to less than the adult value by
the age of 6 months.
[31]
The antidepressant fluvoxamine (Luvox) reduces the clearance of
caffeine by more than 90%, and prolongs its elimination half-life more than tenfold; from 4.9
hours to 56 hours.
[132]

Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system, in
particular, by the CYP1A2 isozyme, into three dimethylxanthines,
[134]
each of which has its own
effects on the body:
Paraxanthine (84%): Increases lipolysis, leading to elevated glycerol and free fatty acid
levels in the blood plasma.
Theobromine (12%): Dilates blood vessels and increases urine volume. Theobromine is
also the principal alkaloid in the cocoa bean, and therefore chocolate.
Theophylline (4%): Relaxes smooth muscles of the bronchi, and is used to treat asthma.
The therapeutic dose of theophylline, however, is many times greater than the levels
attained from caffeine metabolism.
[citation needed]

Each of these metabolites is further metabolized and then excreted in the urine. Caffeine can
accumulate in individuals with severe liver disease, increasing its half-life.
[135]

Some quinolone antibiotics exert an inhibitory effect on CYP1A2, thereby reducing clearance of
caffeine and thus increasing blood levels.
[136]

A 2011 analysis published by PLoS Genetics reviewed five studies covering more than 47,000
subjects of European descent. Researchers determined that habitual caffeine intake is associated
with variations in two genes that regulate how quickly the body processes caffeine. Subjects who
had a high-intake mutation of either gene on both chromosomes consumed 40 mg more caffeine
per day (equivalent to a can of cola) than people who did not.
[137]

Detection in biological fluids
Caffeine can be quantified in blood, plasma, or serum to monitor therapy in neonates, confirm a
diagnosis of poisoning, or facilitate a medicolegal death investigation. Plasma caffeine levels are
usually in the range of 210 mg/L in coffee drinkers, 1236 mg/L in neonates receiving
treatment for apnea, and 40400 mg/L in victims of acute overdosage. Urinary caffeine
concentration is frequently measured in competitive sports programs, for which a level in excess
of 15 mg/L is usually considered to represent abuse.
[138]

Decaffeination
Main article: Decaffeination


Fibrous crystals of purified caffeine. Dark field light microscope image, the image covers an area
of approx. 11 by 7 mm.
Extraction of caffeine from coffee, to produce decaffeinated coffee and caffeine, is an
important
[quantify]
industrial process and can be performed using a number of solvents. Benzene,
chloroform, trichloroethylene, and dichloromethane have all been used over the years but for
reasons of safety, environmental impact, cost, and flavor, they have been superseded by the
following main methods:
Water extraction: Coffee beans are soaked in water. The water, which contains many
other compounds in addition to caffeine and contributes to the flavor of coffee, is then
passed through activated charcoal, which removes the caffeine. The water can then be put
back with the beans and evaporated dry, leaving decaffeinated coffee with its original
flavor. Coffee manufacturers recover the caffeine and resell it for use in soft drinks and
over-the-counter caffeine tablets.
[139]

Supercritical carbon dioxide extraction: Supercritical carbon dioxide is an excellent
nonpolar solvent for caffeine, and is safer than the organic solvents that are otherwise
used. The extraction process is simple: CO
2
is forced through the green coffee beans at
temperatures above 31.1 C and pressures above 73 atm. Under these conditions, CO
2
is
in a "supercritical" state: It has gaslike properties that allow it to penetrate deep into the
beans but also liquid-like properties that dissolve 9799% of the caffeine. The caffeine-
laden CO
2
is then sprayed with high pressure water to remove the caffeine. The caffeine
can then be isolated by charcoal adsorption (as above) or by distillation, recrystallization,
or reverse osmosis.
[139]

Extraction by organic solvents: Certain organic solvents such as ethyl acetate present
much less health and environmental hazard than chlorinated and aromatic organic
solvents used formerly. Another method is to use triglyceride oils obtained from spent
coffee grounds.
[139]

"Decaffeinated" coffees do in fact contain caffeine in many cases some commercially
available decaffeinated coffee products contain considerable levels. One study found that
decaffeinated coffee contained 10 mg of caffeine per cup, compared to approximately 85 mg of
caffeine per cup for regular coffee.
[140]

History


Coffeehouse in Palestine, circa 1900
Main articles: History of chocolate, History of coffee, History of tea, and History of yerba mate
According to Chinese legend, the Chinese emperor Shennong, reputed to have reigned in about
3000 BCE, accidentally discovered tea when he noted that when certain leaves fell into boiling
water, a fragrant and restorative drink resulted.
[141]
Shennong is also mentioned in Lu Yu's Cha
Jing, a famous early work on the subject of tea.
[142]

The earliest credible evidence of either coffee drinking or knowledge of the coffee tree appears
in the middle of the fifteenth century, in the Sufi monasteries of the Yemenin southern
Arabia.
[143]
From Mocha, coffee spread to Egypt and North Africa, and by the 16th century, it
had reached the rest of the Middle East, Persia and Turkey. From the Middle East, coffee
drinking spread to Italy, then to the rest of Europe, and coffee plants were transported by the
Dutch to the East Indies and to the Americas.
[144]

Use of the kola nut, like the coffee berry and tea leaf, appears to have ancient origins. It is
chewed in many West African cultures, individually or in a social setting, to restore vitality and
ease hunger pangs. In 1911, kola became the focus of one of the earliest documented health
scares, when the US government seized 40 barrels and 20 kegs of Coca-Cola syrup in
Chattanooga, Tennessee, alleging the caffeine in its drink was "injurious to health".
[145]
Although
the judge ruled in favor of Coca-Cola, two bills were introduced to the U.S. House of
Representatives in 1912 to amend the Pure Food and Drug Act, adding caffeine to the list of
"habit-forming" and "deleterious" substances, which must be listed on a product's
label.
[146][unreliable source?]

The earliest evidence of cocoa bean use comes from residue found in an ancient Mayan pot dated
to 600 BCE. In the New World, chocolate was consumed in a bitter and spicy drink called
xocolatl, often seasoned with vanilla, chile pepper, and achiote. Xocolatl was believed to fight
fatigue, a belief probably attributable to the theobromine and caffeine content. Chocolate was an
important luxury good throughout pre-Columbian Mesoamerica, and cocoa beans were often
used as currency.
[citation needed]

Xocolatl was introduced to Europe by the Spaniards, and became a popular beverage by 1700.
The Spaniards also introduced the cacao tree into the West Indies and the Philippines. It was
used in alchemical processes, where it was known as "black bean".
[citation needed]

The leaves and stems of the yaupon holly (Ilex vomitoria) were used by Native Americans to
brew a tea called asi or the "black drink".
[147]
Archaeologists have found evidence of this use
stretch back far into antiquity,
[148]
possibly dating to Late Archaic times.
[147]

Discovery


Pierre Joseph Pelletier
In 1819, the German chemist Friedlieb Ferdinand Runge isolated relatively pure caffeine for the
first time; he called it "Kaffebase" (i.e. a base that exists in coffee).
[149]
According to Runge, he
did this at the behest of Johann Wolfgang von Goethe.
[150][151]
In 1821, caffeine was isolated both
by the French chemist Pierre Jean Robiquet and by another pair of French chemists, Pierre-
Joseph Pelletier and Joseph Bienaim Caventou, according to Swedish chemist Jns Jacob
Berzelius in his yearly journal. Furthermore, Berzelius stated that the French chemists had made
their discoveries independently of any knowledge of Runge's or each other's work.
[152]
However,
Berzelius later acknowledged Runge's priority in the extraction of caffeine, stating:
[153]

"However, at this point, it should not remain unmentioned that Runge (in his Phytochemical
Discoveries, 1820, pages 146147) specified the same method and described caffeine under the
name Caffeebase a year earlier than Robiquet, to whom the discovery of this substance is usually
attributed, having made the first oral announcement about it at a meeting of the Pharmacy
Society in Paris."
Pelletier's article on caffeine was the first to use the term in print (in the French form Cafine
from the French word for coffee: caf).
[154]
It corroborates Berzelius's account:
Caffeine, noun (feminine). Crystallizable substance discovered in coffee in 1821 by Mr.
Robiquet. During the same period while they were searching for quinine in coffee because
coffee is considered by several doctors to be a medicine that reduces fevers and because coffee
belongs to the same family as the cinchona [quinine] tree on their part, Messrs. Pelletier and
Caventou obtained caffeine; but because their research had a different goal and because their
research had not been finished, they left priority on this subject to Mr. Robiquet. We do not
know why Mr. Robiquet has not published the analysis of coffee which he read to the Pharmacy
Society. Its publication would have allowed us to make caffeine better known and give us
accurate ideas of coffee's composition ...
Robiquet was one of the first to isolate and describe the properties of pure caffeine,
[155]
whereas
Pelletier was the first to perform an elemental analysis.
[156]

In 1827, M. Oudry isolated "thine" from tea,
[157]
but it was later proved by Mulder
[158]
and by
Carl Jobst
[159]
that theine was actually caffeine.
[151]

In 1895, German chemist Hermann Emil Fischer (18521919) first synthesized caffeine from
raw materials (i.e. a "total synthesis"), and two years later, he also derived the structural formula
of the compound.
[160]
This was part of the work for which Fischer was awarded the Nobel Prize
in 1902.
[161]

Legality
Because caffeine is a psychoactive drug, it is often regulated. In the United States the Food and
Drug Administration (FDA) restricts beverages to containing less than 0.02% caffeine.
[162]

Historically, coffee and thus caffeine was illegal for some classes in Mecca in parts of the 16th
century,
[163]
and in the Ottoman empire.
[164][165]
Charles II of England tried to ban it in
1676,
[166][167]
Frederick II of Prussia banned it in 1777,
[168][169]
and coffee was banned in Sweden
in the years 17561769, 17941796, 17991802, and 18171823. The bans on coffee have often
had religious, economic, or political reasons rather than being based on concerns for the well-
being of the population.
[citation needed]

Religion
Some Seventh-day Adventists, Church of God (Restoration) adherents, and Christian Scientists
do not consume caffeine.
[citation needed]
Some from these religions believe that one is not supposed
to consume a non-medical, psychoactive substance, or believe that one is not supposed to
consume a substance that is addictive. The Church of Jesus Christ of Latter-day Saints has said
the following with regard to caffeinated beverages: "With reference to cola drinks, the Church
has never officially taken a position on this matter, but the leaders of the Church have advised,
and we do now specifically advise, against the use of any drink containing harmful habit-forming
drugs under circumstances that would result in acquiring the habit. Any beverage that contains
ingredients harmful to the body should be avoided."
[170]

Gaudiya Vaishnavas generally also abstain from caffeine, as it is alleged to cloud the mind and
over-stimulate the senses. To be initiated under a guru, one must have had no caffeine, alcohol,
nicotine or other drugs, for at least a year.
[citation needed]

People who refrain from consuming caffeine, for religious or other reasons, may instead use a
substitute that performs a culturally similar role to coffee.
[citation needed]

Caffeinated beverages are widely consumed by Muslims today; in the 16th century, some
Muslim authorities made unsuccessful attempts to ban them as forbidden "intoxicating
beverages" under Islamic dietary laws.
[171][172]

References
1. Lovett R (24 September 2005). "Coffee: The demon drink?". New Scientist (2518).
Retrieved 3 August 2009. (subscription required (help)).
2. Cano-Marquina A, Tarn JJ, Cano A (May 2013). "The impact of coffee on health".
Maturitas 75 (1): 721. doi:10.1016/j.maturitas.2013.02.002. PMID 23465359. Retrieved
15 January 2014.
3. Qi H, Li S (23 July 2003). "Dose-response meta-analysis on coffee, tea and caffeine
consumption with risk of Parkinson's disease". Geriatr Gerontol Int.
doi:10.1111/ggi.12123. PMID 23879665.
4. Ding, M; Bhupathiraju, SN; Satija, A; van Dam, RM; Hu, FB (11 February 2014).
"Long-term coffee consumption and risk of cardiovascular disease: a systematic review
and a dose-response meta-analysis of prospective cohort studies.". Circulation 129 (6):
64359. PMID 24201300.
5. Mayo Clinic staff. "Pregnancy Nutrition: Foods to avoid during pregnancy". Mayo
Clinic. Retrieved 15 April 2012.
6. American College of Obstetricians and Gynecologists (August 2010). "ACOG
CommitteeOpinion No. 462: Moderate caffeine consumption during pregnancy". Obstet
Gynecol 116 (2 Pt 1): 4678. doi:10.1097/AOG.0b013e3181eeb2a1. PMID 20664420.
7. Nehlig A, Daval JL, Debry G (1992). "Caffeine and the central nervous system:
mechanisms of action, biochemical, metabolic and psychostimulant effects". Brain Res.
Brain Res. Rev. 17 (2): 13970. doi:10.1016/0165-0173(92)90012-B. PMID 1356551.
8. Bolton S (1981). "Caffeine: Psychological Effects, Use and Abuse". Orthomolecular
Psychiatry 10 (3): 202211.
9. Snel J, Lorist MM (2011). "Effects of caffeine on sleep and cognition". Prog. Brain Res.
Progress in Brain Research 190: 10517. doi:10.1016/B978-0-444-53817-8.00006-2.
ISBN 978-0-444-53817-8. PMID 21531247.
10. Ker K, Edwards PJ, Felix LM, Blackhall K, Roberts I (2010). "Caffeine for the
prevention of injuries and errors in shift workers". In Ker, Katharine. Cochrane Database
Syst Rev (5): CD008508. doi:10.1002/14651858.CD008508. PMID 20464765.
11. Bishop D (2010). "Dietary supplements and team-sport performance". Sports Med 40
(12): 9951017. doi:10.2165/11536870-000000000-00000. PMID 21058748.
12. Conger SA, Warren GL, Hardy MA, Millard-Stafford ML (2011). "Does caffeine added
to carbohydrate provide additional ergogenic benefit for endurance?". Int J Sport Nutr
Exerc Metab 21 (1): 7184. PMID 21411838.
13. Astorino TA, Roberson DW (2010). "Efficacy of acute caffeine ingestion for short-term
high-intensity exercise performance: a systematic review". J Strength Cond Res 24 (1):
25765. doi:10.1519/JSC.0b013e3181c1f88a. PMID 19924012.
14. Graham TE, Hibbert E, Sathasivam P (September 1998). "Metabolic and exercise
endurance effects of coffee and caffeine ingestion". J. Appl. Physiol. 85 (3): 8839.
PMID 9729561.
15. Tarnopolsky MA (2010). "Caffeine and creatine use in sport". Ann. Nutr. Metab. 57
Suppl 2: 18. doi:10.1159/000322696. PMID 21346331.
16. Hackett PH (2010). "Caffeine at high altitude: java at base cAMP". High Alt. Med. Biol.
11 (1): 137. doi:10.1089/ham.2009.1077. PMID 20367483.
17. Winston AP, Hardwick E, Jaberi N (2005). "Neuropsychiatric effects of caffeine".
Advances in Psychiatric Treatment 11: 432439. doi:10.1192/apt.11.6.432. Retrieved 19
December 2013.
18. Iancu I, Olmer A, Strous RD (2007). "Caffeinism: History, clinical features, diagnosis,
and treatment". In Smith BD, Gupta U, Gupta BS. Caffeine and activation theory: effects
on health and behavior. CRC Press. pp. 331344. ISBN 978-0-8493-7102-8. Retrieved
15 January 2014.
19. Nkondjock A (May 2009). "Coffee consumption and the risk of cancer: an overview".
Cancer Lett. 277 (2): 1215. doi:10.1016/j.canlet.2008.08.022. PMID 18834663.
20. Arab L (2010). "Epidemiologic evidence on coffee and cancer". Nutrition and cancer 62
(3): 27183. doi:10.1080/01635580903407122. PMID 20358464.
21. van Dam RM (2008). "Coffee consumption and risk of type 2 diabetes, cardiovascular
diseases, and cancer". Applied physiology, nutrition, and metabolism 33 (6): 12691283.
doi:10.1139/H08-120. PMID 19088789.
22. Zhang Z, Hu G, Caballero B, Appel L, Chen L (June 2011). "Habitual coffee
consumption and risk of hypertension: a systematic review and meta-analysis of
prospective observational studies". Am. J. Clin. Nutr. 93 (6): 12129.
doi:10.3945/ajcn.110.004044. PMID 21450934.
23. Li M, Wang M, Guo W, Wang J, Sun X (March 2011). "The effect of caffeine on
intraocular pressure: a systematic review and meta-analysis". Graefes Arch. Clin. Exp.
Ophthalmol. 249 (3): 43542. doi:10.1007/s00417-010-1455-1. PMID 20706731.
24. Muriel P, Arauz J (2010). "Coffee and liver diseases". Fitoterapia 81 (5): 297305.
doi:10.1016/j.fitote.2009.10.003. PMID 19825397.
25. O'Connor A (2007). Never shower in a thunderstorm : surprising facts and misleading
myths about our health and the world we live in (1st ed.). New York: Times Books.
p. 144. ISBN 978-0-8050-8312-5. Retrieved 15 January 2014.
26. Gilmore B, Michael M (February 2011). "Treatment of acute migraine headache". Am
Fam Physician 83 (3): 27180. PMID 21302868.
27. Brent RL, Christian MS, Diener RM (2011). "Evaluation of the reproductive and
developmental risks of caffeine". Birth Defects Res. B Dev. Reprod. Toxicol. 92 (2): 152
87. doi:10.1002/bdrb.20288. PMC 3121964. PMID 21370398.
28. Kuczkowski KM (2009). "Caffeine in pregnancy". Arch. Gynecol. Obstet. 280 (5): 695
8. doi:10.1007/s00404-009-0991-6. PMID 19238414.
29. Jahanfar S, Sharifah H (2009). "Effects of restricted caffeine intake by mother on fetal,
neonatal and pregnancy outcome". In Jahanfar, Shayesteh. Cochrane Database Syst Rev
(2): CD006965. doi:10.1002/14651858.CD006965.pub2. PMID 19370665.
30. "Food Standards Agency publishes new caffeine advice for pregnant women". Retrieved
3 August 2009.
31. Fredholm BB, Bttig K, Holmn J, Nehlig A, Zvartau EE (1999). "Actions of caffeine in
the brain with special reference to factors that contribute to its widespread use".
Pharmacol. Rev. 51 (1): 83133. PMID 10049999.
32. Welsh, EJ.; Bara, A.; Barley, E.; Cates, CJ. (2010). "Caffeine for asthma". In Welsh,
Emma J. Cochrane Database of Systematic Reviews (1): CD001112.
doi:10.1002/14651858.CD001112.pub2. PMID 20091514.
33. Mathew OP (2011). "Apnea of prematurity: pathogenesis and management strategies". J
Perinatol 31 (5): 30210. doi:10.1038/jp.2010.126. PMID 21127467.
34. Kugelman A, Durand M (2011). "A comprehensive approach to the prevention of
bronchopulmonary dysplasia". Pediatr Pulmonol 46 (12): 115365.
doi:10.1002/ppul.21508. PMID 21815280.
35. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin
W (2006). "Caffeine therapy for apnea of prematurity". N. Engl. J. Med. 354 (20): 2112
21. doi:10.1056/NEJMoa054065. PMID 16707748.
36. Schmidt B (2005). "Methylxanthine therapy for apnea of prematurity: evaluation of
treatment benefits and risks at age 5 years in the international Caffeine for Apnea of
Prematurity (CAP) trial". Biol. Neonate 88 (3): 20813. doi:10.1159/000087584.
PMID 16210843.
37. Funk GD (2009). "Losing sleep over the caffeination of prematurity". J. Physiol. (Lond.)
587 (Pt 22): 5299300. doi:10.1113/jphysiol.2009.182303. PMC 2793860.
PMID 19915211.
38. Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin
W (November 2007). "Long-term effects of caffeine therapy for apnea of prematurity".
N. Engl. J. Med. 357 (19): 1893902. doi:10.1056/NEJMoa073679. PMID 17989382.
39. Schmidt B, Anderson PJ, Doyle LW, Dewey D, Grunau RE, Asztalos EV, Davis PG, Tin
W, Moddemann D, Solimano A, Ohlsson A, Barrington KJ, Roberts RS (January 2012).
"Survival without disability to age 5 years after neonatal caffeine therapy for apnea of
prematurity". JAMA 307 (3): 27582. doi:10.1001/jama.2011.2024. PMID 22253394.
40. Maughan RJ, Griffin J (2003). "Caffeine ingestion and fluid balance: a review". J Hum
Nutr Diet 16 (6): 41120. doi:10.1046/j.1365-277X.2003.00477.x. PMID 19774754.
41. Anahad O'connor (4 March 2008). "Really? The claim: caffeine causes dehydration".
New York Times. Retrieved 3 August 2009.
42. Armstrong LE, Casa DJ, Maresh CM, Ganio MS (2007). "Caffeine, fluid-electrolyte
balance, temperature regulation, and exercise-heat tolerance". Exerc Sport Sci Rev 35 (3):
13540. doi:10.1097/jes.0b013e3180a02cc1. PMID 17620932.
43. "Caffeine". MedlinePlus: U.S. National Library of Medicine. Retrieved 27 October 2012.
44. American Psychiatric Association. (1994). Diagnostic and Statistical Manual of Mental
Disorders (4th ed.). American Psychiatric Association. ISBN 0-89042-062-9.
45. Lara DR (2010). "Caffeine, mental health, and psychiatric disorders". J. Alzheimers Dis.
20 Suppl 1: S23948. doi:10.3233/JAD-2010-1378. PMID 20164571.
46. Santos C, Costa J, Santos J, Vaz-Carneiro A, Lunet N (2010). "Caffeine intake and
dementia: systematic review and meta-analysis". J. Alzheimers Dis. 20 Suppl 1: S187
204. doi:10.3233/JAD-2010-091387. PMID 20182026.
47. Marques S, Batalha VL, Lopes LV, Outeiro TF (2011). "Modulating Alzheimer's disease
through caffeine: a putative link to epigenetics". J. Alzheimers Dis. 24 (2): 16171.
doi:10.3233/JAD-2011-110032. PMID 21427489.
48. Arendash GW, Cao C (2010). "Caffeine and coffee as therapeutics against Alzheimer's
disease". J. Alzheimers Dis. 20 Suppl 1: S11726. doi:10.3233/JAD-2010-091249.
PMID 20182037.
49. Winston AP (2005). "Neuropsychiatric effects of caffeine". Advances in Psychiatric
Treatment 11 (6): 432439. doi:10.1192/apt.11.6.432.
50. Hughes RN (June 1996). "Drugs Which Induce Anxiety: Caffeine". New Zealand Journal
of Psychology 25 (1): 3642. doi:10.1016/S0278-6915(02)00096-0. PMID 12204388.
51. Vilarim MM, Rocha Araujo DM, Nardi AE (August 2011). "Caffeine challenge test and
panic disorder: a systematic literature review". Expert Rev Neurother 11 (8): 118595.
doi:10.1586/ern.11.83. PMID 21797659.
52. Smith A (September 2002). "Effects of caffeine on human behavior". Food Chem.
Toxicol. 40 (9): 124355. doi:10.1016/S0278-6915(02)00096-0. PMID 12204388.
53. Nehlig A (2010). "Is caffeine a cognitive enhancer?". J. Alzheimers Dis. 20 Suppl 1:
S8594. doi:10.3233/JAD-2010-091315. PMID 20182035.
54. Jarvis MJ (1993). "Does caffeine intake enhance absolute levels of cognitive
performance?". Psychopharmacology (Berl.) 110 (12): 4552.
doi:10.1007/BF02246949. PMID 7870897.
55. Bruce MS, Lader M (February 1989). "Caffeine abstention in the management of anxiety
disorders". Psychol Med 19 (1): 2114. doi:10.1017/S003329170001117X.
PMID 2727208.
56. "Caffeine (Systemic)". MedlinePlus. 25 May 2000. Archived from the original on 23
February 2007. Retrieved 3 August 2009.
57. "Caffeine overdose". MedlinePlus. 4 April 2006. Retrieved 3 August 2009.
58. Verkhratsky A (January 2005). "Physiology and pathophysiology of the calcium store in
the endoplasmic reticulum of neurons". Physiol. Rev. 85 (1): 20179.
doi:10.1152/physrev.00004.2004. PMID 15618481.
59. Holmgren P, Nordn-Pettersson L, Ahlner J (2004). "Caffeine fatalities four case
reports". Forensic Science International 139 (1): 713.
doi:10.1016/j.forsciint.2003.09.019. PMID 14687776.
60. Alstott RL, Miller AJ, Forney RB (1973). "Report of a human fatality due to caffeine".
Journal of Forensic Science 18 (35).
61. Peters JM (1967). "Factors Affecting Caffeine Toxicity: A Review of the Literature". The
Journal of Clinical Pharmacology and the Journal of New Drugs 7 (7): 131141.
doi:10.1002/j.1552-4604.1967.tb00034.x.
62. Rodopoulos N, Wisn O, Norman A (May 1995). "Caffeine metabolism in patients with
chronic liver disease". Scand. J. Clin. Lab. Invest. 55 (3): 22942.
doi:10.3109/00365519509089618. PMID 7638557.
63. Cheston P, Smith L (11 October 2013). "Man died after overdosing on caffeine mints".
The Independent. Retrieved 13 October 2013.
64. Prynne M (11 October 2013). "Warning over caffeine sweets after father dies from
overdose". The Telegraph. Retrieved 13 October 2013.
65. Fricker M (12 October 2013). "John Jackson: Family of dad who died from caffeine
overdose after eating MINTS want them removed from sale". Mirror. Retrieved 13
October 2013.
66. Kerrigan S, Lindsey T (2005). "Fatal caffeine overdose: two case reports". Forensic Sci.
Int. 153 (1): 679. doi:10.1016/j.forsciint.2005.04.016. PMID 15935584.
67. "Information about caffeine dependence". Caffeinedependence.org. Retrieved 25 May
2012.
68. Juliano LM, Griffiths RR (2004). "A critical review of caffeine withdrawal: empirical
validation of symptoms and signs, incidence, severity, and associated features".
Psychopharmacology (Berl.) 176 (1): 129. doi:10.1007/s00213-004-2000-x.
PMID 15448977. Archived from the original on 29 January 2012.
69. Silverman K, Evans SM, Strain EC, Griffiths RR (October 1992). "Withdrawal syndrome
after the double-blind cessation of caffeine consumption". N. Engl. J. Med. 327 (16):
110914. doi:10.1056/NEJM199210153271601. PMID 1528206.
70. Matt Peckham (31 May 2013). "Caffeine Withdrawal Is Now a Mental Disorder". Time.
71. "Caffeine Poisoning in Dogs". AllPetsCo Pets Information. Pet Information. Retrieved 29
February 2012.
72. Paul, Dr. Lisa. "Why Caffeine is Toxic to Birds". HotSpot for Birds. Advin Systems.
Retrieved 29 February 2012.
73. Arnaud MJ (2011). "Pharmacokinetics and metabolism of natural methylxanthines in
animal and man". Handb Exp Pharmacol. Handbook of Experimental Pharmacology
(200): 3391. doi:10.1007/978-3-642-13443-2_3. ISBN 978-3-642-13442-5.
PMID 20859793.
74. Noever R, Cronise J, Relwani RA (29 April 1995). "Using spider-web patterns to
determine toxicity". NASA Tech Briefs (New Scientist magazine) 19 (4): 82.
75. "Newly Discovered Bacteria Lives on Caffeine". Blogs.scientificamerican.com. 24 May
2011. Retrieved 19 December 2013.
76. "Caffeine Content of Food and Drugs". Nutrition Action Health Newsletter. Center for
Science in the Public Interest. 1996. Archived from the original on 14 June 2007.
Retrieved 3 August 2009.
77. "Caffeine Content of Beverages, Foods, & Medications". The Vaults of Erowid. 7 July
2006. Retrieved 3 August 2009.
78. "Caffeine Content of Drinks". Caffeine Informer. Retrieved 8 December 2013.
79. Chin JM, Merves ML, Goldberger BA, Sampson-Cone A, Cone EJ (October 2008).
"Caffeine content of brewed teas". J Anal Toxicol 32 (8): 7024.
doi:10.1093/jat/32.8.702. PMID 19007524.
80. Richardson, Bruce (2009). "Too Easy to be True. De-bunking the At-Home
Decaffeination Myth". Elmwood Inn. Retrieved 12 January 2012.
81. "Traditional Yerba Mate in Biodegradable Bag". Guayaki Yerba Mate. Retrieved 17 July
2010.
82. Geoffrey Burchfield (1997). Meredith Hopes, ed. "What's your poison: caffeine".
Australian Broadcasting Corporation. Retrieved 15 January 2014.
83. Frischknecht PM, Ulmer-Dufek J, Baumann TW (1986). "Purine alkaloid formation in
buds and developing leaflets of Coffea arabica: Expression of an optimal defence
strategy?". Phytochemistry 25 (3): 6136. doi:10.1016/0031-9422(86)88009-8.
84. Nathanson JA (1984). "Caffeine and related methylxanthines: possible naturally
occurring pesticides". Science 226 (4671): 1847. doi:10.1126/science.6207592.
PMID 6207592.
85. Baumann TW (1984). "Metabolism and excretion of caffeine during germination of
Coffea arabica L". Plant and Cell Physiology 25 (8): 14316.
86. Wright GA, Baker DD, Palmer MJ, Stabler D, Mustard JA, Power EF, Borland AM,
Stevenson PC (March 2013). "Caffeine in floral nectar enhances a pollinator's memory of
reward". Science 339 (6124): 12024. doi:10.1126/science.1228806. PMID 23471406.
87. Matissek R (1997). "Evaluation of xanthine derivatives in chocolate: nutritional and
chemical aspects". European Food Research and Technology 205 (3): 17584.
INIST:2861730.
88. "Does Yerba Mat Contain Caffeine or Mateine?". The Vaults of Erowid. 2003.
Retrieved 3 August 2009.
89. "PubChem: mateina". National Library of Medicine. Retrieved 3 August 2009.. Generally
translated as mateine in articles written in English
90. Balentine D. A., Harbowy M. E. and Graham H. N. (1998). "Tea: the Plant and its
Manufacture; Chemistry and Consumption of the Beverage". In G Spiller.
Caffeine.
[clarification needed]

91. "Caffeine". International Coffee Organization. Retrieved 1 August 2009.
92. "Coffee and Caffeine FAQ: Does dark roast coffee have less caffeine than light roast?".
Retrieved 2 August 2009.
93. "All About Coffee: Caffeine Level". Jeremiah's Pick Coffee Co. Archived from the
original on 18 March 2008. Retrieved 3 August 2009.
94. Hicks MB, Hsieh Y-H P, Bell LN (1996). "Tea preparation and its influence on
methylxanthine concentration". Food Research International 29 (34): 325330.
doi:10.1016/0963-9969(96)00038-5.
95. Bempong DK, Houghton PJ, Steadman K (1993). "The xanthine content of guarana and
its preparations". Int J Pharmacog 31 (3): 175181. doi:10.3109/13880209309082937.
ISSN 0925-1618.
96. Smit HJ, Gaffan EA, Rogers PJ (November 2004). "Methylxanthines are the psycho-
pharmacologically active constituents of chocolate". Psychopharmacology (Berl.) 176
(34): 4129. doi:10.1007/s00213-004-1898-3. PMID 15549276.
97. Bennett Alan Weinberg, Bonnie K. Bealer (2001). The World of caffeine: The Science
and Culture of the World's Most Popular Drug. Routledge. p. 195. ISBN 978-0-415-
92723-9. Retrieved 15 January 2014.
98. "LeBron James Shills for Sheets Caffeine Strips, a Bad Idea for Teens, Experts Say".
Abcnews.go.com (ABC News). 10 June 2011. Retrieved 25 May 2012.
99. Nancy Shute (15 April 2007). "Over The Limit:Americans young and old crave high-
octane fuel, and doctors are jittery". US News and World Reports.
[dead link]

100. "F.D.A. Inquiry Leads Wrigley to Halt Energy Gum Sales". New York Times.
Associated Press. 8 May 2013. Retrieved 9 May 2013.
101. http://www.washingtonpost.com/business/controversy-over-inhaled-caffeine-
grows-as-as-sen-schumer-calls-for-fda-probe/2011/12/22/gIQAjQaVDP_story.html
[dead
link]

102. "Caffeine biosynthesis". The Enzyme Database. Trinity College Dublin. Retrieved
24 September 2011.
103. Temple NJ, Wilson T (2003). Beverages in Nutrition and Health. Totowa, NJ:
Humana Press. p. 172. ISBN 1-58829-173-1.
104. US patent 2785162, Swidinsky J, Baizer MM, "Process for the formylation of a 5-
nitrouracil", published 12 March 1957, assigned to New York Quinine and Chemical
Works, Inc.
105. Susan Budavari, ed. (1996). The Merck Index (12th ed.). Whitehouse Station, NJ:
Merck & Co., Inc. p. 1674.
106. This is the pK
a
for protonated caffeine, given as a range of values included in
Harry G. Brittain, Richard J. Prankerd (2007). Profiles of Drug Substances, Excipients
and Related Methodology, volume 33: Critical Compilation of pK
a
Values for
Pharmaceutical Substances. Academic Press. p. 15. ISBN 0-12-260833-X. Retrieved 15
January 2014.
107. Klosterman L (2006). The Facts About Caffeine (Drugs). Benchmark Books
(NY). p. 43. ISBN 0-7614-2242-0.
108. Vallombroso T (2001). Organic Chemistry Pearls of Wisdom. Boston Medical
Publishing Corp. p. 43. ISBN 1-58409-016-2.
109. Keskineva N. "Chemistry of Caffeine" (PDF). Chemistry Department, East
Stroudsburg University. Retrieved 2 January 2014.
110. Ashihara H, Monteiro AM, Gillies FM, Crozier A (1996). "Biosynthesis of
Caffeine in Leaves of Coffee". Plant Physiol. 111 (3): 747753.
doi:10.1104/pp.111.3.747. PMC 157891. PMID 12226327.
111. Simon Tilling. "Crystalline Caffeine". Bristol University. Retrieved 3 August
2009.
112. Zajac MA, Zakrzewski AG, Kowal MG, Narayan S (2003). "A Novel Method of
Caffeine Synthesis from Uracil". Synthetic Communications 33 (19): 32913297.
doi:10.1081/SCC-120023986.
113. Jinka TR, Tien , Drew KL (2011). "Season primes the brain in an arctic
hibernator to facilitate entrance into torpor mediated by adenosine A(1) receptors". J.
Neurosci. 31 (30): 107528. doi:10.1523/JNEUROSCI.1240-11.2011. PMC 3325781.
PMID 21795527.
114. "World of Caffeine". World of Caffeine. 15 June 2013. Retrieved 19 December
2013.
115. Fisone G, Borgkvist A, Usiello A (2004). "Caffeine as a psychomotor stimulant:
mechanism of action". Cell. Mol. Life Sci. 61 (78): 85772. doi:10.1007/s00018-003-
3269-3. PMID 15095008.
116. Latini S, Pedata F (2001). "Adenosine in the central nervous system: release
mechanisms and extracellular concentrations". J. Neurochem. 79 (3): 46384.
doi:10.1046/j.1471-4159.2001.00607.x. PMID 11701750.
117. Basheer R, Strecker RE, Thakkar MM, McCarley RW (2004). "Adenosine and
sleep-wake regulation". Prog. Neurobiol. 73 (6): 37996.
doi:10.1016/j.pneurobio.2004.06.004. PMID 15313333.
118. Huang ZL, Qu WM, Eguchi N, Chen JF, Schwarzschild MA, Fredholm BB,
Urade Y, Hayaishi O (July 2005). "Adenosine A2A, but not A1, receptors mediate the
arousal effect of caffeine". Nat. Neurosci. 8 (7): 8589. doi:10.1038/nn1491.
PMID 15965471.
119. Ribeiro JA, Sebastio AM (2010). "Caffeine and adenosine". J. Alzheimers Dis.
20 Suppl 1: S315. doi:10.3233/JAD-2010-1379. PMID 20164566.
120. Essayan DM (November 2001). "Cyclic nucleotide phosphodiesterases". J.
Allergy Clin. Immunol. 108 (5): 67180. doi:10.1067/mai.2001.119555. PMID 11692087.
121. Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R (June 2008).
"Insights into the regulation of TNF-alpha production in human mononuclear cells: the
effects of non-specific phosphodiesterase inhibition". Clinics (Sao Paulo) 63 (3): 3218.
doi:10.1590/S1807-59322008000300006. PMC 2664230. PMID 18568240.
122. Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U (February 1999).
"Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages". Am.
J. Respir. Crit. Care Med. 159 (2): 50811. doi:10.1164/ajrccm.159.2.9804085.
PMID 9927365.
123. Peters-Golden M, Canetti C, Mancuso P, Coffey MJ. (2005). "Leukotrienes:
underappreciated mediators of innate immune responses". Journal of Immunology 174
(2): 58994. PMID 15634873.
124. Davis JK, Green JM (2009). "Caffeine and anaerobic performance: ergogenic
value and mechanisms of action". Sports Med 39 (10): 81332. doi:10.2165/11317770-
000000000-00000. PMID 19757860.
125. McArdle W (2010). Exercise Physiology (7th ed.). Baltimore, MD: Lippincott
Williams and Wilkins. p. 559. ISBN 978-0-7817-9781-8.
126. Dews PB (1984). Caffeine: Perspectives from Recent Research. Berlin: Springer-
Valerag. ISBN 978-0-387-13532-8.
127. Liguori A, Hughes JR, Grass JA (1997). "Absorption and subjective effects of
caffeine from coffee, cola and capsules". Pharmacol. Biochem. Behav. 58 (3): 7216.
doi:10.1016/S0091-3057(97)00003-8. PMID 9329065.
128. "Koffazon". Swedish Drug Catalog. 10 February 2010.
129. Newton R, Broughton LJ, Lind MJ, Morrison PJ, Rogers HJ, Bradbrook ID
(1981). "Plasma and salivary pharmacokinetics of caffeine in man". Eur. J. Clin.
Pharmacol. 21 (1): 4552. doi:10.1007/BF00609587. PMID 7333346.
130. Graham JR (1954). "Rectal use of ergotamine tartrate and caffeine alkaloid for the
relief of migraine". N. Engl. J. Med. 250 (22): 9368.
doi:10.1056/NEJM195406032502203. PMID 13165929.
131. Brdbaek HB, Damkier P (2007). "The treatment of hyperemesis gravidarum with
chlorobutanol-caffeine rectal suppositories in Denmark: practice and evidence". Ugeskr.
Laeg. (in Danish) 169 (22): 21223. PMID 17553397.
132. "Drug Interaction: Caffeine Oral and Fluvoxamine Oral". Medscape Multi-Drug
Interaction Checker.
133. Hammami, M. M., Al-Gaai, E. A., Alvi, S., & Hammami, M. B. (2010).
"Interaction between drug and placebo effects: A cross-over balanced placebo design
trial". Trials 11 (110): 110. doi:10.1186/1745-6215-11-110. PMC 2995791.
PMID 21092089.
134. "Caffeine". The Pharmacogenetics and Pharmacogenomics Knowledge Base.
Retrieved 25 October 2010.
135. Verbeeck RK (2008). "Pharmacokinetics and dosage adjustment in patients with
hepatic dysfunction". Eur. J. Clin. Pharmacol. 64 (12): 114761. doi:10.1007/s00228-
008-0553-z. PMID 18762933.
136. Janknegt R (1990). "Drug interactions with quinolones". J. Antimicrob.
Chemother. 26 Suppl D: 729. doi:10.1093/jac/26.suppl_D.7. PMID 2286594.
137. Cornelis MC, Monda KL, Yu K, Paynter N, Azzato EM, Bennett SN, Berndt SI,
Boerwinkle E, Chanock S, Chatterjee N, Couper D, Curhan G, Heiss G, Hu FB, Hunter
DJ, Jacobs K, Jensen MK, Kraft P, Landi MT, Nettleton JA, Purdue MP, Rajaraman P,
Rimm EB, Rose LM, Rothman N, Silverman D, Stolzenberg-Solomon R, Subar A,
Yeager M, Chasman DI, van Dam RM, Caporaso NE (April 2011). "Genome-wide meta-
analysis identifies regions on 7p21 (AHR) and 15q24 (CYP1A2) as determinants of
habitual caffeine consumption". In Gibson, Greg. PLoS Genet. 7 (4): e1002033.
doi:10.1371/journal.pgen.1002033. PMC 3071630. PMID 21490707.
138. Baselt R (2011). Disposition of Toxic Drugs and Chemicals in Man (9th ed.). Seal
Beach, CA: Biomedical Publications. pp. 2369. ISBN 0-931890-08-X.
139. Senese F (20 September 2005). "How is coffee decaffeinated?". General
Chemistry Online. Retrieved 3 August 2009.
140. McCusker RR, Fuehrlein B, Goldberger BA, Gold MS, Cone EJ (October 2006).
"Caffeine content of decaffeinated coffee". J Anal Toxicol 30 (8): 6113.
doi:10.1093/jat/30.8.611. PMID 17132260. Lay summary University of Florida News.
141. John C. Evans (1992). Tea in China: The History of China's National Drink.
Greenwood Press. p. 2. ISBN 0-313-28049-5.
142. Yu L (1995). The Classic of Tea: Origins & Rituals. Ecco Pr. ISBN 0-88001-416-
4.
[page needed]

143. Bennett Alan Weinberg, Bonnie K. Bealer (2001). The World of Caffeine: The
Science and Culture of the World's Most Popular Drug. Routledge. pp. 34. ISBN 978-0-
415-92723-9.
144. Meyers, Hannah (7 March 2005). ""Suave Molecules of Mocha" Coffee,
Chemistry, and Civilization". New Partisan. Archived from the original on 9 March 2005.
Retrieved 3 February 2007.
145. Benjamin LT, Rogers AM, Rosenbaum A (1991). "Coca-Cola, caffeine, and
mental deficiency: Harry Hollingworth and the Chattanooga trial of 1911". J Hist Behav
Sci 27 (1): 4255. doi:10.1002/1520-6696(199101)27:1<42::AID-
JHBS2300270105>3.0.CO;2-1. PMID 2010614.
146. "The Rise and Fall of Cocaine Cola". Lewrockwell.com. Retrieved 25 May
2012.
[unreliable source?]

147. Fairbanks, Charles H. (2004). "The function of black drink among the Creeks". In
Hudson, Charles M.. Black Drink. University of Georgia Press. p. 123. ISBN 978-0-
8203-2696-2.
148. Crown PL, Emerson TE, Gu J, Hurst WJ, Pauketat TR, Ward T (August 2012).
"Ritual Black Drink consumption at Cahokia". Proc. Natl. Acad. Sci. U.S.A. 109 (35):
1394413949. doi:10.1073/pnas.1208404109. PMC 3435207. PMID 22869743.
149. Runge, Friedlieb Ferdinand (1820). Neueste phytochemische Entdeckungen zur
Begrndung einer wissenschaftlichen Phytochemie [Latest phytochemical discoveries for
the founding of a scientific phytochemistry]. Berlin: G. Reimer. pp. 144159. Retrieved 8
January 2014.
150. In 1819, Runge was invited to show Goethe how belladonna caused dilation of the
pupil, which Runge did, using a cat as an experimental subject. Goethe was so impressed
with the demonstration that: "Nachdem Goethe mir seine grte Zufriedenheit sowol ber
die Erzhlung des durch scheinbaren schwarzen Staar Geretteten, wie auch ber das
andere ausgesprochen, bergab er mir noch eine Schachtel mit Kaffeebohnen, die ein
Grieche ihm als etwas Vorzgliches gesandt. "Auch diese knnen Sie zu Ihren
Untersuchungen brauchen," sagte Goethe. Er hatte recht; denn bald darauf entdeckte ich
darin das, wegen seines groen Stickstoffgehaltes so berhmt gewordene Coffein." (After
Goethe had expressed to me his greatest satisfaction regarding the account of the man
[whom I'd] rescued [from serving in Napoleon's army] by apparent "black star" [i.e.,
amaurosis, blindness] as well as the other, he handed me a carton of coffee beans, which
a Greek had sent him as a delicacy. "You can also use these in your investigations," said
Goethe. He was right; for soon thereafter I discovered therein caffeine, which became so
famous on account of its high nitrogen content.)
This account appeared in Runge's book Hauswirtschaftlichen Briefen (Domestic Letters
[i.e., personal correspondence]) of 1866. It was reprinted in: Johann Wolfgang von
Goethe with F.W. von Biedermann, ed., Goethes Gesprche, vol. 10: Nachtrge, 1755
1832 (Leipzig, (Germany): F.W. v. Biedermann, 1896), pages 8996; see especially page
95.
151. Bennett Alan Weinberg, Bonnie K. Bealer (2001). The World of Caffeine: The
Science and Culture of the World's Most Popular Drug. Routledge. ISBN 978-0-415-
92723-9.
[page needed]

152. Berzelius, Jns Jakob (1825). Jahres-Bericht ber die Fortschritte der physischen
Wissenschaften von Jacob Berzelius [Annual report on the progress of the physical
sciences by Jacob Berzelius] (in German) 4. p. 180. From page 180: "Cafin ist eine
Materie im Kaffee, die zu gleicher Zeit, 1821, von Robiquet und Pelletier und Caventou
entdekt wurde, von denen aber keine etwas darber im Drucke bekannt machte."
(Caffeine is a material in coffee, which was discovered at the same time, 1821, by
Robiquet and [by] Pelletier and Caventou, by whom however nothing was made known
about it in the press.)
153. Berzelius JJ (1828). Jahres-Bericht ber die Fortschritte der physischen
Wissenschaften von Jacob Berzelius [Annual Report on the Progress of the Physical
Sciences by Jacob Berzelius] (in German) 7. p. 270. From page 270: "Es darf indessen
hierbei nicht unerwhnt bleiben, dass Runge (in seinen phytochemischen Entdeckungen
1820, p. 146-7.) dieselbe Methode angegeben, und das Caffein unter dem Namen
Caffeebase ein Jahr eher beschrieben hat, als Robiquet, dem die Entdeckung dieser
Substanz gewhnlich zugeschrieben wird, in einer Zusammenkunft der Societ de
Pharmacie in Paris die erste mndliche Mittheilung darber gab." (However, at this
point, it should not remain unmentioned that Runge (in his Phytochemical Discoveries,
1820, pages 146147) specified the same method and described caffeine under the name
Caffeebase a year earlier than Robiquet, to whom the discovery of this substance is
usually attributed, having made the first oral announcement about it at a meeting of the
Pharmacy Society in Paris.)
154. Pelletier, Pierre Joseph (1822). "Cafeine". Dictionnaire de Mdecine (in French)
4. Paris: Bchet Jeune. pp. 3536. Retrieved 3 March 2011.
155. Robiquet, Pierre Jean (1823). "Cafe". Dictionnaire Technologique, ou Nouveau
Dictionnaire Universel des Arts et Mtiers (in French) 4. Paris: Thomine et Fortic.
pp. 5061. Retrieved 3 March 2011.
156. Dumas and Pelletier (1823). "Recherches sur la composition lmentaire et sur
quelques proprits caractristiques des bases salifiables organiques" [Studies into the
elemental composition and some characteristic properties of organic bases]. Annales de
Chimie et de Physique (in French) 24: 163191.
157. Oudry M (1827). "Note sur la Thine". Nouvelle bibliothque mdicale (in
French) 1: 477479.
158. Mulder, G. J. (1838). "Ueber Then und Caffen" [Concerning theine and
caffeine]. Journal fr Praktische Chemie 15: 280284. doi:10.1002/prac.18380150124.
159. Jobst, Carl (1838). "Thein identisch mit Caffein" [Theine is identical to caffeine)].
Liebig's Annalen der Chemie und Pharmacie 25: 6366.
160. Fischer began his studies of caffeine in 1881; however, understanding of the
molecule's structure long eluded him. In 1895 he synthesized caffeine, but only in 1897
did he finally fully determine its molecular structure.
Fischer E (1881). "Ueber das Caffen" [On caffeine]. Berichte der Deutschen
chemischen Gesellschaft zu Berlin (in German) 14: 637644.
doi:10.1002/cber.188101401142.
Fischer E (1881). "Ueber das Caffen. Zweite Mitteilung" [On caffeine. Second
communication.]. Berichte der Deutschen chemischen Gesellschaft zu Berlin (in
German) 14 (2): 19051915. doi:10.1002/cber.18810140283.
Fischer E (1882). "Ueber das Caffen. Dritte Mitteilung" [On caffeine. Third
communication.]. Berichte der Deutschen chemischen Gesellschaft zu Berlin (in
German) 15: 2933. doi:10.1002/cber.18820150108.
Fischer E, Ach L (1895). "Synthese des Caffens" [On caffeine. Third
communication.]. Berichte der Deutschen chemischen Gesellschaft zu Berlin (in
German) 28 (3): 31353143. doi:10.1002/cber.189502803156.
Fischer E (1897). "Ueber die Constitution des Caffens, Xanthins, Hypoxanthins
und verwandter Basen" [On the constitution of caffeine, xanthin, hypoxanthin,
and related bases.]. Berichte der Deutschen chemischen Gesellschaft zu Berlin (in
German) 30: 549559. doi:10.1002/cber.189703001110.
161. Hj. Thel (1902). "Nobel Prize Presentation Speech". Retrieved 3 August 2009.
162. "Code of Federal Regulations Title 21". Code of Federal Regulations Title 21. 30
July 2013.
163. Brown, Daniel W (2004). A new introduction to Islam. Chichester, West Sussex:
Wiley-Blackwell. pp. 14951. ISBN 1-4051-5807-7.
164. goston, Gbor; Masters, Bruce (2009). Encyclopedia of the Ottoman Empire.
ISBN 978-1-4381-1025-7. Retrieved 15 January 2014.
[page needed]

165. Hopkins, Kate (24 March 2006). "Food Stories: The Sultan's Coffee Prohibition".
Accidental Hedonist. Retrieved 3 January 2010.
166. "By the King. A PROCLAMATION FOR THE Suppression of Coffee-Houses".
Retrieved 18 March 2012.
167. Pendergrast 2001, p. 13
168. Pendergrast 2001, p. 11
169. Bersten 1999, p. 53
170. Doctrine and Covenants Student Manual: Religion 324 and 325. Salt Lake City:
LDS Church. 2001. p. 209. Retrieved 15 January 2014.
171. Juan Eduardo Campo (1 January 2009). Encyclopedia of Islam. Infobase
Publishing. p. 154. ISBN 978-1-4381-2696-8. Retrieved 1 November 2012.
172. Daniel W. Brown (24 August 2011). A New Introduction to Islam. John Wiley &
Sons. p. 149. ISBN 978-1-4443-5772-1.
Cafeina (sin. cofein) este un alcaloid din grupa purinelor, care se se gsete n cafea, ceai, nuci
de cola, mate, guaran i cacao. Este unul dintre cei mai vechi stimuleni naturali folosii de om.
Cuprins
1 Istoric
2 Denumire i structur chimic
3 Proprieti fizice
4 Utilizare
5 Efecte biologice
6 Legturi externe
Istoric


Model spaial al moleculei de cafein
n 1820, la solicitarea lui Goethe, farmacistul german Friedlieb Ferdinand Rungef izoleaz
cofein pur din boabele de cafea. n 1821, independent de Runge, farmacitii francezi Pierre
Joseph Pelletier, Joseph Bienaim Caventou i Pierre Robiquet reuesc de asemenea s izoleze
cafeina. n anul 1832 Pfaff i Justus von Liebig descoper formula chimic a cofeinei
(C
8
H
10
N
4
O
2
) Formula structural va fi descoperit n 1895 de Hermann Emil Fischer.
Mecanismul de aciune al cafeinei a fost studiat n secolul XX.
Denumire i structur chimic
Numele de cafein provine de la cafea, din care a fost izolat pentru prima oar substana. Dup
nomenclatura IUPAC, denumirea cafeinei este 1,3,7-Trimethyl-2,6-purindiona sau, pe scurt,
1,3,7-Trimethylxanthina . Cafeina face parte din grupul purinelor, ca i teofilina i teobromina.
Structura cafeinei const dintr-un inel dublu, care la exterior are o serie de substitueni, n centru
fiind nucleul purinic.
Proprieti fizice
Cafeina pur se prezint sub form de cristale prismatice hexagonale incolore, inodore cu gust
amar.
Raportul de solubilitate a cofeinei
n:
ap la temperatur normal este de: 21,74 g/l
ap la temperatura de 80 C: 181,82 g/l
etanol la temperatur normal: 15,15 g/l
etanol la temperatura de 60 C: 45,45 g/l
aceton: 20,00 g/l
cloroform: 181,82 g/l
Derivaii xantinei, clasificai ca alcaloizi de natur vegetal (din care face parte i cafeina), sunt
considerai baze slabe, deoarece atomii de azot pot accepta protoni. Cu toate acestea, derivaii
xantinei sub form de soluie nu sunt alcalini.
Utilizare
Cafeina este larg utilizat n alimentaie, prin consumul de cafea.
o ceac de cafea (150 ml) conine ntre 30 - 100 mg de cafein.
o ceac de cafea expresso (30 ml) conine cca. 40 mg de cafein
o ceac de cacao conine 6 mg de cofein.
ciocolata conine cofein ntre 15 - 90 mg/100 g.
Efecte biologice
Cofeina acioneaz ca:
stimulant al SNC
creterea pulsului i tensiunii arteriale
dilatator bronhial
diuretic
stimulant al peristaltismului intestinal

Caffeine (C
8
H
10
N
4
O
2
) is the common name for trimethylxanthine (systematic name is 1,3,7-
trimethylxanthine or 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione). The chemical is also known as
coffeine, theine, mateine, guaranine, or methyltheobromine. Caffeine is naturally produced by several
plants, including coffee beans, guarana, yerba mat, cacao beans, and tea. For the plants, caffeine acts
as a natural pesticide. It paralyzes and kills insects that attempt to feed on the plants. The molecule was
first isolated by the German chemist Friedrich Ferdinand Runge in 1819.
When purified, caffeine is an intensely bitter white powder. It is added to colas and other soft
drinks to impart a pleasing bitter note. However, caffeine is also an addictive stimulant. In
humans, it stimulates the central nervous system, heart rate, and respiration, has psychotropic
(mood altering) properties, and acts as a mild diuretic.
A normal dose of caffeine is generally considered to be 100 mg, which is roughly the amount
found in a cup of coffee. However, more than half of all American adults consume more than
300 mg of caffeine every day, which makes it America's most popular drug. Caffeine is generally
consumed in coffee, cola, chocolate, and tea, although it is also available over-the-counter as a
stimulant.
Caffeine is believed to work by blocking adenosine receptors in the brain and other organs. This
reduces the ability of adenosine to bind to the receptors, which would slow down cellular
activity. The stimulated nerve cells release the hormone epinephrine (adrenaline), which
increases heart rate, blood pressure, and blood flow to muscles, decreases blood flow to the skin
and organs, and causes the liver to release glucose. Caffeine also increases levels of the
neurotransmitter dopamine.
Caffeine is quickly and completely removed from the brain. Its effects are short-lived and it
tends not to negatively affect concentration or higher brain functions. However, continued
exposure to caffeine leads to developing a tolerance to it. Tolerance causes the body to become
sensitized to to adenosine, so withdrawal causes blood pressure to drop, which can result in a
headache and other symptoms. Too much caffeine can result in caffeine intoxication, which is
characterized by nervousness, excitement, increased urination, insomnia, flushed face, cold
hands/feet, intestinal complaints, and sometimes hallucinations. Some people experience the
symptoms of caffeine intoxication after ingesting as little as 250 mg per day. The lethal ingested
dose, for an adult person, is estimated to be 13-19 grams. While generally considered safe for
people, caffeine can be very toxic to household pets, such as dogs, horses, or parrots. Caffeine
intake has been demonstrated to reduce the risk of type II diabetes mellitus. In addition to use as
a stimulant and flavoring agent, caffeine is included in many over-the-counter headache
remedies.
Caffeine is a xanthine alkaloid compound that acts as a stimulant in humans. Caffeine is sometimes
called guaranine when found in guarana, mateine when found in mate, and theine when found in tea. It
is found in the leaves and beans of the coffee plant, in tea, yerba mate, and guarana berries, and in small
quantities in cocoa, the kola nut and the Yaupon Holly. Overall, caffeine is found in the beans, leaves,
and fruit of over 60 plants, where it acts as a natural pesticide that paralyzes and kills certain insects
feeding upon them.
Caffeine is a central nervous system (CNS) stimulant, having the effect of temporarily warding off
drowsiness and restoring alertness.
Beverages containing caffeine, such as coffee, tea, soft drinks and energy drinks enjoy great popularity:
caffeine is the world's most widely consumed psychoactive substance. In North America, 90% of adults
consume caffeine daily.
[1]
Many natural sources of caffeine also contain widely varying mixtures of other
xanthine alkaloids, including the cardiac stimulants theophylline and theobromine and other substances
such as polyphenols which can form insoluble complexes with caffeine.
[2]
.
Chemical and Physical Properties of Caffeine
General
Systematic
name
1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione
Other names
1,3,7-trimethylxanthine, trimethylxanthine,
theine, mateine, guaranine,
methyltheobromine
Molecular
formula
C
8
H
10
N
4
O
2

SMILES O=C1C2=C(N=CN2C)N(C(=O)N1C)C
Molar mass 194.19 g mol
1

Appearance Odorless, white needles or powder
CAS number [58-08-2]
Properties
Density and
phase
1.2 g/cm, solid
Solubility in
water
Slightly soluble
Other solvents
Soluble in ethyl acetate, chloroform, pyrimidine, pyrrole, tetrahydrofuran solution;
moderately soluble in alcohol, acetone; slightly soluble in petroleum ether, ether,
benzene.
Melting point 237 C
Boiling point 178 C (sublimes)
Acidity (pK
a
) 10.4 (40 C)
Hazards
MSDS External MSDS
Main hazards
May be fatal if inhaled, swallowed
or absorbed through the skin.
Flash point N/A
RTECS
number
EV6475000
Except where noted otherwise, data are given for
materials in their standard state (at 25 C, 100 kPa)
Infobox disclaimer and references
Sources
Caffeine is a plant alkaloid, found in numerous plant species, where it acts as a natural pesticide that
paralyzes and kills certain insects feeding upon them.
[3]
The most commonly used caffeine-containing
plants are coffee, tea, and to some extent cocoa. Other, less commonly used, sources of caffeine include
the yerba mate
[4]
and guaran plants, which are sometimes used in the preparation of teas and energy
drinks. Two of caffeine's alternative names, mateine
[5]
and guaranine,
[6]
are derived from the names of
these plants.
The world's primary source of caffeine is the coffee bean (the seed of the coffee plant), from which coffee
is brewed. Caffeine content in coffee varies widely depending on the type of coffee bean and the method
of preparation used;
[7]
even beans within a given bush can show variations in concentration. In general
one serving of coffee ranges from about 40 milligrams for a single shot (30 milliliters) of arabica-variety
espresso to about 100 milligrams for strong drip coffee. Generally, dark-roast coffee has less caffeine
than lighter roasts because the roasting process reduces the bean's caffeine content. Arabica coffee
normally contains less caffeine than the robusta variety.
[7]
Coffee also contains trace amounts of
theophylline, but no theobromine.
Tea is another common source of caffeine. Tea usually contains about half as much caffeine per serving
as coffee, depending on the strength of the brew. Certain types of tea, such as black and oolong, contain
somewhat more caffeine than most other teas. Tea contains small amounts of theobromine and slightly
higher levels of theophylline than coffee. Preparation has a significant impact on tea, and color is a very
poor indicator of caffeine content.
[8]
Teas like the green Japanese gyokuro, for example, contain far more
caffeine than much darker teas like lapsang souchong, which has very little.---Chocolate derived from
cocoa contains a small amount of caffeine. Chocolate is a weak stimulant, which is mostly due to its
content of theobromine and theophylline.
[9]
It contains too little of these compounds for a reasonable
serving to create effects in humans that are on par with coffee. A typical 28-gram serving of a milk
chocolate bar has about as much caffeine as a cup of decaffeinated coffee.
Caffeine is also a common ingredient of soft drinks such as cola, originally prepared from kola nuts. Soft
drinks typically contain about 10 to 50 milligrams of caffeine per serving. By contrast, energy drinks such
as Red Bull contain as much as 80 milligrams of caffeine per serving. The caffeine in these drinks either
originates from the ingredients used or is an additive derived from the product of decaffeination or from
chemical synthesis. Guarana, a prime ingredient of energy drinks, contains large amounts of caffeine with
small amounts of theobromine and theophylline in a naturally occurring slow-release excipient.
[10]

History of use
Humans have consumed caffeine since the Stone Age.
[11]
Early peoples found that chewing the seeds,
bark, or leaves of certain plants had the effects of easing fatigue, stimulating awareness, and elevating
mood. Only much later was it found that the effect of caffeine was increased by steeping such plants in
hot water. Many cultures have legends that attribute the discovery of such plants to people living many
thousands of years ago.
According to one popular Mongolian legend, the Emperor of China Shennong, reputed to have reigned in
about 3,000 BC, accidentally discovered that when some leaves fell into boiling water, a fragrant and
restorative drink resulted.
[12]
Shennong is also mentioned in Lu Yu's Cha Jing, a famous early work on the
subject of tea.
[13]

The early history of coffee is obscure, but a popular myth traces its discovery to Ethiopia, where Coffea
arabica originates. According to this myth, a goatherder named Kaldi observed goats that became elated
and sleepless at night after browsing on coffee shrubs and, upon trying the berries that the goats had
been eating, experienced the same vitality. The earliest literary mention of coffee may be a reference to
Bunchum in the works of the 9th century Persian physician al-Razi. In 1587, Malaye Jaziri compiled a
work tracing the history and legal controversies of coffee, entitled "Umdat al safwa fi hill al-qahwa". In this
work, Jaziri recorded that one Sheikh, Jamal-al-Din al-Dhabhani, mufti of Aden, was the first to adopt the
use of coffee in 1454, and that in the 15th century the Sufis of Yemen routinely used coffee to stay awake
during prayers.
Towards the close of the 16th century, the use of coffee was recorded by a European resident in Egypt,
and about this time it came into general use in the Near East. The appreciation of coffee as a beverage in
Europe, where it was first known as "Arabian wine," dates from the 17th century. During this time "coffee
houses" were established, the first being opened in Constantinople and Venice. In Britain, the first coffee
houses were opened in London in 1652, at St Michael's Alley, Cornhill. They soon became popular
throughout Western Europe, and played a significant role in social relations in the 17th and 18th
centuries.
[14]

The kola nut, like the coffee berry and tea leaf, appears to have ancient origins. It is chewed in many
West African cultures, individually or in a social setting, to restore vitality and ease hunger pangs. In
1911, kola became the focus of one of the earliest documented health scares when the US government
seized 40 barrels and 20 kegs of Coca-Cola syrup in Chattanooga, Tennessee, alleging that the caffeine
in its drink was "injurious to health".
[15]
On March 13, 1911, the government initiated The United States vs.
Forty Barrels and Twenty Kegs of Coca-Cola, hoping to force Coca-Cola to remove caffeine from its
formula by making exaggerated claims, such as that the excessive use of Coca-Cola at one girls' school
led to "wild nocturnal freaks, violations of college rules and female proprieties, and even immoralities."
[16]

Although the judge ruled in favor of Coca-Cola, two bills were introduced to the U.S. House of
Representatives in 1912 to amend the Pure Food and Drug Act, adding caffeine to the list of "habit-
forming" and "deleterious" substances which must be listed on a product's label.
The earliest evidence of cocoa use comes from residue found in an ancient Mayan pot dated to 600 BC.
In the New World, chocolate was consumed in a bitter and spicy drink called xocoatl, often seasoned with
vanilla, chile pepper, and achiote. Xocoatl was believed to fight fatigue, a belief that is probably
attributable to the theobromine and caffeine content. Chocolate was an important luxury good throughout
pre-Columbian Mesoamerica, and cocoa beans were often used as currency.
Chocolate was introduced to Europe by the Spaniards and became a popular beverage by 1700. They
also introduced the cacao tree into the West Indies and the Philippines. It was used in alchemical
processes, where it was known as Black Bean.
The first coffee house in Europe was opened Paris in the 1800s by an French-Armenian named Pascal.
Armenian merchants played in role in the more modern history of coffee and this is the reason why the
coffee growing region in is named the Armenia Region of Columbia.In 1819, the German chemist
Friedrich Ferdinand Runge isolated relatively pure caffeine for the first time. According to a legend, he did
this at the behest of Johann Wolfgang von Goethe.
[17]
Today, global consumption of caffeine has been
estimated at 120,000 tons per annum,
[18]
making it the world's most popular psychoactive substance. This
number equates to one serving of a caffeinic beverage for every person, per day. In North America, 90%
of adults consume some amount of caffeine daily.
Pharmacology
Caffeine is a central nervous system and metabolic stimulant,
[19]
and is used both recreationally and
medically to reduce physical fatigue and restore mental alertness when unusual weakness or drowsiness
occurs. Caffeine stimulates the central nervous system first at the higher levels, resulting in increased
alertness and wakefulness, faster and clearer flow of thought, increased focus, and better general body
coordination, and later at the spinal cord level at higher doses.
[20]
Once inside the body, it has a complex
chemistry, and acts through several mechanisms as described below.
Metabolism
affeine is metabolized in the liver into three primary metabolites: paraxanthine (84%), theobromine (12%),
and theophylline (4%) Caffeine is completely absorbed by the stomach and small intestine within 45
minutes of ingestion. After ingestion it is distributed throughout all tissues of the body and is eliminated by
first-order kinetics.
[21]

The half-life of caffeine , the time required for the body to eliminate one-half of the total amount of caffeine
consumed at a given time varies widely among individuals according to such factors as age, liver
function, pregnancy, some concurrent medications, and the level of enzymes in the liver needed for
caffeine metabolism. In healthy adults, caffeine's half-life is approximately 3-4 hours. In women taking oral
contraceptives this is increased to 5-10 hours,
[22]
and in pregnant women the half-life is roughly 9-11
hours.
[23]
Caffeine can accumulate in individuals with severe liver disease when its half-life can increase
to 96 hours.
[24]
In infants and young children, the half-life may be longer than in adults; half-life in a
newborn baby may be as long as 30 hours. Other factors such as smoking can shorten caffeine's half-
life.
[25]

Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system (specifically, the 1A2
isozyme) into three metabolic dimethylxanthines,
[26]
which each have their own effects on the body:
Paraxanthine (84%) Has the effect of increasing lipolysis, leading to elevated glycerol and free
fatty acid levels in the blood plasma.
Theobromine (12%) Dilates blood vessels and increases urine volume. Theobromine is also the
principal alkaloid in cocoa, and therefore chocolate.
Theophylline (4%) Relaxes smooth muscles of the bronchi, and is used to treat asthma. The
therapeutic dose of theophylline, however, is many times greater than the levels attained from
caffeine metabolism.
Each of these metabolites is further metabolized and then excreted in the urine.
Mechanism of Action
Caffeine's principal mode of action is as an antagonist of adenosine receptors in the brain.
Caffeine acts through multiple mechanisms involving both action on receptors and channels at the cell
membrane, as well as intracellular action on Calcium and cAMP pathways. By virtue of its purine structure
it can act on some of the same targets as adenosine related nucleosides and nucleotides, like the cell
surface P1 GPCRs for adenosine, as well as the intracellular Ryanodine receptor which is the
physiological target of cADPR (cyclic ADP ribose), and cAMP-phosphodiesterase (cAMP-PDE). Although
the action is agonistic in some cases, it is antagonistic in others. Physiologically, however, caffeine action
is unlikely due to increased RyR opening, as it requires plasma concentration above lethal dosage. The
action is most likely through adenosine receptors.
The principal mode of action of caffeine is as an antagonist of adenosine receptors in the brain.
[27]
The
caffeine molecule is structurally similar to adenosine, and binds to adenosine receptors on the surface of
cells without activating them (an "antagonist" mechanism of action). Therefore, caffeine acts as a
competitive inhibitor. The reduction in adenosine activity results in increased activity of the
neurotransmitter dopamine, largely accounting for the stimulatory effects of caffeine. Caffeine can also
increase levels of epinephrine/adrenaline,
[28]
possibly via a different mechanism. Acute usage of caffeine
also increases levels of serotonin, causing positive changes in mood.
The inhibition of adenosine may be relevant in its diuretic properties. Because adenosine is known to
constrict preferentially the afferent arterioles of the glomerulus, its inhibition may cause vasodilation, with
an increase in renal blood flow (RBF) and glomerular filtration rate (GFR). This effect, called competitive
inhibition, interrupts a pathway that normally serves to regulate nerve conduction by suppressing post-
synaptic potentials. The result is an increase in the levels of epinephrine and
norepinephrine/noradrenaline released via the hypothalamic-pituitary-adrenal axis.
[29]
Epinephrine, the
natural endocrine response to a perceived threat, stimulates the sympathetic nervous system, leading to
an increased heart rate, blood pressure and blood flow to muscles, a decreased blood flow to the skin
and inner organs and a release of glucose by the liver.
Caffeine is also a known competitive inhibitor of the enzyme cAMP-phosphodiesterase (cAMP-PDE),
which converts cyclic AMP (cAMP) in cells to its noncyclic form, allowing cAMP to build up in cells. Cyclic
AMP participates in the messaging cascade produced by cells in response to stimulation by epinephrine,
so by blocking its removal caffeine intensifies and prolongs the effects of epinephrine and epinephrine-
like drugs such as amphetamine, methamphetamine, or methylphenidate. Increased concentrations of
cAMP in parietal cells causes an increased activation of protein kinase A (PKA) which in turn increases
activation of H+/K+ ATPase, resulting finally in increased gastric acid secretion by the cell.
Caffeine (and theophylline) can freely diffuse into cells and causes intracellular calcium release
(independent of extracellular calcium) from the calcium stores in the Endoplasmic Reticulum(ER). This
release is only partially blocked by Ryanodine receptor blockade with ryanodine, dantrolene, ruthenium
red, and procaine (thus may involve ryanodine receptor and probably some additional calcium channels),
but completely abolished after calcium depletion of ER by SERCA inhibitors like Thapsigargin (TG) or
cyclopiazonic acid (CPA).
[30]
The action of caffeine on the ryanodine receptor may depend on both
cytosolic and the luminal ER concentrations of Ca2+. At low millimolar concentration of caffeine, the RyR
channel open probability (Po) is significantly increased mostly due to a shortening of the lifetime of the
closed state. At concentrations >5 mM, caffeine opens RyRs even at picomolar cytosolic Ca2+ and
dramatically increases the open time of the channel so that the calcium release is stronger than even an
action potential can generate. This mode of action of caffeine is probably due to mimicking the action of
the physiologic metabolite of NAD called cADPR (cyclic ADP ribose) which has a similar potentiating
action on Ryanodine receptors.
Caffeine may also directly inhibit delayed rectifier and A-type K+ currents and activate plasmalemmal
Ca2+ influx in certain vertebrate and invertebrate neurons.
The metabolites of caffeine contribute to caffeine's effects. Theobromine is a vasodilator that increases
the amount of oxygen and nutrient flow to the brain and muscles. Theophylline, the second of the three
primary metabolites, acts as a smooth muscle relaxant that chiefly affects bronchioles and acts as a
chronotrope and inotrope that increases heart rate and efficiency. The third metabolic derivative,
paraxanthine, is responsible for an increase in the lipolysis process, which releases glycerol and fatty
acids into the blood to be used as a source of fuel by the muscles.
[31]

Effects when taken in moderation
The precise amount of caffeine necessary to produce effects varies from person to person depending on
body size and degree of tolerance to caffeine. It takes less than an hour for caffeine to begin affecting the
body and a mild dose wears off in three to four hours.
[20]
Consumption of caffeine does not eliminate the
need for sleep: it only temporarily reduces the sensation of being tired.
With these effects, caffeine is an ergogenic: increasing the capacity for mental or physical labor. A study
conducted in 1979 showed a 7% increase in distance cycled over a period of two hours in subjects who
consumed caffeine compared to control tests.
[32]
Other studies attained much more dramatic results; one
particular study of trained runners showed a 44% increase in "race-pace" endurance, as well as a 51%
increase in cycling endurance, after a dosage of 9 milligrams of caffeine per kilogram of body weight.
[33]

The extensive boost shown in the runners is not an isolated case; additional studies have reported similar
effects. Another study found 5.5 milligrams of caffeine per kilogram of body mass resulted in subjects
cycling 29% longer during high intensity circuits.
[34]

Breathing problems in premature infants, apnea of prematurity, are sometimes treated with citrated
caffeine, which is available only by prescription in many countries.
[35]
A reduction in bronchopulmonary
dysplasia has been exhibited in premature infants treated with caffeine citrate therapy regimens. It is
speculated that this reduction in bronchopulmonary dysplasia is tied to a reduction in exposure to positive
airway pressure.
[citation needed]
The only short term risk associated with this treatment is a temporary
reduction in weight gain during the therapy.
[36]

While relatively safe for humans, caffeine is considerably more toxic to some other animals such as dogs,
horses and parrots due to a much poorer ability to metabolize this compound. Caffeine has a much more
significant effect on spiders, for example, than most other drugs do.
[37]


Caffeine has a significant effect on spiders, which is
reflected in their web construction
Tolerance and withdrawal
Caffeine content of select common food and drugs
[38][39]

Product Serving size
Caffeine per serving
(mg)
Caffeine tablet 1 tablet 200
Excedrin tablet 1 tablet 65
Coffee, brewed 240 mL (8 US fl oz) 135*
Coffee, decaffeinated 240 mL (8 US fl oz) 5*
Coffee, espresso 57 mL (2 US fl oz) 100*
Chocolate, Dark (Hershey's Special Dark) 1 bar (43 g; 1.5 oz) 31
Chocolate, Milk (Hershey Bar) 1 bar (43 g; 1.5 oz) 10
Red Bull 240 mL (8.2 US fl oz) 80
Cocaine Energy Drink 250 mL (8.4 US fl oz) 280
Buckfast Tonic Wine 750 ml (1 bottle) 280
Bawls Guarana 296 mL (10 US fl oz) 67
Foosh Energy Mints 1 mint 100
Buzz Bites Chocolate Energy Chews 1 chocolate 100
Soft drink, Mountain Dew "Dew Fuel" 355 mL (12 US fl oz) 54.5
Soft drink, Coca-Cola Classic 355 mL (12 US fl oz) 34
Atomic Rush 255 mL (7 US fl oz) 100
Tea, green 240 mL (8 US fl oz) 15
Tea, leaf or bag 240 mL (8 US fl oz) 50
* Estimated average caffeine content per serving. Actual content varies according to preparation.
Because caffeine is primarily an antagonist of the central nervous system's receptors for the
neurotransmitter adenosine, the bodies of individuals who regularly consume caffeine adapt to the
continual presence of the drug by substantially increasing the number of adenosine receptors in the
central nervous system. This increase in the number of the adenosine receptors makes the body much
more sensitive to adenosine, with two primary consequences.
[40]
First, the stimulatory effects of caffeine
are substantially reduced, a phenomenon known as a tolerance adaptation. Second, because these
adaptive responses to caffeine make individuals much more sensitive to adenosine, a reduction in
caffeine intake will effectively increase the normal physiological effects of adenosine, resulting in
unwelcome withdrawal symptoms in tolerant users.
[40]

Because adenosine, in part, serves to regulate blood pressure by causing vasodilation, the increased
effects of adenosine cause the blood vessels of the head to dilate, leading to an excess of blood in the
head and causing a headache and nausea. Reduced catecholamine activity may cause feelings of fatigue
and drowsiness. A reduction in serotonin levels when caffeine use is stopped can cause anxiety,
irritability, inability to concentrate and diminished motivation to initiate or to complete daily tasks; in
extreme cases it may cause mild depression.
Withdrawal symptoms possibly including headache, irritability, an inability to concentrate, and
stomach aches
[citation needed]
may appear within 12 to 24 hours after discontinuation of caffeine intake,
peak at roughly 48 hours, and usually last from one to five days - representing the time required for the
number of adenosine receptors in the brain to revert to "normal" levels, uninfluenced by caffeine
consumption. Caffeine causes excess release of stomach acids during ingestion.
[citation needed]
When in
withdrawal the stomach acid levels decrease substantially and can cause some stomach aches in certain
people.
[citation needed]
The aches normally last between 24-48 hours and can be confused with
constipation.
[citation needed]
Analgesics, such as aspirin, can relieve the pain symptoms, as can a small dose
of caffeine.
[41]
Most effective is a combination of both an analgesic and a small amount of caffeine.
This is not the only case where caffeine increases the effectiveness of a drug. Caffeine makes pain
relievers 40% more effective in relieving headaches and helps the body absorb headache medications
more quickly, bringing faster relief.
[42]
For this reason, many over-the-counter headache drugs include
caffeine in their formula. It is also used with ergotamine in the treatment of migraine and cluster
headaches as well as to overcome the drowsiness caused by antihistamines
Overuse
Caffeine is a drug that in large amounts, especially over an extended period of time, can lead to a
condition termed "caffeinism." Caffeinism usually combines physical addiction with a wide range of
unpleasant physical and mental conditions including nervousness, irritability, anxiety, tremulousness,
muscle twitching (hyperreflexia), insomnia, and heart palpitations.
[43]
(Under a rigid definition of addiction,
meaning a process of escalating use, "caffeine dependency" would be a more descriptive term. However,
under the widely accepted definition "chronic pattern of behavior that is perceived to be difficult to quit,"
caffeine may be said to be addictive.) Furthermore, because caffeine increases the production of stomach
acid, high usage over time can lead to peptic ulcers, erosive esophagitis, and gastroesophageal reflux
disease.
[44]
However, since both "regular" and decaffeinated coffees have also been shown to stimulate
the gastric mucosa and increase stomach acid secretion, caffeine is probably not the only component of
coffee responsible.
[45]

There are four caffeine-induced psychiatric disorders recognized by the Diagnostic and Statistical Manual
of Mental Disorders, Fourth Edition: caffeine intoxication, caffeine-induced anxiety disorder, caffeine-
induced sleep disorder, and caffeine-related disorder not otherwise specified (NOS).
Caffeine intoxication
An acute overdose of caffeine, usually in excess of 250 milligrams (more than 2-3 cups of brewed coffee),
can result in a state of central nervous system overstimulation called caffeine intoxication. The symptoms
of caffeine intoxication may include restlessness, nervousness, excitement, insomnia, flushing of the face,
increased urination, gastrointestinal disturbance, muscle twitching, a rambling flow of thought and
speech, irregular or rapid heart beat, and psychomotor agitation.
[43][46]

In cases of extreme overdose, death can result. The median lethal dose (LD
50
) of caffeine is
192 milligrams per kilogram in rats.
[47]
The LD
50
of caffeine is dependent on weight and individual
sensitivity and estimated to be about 150 to 200 milligrams per kilogram of body mass, roughly 140 to
180 cups of coffee for an average adult taken within a limited timeframe that is dependent on half-life.
Though achieving lethal dose with caffeine would be exceptionally difficult with regular coffee, there have
been reported deaths from overdosing on caffeine pills.
[48][49][50][51]

Treatment of severe caffeine intoxication is generally supportive, providing treatment of the immediate
symptoms, but if the patient has very high serum levels of caffeine then peritoneal dialysis, hemodialysis,
or hemofiltration may be required.
Anxiety and sleep disorders
Long-term overuse of caffeine can elicit a number of psychiatric disturbances. Two such disorders
recognized by the APA are caffeine-induced sleep disorder and caffeine-induced anxiety disorder.In the
case of caffeine-induced sleep disorder, an individual regularly ingests high doses of caffeine sufficient to
induce a significant disturbance in his or her sleep, sufficiently severe to warrant clinical attention.
[52]

In some individuals, the large amounts of caffeine can induce anxiety severe enough to necessitate
clinical attention. This caffeine-induced anxiety disorder can take many forms, from generalized anxiety,
to panic attacks, obsessive-compulsive symptoms, or even phobic symptoms.
[52]
Because this condition
can mimic organic mental disorders, such as panic disorder, generalized anxiety disorder, bipolar
disorder, or even schizophrenia, a number of medical professionals believe caffeine-intoxicated people
are routinely misdiagnosed and unnecessarily medicated when the treatment for caffeine-induced
psychosis would simply be to withhold further caffeine.
[53]
A Study in the British Journal of Addiction
concluded that caffeinism, although infrequently diagnosed, may afflict as many as one person in ten of
the population.
[54]

Extraction of pure caffeine
Caffeine extraction is an important industrial process and can be performed using a number of different
solvents. Benzene, chloroform, trichloroethylene and dichloromethane have all been used over the years
but for reasons of safety, environmental impact, cost and flavor, they have been superseded by the
following main methods:
Water extraction
Coffee beans are soaked in water. The water, which contains not only caffeine but also many other
compounds which contribute to the flavor of coffee, is then passed through activated charcoal, which
removes the caffeine. The water can then be put back with the beans and evaporated dry, leaving
decaffeinated coffee with a good flavor.
[55]
Coffee manufacturers recover the caffeine and resell it for use
in soft drinks and medicines.
Supercritical carbon dioxide extraction
Supercritical carbon dioxide is an excellent nonpolar solvent for caffeine (as well as many other organic
compounds), and is safer than the organic solvents that are used for caffeine extraction. The extraction
process is simple: CO
2
is forced through the green coffee beans at temperatures above 31.1 C and
pressures above 73 atm. Under these conditions, CO
2
is in a "supercritical" state: it has gaslike properties
which allow it to penetrate deep into the beans but also liquid-like properties which dissolve 97-99% of the
caffeine. The caffeine-laden CO
2
is then sprayed with high pressure water to remove the caffeine. The
caffeine can then be isolated by charcoal adsorption (as above) or by distillation, recrystallization, or
reverse osmosis.
[55]

Extraction by nonhazardous organic solvents
Organic solvents such as ethyl acetate present much less health and environmental hazard than
previously used chlorinated and aromatic solvents. The hydrolysis products of ethyl acetate are ethanol
and acetic acid, both nonhazardous in small quantities. Another method is to use triglyceride oils obtained
from spent coffee grounds.
References
1. Lovett, Richard (24 September 2005). "Coffee: The demon drink?". New Scientist (2518).
2. Balentine DA, Harbowy ME and Graham HN, Tea: the Plant and its Manufacture; Chemistry and
Consumption of the Beverage in Caffeine (1998), ed. G Spiller
3. Nathanson, JA (12 October 1984). "Caffeine and related methylxanthines: possible naturally
occurring pesticides". Science 226 (4671): 184-7. PMID 6207592.
4. Erowid (Dec 2003). Does Yerba Mat Contain Caffeine or Mateine?. The Vaults of Erowid.
Retrieved on 2006-08-16.
5. PubChem: mateina. National Library of Medicine. Retrieved on 2006-08-16.. Generally translated
as mateine in articles written in English
6. PubChem: guaranine. National Library of Medicine. Retrieved on 2006-08-16.
7.
a

b
Caffeine. International Coffee Organization. Retrieved on 2006-08-21.
8. Caffeine in tea vs. steeping time (September 1996). Retrieved on 2006-08-12.
9. Smit, HJ; Gaffan EA, Rogers PJ. (2004 Nov). "Methylxanthines are the psycho-pharmacologically
active constituents of chocolate". Psychopharmacology 176 (3-4): 412-9.
10. Haskell, CF; Kennedy D, Wesnes KA, Milne AL, Scholey AB (13 March 2006). "A double-blind,
placebo-controlled, multi-dose evaluation of the acute behavioural effects of guarana in humans".
J Psychopharmacol 0 (0): 0-0. PMID 16533867.; [Epub ahead of print]
11. Escohotado, Antonio; Ken Symington (May 1999). A Brief History of Drugs: From the Stone Age
to the Stoned Age. Park Street Press. ISBN 0-89281-826-3.
12. Chow p. 19-20 (Czech edition); also Arcimovicova p. 9, Evans p. 2 and others
13. Yu, Lu (October 1995). The Classic of Tea: Origins & Rituals. Ecco Pr; Reissue edition. ISBN 0-
88001-416-4.
14. "Coffee". Encyclopdia Britannica. (1911).
15. Benjamin, LT Jr; Rogers AM, Rosenbaum A (1991 Jan). "Coca-Cola, caffeine, and mental
deficiency: Harry Hollingworth and the Chattanooga trial of 1911". J Hist Behav Sci 27 (1): 42-55.
PMID 2010614.
16. Jarvis, Gail (May 21, 2002). The Rise and Fall of Cocaine Cola. Retrieved on 2006-08-19.
17. Weinberg, BA; BK Bealer (January 2001). The World of Caffeine. Routledge. ISBN 0-415-92722-
6.
18. Whats your poison: caffeine. Australian Broadcasting Corporation (1997). Retrieved on 2006-08-
20.
19. Nehlig, A; Daval JL, Debry G (1992 May-Aug). "Caffeine and the central nervous system:
Mechanisms of action, biochemical, metabolic, and psychostimulant effects". Brain Res Brain
Res Rev 17 (2): 139-70. PMID 1356551.
20.
a

b
Bolton, Ph.D., Sanford; Gary Null, M.S. (1981). "Caffeine: Psychological Effects, Use and
Abuse". Orthomolecular Psychiatry 10 (3): 202-211. Retrieved on 2006-08-12.
21. ^ Newton, R; Broughton LJ, Lind MJ, Morrison PJ, Rogers HJ, Bradbrook ID (1981). "Plasma and
salivary pharmacokinetics of caffeine in man". European Journal of Clinical Pharmacology 21 (1):
45-52. PMID 7333346.
22. Meyer, FP; Canzler E, Giers H, Walther H. (1991). "Time course of inhibition of caffeine
elimination in response to the oral depot contraceptive agent Deposiston. Hormonal
contraceptives and caffeine elimination". Zentralbl Gynakol 113 (6): 297-302. PMID 2058339.
23. Ortweiler, W; Simon HU, Splinter FK, Peiker G, Siegert C, Traeger A. (1985). "Determination of
caffeine and metamizole elimination in pregnancy and after delivery as an in vivo method for
characterization of various cytochrome p-450 dependent biotransformation reactions". Biomed
Biochim Acta. 44 (7-8): 1189-99. PMID 4084271.
24. Bolton, Ph.D., Sanford; Gary Null, M.S. (1981). "Caffeine: Psychological Effects, Use and Abuse".
Orthomolecular Psychiatry 10 (3): 202-211. Retrieved on 2006-08-14.
25. Springhouse (January 1, 2005). Physician's Drug Handbook; 11th edition. Lippincott Williams &
Wilkins. ISBN 1-58255-396-3.
26. Caffeine. The Pharmacogenetics and Pharmacogenomics Knowledge Base. Retrieved on 2006-
08-14.
27. Fisone G, G; Borgkvist A, Usiello A (2004 Apr). "Caffeine as a psychomotor stimulant:
mechanism of action". Cell Mol Life Sci 61 (7-8): 857-72. PMID 15095008.
28. Graham T, Rush J, van Soeren M (1994). "Caffeine and exercise: metabolism and performance.".
Can J Appl Physiol 19 (2): 111-38. PMID 8081318.
29. Fredholm B, Bttig K, Holmn J, Nehlig A, Zvartau E (1999). "Actions of caffeine in the brain
with special reference to factors that contribute to its widespread use.". Pharmacol Rev 51 (1):
83-133. PMID 10049999.Full text
30. Alexei Verkhratsky. Physiology and Pathophysiology of the Calcium Store in the Endoplasmic
Reticulum of Neurons. Physiol. Rev. 85: 201-279, 2005. doi:10.1152/physrev.00004.2004
31. Dews, P.B. (1984). "Caffeine: Perspectives from Recent Research". Berlin: Springer-Valerag
32. Ivy, JL; Costill DL, Fink WJ, Lower RW (1979 Spring). "Influence of caffeine and carbohydrate
feedings on endurance performance". Med Sci Sports 11 (1): 6-11. PMID 481158.
33. Graham, TE; Spriet, LL (1991 Dec). "Performance and metabolic responses to a high caffeine
dose during prolonged exercise". J Appl Physiol 71 (6): 2292-8. PMID 1778925.
34. Trice, I; Haymes, EM (Mar 1995). "Effects of caffeine ingestion on exercise-induced changes
during high-intensity, intermittent exercise". Int J Sport Nutr 5 (1): 37-44. PMID 7749424.
35. Caffeine (Systemic). MedlinePlus (05/25/2000). Retrieved on 2006-08-12.
36. Schmidt, B; Roberts, RS, Davis, P, Doyle, LW, et al (May 18, 2006). "Caffeine therapy for apnea
of prematurity". N Engl J Med 354 (20): 2112-21.
37. Noever, R., J. Cronise, and R. A. Relwani. 1995. Using spider-web patterns to determine toxicity.
NASA Tech Briefs 19(4):82. Published in New Scientist magazine, 27 April 1995.
38. Caffeine Content of Food and Drugs. Nutrition Action Health Newsletter. Center For Science in
the Public Interest (December 1996). Retrieved on 2006-08-22.
39. Erowid (July 7, 2006). Caffeine Content of Beverages, Foods, & Medications. The Vaults of
Erowid. Retrieved on 2006-08-22.
40.
a

b
Green, RM; Stiles GL (Jan 1986). "Chronic caffeine ingestion sensitizes the A1 adenosine
receptor-adenylate cyclase system in rat cerebral cortex". J Clin Invest 77 (1): 222-227. PMID
3003150.
41. Sawynok, J (Jan 1995). "Pharmacological rationale for the clinical use of caffeine.". Drugs 49 (1):
37-50. PMID 7705215. Retrieved on 2006-08-14.
42. Headache Triggers: Caffeine. WebMD (June 2004). Retrieved on 2006-08-14.
43. Caffeine-related disorders. Encyclopedia of Mental Disorders. Retrieved on 2006-08-14.
44. Gastroesophageal Reflux Disease (GERD). Cedars-Sinai. Retrieved on 2006-08-14.
45. Erowid Caffeine Vault: Effects. The Vaults of Erowid (Jul 08, 2006). Retrieved on 2006-08-14.
46. Kamijo, Y; Soma K, Asari Y, Ohwada T (1999 Dec). "Severe rhabdomyolysis following massive
ingestion of oolong tea: caffeine intoxication with coexisting hyponatremia". Veterinary and
Human Toxicology 41 (6): 381-3. PMID 10592946.
47. Erowid Caffeine Vault: Caffeine Dosage. The Vaults of Erowid (Jul 08, 2006). Retrieved on 2006-
08-14.
48. Kerrigan, S; Lindsey T (2005). "Fatal caffeine overdose: two case reports". Forensic Sci Int 153
(1): 67-9.
49. Holmgren, P; Norden-Pettersson L, Ahlner J (2004). "Caffeine fatalities four case reports".
Forensic Sci Int 139 (1): 71-3.
50. Walsh, I; Wasserman GS, Mestad P, Lanman RC (Dec 1987). "Near-fatal caffeine intoxication
treated with peritoneal dialysis". Pediatr Emerg Care 3 (4): 244-9. PMID 3324064.
51. Mrvos, RM; Reilly PE, Dean BS, Krenzelok EP (Dec 1989). "Massive caffeine ingestion resulting
in death". Vet Hum Toxicol 31 (6): 571-2. PMID 2617841.
52. (1994) Diagnostic and Statistical Manual of Mental Disorders, fourth Edition.. American
Psychiatric Association. ISBN 0-89042-062-9.
53. Shannon, MW; Haddad LM, Winchester JF (1998). Clinical Management of Poisoning and Drug
Overdose, 3rd ed.. ISBN 0-7216-6409-1.
54. James, JE; KP Stirling (Sep 1983). "Caffeine: A summary of some of the known and suspected
deleterious effects of habitual use". British Journal of Addiction 78 (3): 251-8. PMID 6354232.
55. Senese, Fred (2005-09-20). How is coffee decaffeinated?. General Chemistry Online. Retrieved
on 2006-08-21.
External links
Caffeine: How Stuff Works
National Geographic January 2005
Erowid Caffeine Vaults
Caffeine Information Archive
US National Library of Medicine: MedlinePlus Drug Information: Caffeine
Naked Scientists Online: Why do plants make caffeine?
Is Caffeine a Health Hazard?
The Coffee and Caffeine FAQ
The Physician and Sportsmedicine: Caffeine: A User's Guide
Caffeine: The Inside Scoop
Caffeine: Psychological Effects, Use & Abuse
Caffeine 3D view and pdb-file
Alcohol and Drugs History Society: Caffeine news page
eMedicine Caffeine-Related Psychiatric Disorders
The Consumers Union Report on Licit and Illicit Drugs, Caffeine-Part 1 Part 2
Coffee: A Little Really Does Go a Long Way, NPR, September 28, 2006
NASA Caffeine Findings (the web of a caffeinated spider)
Caffeine in the news - news archives

Article
Web sites
Bibliography
Year in Review
Recent Edits
Contributors
caffeine, nitrogenous organic compound of the alkaloid group, substances that have marked
physiological effects. Caffeine occurs in tea, coffee, guarana, mat, kola nuts, and cacao.
Pure caffeine (trimethylxanthine) occurs as a white powder or as silky needles, which melt at 238
C (460 F); it sublimes at 178 C (352 F) at atmospheric pressure. It is very soluble in hot
water; upon cooling, the solution deposits crystals of caffeine monohydrate. Caffeine is generally
less soluble in organic solvents than in hot water. It is odourless but has a bitter taste.
Caffeine is present in ground coffee in amounts ranging between 0.75 and 1.5 percent by weight.
The average cup of coffee thus contains about 100 mg (0.003 ounce) of caffeine. The caffeine
content of tea varies greatly depending on the strength of the tea, but it averages about 40 mg.
There are also about 40 mg (0.0014 ounce) of caffeine in a 12-ounce glass of carbonated cola
beverage.
Caffeine has a stimulating effect on the central nervous system, heart, blood vessels, and
kidneys. It also acts as a mild diuretic. Caffeines potent stimulatory action makes it a valuable
antidote to respiratory depression induced by drug overdose (e.g., from morphine or
barbiturates). The positive effects that have been described in people who use caffeine include
improved motor performance, decreased fatigue, enhanced sensory activity, and increased
alertness. These positive effects may partly explain the compulsion of many adults to consume
coffee or other caffeine-containing beverages as part of the morning ritual of awakening.
However, caffeine intake may also produce in people such negative effects as irritability,
nervousness or anxiety, jitteriness, headaches, and insomnia. By the mid-1980s decaffeinated
coffee and soft drinks had become widely available, giving consumers the choice of regulating
their caffeine intake while continuing to enjoy these beverages.
Images
Videos
quizzes
Lists
http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=2519
I WHAT IS CAFFEINE:
Caffeine Synonyms: 1-methyltheobromine
7-methyltheophylline
methyltheobromide
3,7-dihydro-1,3,7-trimethyl-1h-purine-2,6-
dione
1,3,7-trimethyl-2,6-dioxopurine
theine
caffeine
thein
guarainine
no-doz
eldiatric c
nci-c02733
organex
1,3,7-trimethyl-2,6-dioxo-1,2,3,6-
tetrahydopurine
caffenium
anhydrous caffeine
alert-pep
cafeina
cafipel
koffeine
mateina
refreshn
stim
tri-aqua
The most common names for caffeine are 3,7-dihydro-1,3,7-trimethyl-1h-purine-2,6-
dione and 1,3,7-trimethylxanthine.
Figure

CH3
|
N
/ \
N----C C==O
|| || |
|| || |
CH C N--CH3
\ / \ /
N C
| ||
CH3 O


Also see
www.geocities.com/CapeCanaveral/Launchpad/6202/che.htm
Physical Properties: Molecular Formula = C
8
H
10
N
4
O
2

Molecular Weight = 194.19
Number of Chiral Centers: Zero
Optical Activity: None
UV max (10mM HClO
4
+ 10mM NaClO
4
70%) + (CH
3
CN 30%): 210nm, local max
at 275nm
Half-Life: in human body varies between 3 to 7 hours
Properties: Soft, white crystal or powder, odorless, slightly bitter taste
Melting Point: 235-238
o
C
Caffeine is classified as a central nervous system stimulant and it belongs to xanthine
chemical group. There are three distinguished compounds in xanthine group:
Caffeine: 1,3,7-trimethylxanthine
Sources: Coffee, tea, cola nuts, mate, guarana
Effects: Stimulant of central nervous system, cardiac muscle, and respiratory
system, diuretic Delays fatigue
Theophylline: 1,3-dimethylxanthine
Sources: Tea
Effects: Cardiac stimulant, smooth muscle relaxant, diuretic, vasodilator
Theobromine: 3,7-dimethylxanthine
Sources: Principle alkaloid of the cocoa bean, Cola nuts, and tea
Effects: Diuretic, smooth muscle relaxant, cardiac stimulant, vasodilator
They are very similar and differ only by the presence of methyl groups in two
positions of the chemical structure. They are easily oxidized to uric acid and other
methyluric acids, which are also similar in chemical structure.
II SOURCES OF CAFFEINE:
Drinks:

Item Item Size Caffeine Content (mg)
Tea 150 ml 2-5
Hot Cocoa 150 ml 1-8
Chocolate Milk 225 ml 2-7
Jolt Cola 12 oz 71
Josta 12 oz 58
Mountain Dew 12 oz 54
Kick Citrus 12 oz 54
Mello Yellow 12 oz 53
Surge 12 oz 51
Tab 12 oz 47
Diet Coca Cola 12 oz 46
Coca Cola 12 oz 46
Dr. Pepper 12 oz 41
Mr. Pibb 12 oz 40
Pepsi Cola 12 oz 38
Aspen 12 oz 36
Canada Dry Cola 12 oz 30
RC Cola 12 oz 18
Mug Root Beer 12 oz 0
Sprite 12 oz 0
7-Up 12 oz 0
Coffee:

Item Item Size Caffeine Content (mg)
Coffee, Brewed 8 oz 135
General Foods International Coffee, Orange
Cappuccino
8 oz 102
Coffee, instant 8 oz 95
General Foods International
Coffee, Caf Vienna
8 oz 90
Maxwell House Cappuccino, Mocha 8 oz 60-65
General Foods International Coffee, Swiss
Mocha
8 oz 55
Maxwell House Cappuccino, French Vanilla or
Irish Cream
8 oz 45-50
Maxwell House cappuccino, Amaretto 8 oz 25-30
General Foods International Coffee, Viennese
Chocolate Caf
8 oz 26
Maxwell House Cappuccino, Decaffeinated 8 oz 3-6
Coffee, Decaffeinated 8 oz 5
Food:

Item Item Size Caffeine Content (mg)
Ben/Jerry No Fat Coffee
Fudge Froz. Yog.
1 cup 85
Starbucks Coffee Ice
Cream
1 cup 40-60
Dannon Coffee Yogurt 8 oz. 45
Chocolate Bar 50 g 3-63
Chunky Bar 1 bar (40g) 11.6
100 Grand Bar 1 bar (43g) 11.2
Nestle Crunch Bar 1 bar (40g) 10
Krackel Bar 1 bar (47g) 8.5
Peanut Butter Cup 1 pk (51g) 5.6
Kit Kat Bar 1 bar (46g) 5
Mr. Goodbar 1 bar (50g) 5
Raisinets 10 pieces (10g) 2.5
Butterfinger Bar 1 bar (61g) 2.4
Baby Ruth Bar 1 bar (60g) 2.4
Special Dark Sweet
Chocolate Bar
1 bar (41g) 31
Chocolate Brownie 1.25 oz 8
Chocolate Chip Cookie 30 g 3-5
Chocolate Ice Cream 50 g 2-5
Milk Chocolate 1 oz 1-15
Bittersweet Chocolate 1 oz 5-35
After Eight Mint 2 pc (8g) 1.6
Jell-O Pudding Pop
Chocolate
1 bar (77g) 2
Jell-O Mix Chocolate
Mousse
95 g 6
Jell-O Chocolate Fudge
Mousse
86 g 12
Non-prescription Drugs:

Item (1 tablet or capsule) Caffeine Content (mg)
Dextrim 200
Vivarin 200
No Doz 100
Excedrin 65
Vanquish 33
Anacin 32
Midol 32
Triaminicin 30
Dristan 16
III HOW CAFFEINE WORKS:
To a nerve cell, caffeine looks like adenosine that causes drowsiness by slowing down
nerve cell activity. Caffeine therefore binds to the adenosine receptor. However, it does
not slow down the cell/s activity like adenosine would. So the cell cannot see adenosine
anymore because caffeine is taking up all the receptors adenosine binds to. Therefore
instead of slowing down because of the adenosine level, the cells speed up. You can
see that caffeine also causes the brains blood vessels to constrict, because it blocks
adenosines ability to open them up.
IV OVERDOSE:
The lethal dosage varies from individual to individual according to weight. In massive
doses, caffeine is lethal. A fatal dose of caffeine has been calculated to be more than 10
grams, about 80 to 100 cups of coffee in rapid succession.

Caffeine belongs to the family of heterocyclic compounds known as purines. It has the
systematic name 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione; it is also known as 1,3,7-
trimethylxanthine, and 1,3,7-trimethyl-2,6-dioxopurine. Caffeine can be classified as an alkaloid
, a term used for substances produced as end products of nitrogen metabolism in some plants.
The chemical formula is C
8
H
10
N
4
O
2
. Caffeine has a molar mass of 194.19 grams (6.85
ounces). It is soluble in water and in many organic solvents, and it appears in pure form as white
crystals. Caffeine can be prepared by extraction from natural sources or by synthesis from uric
acid.
More than sixty plants, including those that give us coffee, tea, cola, and cacao, produce caffeine
from the purine xanthine. Whereas caffeine is a natural constituent in coffee, tea, chocolate, and
some cola drinks, it is added to consumer products such as soft drinks, diet pills, and analgesics .
Caffeine is said to be the most widely used drug in the world, and more than 100 million people
in the United States consume caffeine each day. It has pharmacological uses: as a cardiac and
respiratory stimulant and as an agent that promotes kidney diuresis. A therapeutic dose of
caffeine is about the same as the amount found in an average cup of coffee, between 100 and 200
milligrams (0.0071 ounces). Decaffeinated coffee can be prepared through extraction with a
solvent (such as methylene chloride), water extraction, or steam extraction.
Caffeine enters the bloodstream about ten minutes after its ingestion and stays in the body for up
to twelve hours. Like other alkaloids, caffeine has powerful physiological effects on humans and
animals. It stimulates heart muscle and relaxes certain structures that contain smooth muscle,
including the coronary arteries and the bronchi. It is a diuretic. Theophylline and theobromine,
two other plant alkaloid derivatives of xanthine, have physiological effects similar to those of
caffeine.
Caffeine acts as a stimulant of the central nervous system (CNS) through several proposed
mechanisms. The most important seems to be its interference with the ability of the
neurotransmitter adenosine to bind to its nerve cell receptor . Also, caffeine inhibits the enzyme
cyclic nucleotide phosphodiesterase, which breaks down intracellular cyclic adenosine
monophosphate (cAMP), another messenger involved in the transmission of nerve signals from
hormones originating outside the central nervous system

Coffee drinks are among the most popular sources of caffeine, believed to be the most commonly
used drug worldwide.
such as epinephrine and glucagonhormones that initiate the "fight or flight" response in
animals. Other proposed mechanisms have to do with effects on CNS intracellular calcium ion
concentrations.
Caffeine is moderately habit-forming, but because caffeine users can usually control its use, it is
not listed as an addicting stimulant by the American Psychiatric Association. Caffeine is not
regarded as being harmful to the average healthy adult. In fact there are beneficial effects to be
derived from moderate caffeine intake (about three cups of coffee per day). It relieves tiredness,
improves thought processes, increases alertness, and enhances physical performance. It may be
used to treat respiratory depression and, because it constricts blood vessels in the brain, is often
an ingredient in headache remedies. There is some evidence that caffeine may help to mitigate
symptoms of migraine headache and lower the risk of gallstones. Some studies show that
caffeine may protect against Parkinson's disease, perhaps by inhibiting the depletion of the
neurotransmitter dopamine in brain cells.
There may be some adverse effects due to excessive caffeine intake, such as restlessness,
headaches, heart palpitations, heartburn, and insomnia. Some individuals may have a toxic
reaction to it. Ingestion by pregnant women and nursing mothers may have adverse effects on
fetuses and babies; caffeine crosses the placenta and gets into breast milk. Caffeine has a wide
margin of safety. A lethal dose for most people would be the amount of caffeine found in about
one hundred cups of coffee.
Some investigations into caffeine-related health issues are inconclusive. Studies have shown no
correlation between caffeine intake and increased risk of osteoporosis or increased risk of
spontaneous abortion. There is no conclusive evidence linking caffeine intake (as coffee) with
bladder, pancreatic, breast, or colon cancer. There is also no conclusive evidence that moderate
caffeine intake contributes to heart disease or heart arrhythmias; however, one study has shown
that relatively high coffee consumption elevates blood levels of homocysteine (an amino acid)
a situation that may contribute to heart attack or Alzheimer's disease. There is continuing
controversy over whether heavy caffeine intake increases blood pressure, a woman's risk of
developing breast lumps, or the incidence of miscarriage.
SEE ALSO Dopamine ; Epinephrine ; Stimulants .
Sharron W. Smith
Bibliography
"Coffee: How Much Is Too Much?" (2001). Consumer Reports (May): 6465.

Read more: http://www.chemistryexplained.com/Bo-Ce/Caffeine.html#ixzz2zcWclMXT


Verification of Aspirin
Place a small amount of your aspirin sa
mple (about 0.10 g) in a 10-mL or
20-mL beaker. Add approximately 2
mL of ethanol. Stir or swirl to dissolve. If necessary, warm the mixture slightly on a hot plate
to assist in solution.
CAUTION: Ethanol is flammable. Do not allow it to boil.
Place one or two drops of the acetaminophe
n solution on a disposable IR card.
Allow the ethanol to evaporate.
Run an IR of your aspirin.
Compare your IR spectrogram with the
standard IR spectra of salicylic acid
and acetylsalicylic acid (aspirin). How
do they agree?
OPTION 2: THE PREPARATION OF ACETAMINOPHEN
Materials Needed
p
-aminophenol
Acetic anhydride
Phosphoric acid, concentrated
Ethanol
Dropper
Erlenmeyer flask, 125-mL
Beakers, 2 400-mL, 100-mL, 10 or 20-mL
Graduated cylinders, 10-mL, 25-mL
Watch glass
Stirring rod
Vial to hold aspirin sample
Ring stand
Clamp (to hold 125-mL Erlenmeyer flask)
Buchner funnel
Filter paper to fit Buchner funnel
Vacuum filtration flask
Rubber tubing for vacuum flask
Ice
Melting point capillary tube
Melting point apparatus
dropper
Disposable IR card
Optional: rubber gloves
Verification of Aspirin
Place a small amount of your aspirin sa
mple (about 0.10 g) in a 10-mL or
20-mL beaker. Add approximately 2
mL of ethanol. Stir or swirl to dissolve. If necessary, warm the mixture slightly on a hot plate
to assist in solution.
CAUTION: Ethanol is flammable. Do not allow it to boil.
Place one or two drops of the acetaminophe
n solution on a disposable IR card.
Allow the ethanol to evaporate.
Run an IR of your aspirin.
Compare your IR spectrogram with the
standard IR spectra of salicylic acid
and acetylsalicylic acid (aspirin). How
do they agree?
OPTION 2: THE PREPARATION OF ACETAMINOPHEN
Materials Needed
p
-aminophenol
Acetic anhydride
Phosphoric acid, concentrated
Ethanol
Dropper
Erlenmeyer flask, 125-mL
Beakers, 2 400-mL, 100-mL, 10 or 20-mL
Graduated cylinders, 10-mL, 25-mL
Watch glass
Stirring rod
Vial to hold aspirin sample
Ring stand
Clamp (to hold 125-mL Erlenmeyer flask)
Buchner funnel
Filter paper to fit Buchner funnel
Vacuum filtration flask
Rubber tubing for vacuum flask
Ice
Melting point capillary tube
Melting point apparatus
dropper
Disposable IR card
Optional: rubber gloves
Procedure
Fill a 400-mL beaker about half full w
ith water. Place the beaker and water
on a hot plate and bring to a boil.
Weigh out 1.5 g of p-aminophenol and transfer it into a 125-mL Erlenmeyer flask. (Avoid
contact with skin. You
may wish to wear gloves.)
Add 25 mL of water. Add 20 drops of concentrated phosphoric acid, H
3
PO
4
, and swirl the flask until all of the
amine dissolves. If not, add a few more drops of phosphoric acid.
Turn off the hot plate. Place the flask in
the hot water. Carefully add 2 mL of
acetic anhydride to the flask. Leave
the flask in the warm water for 10 minutes.
Remove the flask and place it an ice-water bath. Stir th
e mixture to crystallize the acetaminophen. You may need
to scratch the walls of the flask to st
art the crystallization. If no crystals
appear, add a small seed of acetaminophen
to start the crystal formation. Allow the flask to stay in the ice-water bath for 30 minutes.
Collect the crystals in a Buchner
funnel using vacuum filtration.
Wash the crystals with 10 mL of cold water. Allow the crystals to dry.
Determine the mass of the crude acetaminophen.
Recrystallization of the Acetaminophen
Place the crude acetaminophen in a 100-mL beaker. Add 20 mL
of water and heat on a hot plate until the crystals
dissolve. If the solution boils and crystals remain, add another 10 mL of water.
Remove the beaker and allow the solution
to cool. When crystals begin to a
ppear, place the beaker
in an ice bath
for 20 minutes. If no crystals appear, scratch the inside walls of the beaker.
Collect the crystals using the Buchner filtration apparatus. Wash with 10 mL of cold water.
Transfer the filter paper and crystals to a watch glass and let dry.
Determine the mass of the purified acetaminophen.
Determine the Melting Point of the Acetaminophen Sample
Fill a capillary melting point tube to a depth of
0.2 cm with the recrystallized acetaminophen.
Place the capillary tube in the melting point apparatus.
Determine its melting point. (Your instructor will
demonstrate the use of this apparatus.)
The melting point of acetaminophen is 169-171

C. p-aminophenol melts at 189-190

C.
The acetaminophen sample should be labele
d with your name, the mass of the
acetaminophen, the percent yield, and
its melting point.
NOTE:
Don't use your acetaminophen for a h
eadache! Its purity is not assured.
Verification of Acetaminophen
Place a small amount of your acetami
nophen sample (about 0.10 g) in a 10-mL or 20-mL beaker. Add
approximately 2 mL of ethanol. Stir or swirl to dissolve. If necessary, warm the mixture
slightly on a hot plate to
assist in solution. CAUTION: Ethanol is flammable. Do not allow it to boil.
Place one or two drops of the acetaminophe
n solution on a disposable IR card.
Allow the ethanol to evaporate.
Run an IR of your acetaminophen.
Compare your IR spectrogram with th
e standard IR spectra of p-ami
nophenol and acetaminophe
n. How do they
agree?













































Caffeine (C
8
H
10
N
4
O
2
) is the common name for trimethylxanthine (systematic name is 1,3,7-
trimethylxanthine or 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione). The chemical is also
known as coffeine, theine, mateine, guaranine, or methyltheobromine. Caffeine is naturally
produced by several plants, including coffee beans, guarana, yerba mat, cacao beans, and tea.
For the plants, caffeine acts as a natural pesticide. It paralyzes and kills insects that attempt to
feed on the plants. The molecule was first isolated by the German chemist Friedrich Ferdinand
Runge in 1819. When purified, caffeine is an intensely bitter white powder. It is added to colas
and other soft drinks to impart a pleasing bitter note. However, caffeine is also an addictive
stimulant. In humans, it stimulates the central nervous system, heart rate, and respiration, has
psychotropic (mood altering) properties, and acts as a mild diuretic.
A normal dose of caffeine is generally considered to be 100 mg, which is roughly the amount
found in a cup of coffee. However, more than half of all American adults consume more than
300 mg of caffeine every day, which makes it America's most popular drug. Caffeine is generally
consumed in coffee, cola, chocolate, and tea, although it is also available over-the-counter as a
stimulant.
Caffeine is believed to work by blocking adenosine receptors in the brain and other organs. This
reduces the ability of adenosine to bind to the receptors, which would slow down cellular
activity. The stimulated nerve cells release the hormone epinephrine (adrenaline), which
increases heart rate, blood pressure, and blood flow to muscles, decreases blood flow to the skin
and organs, and causes the liver to release glucose. Caffeine also increases levels of the
neurotransmitter dopamine.
Caffeine is quickly and completely removed from the brain. Its effects are short-lived and it
tends not to negatively affect concentration or higher brain functions. However, continued
exposure to caffeine leads to developing a tolerance to it. Tolerance causes the body to become
sensitized to to adenosine, so withdrawal causes blood pressure to drop, which can result in a
headache and other symptoms. Too much caffeine can result in caffeine intoxication, which is
characterized by nervousness, excitement, increased urination, insomnia, flushed face, cold
hands/feet, intestinal complaints, and sometimes hallucinations. Some people experience the
symptoms of caffeine intoxication after ingesting as little as 250 mg per day. The lethal ingested
dose, for an adult person, is estimated to be 13-19 grams. While generally considered safe for
people, caffeine can be very toxic to household pets, such as dogs, horses, or parrots. Caffeine
intake has been demonstrated to reduce the risk of type II diabetes mellitus. In addition to use as
a stimulant and flavoring agent, caffeine is included in many over-the-counter headache
remedies.


Caffeine is a bitter, white crystalline xanthine alkaloid and a stimulant drug. Caffeine is found in
varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural
pesticide that paralyzes and kills certain insects feeding on the plants, as well as enhancing the
reward memory of pollinators. It is most commonly consumed by humans in infusions extracted
from the seed of the coffee plant and the leaves of the tea bush, as well as from various foods and
drinks containing products derived from the kola nut. Other sources include yerba mat, guarana
berries, guayusa, and the yaupon holly.
In humans, caffeine acts as a central nervous system stimulant, temporarily warding off
drowsiness and restoring alertness. It is the world's most widely consumed psychoactive drug,
but unlike many other psychoactive substances, it is legal and unregulated in nearly all parts of
the world. Beverages containing caffeine, such as coffee, tea, soft drinks, and energy drinks,
enjoy great popularity. In North America, 90% of adults consume caffeine daily.
[1]

Part of the reason caffeine is classified by the Food and Drug Administration as generally
recognized as safe is that toxic doses (over 10 grams for an average adult) are much higher than
typically used doses (less than 500 milligrams). Ordinary consumption has low health risks, even
when carried on for years there may be a modest protective effect against some diseases,
including Parkinson's disease,
[2][3]
heart disease,
[4]
and certain types of cancer. Some people
experience sleep disruption if they consume caffeine, especially during the evening hours, but
others show little disturbance and the effect of caffeine on sleep is highly variable.
Evidence of a risk to pregnancy is equivocal, with some authorities concluding that it is wise for
pregnant women to limit consumption to the equivalent of two cups of coffee per day or less.
[5][6]

Caffeine has pressor and mild diuretic effects when administered to people who are not used to
it, but regular users develop a tolerance to this effect, and studies have generally failed to support
the common notion that ordinary consumption contributes significantly to dehydration. With
heavy use, tolerance develops rapidly to autonomic effects such as elevated heart rate and muscle
twitching, but not to the cognitive or arousal effects of caffeine. The degree to which caffeine
can produce significant dependency and caffeine addiction remains a subject of controversy in
the medical literature.
Contents
1 Health effects
o 1.1 Stimulant effects
o 1.2 Physical effects
o 1.3 Psychological effects
o 1.4 Caffeine toxicity
o 1.5 Addiction and tolerance
o 1.6 Withdrawal
o 1.7 Other animals
o 1.8 Microbial remediation
2 Sources and consumption
3 Chemical properties and biosynthesis
4 Pharmacology
o 4.1 Mechanism of action
o 4.2 Metabolism
5 Detection in biological fluids
6 Decaffeination
7 History
o 7.1 Discovery
o 7.2 Legality
8 Religion
9 References
10 Bibliography
11 External links
Health effects
Main article: Health effects of caffeine


Health effects of caffeine
Stimulant effects
Caffeine is a central nervous system and metabolic stimulant,
[7]
and is used both recreationally
and medically to reduce physical fatigue and to restore alertness when drowsiness occurs. It
produces increased wakefulness, faster and clearer flow of thought, increased focus, and better
general body coordination.
[8]
The amount of caffeine needed to produce effects varies from
person to person, depending on body size and degree of tolerance. Effects begin less than an hour
after consumption, and a moderate dose usually wears off in about five hours.
[8]

Caffeine has a number of effects on sleep, but does not affect all people in the same way. It
improves performance during sleep deprivation but may lead to subsequent insomnia.
[9]
In shift
workers it leads to fewer mistakes caused by tiredness.
[10]
In athletics, moderate doses of caffeine
can improve sprint,
[11]
endurance,
[12]
and team sports performance,
[13]
but the improvements are
usually not very large. Interestingly, some evidence suggests that coffee does not produce the
ergogenic effects observed in other caffeine sources.
[14]
High doses of caffeine, however, can
impair athletic performance by interfering with coordination.
[15]
Evidence shows that, contrary to
common advice, caffeine may be helpful at high altitude.
[16]

Physical effects
Consumption of 10001500 mg per day is associated with a condition known as caffeinism.
[17]

Caffeinism usually combines caffeine dependency with a wide range of unpleasant physical and
mental conditions including nervousness, irritability, restlessness, insomnia, headaches, and heart
palpitations after caffeine use.
[18]

Coffee consumption is associated with a lower overall risk of cancer.
[19]
This is primarily due to
a decrease in the risks of hepatocellular and endometrial cancer, but it may also have a modest
effect on colorectal cancer.
[20]
There does not appear to be a significant protective effect against
other types of cancers, and heavy coffee consumption may increase the risk of bladder cancer.
[20]

Moderate coffee consumption may decrease the risk of cardiovascular disease,
[4]
and it may
somewhat reduce the risk of type 2 diabetes.
[21]
Drinking four or more cups of coffee per day
does not affect the risk of hypertension compared to drinking little or no coffee. However those
who drink 13 cups per day may be at a slightly increased risk.
[22]
Caffeine increases intraocular
pressure in those with glaucoma but does not appear to affect normal individuals.
[23]
It may
protect people from liver cirrhosis.
[24]
There is no evidence that coffee stunts a child's growth.
[25]

Caffeine may increase the effectiveness of some medications including ones used to treat
headaches.
[26]
Similarly, intravenous caffeine is often used in hospitals to provide temporary pain
relief for headaches caused by low cerebrospinal fluid pressure.
Caffeine consumption during pregnancy does not appear to increase the risk of congenital
malformations, miscarriage or growth retardation even when consumed in moderate to high
amounts.
[27]
However as the data supporting this conclusion is of poor quality some suggest
limiting caffeine consumption during pregnancy.
[28][29]
For example the UK Food Standards
Agency has recommended that pregnant women should limit their caffeine intake, out of
prudence, to less than 200 mg of caffeine a day the equivalent of two cups of instant coffee, or
one and a half to two cups of fresh coffee.
[30]
The American Congress of Obstetricians and
Gynecologists (ACOG) concluded in 2010 that caffeine consumption is safe up to 200 mg per
day in pregnant women.
[6]
Although the evidence that caffeine may be harmful during pregnancy
is equivocal, there is some evidence that the hormonal changes associated with pregnancy slow
the metabolic clearance of caffeine from the system, causing a given dose to have longer-lasting
effects (as long as 15 hours in the third trimester).
[31]

Caffeine is a weak bronchodilator. In clinical tests on adults with athsma, at fairly low doses
(5mg/kg of body weight), caffeine has been shown to provide a small improvement in lung
function, such that it needs to be controlled for in diagnostic tests.
[32]
Caffeine is the primary
treatment of the breathing disorders apnea of prematurity
[33]
and may also be effective in
preventing bronchopulmonary dysplasia in premature infants.
[34]
The only short-term risk
associated with caffeine citrate treatment is a temporary reduction in weight gain during the
therapy,
[35]
and longer term studies (18 to 21 months) have shown lasting benefits of treatment of
premature infants with caffeine.
[36]
While some authors have raised the possibility of subtle long-
term problems,
[37]
follow-up neurological data at 18 months and at five years after neonatal
caffeine treatment revealed the opposite; treatment appears to be neuroprotective, as caffeine-
treated children were significantly less likely to have cerebral palsy and had reduced rates of
language and cognitive delay.
[38][39]

When doses of caffeine equivalent to 23 cups of coffee are administered to people who have not
consumed caffeine during prior days, they produce a mild increase in urinary output.
[40]
Because
of this diuretic effect, some authorities have recommended that athletes or airline passengers
avoid caffeine to reduce the risk of dehydration.
[40]
Most people who consume caffeine, however,
ingest it daily. Regular users of caffeine have been shown to develop a strong tolerance to the
diuretic effect,
[40]
and studies have generally failed to support the notion that ordinary
consumption of caffeinated beverages contributes significantly to dehydration, even in
athletes.
[41][42]

Psychological effects
The US National Institutes of Health states: "[Too] much caffeine can make you restless,
anxious, and irritable. It may also keep you from sleeping well and cause headaches, abnormal
heart rhythms, or other problems. If you stop using caffeine, you could get withdrawal
symptoms. Some people are more sensitive to the effects of caffeine than others. They should
limit their use of caffeine. So should pregnant and nursing women.
[43]
"
Four caffeine-induced disorders are recognized by the American Psychiatric Association (APA)
including: caffeine intoxication, caffeine-induced sleep disorder, caffeine-induced anxiety
disorder and caffeine-related disorder not otherwise specified (NOS).
[44]
The DSM-IV defines a
person with caffeine-induced sleep disorder as an individual who regularly ingests high doses of
caffeine sufficient to induce a significant disturbance in his or her sleep, sufficiently severe to
warrant clinical attention.
[44]
As of 2010 the effect of caffeine on people with ADHD is not
known.
[45]
Some studies have however found a modest protective effect against Alzheimer
disease, but the evidence is inconclusive.
[46][47][48]

Caffeine can have negative effects on anxiety disorders.
[49]
A number of clinical studies have
shown a positive association between caffeine and anxiogenic effects and/or panic disorder.
[50][51]

At high doses, typically greater than 300 mg, caffeine can both cause and worsen anxiety
[52]
or,
rarely, trigger mania or psychosis. In moderate doses caffeine may reduce symptoms of
depression and lower suicide risk.
[45]
In moderate doses caffeine typically does not affect
learning or memory,
[53]
and can improve cognitive functions, especially in people who are
fatigued, possibly due to its effect on alertness.
[54]
For some people, anxiety can be very much
reduced by discontinuing caffeine use.
[55]

Caffeine toxicity


Primary symptoms of caffeine intoxication
[56]

Caffeine overdose can result in a state of central nervous system over-stimulation called caffeine
intoxication (DSM-IV 305.90).
[44]
This syndrome typically occurs only after ingestion of large
amounts of caffeine, well over the amounts found in typical caffeinated beverages and caffeine
tablets (e.g., more than 400500 mg at a time). The symptoms of caffeine intoxication are
comparable to the symptoms of overdoses of other stimulants: they may include restlessness,
fidgeting, anxiety, excitement, insomnia, flushing of the face, increased urination,
gastrointestinal disturbance, muscle twitching, a rambling flow of thought and speech,
irritability, irregular or rapid heart beat, and psychomotor agitation.
[56]
In cases of much larger
overdoses, mania, depression, lapses in judgment, disorientation, disinhibition, delusions,
hallucinations, or psychosis may occur, and rhabdomyolysis (breakdown of skeletal muscle
tissue) can be provoked.
[57][58]

Extreme overdose can result in death.
[59][60]
The median lethal dose (LD
50
) given orally is 192
milligrams per kilogram in rats. The LD
50
of caffeine in humans is dependent on individual
sensitivity, but is estimated to be about 150 to 200 milligrams per kilogram of body mass or
roughly 80 to 100 cups of coffee for an average adult.
[61]
Though achieving lethal dose of
caffeine would be difficult with regular coffee, it is easier to reach high doses with caffeine pills,
and the lethal dose can be lower in individuals whose ability to metabolize caffeine is impaired.
Chronic liver disease is one factor that can slow the metabolism of caffeine.
[62]
There has been a
reported death of a man who had liver cirrhosis overdosing on caffeinated mints.
[63][64][65]
Drugs
such as fluvoxamine or levofloxacin can have a similar effect by blocking the liver enzyme
responsible for the metabolism of caffeine, thus increasing the central effects and blood
concentrations of caffeine five-fold.
[58][59][60][66]
The exact cause of death in such cases is
uncertain, but may result from cardiac arrhythmia leading to cardiac arrest.
Treatment of severe caffeine intoxication is generally supportive, providing treatment of the
immediate symptoms, but if the patient has very high serum levels of caffeine then peritoneal
dialysis, hemodialysis, or hemofiltration may be required.
[56]

Addiction and tolerance
Main article: Caffeine addiction
With repetitive use, physical dependence or addiction may occur. Also, some effects of caffeine,
particularly the autonomic effects, decrease over time, a phenomenon known as a tolerance.
Tolerance develops quickly to some (but not all) effects of caffeine, especially among heavy
coffee and energy drink consumers.
[67]
Some coffee drinkers develop tolerance to its sleep-
disrupting effects, but others apparently do not.
[31]

Withdrawal
Withdrawal symptoms including headaches, irritability, inability to concentrate, drowsiness,
insomnia, and pain in the stomach, upper body, and joints may appear within 12 to 24 hours
after discontinuation of caffeine intake, peak at roughly 48 hours, and usually last from 2 to 9
days.
[68]
Withdrawal headaches are experienced by 52% of people who stopped consuming
caffeine for two days after an average of 235 mg caffeine per day prior to that.
[69]
In prolonged
caffeine drinkers, symptoms such as increased depression and anxiety, nausea, vomiting,
physical pains and intense desire for caffeine containing beverages are also reported. Peer
knowledge, support and interaction may aid withdrawal.
Caffeine withdrawal is categorized as a mental disorder in the DSM-5 (the 5th edition of the
Diagnostic and Statistical Manual published by the American Psychiatric Association).
[70]

Previous versions of the manual included "caffeine intoxication" but not caffeine withdrawal.
Other animals


Caffeine has a significant effect on spiders, which is illustrated here in the erratic construction of their
webs.
See also: Effect of psychoactive drugs on animals
While safe in humans, caffeine is considerably more toxic to various animals, such as dogs and
birds.
[71][72]
The increased toxicity of caffeine in some animals is at least partly due to a poorer
ability to metabolize the compound.
[73]
Caffeine also has a pronounced effect on mollusks,
various insects, and spiders.
[74]

Microbial remediation
Pseudomonas putida CBB5 can live on pure caffeine and has been observed to break caffeine
down into carbon dioxide and ammonia.
[75]

Sources and consumption
See also: Caffeinated drink
Caffeine Content in Select Food and
Drugs
[76][77][78][79][80]

Product Serving size
Caffeine
per
serving
(mg)
Caffeine
(mg/L)
Caffeine
tablet
(regular-
strength)
1 tablet 100
Caffeine
tablet (extra-
strength)
1 tablet 200
Excedrin
tablet
1 tablet 65
Hershey's
Special Dark
(45% cacao
content)
1 bar (43 g or
1.5 oz)
31
Hershey's
Milk
Chocolate
(11% cacao
content)
1 bar (43 g or
1.5 oz)
10
Percolated
coffee
207 mL
(7.0 US fl oz)
80135 386652
Caffeine Content in Select Food and
Drugs
[76][77][78][79][80]

Product Serving size
Caffeine
per
serving
(mg)
Caffeine
(mg/L)
Drip coffee
207 mL
(7.0 US fl oz)
115
175
555845
Coffee,
decaffeinated
207 mL
(7.0 US fl oz)
515 2472
Coffee,
espresso
4460 mL
(1.5
2.0 US fl oz)
100
1,691
2,254
Tea black,
green, and
other
types,
steeped for 3
min.
177 millilitres
(6.0 US fl oz)
22
74
[79][80]

124416
Guayak
yerba mate
(loose leaf)
6 g (0.21 oz) 85
[81]
approx. 358
Coca-Cola
Classic
355 mL
(12.0 US fl oz)
34 96
Mountain
Dew
355 mL
(12.0 US fl oz)
54 154
Pepsi Max
355 mL
(12.0 US fl oz)
69 194
Guaran
Antarctica
350 mL
(12 US fl oz)
30 100
Jolt Cola
695 mL
(23.5 US fl oz)
280 403
Red Bull
250 mL
(8.5 US fl oz)
80 320
Global consumption of caffeine has been estimated at 120,000 tonnes per year, making it the
world's most popular psychoactive substance. This amounts to one serving of a caffeinated
beverage for every person every day.
[82]

Caffeine is found in many plant species, where it acts as a natural pesticide, with high caffeine
levels being observed in seedlings still developing foliage but lacking mechanical protection;
[83]

caffeine paralyzes and kills certain insects feeding on the plant.
[84]
High caffeine levels have also
been found in the surrounding soil of coffee bean seedlings. Therefore, caffeine is understood to
have a natural function as both a natural pesticide and an inhibitor of seed germination of other
nearby coffee seedlings, thus giving it a better chance of survival.
[85]
Caffeine has also been
found to enhance the reward memory of honeybees, improving the reproductive success of the
plant.
[86]

Common sources of caffeine are coffee, tea, soft drinks and energy drinks, caffeine supplements,
and (to a lesser extent) chocolate derived from cocoa beans.
[87]
Less commonly used sources of
caffeine include the yerba mat, guarana and ilex guayusa plants,
[88]
which are sometimes used in
the preparation of teas and energy drinks. Two of caffeine's alternative names, mateine and
guaranine, are derived from the names of these plants.
[89]

The disparity in experience and effects between the various natural caffeine sources could be
because plant sources of caffeine also contain widely varying mixtures of other xanthine
alkaloids, including the cardiac stimulants theophylline and theobromine, and other substances
such as polyphenols that can form insoluble complexes with caffeine.
[90][clarification needed]

One of the world's primary sources of caffeine is the coffee "bean" (which is the seed of the
coffee plant), from which coffee is brewed. Caffeine content in coffee varies widely depending
on the type of coffee bean and the method of preparation used;
[91]
even beans within a given bush
can show variations in concentration. In general, one serving of coffee ranges from 80 to 100
milligrams, for a single shot (30 milliliters) of arabica-variety espresso, to approximately 100
125 milligrams for a cup (120 milliliters) of drip coffee.
[92][93]
Arabica coffee typically contains
half the caffeine of the robusta variety.
[91]

In general, dark-roast coffee has very slightly less caffeine than lighter roasts because the
roasting process reduces a small amount of the bean's caffeine content.
[92][93]

Tea contains more caffeine than coffee by dry weight. A typical serving, however, contains
much less, since tea is normally brewed much weaker. Also contributing to caffeine content are
growing conditions, processing techniques, and other variables. Thus, certain types of tea may
contain somewhat more caffeine than other teas.
[94]

Tea contains small amounts of theobromine and slightly higher levels of theophylline than
coffee. Preparation and many other factors have a significant impact on tea, and color is a very
poor indicator of caffeine content. Teas like the pale Japanese green tea, gyokuro, for example,
contain far more caffeine than much darker teas like lapsang souchong, which has very little.
[94]



No-Doz 100 mg caffeine tablets
Caffeine is also a common ingredient of soft drinks, such as cola, originally prepared from kola
nuts. Soft drinks typically contain about 10 to 50 milligrams of caffeine per serving. By contrast,
energy drinks, such as Red Bull, can start at 80 milligrams of caffeine per serving. The caffeine
in these drinks either originates from the ingredients used or is an additive derived from the
product of decaffeination or from chemical synthesis. Guarana, a prime ingredient of energy
drinks, contains large amounts of caffeine with small amounts of theobromine and theophylline
in a naturally occurring slow-release excipient.
[95]

Chocolate derived from cocoa beans contains a small amount of caffeine. The weak stimulant
effect of chocolate may be due to a combination of theobromine and theophylline, as well as
caffeine.
[96]
A typical 28-gram serving of a milk chocolate bar has about as much caffeine as a
cup of decaffeinated coffee, although dark chocolate has about the same caffeine as coffee by
weight. Some dark chocolate currently in production contains as much as 160 mg per 100 g
[77]

which is double the caffeine content of the highest caffeinated drip coffee by weight.
Various manufacturers market caffeine tablets, claiming that using caffeine of pharmaceutical
quality improves mental alertness. These effects have been borne out by research that shows
caffeine use (whether in tablet form or not) results in decreased fatigue and increased
attentiveness.
[8]

These tablets are commonly used by students studying for their exams and by people who work
or drive for long hours.
[97]
One U.S. company is also marketing dissolving caffeine strips as an
alternative to energy drinks.
[98]
Another unusual intake route is SpazzStick, a caffeinated lip
balm.
[99]
As of 2013, a number of innovative caffeinated products such as Alert Energy Caffeine
Gum, a Wrigley product, had been introduced in the United States, but were under scrutiny; after
announcement of an investigation by the FDA of the health effects of added caffeine in foods,
Alert Energy Caffeine Gum was voluntarily withdrawn from sale.
[100]

As of 2011, inhaled caffeine is a distribution method under scrutiny by some U.S. lawmakers.
[101]

Chemical properties and biosynthesis


Caffeine biosynthesis
[102]



Caffeine laboratory synthesis
[103][104]

Pure anhydrous caffeine is a white colorless powder with a melting point of 227228 C.
Caffeine is moderately soluble in water at room temperature (2 g/100 mL), but very soluble in
boiling water (66 g/100 mL).
[105]
It is also moderately soluble in ethanol (1.5 g/100 mL).
[105]
It is
weakly basic (pK
a
= ~0.6) requiring strong acid to protonate it.
[106]

Caffeine does not contain any stereogenic centers
[107]
and hence is classified as an achiral
molecule.
[108]

The xanthine core of caffeine contains two fused rings, a pyrimidinedione and imidazole. The
pyrimidinedione in turn contains two amide functional groups that exist predominately in a
zwitterionic resonance form where the nitrogen atoms are double bonded to their adjacent amide
carbons atoms. Hence all six of the atoms within the pyrimidinedione ring system are sp
2

hybridized and planar. Therefore the fused 5,6 ring core of caffeine contains a total of ten pi
electrons and hence according to Hckel's rule is aromatic.
[109]

Caffeine is synthesized in plants from the purine nucleotides AMP, GMP, and IMP. These in
turn are transformed into xanthosine and then theobromine, the latter being the penultimate
precursor of caffeine.
[110]
Being readily available as a byproduct of decaffeination, caffeine is not
usually synthesized chemically.
[111]
If desired, it may be synthesized from dimethylurea and
malonic acid.
[103][104][112]

Pharmacology
Inside the body caffeine acts through several mechanisms, but its most important effect is to
counteract a substance called adenosine that naturally circulates at high levels throughout the
body, and especially in the nervous system. In the brain, adenosine plays a generally protective
role, part of which is to reduce neural activity levels for example, there is some evidence that
adenosine helps to induce torpor in animals that seasonally hibernate.
[113]

Mechanism of action


Caffeine's primary mechanism of action is as an antagonist of adenosine receptors in the brain
Adenosine acts as an inhibitory neurotransmitter that suppresses activity in the central nervous
system. "Largely as a consequence of its blockade of adenosine receptors, caffeine also has
profound effects on most of the other major neurotransmitters, including dopamine,
acetylcholine, serotonin, and, in high doses, on norepinephrine",
[114]
and to a small extent
epinephrine, glutamate, and cortisol.
[citation needed]
At high doses, exceeding 500 milligrams,
caffeine inhibits GABA neurotransmission. GABA reduction explains why caffeine increases
anxiety, insomnia, rapid heart and respiration rate.
[citation needed]

Because caffeine is both water- and lipid-soluble, it readily crosses the bloodbrain barrier that
separates the bloodstream from the interior of the brain. Once in the brain, the principal mode of
action is as a nonselective antagonist of adenosine receptors (in other words, an agent that
reduces the effects of adenosine). The caffeine molecule is structurally similar to adenosine, and
is capable of binding to adenosine receptors on the surface of cells without activating them,
thereby acting as a competitive inhibitor.
[115]

Adenosine is found in every part of the body, because it plays a role in the fundamental
adenosine triphosphate (ATP) related energy producing mechanism and is also needed for RNA
synthesis, but it has additional functions in the brain. The evidence indicates that brain adenosine
acts to protect the brain by suppressing neural activity and by increasing blood flow via receptors
located on vascular smooth muscle.
[116]
Brain adenosine levels are increased by various types of
metabolic stress, including lack of oxygen and interruption of blood flow. There is evidence that
adenosine functions as a synaptically released neurotransmitter in some parts of the brain;
however, stress-related adenosine increases appear to be produced mainly by extracellular
metabolism of ATP. Unlike most neurotransmitters, adenosine does not seem to be packaged
into vesicles that are released in a voltage-controlled manner, but the possibility of such a
mechanism has not been fully ruled out.
[116]

Several classes of adenosine receptors have been described, with different anatomical
distributions. A
1
receptors are widely distributed, and act to inhibit calcium uptake. A
2A
receptors
are heavily concentrated in the basal ganglia, an area that plays a critical role in behavior control,
but can be found in other parts of the brain as well, in lower densities. There is evidence that A
2A

receptors interact with the dopamine system, which is involved in reward and arousal. (A
2A

receptors can also be found on arterial walls and blood cell membranes.)
[117]

Beyond its general neuroprotective effects, there are reasons to believe that adenosine may be
more specifically involved in control of the sleepwake cycle. Robert McCarley and his
colleagues have argued that accumulation of adenosine may be a primary cause of the sensation
of sleepiness that follows prolonged mental activity, and that the effects may be mediated both
by inhibition of wake-promoting neurons via A
1
receptors, and activation of sleep-promoting
neurons via indirect effects on A
2A
receptors.
[117]
More recent studies have provided additional
evidence for the importance of A
2A
, but not A
1
, receptors.
[118]

Caffeine, like other xanthines, also acts as a phosphodiesterase inhibitor.
[119]
As a competitive
nonselective phosphodiesterase inhibitor,
[120]
caffeine raises intracellular cAMP, activates protein
kinase A, inhibits TNF-alpha
[121][122]
and leukotriene
[123]
synthesis, and reduces inflammation and
innate immunity.
[123]

A number of potential mechanisms have been proposed for the athletic performance-enhancing
effects of caffeine.
[124]
In the classic, or metabolic theory, caffeine may increase fat utilization
and decrease glycogen utilization. Caffeine mobilizes free fatty acids from fat and/or
intramuscular triglycerides by increasing circulating epinephrine levels. The increased
availability of free fatty acids increases fat oxidation and spares muscle glycogen, thereby
enhancing endurance performance. In the nervous system, caffeine may reduce the perception of
effort by lowering the neuron activation threshold, making it easier to recruit the muscles for
exercise.
[125]

Caffeine metabolites
Metabolites of caffeine also contribute to caffeine's effects. Paraxanthine is responsible for an
increase in the lipolysis process, which releases glycerol and fatty acids into the blood to be used
as a source of fuel by the muscles. Theobromine is a vasodilator that increases the amount of
oxygen and nutrient flow to the brain and muscles. Theophylline acts as a smooth muscle
relaxant that chiefly affects bronchioles and acts as a chronotrope and inotrope that increases
heart rate and force of contraction.
[126]

Metabolism


Caffeine is metabolized in the liver into three primary metabolites: paraxanthine (84%), theobromine
(12%), and theophylline (4%)
Caffeine from coffee or other beverages is absorbed by the small intestine within 45 minutes of
ingestion and then distributed throughout all tissues of the body.
[127]
Peak blood concentration is
reached within 12 hours.
[128]
It is eliminated by first-order kinetics.
[129]
Caffeine can also be
absorbed rectally, evidenced by the formulation of suppositories of ergotamine tartrate and
caffeine (for the relief of migraine)
[130]
and chlorobutanol and caffeine (for the treatment of
hyperemesis).
[131]

The biological half-life of caffeine the time required for the body to eliminate one-half of the
total amount of caffeine varies widely among individuals according to such factors as age, liver
function, pregnancy, some concurrent medications, and the level of enzymes in the liver needed
for caffeine metabolism. It can also be significantly altered by drugs or hormonal states. In
healthy adults, caffeine's half-life has been measured with a range of results. Some measures get
4.9 hours,
[132]
and others are at around 6 hours.
[133]
Heavy cigarette smokers show a decrease in
half-life of 3050%,
[31]
oral contraceptives can double it,
[31]
and pregnancy can raise it even
more, to as much as 15 hours during the last trimester.
[31]
In newborn infants the half-life can be
80 hours or more; however it drops very rapidly with age, possibly to less than the adult value by
the age of 6 months.
[31]
The antidepressant fluvoxamine (Luvox) reduces the clearance of
caffeine by more than 90%, and prolongs its elimination half-life more than tenfold; from 4.9
hours to 56 hours.
[132]

Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system, in
particular, by the CYP1A2 isozyme, into three dimethylxanthines,
[134]
each of which has its own
effects on the body:
Paraxanthine (84%): Increases lipolysis, leading to elevated glycerol and free fatty acid levels in
the blood plasma.
Theobromine (12%): Dilates blood vessels and increases urine volume. Theobromine is also the
principal alkaloid in the cocoa bean, and therefore chocolate.
Theophylline (4%): Relaxes smooth muscles of the bronchi, and is used to treat asthma. The
therapeutic dose of theophylline, however, is many times greater than the levels attained from
caffeine metabolism.
[citation needed]

Each of these metabolites is further metabolized and then excreted in the urine. Caffeine can
accumulate in individuals with severe liver disease, increasing its half-life.
[135]

Some quinolone antibiotics exert an inhibitory effect on CYP1A2, thereby reducing clearance of
caffeine and thus increasing blood levels.
[136]

A 2011 analysis published by PLoS Genetics reviewed five studies covering more than 47,000
subjects of European descent. Researchers determined that habitual caffeine intake is associated
with variations in two genes that regulate how quickly the body processes caffeine. Subjects who
had a high-intake mutation of either gene on both chromosomes consumed 40 mg more caffeine
per day (equivalent to a can of cola) than people who did not.
[137]

Detection in biological fluids
Caffeine can be quantified in blood, plasma, or serum to monitor therapy in neonates, confirm a
diagnosis of poisoning, or facilitate a medicolegal death investigation. Plasma caffeine levels are
usually in the range of 210 mg/L in coffee drinkers, 1236 mg/L in neonates receiving
treatment for apnea, and 40400 mg/L in victims of acute overdosage. Urinary caffeine
concentration is frequently measured in competitive sports programs, for which a level in excess
of 15 mg/L is usually considered to represent abuse.
[138]

Decaffeination
Main article: Decaffeination


Fibrous crystals of purified caffeine. Dark field light microscope image, the image covers an area of
approx. 11 by 7 mm.
Extraction of caffeine from coffee, to produce decaffeinated coffee and caffeine, is an
important
[quantify]
industrial process and can be performed using a number of solvents. Benzene,
chloroform, trichloroethylene, and dichloromethane have all been used over the years but for
reasons of safety, environmental impact, cost, and flavor, they have been superseded by the
following main methods:
Water extraction: Coffee beans are soaked in water. The water, which contains many other
compounds in addition to caffeine and contributes to the flavor of coffee, is then passed
through activated charcoal, which removes the caffeine. The water can then be put back with
the beans and evaporated dry, leaving decaffeinated coffee with its original flavor. Coffee
manufacturers recover the caffeine and resell it for use in soft drinks and over-the-counter
caffeine tablets.
[139]

Supercritical carbon dioxide extraction: Supercritical carbon dioxide is an excellent nonpolar
solvent for caffeine, and is safer than the organic solvents that are otherwise used. The
extraction process is simple: CO
2
is forced through the green coffee beans at temperatures
above 31.1 C and pressures above 73 atm. Under these conditions, CO
2
is in a "supercritical"
state: It has gaslike properties that allow it to penetrate deep into the beans but also liquid-like
properties that dissolve 9799% of the caffeine. The caffeine-laden CO
2
is then sprayed with
high pressure water to remove the caffeine. The caffeine can then be isolated by charcoal
adsorption (as above) or by distillation, recrystallization, or reverse osmosis.
[139]

Extraction by organic solvents: Certain organic solvents such as ethyl acetate present much less
health and environmental hazard than chlorinated and aromatic organic solvents used formerly.
Another method is to use triglyceride oils obtained from spent coffee grounds.
[139]

"Decaffeinated" coffees do in fact contain caffeine in many cases some commercially
available decaffeinated coffee products contain considerable levels. One study found that
decaffeinated coffee contained 10 mg of caffeine per cup, compared to approximately 85 mg of
caffeine per cup for regular coffee.
[140]

History


Coffeehouse in Palestine, circa 1900
Main articles: History of chocolate, History of coffee, History of tea, and History of yerba mate
According to Chinese legend, the Chinese emperor Shennong, reputed to have reigned in about
3000 BCE, accidentally discovered tea when he noted that when certain leaves fell into boiling
water, a fragrant and restorative drink resulted.
[141]
Shennong is also mentioned in Lu Yu's Cha
Jing, a famous early work on the subject of tea.
[142]

The earliest credible evidence of either coffee drinking or knowledge of the coffee tree appears
in the middle of the fifteenth century, in the Sufi monasteries of the Yemenin southern
Arabia.
[143]
From Mocha, coffee spread to Egypt and North Africa, and by the 16th century, it
had reached the rest of the Middle East, Persia and Turkey. From the Middle East, coffee
drinking spread to Italy, then to the rest of Europe, and coffee plants were transported by the
Dutch to the East Indies and to the Americas.
[144]

Use of the kola nut, like the coffee berry and tea leaf, appears to have ancient origins. It is
chewed in many West African cultures, individually or in a social setting, to restore vitality and
ease hunger pangs. In 1911, kola became the focus of one of the earliest documented health
scares, when the US government seized 40 barrels and 20 kegs of Coca-Cola syrup in
Chattanooga, Tennessee, alleging the caffeine in its drink was "injurious to health".
[145]
Although
the judge ruled in favor of Coca-Cola, two bills were introduced to the U.S. House of
Representatives in 1912 to amend the Pure Food and Drug Act, adding caffeine to the list of
"habit-forming" and "deleterious" substances, which must be listed on a product's
label.
[146][unreliable source?]

The earliest evidence of cocoa bean use comes from residue found in an ancient Mayan pot dated
to 600 BCE. In the New World, chocolate was consumed in a bitter and spicy drink called
xocolatl, often seasoned with vanilla, chile pepper, and achiote. Xocolatl was believed to fight
fatigue, a belief probably attributable to the theobromine and caffeine content. Chocolate was an
important luxury good throughout pre-Columbian Mesoamerica, and cocoa beans were often
used as currency.
[citation needed]

Xocolatl was introduced to Europe by the Spaniards, and became a popular beverage by 1700.
The Spaniards also introduced the cacao tree into the West Indies and the Philippines. It was
used in alchemical processes, where it was known as "black bean".
[citation needed]

The leaves and stems of the yaupon holly (Ilex vomitoria) were used by Native Americans to
brew a tea called asi or the "black drink".
[147]
Archaeologists have found evidence of this use
stretch back far into antiquity,
[148]
possibly dating to Late Archaic times.
[147]

Discovery


Pierre Joseph Pelletier
In 1819, the German chemist Friedlieb Ferdinand Runge isolated relatively pure caffeine for the
first time; he called it "Kaffebase" (i.e. a base that exists in coffee).
[149]
According to Runge, he
did this at the behest of Johann Wolfgang von Goethe.
[150][151]
In 1821, caffeine was isolated both
by the French chemist Pierre Jean Robiquet and by another pair of French chemists, Pierre-
Joseph Pelletier and Joseph Bienaim Caventou, according to Swedish chemist Jns Jacob
Berzelius in his yearly journal. Furthermore, Berzelius stated that the French chemists had made
their discoveries independently of any knowledge of Runge's or each other's work.
[152]
However,
Berzelius later acknowledged Runge's priority in the extraction of caffeine, stating:
[153]

"However, at this point, it should not remain unmentioned that Runge (in his Phytochemical
Discoveries, 1820, pages 146147) specified the same method and described caffeine under the
name Caffeebase a year earlier than Robiquet, to whom the discovery of this substance is usually
attributed, having made the first oral announcement about it at a meeting of the Pharmacy
Society in Paris."
Pelletier's article on caffeine was the first to use the term in print (in the French form Cafine
from the French word for coffee: caf).
[154]
It corroborates Berzelius's account:
Caffeine, noun (feminine). Crystallizable substance discovered in coffee in 1821 by Mr.
Robiquet. During the same period while they were searching for quinine in coffee because
coffee is considered by several doctors to be a medicine that reduces fevers and because coffee
belongs to the same family as the cinchona [quinine] tree on their part, Messrs. Pelletier and
Caventou obtained caffeine; but because their research had a different goal and because their
research had not been finished, they left priority on this subject to Mr. Robiquet. We do not
know why Mr. Robiquet has not published the analysis of coffee which he read to the Pharmacy
Society. Its publication would have allowed us to make caffeine better known and give us
accurate ideas of coffee's composition ...
Robiquet was one of the first to isolate and describe the properties of pure caffeine,
[155]
whereas
Pelletier was the first to perform an elemental analysis.
[156]

In 1827, M. Oudry isolated "thine" from tea,
[157]
but it was later proved by Mulder
[158]
and by
Carl Jobst
[159]
that theine was actually caffeine.
[151]

In 1895, German chemist Hermann Emil Fischer (18521919) first synthesized caffeine from
raw materials (i.e. a "total synthesis"), and two years later, he also derived the structural formula
of the compound.
[160]
This was part of the work for which Fischer was awarded the Nobel Prize
in 1902.
[161]

Legality
Because caffeine is a psychoactive drug, it is often regulated. In the United States the Food and
Drug Administration (FDA) restricts beverages to containing less than 0.02% caffeine.
[162]

Historically, coffee and thus caffeine was illegal for some classes in Mecca in parts of the 16th
century,
[163]
and in the Ottoman empire.
[164][165]
Charles II of England tried to ban it in
1676,
[166][167]
Frederick II of Prussia banned it in 1777,
[168][169]
and coffee was banned in Sweden
in the years 17561769, 17941796, 17991802, and 18171823. The bans on coffee have often
had religious, economic, or political reasons rather than being based on concerns for the well-
being of the population.
[citation needed]

Religion
Some Seventh-day Adventists, Church of God (Restoration) adherents, and Christian Scientists
do not consume caffeine.
[citation needed]
Some from these religions believe that one is not supposed
to consume a non-medical, psychoactive substance, or believe that one is not supposed to
consume a substance that is addictive. The Church of Jesus Christ of Latter-day Saints has said
the following with regard to caffeinated beverages: "With reference to cola drinks, the Church
has never officially taken a position on this matter, but the leaders of the Church have advised,
and we do now specifically advise, against the use of any drink containing harmful habit-forming
drugs under circumstances that would result in acquiring the habit. Any beverage that contains
ingredients harmful to the body should be avoided."
[170]

Gaudiya Vaishnavas generally also abstain from caffeine, as it is alleged to cloud the mind and
over-stimulate the senses. To be initiated under a guru, one must have had no caffeine, alcohol,
nicotine or other drugs, for at least a year.
[citation needed]

People who refrain from consuming caffeine, for religious or other reasons, may instead use a
substitute that performs a culturally similar role to coffee.
[citation needed]

Caffeinated beverages are widely consumed by Muslims today; in the 16th century, some
Muslim authorities made unsuccessful attempts to ban them as forbidden "intoxicating
beverages" under Islamic dietary laws.
[171][172]


http://www.chemspider.com/Chemical-Structure.2424.html
http://www.umich.edu/~chemh215/CHEM216/Honors%20Cup_old/HCProposal/caffeine.pdf
http://prezi.com/bvftig-smerz/caffeine-synthesis/

http://www.organic-chemistry.org/Highlights/2010/07June.shtm
http://totallysynthetic.com/blog/?p=2111