ANALGETIK

Oleh :
Dimas P.Nugraha
Departemen farmakologi FK UR
 Analgetik adalah zat yang pada
dosis terapeutik dapat
menghilangkan atau menekan nyeri
Mechanisms of Pain and Nociception
• Nociception is the mechanism whereby
noxious peripheral stimuli are transmitted to
the central nervous system. Pain is a
subjective experience, not always associated
with nociception.
Mechanisms of Pain and Nociception
• Polymodal nociceptors (PMN) are the main
type of peripheral sensory neuron that
responds to noxious stimuli. The majority are
non-myelinated C-fibres whose endings
respond to thermal, mechanical and chemical
stimuli.
 Pain
mechanisms
and
pathways
 Natural painkillers

 They are produced naturally in the body.

 Endorphins and enkephalins are the natural
opiates found in the part of the brain and the
spinal cord that transmit pain impulses. They
are able to bind to neuro-receptors in the
brain and produce relief from pain.
 The temporary loss of pain immediately after
an injury is associated with the production of
these chemicals.
 Pain sensation can be influenced or
modified as follows:
Elimination of the cause of pain

Lowering of the sensitivity of nociceptors (antipyretic analgesics,

local anesthetics)
Interrupting nociceptive conduction in sensory nerves (local
anesthetics)
Suppression of transmission of nociceptive impulses in the spinal
medulla (opioids)

Inhibition of pain perception (opioids, general anesthetics)

Altering emotional responses to pain, i. e., pain behavior

(antidepressants as co-analgesics)
 Klasifikasi
• Berdasarkan pada kekuatan efek, mekanisme
kerja dan efek samping, obat analgetik di
kelompokkan dalam 3 golongan :
1. Analgetik mirip Opioid / analgetik
narkotik/Hipnoanalgetik
→Efek kuat dan bekerja sentral
→Penggunaan terapi untuk nyeri kuat, sampai yang
paling kuat, nyeri tumor.
→Contoh semua opiat dan derivat semisintetiknya
2. Analgetik Non opioid
→Berefek lemah hingga sedang dan bekerja
perifer
→Mempunyai efek antiinflamasi, antipiretik dan
sebagian antirematik
→Senyawa asam : derivat as.salisilat (as.asetil
salisilat), derivat as.arilasetat (diklofenak,
indometasin), derivat asam arilpropionat
(ibuprofen)→NSAID’s
→Senyawa bukan asam : anilda (parasetamol),
pirazolon yang tidak asam (metamizol)
3. Analgetik nonopioid tanpa efek antipiretik
→Flupirtin
→Nefopam
 OPIOIDS (MORPHINE-LIKE) ANALGESICS
AND ANTAGONISTS

Opioids –
natural or synthetic; produce morphine-like effects.
They act by binding to specific opioid receptors in the CNS »»»
effects mimic the action of endogenous peptide neurotransmitters
(e.g., leu- and met-enkephalins).
They relieve severe pain - essential in treatment of major diseases,
trauma, and surgery.
Danger of the drug abuse.
Although the opioids have a broad range of effects, their primary use
is to relieve intense pain and the anxiety that accompanies it.
Antagonists – they can reverse actions of opioids, important
clinically – treatment of overdose.
 History of Opioids
• Opium is extracted from poppy seeds (Paper
somniforum)
• Used for thousands of years to produce:
– Euphoria
– Analgesia
– Sedation
– Relief from diarrhea
– Cough suppression
 Opioid Receptors
μ-receptors are thought to be responsible for most of the analgesic
effects of opioids, and for some major unwanted effects (e.g.
respiratory depression, euphoria, sedation and dependence). Most of
the analgesic opioids are μ-receptor agonists.

δ-receptors are probably more important in the periphery, but may

also contribute to analgesia.

κ-receptors contribute to analgesia at the spinal level, and may elicit

sedation and dysphoria, but produce relatively few unwanted effects,
and do not contribute to dependence. Some analgesics are relatively κ-
selective.
 Mu and Kappa Receptor Activation

Response Mu-1 Mu-2 Kappa

Analgesia

Respiratory
Depression
Euphoria

Dysphoria

Decrease GI
motility
Physical
Dependence
 Division (in relation to the activity)

1. Strong agonists (e.g. morphine, meperidine=pethidine,

methadone, fentanyl, sufentanil, alfentanil, remifentanil)
2. Moderate agonists (e.g. propoxyphene, codein, oxycodone)
3. Mixed agonist-antagonists (e.g. pentazocine, buprenorphine,
nalbuphine, butorphanol)
4. Other analgesics ( tramadol)
5. Antagonists (naloxone, naltrexone)
OPIOID ANALGESICS AND ANTAGONISTS

STRONG AGONISTS
Alfentanil
Fentanyl
Heroin
Meperidine
Methadone
Morphine
Remifentanil
Sufentanil
MODERATE/LOW AGONISTS
Codeine
Oxycodone
Propoxyphene
MIXED AGONIST-ANTAGONISTS AND PARTIAL AGONISTS
Buprenorphine
Butorphanol
Nalbuphine
Pentazocine
ANTAGONISTS
Naloxone
Naltrexone
OTHER ANALGESICS (according to
Lippincott´s
Tramadol Pharmacology, 2006
 Morphine
CNS effects
– Respiratory depression and suppression of
cough: reducing the responsiveness of the
respiratory centers in the brain stem to blood
levels of carbon dioxide and inhibiting directly
the respiratory center.
 Morphine
CNS effects
– Nausea and vomiting: stimulating the
chemoreceptor trigger zone. In most cases,
after therapeutic dose, subsequent doses of
morphine do not produce vomiting.
– Miosis: pinpoint pupils are indicative of toxic
dosage prior to asphyxia. It can be block with
atropine.
 Morphine
Cardiovascular effects:
– Orthostatic hypotention can occur due to
vasomotor medullary depression and
histamine release.
Gastrointestinal effect:
– Reduces gastrointestinal motility, causing
constipation
– Decreases biliary and pancreatic secretions.
– Constriction at the spincter of Oddi causes an
increase in biliary pressure.
 Morphine
Other systemic effects:
– Increases detrusor muscle tone in the urinary
bladder, producing a feeling of urinary. Vesical
sphincter tone is also increased, making
voiding
– Inhibits the cellular immunity and humoral
immunity, which is significant in withdrawal
syndrome and tolerant in chronic
administration.
Farmakokinetik Opioid
 Therapeutic uses
Analgesia, such as the relief of pain from myocardial infaction, terminal
illness, surgery, biliary colic and renal colic (combined with atropine)

Dyspnea due to pulmonary edema because of sedative, vascular

dilataltion and inhibition of the respiratory centers responsiveness to
CO2

Treating severe diarrhea because of constipating effects

Treating cough (usually insteaded by codeine)

 Adverse effects
Respiratory depression is the most important effect.

Nausea and sometimes dysphoria can occur.

Increase biliary tract pressure.

Allergic reactions.

Bronchoconstrictive action.

Tolerance and Dependence

Contraindications and cautions

Use in patients with head injures

Use during pregnancy

Use in patients with impaired

pulmonary function

Use in patients with impaired hepatic or

renal function
 Interaksi Obat
• Obat yang bekerja secara sentral seperti
barbiturat, fenotiazin, penghambat MAO,
antidepresan trisiklik→↑efek sedatif dan
depresi pernafasan
• Fenotiazin→↑efek menurunkan tek.darah
• Amphetamine→↑analgesia dari morphin dan
mengurangi efek sedasi dan depresi
pernafasan
 Keracunan Akut Morfin
• Gejala : coma, miosis, ↓eksterm dari pernafasan
(hingga 2-4 tarikan nafas permenit), sianosis,
suhu tubuh rendah, kehilangan tonus otot
rangka.
• Tindakan :
→Pembebasan jalan nafas dan pemberian O2
→memberikan suatu antagonis morfin untuk
menghilangkan kelumpuhan pernafasan
(naloxone sbg antagonis kompetitif)
→Shock ditangani, mungkin perlu pemberian Ab
untuk pencegahan pneumonia
 Codeine
Although the pharmacologic effects of
codeine are similar to those of
morphine, it has about one-twelfth the
analgesic potency of morphine.

Be used mainly for cough suppressant

and milder pain.

It produces less sedation, respiratory

depression, fewer gastrointestinal
effects, and less addiction and
withdrawal.
 Pethidine

It is very similar to morphine (one-seventh to one-tenth potent) in

pharmacologic effects by μ-receptor agonists.

Therapeutic uses: analgesic, cardiac asthma, sedation (decrease the

dosage of anesthetic )and artificial hibernation.

It has no gastrointestinal or antitussive action because of shorter-acting.

Adverse effect: also causes respiratory depression and possesses

addiction liability, although withdrawal effects are less severe than with
morphine.
Non-steroidal anti-inflammatory drugs
(NSAIDs)
• An analgesic effect: decreased prostaglandin
generation means less sensitisation of
nociceptive nerve endings to inflammatory
mediators such as bradykinin and 5-
hydroxytryptamine.
• Relief of headache is probably due to
decreased prostaglandin-mediated
vasodilatation.
Categories of NSAIDs

There are two major categories

for non-steroidal anti-
inflammatory drugs

The first is non-selective anti-

inflammatory drugs.

The second is selective anti-

inflammatory drugs, COX-2
inhibitors.
 Effects of COX Inhibition
by Most NSAIDS
COX-1 COX-2

Gastric ulcers Reduce inflammation

Bleeding Reduce pain

Acute renal failure Reduce fever

NSAIDs : anti-platelet—decreases ability of blood to clot

COX Expression Function Inhibitors

organ pain, platelet

constitutively function, stomach NSAIDs including
COX-1
throughout the body aspirin
protection
Inducible: inflammation, NSAIDs, COX 2
Inducible and pain, fever inhibitors including
COX-2 constitutively in brain, Constitutive: synaptic celecoxib
kidney
plasticity (Celobrex )

Constitutively, high in pain pathways, not acetaminophen

COX-3
brain, heart inflammation pathways some NSAIDs
 The Salicylates: Aspirin
• Aspirin (acetylsalicylic acid) was first isolated in 1829
by Leroux from willow bark.

• It can cause irreversible inactivation of cyclo-

oxygenase, acting on both COX-1 and COX-2.
 Salicylates
Aspirin is rapidly and almost completely absorbed
from the stomach and small intestine.

It reaches its peak effects in 30 minutes when

taken on an empty stomach.
Buffered tablets reach their peak effect in 20
minutes.
Most aspirin is coated because it is irritating to the
stomach.

Aspirin can be administered rectally.

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 Salicylates
• Pharmacologic Effects
– Analgesic
• It is used to treat mild to moderate pain, including
dental pain.
– Antipyretic
• Aspirin reduces fever because of its ability to inhibit
prostaglandin synthesis in the hypothalamus.
• Aspirin reduces fever by inducing peripheral
vasodilation and sweating.

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 Salicylates
• Pharmacologic Effects
– Antiinflammatory
• This effect is also from aspirin’s ability to block
prostaglandin synthesis.
• Aspirin reduces redness and swelling at the inflamed
area.
– Antiplatelet
• Aspirin irreversibly binds to platelets.
• Aspirin inhibits both prostacyclin and thromboxane A2
depending on the dose used. This helps prevent blood
from clotting.

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 Salicylates
• Uses
– Mild to moderate pain
– Fever
– Inflammation
– Prevention of stroke or heart attack
– Antiplatelet effects

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 Salicylates
• Adverse Reactions
– Aspirin’s adverse reactions are many. These
reactions have limited aspirin’s everyday use.
– The many adverse reactions of aspirin include:
• Gastrointestinal – They are a direct result of
direct gastric irritation and blockage of
prostaglandins.
• Bleeding – Bleeding time is prolonged because
of aspirin’s effects on platelets and
prostaglandins.

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 Salicylates
• Adverse Reactions
– Reye syndrome
– Hepatotoxicity
– Renal toxicity
– Hypersensitivity
• Patients with asthma are at a higher risk for
hypersensitivity or allergic reactions.

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Salicylates

9
Propionic acid derivatives

Ibuprofen, naproxen, ketoprofen, oxaprozin

These drugs possess anti-inflammatory, analgesic,

and antipyretic activity; additionally, they can can
alter platelet function and prolong bleeding time

Reversible inhibitors of the cyclooxygenases and,

thus, like aspirin, inhibit the synthesis of
prostaglandins but not of leukotrienes.
 Acetic acid derivatives

Indomethacin, sulindac, etodolac

All have anti-inflammatory, analgesic, and antipyretic

activity. They act by reversibly inhibiting cyclooxygenase.

Uses: acute gouty arthritis, ankylosing spondylitis, and

osteoarthritis
 Oxicam derivatives
Piroxicam, meloxicam.

Use: RA, ankylosing spondylitis, and osteoarthritis

Have long half-lives, which permit once-daily administration

Meloxicam inhibits both COX-1 and COX-2, with preferential binding for COX-
2, and at low to moderate doses shows less GI irritation than piroxicam
 Fenamates
Mefenamic acid and meclofenamate

have no advantages over other NSAIDs as anti-

inflammatory agents

side effects, such as diarrhea, can be severe, and

they are associated with inflammation of the bowel

Cases of hemolytic anemia have been reported.

 Heteroaryl acetic acids
• Diclofenac , tolmetin, ketolarac.
• Approved for long-term use in the treatment of
RA, osteoarthritis, and ankylosing spondylitis
• Diclofenac is more potent than indomethacin or
naproxen
• Ketorolac is a potent analgesic but has moderate
anti-inflammatory effects. available for oral
administration, for intramuscular use in the
treatment of postoperative pain, and for topical
use for allergic conjunctivitis.
• Ketorolac can cause fatal peptic ulcers as well
as GI bleeding and/or perforation of the
stomach or intestines.
• Ketolarac to be avoided in pediatric patients;
patients with mild pain, and those with
chronic conditions, the dose should not
exceed 40 mg/day
 Celecoxib
• Celecoxib is significantly more selective for
inhibition of COX-2 than of COX-1
• Celecoxib should be avoided in patients with
chronic renal insufficiency, severe heart
disease, volume depletion, and/or hepatic
failure.
• Celecoxib is contraindicated in patients who
are allergic to sulfonamides
NSAIDs

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NSAIDs

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Summary of Nonsteroidal anti-
inflammatory agents (NSAIDs)
 Acetaminophen
(N-Acetyl-P-Aminophenol)
Acetaminophen is not related to salicylates or NSAIDs.

It is rapidly and completely absorbed from the gastrointestinal tract.

It achieves peak levels in 1-3 hours.

Acetaminophen is metabolized by the liver.

If large doses are ingested, an intermediate metabolite, N-acetyl-p-

benzoquinonamine is formed. This metabolite is toxic.

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 Penggunaan
Acetaminophen has both analgesic and
antipyretic effects.

It is useful for children because it is not

known to cause Reye syndrome.

It does not have any real gastrointestinal

effects.
useful in patients with aspirin or NSAID
hypersensitivity
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 Comparison of
antipyretic
analgesics with a
nonsteroidal anti-
inflammatory drug
• Adverse Effects
– Hepatotoxicity
• Can occur after the ingestion of a single toxic dose (20-25
gm) or after long term use of therapeutic doses.
• Children are at high risk for hepatotoxicity because they are
often given doses that are not age- and weight-appropriate.
• Signs and symptoms include nausea, vomiting, abdominal
pain, anorexia.
– Nephrotoxicity
• It has been associated with long-term use.T
→Treatment for overdose: Acetylcysteine

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 Disease-Modifying Antirheumatic
Agents
• Disease-modifying antirheumatic drugs (DMARDs) are
used in the treatment of RA and have been shown to
slow the course of the disease, induce remission, and
prevent further destruction of the joints and involved
tissues
• When a patient is diagnosed with RA, the American
College of Rheumatology recommends initiation of
therapy with DMARDs within 3 months of diagnosis (in
addition to NSAIDs, low-dose corticosteroids, physical
therapy, and occupational therapy)
• Therapy with DMARDs is initiated rapidly to help stop
the progression of the disease at the earlier stages
Most experts begin DMARD therapy with one of the traditional drugs, such
as methotrexate or hydroxychloroquine.

These agents are efficacious and are generally well tolerated, with well-
known side-effect profiles.

Inadequate response to the traditional agents may be followed by use of

newer DMARDs, such as leflunomide, anakinra, and TNF-inhibitors
(adalimumab, etanercept, and infliximab).

Combination therapies are both safe and efficacious

ALHAMDULILLAH….