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Analgesic Drugs
The control of pain is one of the most important uses to which
drugs are put.
Analgesic drugs fall into four main categories:
1 Morphine-like drugs (opioids).
2 Non-steroidal anti-inflammatory drugs (aspirin and related
substances).
3 Local anesthetics.
4 Various centrally acting non-opioid drugs, e.g.:
Antidepressants (e.g. amitriptyline), which appear to have an
analgesic action in
patients who are not suffering from depression.
Drugs used for specific painful conditions, e.g. carbamazepine
(used in trigeminal 2
:Neural mechanisms of pain sensation
Under normal conditions, pain is associated with electrical
activity in small diameter primary afferent fibers of
peripheral nerves.
These nerves have sensory endings in peripheral tissues, and
are activated by stimuli of various kinds (mechanical,
thermal, chemical).
Nociception is the mechanism whereby noxious
peripheral stimuli are transmitted to the central
nervous system.

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Pain sensation can be influenced or modified
:as Elimination
1 follows of the cause of pain.
. Lowering of the sensitivity of noci-ceptors (antipyretic
2 analgesics, local
3
. anesthetics)
. Interrupting nociceptive conduction in sensory nerves
4 (local anesthetics) Suppression of transmission of
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. nociceptive impulses in the spinal medulla (opioids)
. Inhibition of pain perception (opioids, general anesthetics)
6 Altering emotional responses to pain, i.e., pain behavior
. (antidepressants as
co-analgesics).

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Morphine-like drugs (Opioid
: The
analgesic)
term opioid applies to any substance, whether endogenous
or synthetic, that produces morphine-like effects that are blocked
by antagonists such as naloxone.
Opium is an extract of the juice of the poppy papaver
somniferum.
It contains about 20 alkaloids, including morphine, codeine,
Thebaine, and
papaverine.
Thebaine and papaverine are not analgesic agents, but thebaine
is the precursor of several semisynthetic opioid agonists (e.g.
etorphine, a veterinary agent 500 - 1000 times as potent as
morphine) and antagonists (naloxone).
Papaverine is a vasodilator. 7
:Chemical Aspects
The structure of morphine was determined in 1902 and
since then many semisynthetic compounds, and fully
synthetic opiates have been studied.
The main groups of drugs are:
1Morphine analogues: these are compounds closely related
in structure to morphine, and often synthesized from it. They
may be agonists (e.g. morphine, diamorphine (heroin) and
codeine), partial agonists (e.g. nalorphine and levallorphan), or
antagonists (e.g. naloxone).
2 Synthetic derivatives with structures unrelated to
morphine:
a. Phenylpiperidine series, e.g. pethidine and fentanyl.
b. Methadone series, e.g. methadone and dextropropoxyphene.
c.Benzomorphan series, e.g. pentazocine and cyclazocine.
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:Opioid Receptors
Three major classes of opioid receptors have been identified in
various nervous system sites and in other tissues.
The major classes of receptors are (mu for morphine), delta
(), and kappa ().

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Functional effects associated with the main types of
opioid receptor

Analge
+++ - -
sia:
++ ++ +
Supraspin
++ - ++
al Spinal
Peripheral
Respiratory depression +++ ++ -
Pupil constriction ++ - +
Reduced GI motility ++ ++ +
Euphoria +++ - -
Dysphoria - - +++
Sedation ++ - ++
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:Agonists and antagonists
Opioids vary not only in their receptor specificity, but also in
their efficacy at the different types of receptor. Thus some
agents act as agonists on one type of receptor and antagonists
or partial agonists at another, producing a very complicated
pharmacological picture.
The main
categories are:
1- Pure agonists:
This group
includes most of
the typical
morphine-like
drugs.
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They all have high
2- Partial agonists and mixed agonist-antagonists:
These drugs typified by nalorphine and pentazocine combine a
degree of agonist and antagonist activity on different receptors,
e.g. nalorphine is an agonist when tested on guinea-pig ileum,
but it also inhibits competitively the effect of morphine on this
tissue.
Pentazocine and cyclazocine are antagonists at -receptors, but
partial agonists
on - and - receptors.
Most of the drugs in this group tend to cause dysphoria, rather
than euphoria.
3- Antagonists:
These drugs produce very little effect when given on their own,
but block the effects of opioids. The most important examples
are naloxone and naltrexone. 13
:Mechanism of action of opioids
Opioids promote the opening of
potassium channels and inhibit the
opening of voltage- gated calcium
channels, which are the main
effects seen at the membrane
level.
These membrane effects reduce both
neuronal excitability (since the
increased potassium conductance
causes hyperpolarisation of the
membrane) and transmitter release
(due to inhibition of calcium entry).
The overall effect is therefore
inhibitory at the cellular level.
Opioids increase activity in some 14
Therefore, Opioids
(Narcotic)
cause analgesia by:
A.Activating the
descending
pathway.
B.Inhibiting
transmission in dorsal
horn.
C.Inhibiting excitation
of
peripheral noceptives.
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:Pharmacological actions
The most important effects of morphine (typical of many opioid
analgesics) are on the central nervous system and the
gastrointestinal tract, though numerous effects of lesser
significance on many other system have been described.
A- Effects on the central nervous system:
1.Analgesia.
2.Euphoria:
.Euphoria appears to be mediated through receptors, and to be
balanced by the dysphoria associated with k-receptor
activation. Thus, different opioid drugs vary greatly in the
amount of euphoria that they produce.
3. Sedation.
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4. Respiratory depression:
Respiratory depression occurs with a normal analgesic dose
of morphine or related compounds.
Analgesia and respiratory depression are both mediated by
-receptors.
Respiratory depression by opioids is not accompanied by
depression of the medullary centers controlling cardiovascular
function (in contrast to the action of anaesthetics and other
general depressants).
5. Depression of cough reflex:
Cough suppression does not correlate closely with the analgesic
and respiratory
depressant actions of opioids, and its mechanism at the receptor
level is unclear.
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6. Nausea and vomiting:
Nausea and vomiting following morphine injection are usually
transient, and disappears with repeated administration.
7. Pupillary constriction (miosis):
Pinpoint pupils are an important diagnostic feature in over dosage
with morphine and related drugs.
8. Truncal rigidity:
An intensification of tone in the large trunk muscles has been
noted with a
number of opioids.
Truncal rigidity may be overcome by administration of an
opioid antagonist, which of course will also antagonize the
analgesic action of the opioid.
Preventing truncal rigidity while preserving analgesia 18
:B- Effects on the gastrointestinal tract
Morphine reduces motility in many parts of the gastrointestinal
system, resulting in constipation, which may be severe, and very
troublesome to the patient.
The resulting delay in gastric emptying can considerably retard
the absorption of
other drugs.
Pressure in the biliary tract increases because of contraction of
the gall bladder and constriction of the biliary sphincter. This
effect is harmful in patients suffering from biliary colic due to
gallstones, in whom pain may be increased rather than relieved.

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:C- Other actions of opioids
Morphine releases histamine from mast cells, by an action
unrelated to opioid receptors.
This release of histamine can cause local effects, such as
urticaria and itching at the site of the injection, or systemic
effects, namely bronchoconstriction and hypotension.
The bronchoconstrictor effect can have serious consequences
for asthmatic patients, to whom morphine should not be
given. Pethidine does not produce this effect.
Hypotension and bradycardia occur with large doses of most
opioids, due to an action on the medulla.
Spasm of the ureters, bladder and uterus sometimes occur.
Opioids also exert complex immunosuppressant effects. There is
evidence in humans that the immune system is depressed by20
:D- Tolerance and dependence
Tolerance to opioids (i.e. an increase in the dose needed to
produce a given pharmacological effect) develops rapidly,
and is readily demonstrated.
Dependence is a different phenomenon, which involves two
separate
components, namely physical and psychological
dependence.
Physical dependence is associated with a physiological
withdrawal syndrome (or
abstinence syndrome); it appears to be closely related to
tolerance.
Human addicts show a similar abstinence syndrome,
somewhat resembling severe influenza, with yawning,
pupillary dilatation, fever, sweating, nausea, diarrhea and 21
:Pharmacokinetic aspects
Morphine is slowly and erratically absorbed, and is
commonly given by intravenous or intramuscular
injection to treat acute severe pain.
Codeine is well absorbed, and normally given by mouth.
Most morphine-like drugs undergo considerable first-pass
metabolism, and are therefore markedly less potent when
taken orally than when injected.
The plasma half-life of most morphine analogues is 3-6 hours.
Hepatic metabolism is the main mode of inactivation, usually by
conjugation with glucuronide.
Morphine-6-glucuronide is more active as an analgesic than
morphine itself, and
contributes substantially to the pharmacological effect.
Because of low conjugating capacity in neonates, morphine- 22
:Unwanted effects
Acute over-dosage with morphine results in coma and
respiratory depression, with characteristically constricted
pupils.
It is treated by giving naloxone intravenously. There is a danger
of precipitating a severe withdrawal syndrome with naloxone,
since opioid poisoning occurs mainly in addicts

Clinical use of opioid analgesics:

1 Analgesic.
2 Acute pulmonary edema.
3 Cough.
4 Diarrhea. 23
:The opioid Antagonists
The pure opioid antagonist drugs naloxone, naltrexone, and
nalmefene.
These agents have a relatively high affinity for mu opioid binding
sites.
They have lower affinity for the other receptors but can also
reverse agonists at delta and kappa sites.
Pharmacokinetics:
Naloxone has poor efficacy when given by the oral route and a
short duration of action (1-2 hours) when given by injection.
Naltrexone is well absorbed after oral administration but may
undergo rapid-first-
pass metabolism.
It has half-life of 10 hours, and a single oral dose of 100 mg will
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:Pharmacodynamics
When given intravenously to a morphine-treated subject, the
antagonist will completely and dramatically reverse the
opioid effects within 1-3 minutes.
In individuals who are acutely depressed by an over-dose of an
opioid, the antagonist will effectively normalize respiration, level
of consciousness, pupil size, bowel activity, etc.
In dependent subjects who appear normal while taking opioids,
naloxone or
naltrexone will almost instantaneously precipitate an abstinence
syndrome.
Clinical use:
The major application of naloxone is in the treatment of acute
opioid over-dose.
Careful titration of the naloxone dosage can often eliminate the
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