Pharmacology & Toxicology Dept

Dr. Mariam Yousif

19/12/2006
 OBJECTIVES
After studying this material you should know the:

• Classification of narcotic agonists, antagonists

and prototype agents for each class.
• Main opioid receptor subtypes and mechanism by
which the narcotic agonists produce their
pharmacological effects.
• Pharmacokinetics of opioid agonists.
• Pharmacological actions and adverse effects of
opioid analgesics on various organ systems
• Clinical uses of analgesics.
 Narcotic Analgesics?
Narcotic refers to any derivative of the opium
plant or any synthetic drug that imitates natural
narcotics.

Narcotic agonists (narcotic analgesics) include

opium derivatives and synthetic drugs with similar
properties.

They are used to relieve or decrease pain without

causing the person to lose consciousness.
 Opioid Peptides
Endogenous analgesic compounds,
endorphins, are released in response to pain
in certain parts of the CNS.

Many endorphins have been identified, they

are all peptides (opioid peptides), defined as
peptides with opiate-like pharmacological
effects.
e.g. β-endorphin, met-enkephalin, nociceptin
 Opioid Analgesics

Opioid analgesics are agonists at endorphin

receptors.
The actions of opioid analgesics stem from
their ability to mimic the actions of
endogenous mediators, the opioid peptides.
 Morphine-Like Drugs
The term opioid applies to any substance, that
produces morphine-like effects that are blocked by
antagonists like naloxone.

Opium is an extract of the juice of the poppy

Papaver somniferum, which has been used to
produce euphoria, analgesia and sleep.

Opium contains many alkaloids related to morphine.

 Analgesic Drugs
# Phenanthrene derivatives (Morphine analogues):
closely related in structure to morphine.
Can be agonists (e.g. diamorphine (heroin) and
codeine), partial agonists (e.g. nalorphine) or
antagonists (e.g. naloxone).

# Synthetic derivatives with structures unrelated to

morphine but similar pharmacological effects.
Piperidines ( e.g. pethidine, known as meperidine
in USA, fentanyl)
Methadone, pentazocine
 Opioid Receptors

All opioid drugs, whether naturally occurring

such as morphine, or chemically synthesized,
interact with specific opioid receptors to
produce their pharmacologic effects.

Three types of opioid receptors, termed µ, δ

and к, mediate the main pharmacological
effects of opiates.
 Opioid Agonists and Antagonists
# Full agonists e.g. morphine, methadone, codeine
High affinity for µ-receptors and lower affinity for
δ- and к-receptors.

# Partial agonists (mixed agonists-antagonists)

Combined degree of agonist and antagonist
activity at different receptors
e.g. pentazocine, nalorphine

# Antagonists e.g. naloxone, naltrexone.

 Pharmacokinetics

Opioid analgesics may be given orally, by injection

or intrathecally to produce analgesia

Morphine is metabolized to morphine 6-glucoronide

(M6G), which is more potent as an analgesic.
Morphine and M6G are the active metabolites of
diamorphine and codeine.

Acute overdosage with morphine produces coma

and respiratory depression.
 Mechanism of action of opioids

All opioid receptors are linked through G-

proteins to inhibition of adenylate cyclase,
thus, reducing cAMP content. All three
receptor subtypes exert this effect, and
they also exert effects on ion channels.
 Mechanism of action of opioids

Opioids promote the opening of potassium

channels (causing hyperpolarization) and
inhibit the opening of voltage-gated
calcium channels.

Narcotic analgesics inhibit pain

transmission by inhibiting the release of
substance P (a pain neurotransmitter).
 Pharmacological Actions
Morphine is typical of many opioid analgesics and
will be taken as the reference compound

Effects on the CNS

Analgesia

Euphoria and sedation

Respiratory depression: Commonest cause of death

in acute opioid poisoning.
 Pharmacological Actions
Effects on the CNS
Depression of cough reflex : Codeine suppresses
cough in sub-analgesic doses and is often used in
cough medicines.

Pupillary constriction: Pinpoint pupils are important

diagnostic feature in overdosage with morphine.

Nausea and vomiting

 Effects on GIT
Morphine reduces gastrointestinal motility causing
constipation.

The resulting delay in gastric emptying can retard

the absorption of other drugs.

Opiates should be avoided in patients suffering

from biliary colic caused by gallstones. Pressure in
the biliary tract increases because of contraction of
the gall bladder and constriction of the biliary
sphincter.
 Other Actions of Opioids
Histamine Release
Morphine releases histamine from mast cells.
Morphine should not be given to asthmatic
patients, as the bronchoconstriction effect can
have serious consequences.

Pethidine does not produce this effect.

 Tolerance and Dependence

Tolerance to the analgesic effect of

opioids develops rapidly and can often be
detected within 12-24 hrs of
administration.

As a result, larger and larger doses of the

drug are needed to achieve the same
clinical effect, leading to an increased
severity and incidence of adverse effects.
 Tolerance and Dependence

Physical dependence develops rapidly,

accompanied by physical withdrawal
syndrome.

This syndrome comprises a complex

mixture of irritable and sometimes
aggressive behavior coupled with
extremely unpleasant autonomic
symptoms.
 Tolerance and Dependence

Weak, long acting µ-receptor agonists, such

as methadone, may be used to relieve
withdrawal symptoms.

Certain opioid analgesics, such as codeine

and pentazocine, are much less likely to
cause physical or psychological
dependence.
 Adverse Effects of Opioids

The adverse effects limit the dose that can

be given and the analgesia that can be
maintained.

All are direct consequences of opioid

receptor activation. They can be inhibited
by opioid receptor antagonists such as
naloxone.
 Adverse Effects of Opioids
Respiratory depression:
The most serious side effect, the most common
cause of death from opioid overdose.

Constipation

Pupillary constriction (miosis)

Vomiting
 Other Opioid Analgesics
Drugs as nalorphine and pentazocine, produce a
mixture of agonist and antagonist effects (partial
agonists).

READING ASSIGNMENT FROM PHARMACOLOGY

TEXTBOOK, RANG ET AL 5TH ED. PAGES 581-582.

Other Opioid Analgesics

Diamorphine (Heroin), Codeine, Pethidine
(meperidine), Fentanyl, Methadone, Pentazocine
 Clinical Uses of Analgesics
# Analgesics are used to treat and prevent
pain, such as:

Pre- and postoperative pain.

Common painful conditions including headache,
dysmenorrhea, labour, trauma and burns.
Many medical and surgical emergencies (e.g.
myocardial infarction).
Terminal disease (especially metatastic cancer)
 Clinical Uses of Analgesics

The choice and route of administration of

analgesic drugs depends on the nature and
duration of the pain.

A progressive approach is often used,

starting with NSAIDs, supplemented first
by weak opioid analgesics and then by
strong opioids.
 Clinical Uses of Analgesics
In general, severe acute pain is treated with
strong opioids (e.g. morphine, fentanyl) given by
injection.

Mild inflammatory pain is treated with NSAIDs

supplemented by weak opioids (e.g. codeine).

Severe pain (e.g. cancer pain) is treated with

strong opioid given orally, intrathecally,
epidurally or by subcutaneous injection.
 Opioid Antagonists

Pure antagonists include naloxone (short acting)

and naltrexone (long acting).

Naloxone
Main clinical uses in treatment of respiratory
depression caused by opioid overdose & to
improve breathing in newborn babies affected by
opioid analgesics given to their mother during
labour.
 Opioid Antagonists
Naltrexone

Very similar to naloxone but with the

advantage of a much longer duration of
action. It may be given to addicts.
 DRUG LIST
Morphine
Diamorphine (heroin)
Codeine
Methadone
Fentanyl
Pethidine (Meperidine)
Pentazocine
Nalorphine
Naloxone
Naltrexone