Transcript 2nd Term 8th Lecture

Pharmacology-1 PHL 211
2nd Term
8th Lecture
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Narcotic analgesics (Opioid Analgesics),
Introduction
 The term narcotic was derived from the Greek word for "stupor." At one time, the term
referred to any drug that induced sleep, but then it became associated with opioids. It often
is used in a legal context to refer to a variety of substances with abuse or addictive
potential state of unconsciousness
 The term opioid refers broadly to all compounds related to opium and applies to any
substance, whether endogenous (e.g., endorphins), synthetic (e.g., Pethidine “known as
meperidine in the USA”, the first fully synthetic morphine-like drug) or semisynthetic (e.g.,
buprenorphine; a highly lipophilic opioid derived from thebaine) that produces morphinelike effects that are blocked by antagonists such as naloxone
 Opium is an extract of the juice of Papaver somniferum, which has been used for social
and medicinal purposes for thousands of years as an agent to produce euphoria,
analgesia and sleep, and to prevent diarrhoea
 Opiates are drugs derived from opium, and they include the natural products morphine,
codeine, and thebaine, and many semisynthetic derivatives such as buprenorphine.
Endogenous opioid peptides are the naturally occurring ligands for opioid receptors. The
term endorphin is used synonymously with endogenous opioid peptides
 Opioid analgesics are used for moderate to severe pain
 Opioids such as heroin and morphine exert their effects by mimicking naturally occurring
substances, called endogenous opioid peptides or endorphins
Narcotic analgesics (Opioid Analgesics),
Receptors
 Three classical types of opioid receptor, termed μ, δ and κ (all of them typical G-proteincoupled receptors), mediate the main pharmacological effects of opiates
 μ-Receptors are responsible for most of the analgesic effects of opioids, and for some major
unwanted effects (e.g. respiratory depression, euphoria, sedation and dependence)
 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
 All opioid receptors are linked through G-proteins to inhibition of adenylate cyclase. They
also facilitate opening of potassium channels (causing hyperpolarisation) and inhibit opening
of calcium channels (inhibiting transmitter release)
 Most of the clinically used opioids are relatively selective for μ-receptors, reflecting their
similarity to morphine. However, drugs that are relatively selective at standard doses will
interact with additional receptor subtypes when given at sufficiently high doses, leading to
possible changes in their pharmacological profile
Narcotic analgesics (Opioid Analgesics),
Classification & MOA
 The main pharmacological categories of opioids are:
I. Pure agonists. This group includes most of the typical morphine-like drugs such as
morphine, pethidine, methadone (long acting) and fentanyl. They all have high affinity for μ
receptors and generally lower affinity for δ and κ sites
II. Partial agonists and mixed agonist-antagonists. These drugs combine a degree of agonist
and antagonist activity on different receptors. For example, pentazocine and cyclazocine
are antagonists at μ-receptors but partial agonists on δ and κ-receptors. Most of the drugs
in this group tend to cause dysphoria rather than euphoria, probably by acting on the κreceptor
III. Antagonists. These drugs produce very little or no effect when given on their own but block
the effects of opiates. The most important examples are naloxone and naltrexone
 MECHANISM OF ACTION:
 Opioid receptors belong to the family of GiPCRs, and all three receptor subtypes inhibit
adenylyl cyclase, so reducing the intracellular cAMP content, secondarily affecting protein
phosphorylation pathways and hence cell function
 They also exert effects on ion channels through a direct G-protein coupling to the channel.
By these means, opiates promote the opening of K+ channels and inhibit the opening of
voltage-gated Ca2+ channels, which are the main effects seen at the membrane level:
These membrane effects reduce both neuronal excitability (because the increased K +
conductance causes hyperpolarisation of the membrane) and transmitter release (due to
inhibition of Ca2+ entry). The overall effect is therefore inhibitory at the cellular level
Narcotic analgesics (Opioid Analgesics), Actions
 Morphine is typical of many opiate analgesics and will be taken as the reference
compound
 The most important effects of morphine are on the CNS and the GIT, although numerous
effects of lesser significance on many other systems have been described
 Effects on the CNS:
 Analgesia. Morphine is effective in most kinds of acute and chronic pain, such as pain
associated with tissue injury, inflammation and tumour growth
 Euphoria. Morphine causes a powerful sense of contentment and well-being. This is an
important component of its analgesic effect, because the agitation and anxiety associated
with a painful illness or injury are thereby reduced
 Euphoria is mediated through μ receptors, and to be balanced by the dysphoria associated
with κ-receptor activation. Thus, different opiate drugs vary greatly in the amount of euphoria
that they produce. It does not occur with codeine or with pentazocine to any marked extent,
and nalorphine (mixed agonist-antagonist), in doses sufficient to cause analgesia, produces
dysphoria
 Respiratory depression. It occurs with a normal analgesic dose of morphine or related
compounds. It is associated with a decrease in the sensitivity of the respiratory centre to
Pco2. Analgesia and respiratory depression are both mediated by μ-receptors
 Respiratory depression is the most troublesome unwanted effect of these drugs and, unlike
that due to general CNS depressant drugs, it occurs at therapeutic doses. It is the
commonest cause of death in acute opiate poisoning
Narcotic analgesics (Opioid Analgesics), Actions
 Depression of cough reflex. Cough suppression does not correlate closely with the
analgesic and respiratory depressant actions of opiates. Codeine suppresses cough in
subanalgesic doses and is often used in cough medicines. Pholcodine is even more
selective, although these agents cause constipation as an unwanted effect
 Nausea and vomiting. They occur in up to 40% of patients to whom morphine is
given, and do not seem to be separable from the analgesic effect among a range of
opiate analgesics. The site of action is the chemoreceptor trigger zone (a region of the
medulla where chemical stimuli of many kinds may initiate vomiting). Nausea and
vomiting following morphine injection are usually transient and disappear with repeated
administration
 Pupillary constriction. It is caused by μ and κ receptor-mediated stimulation of the
oculomotor nucleus. Pinpoint pupils are an important diagnostic feature in opiate
poisoning, because most other causes of coma and respiratory depression produce
pupillary dilatation
Effects on the GIT:
Morphine increases tone and reduces motility in many parts of the GI system, resulting
in constipation. Pressure in the biliary tract increases because of contraction of the gall
bladder and constriction of the biliary sphincter. Opiates should be avoided in patients
suffering from biliary colic due to gallstones, in whom pain may be increased rather than
relieved
The receptors involved in these effects are of the μ, κ and δ type
Narcotic analgesics (Opioid Analgesics), Actions
 Other actions of opiates:
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 opiates, due to an action
on the medulla. With morphine and similar drugs, histamine release may contribute to
the hypotension
Effects on smooth muscle other than that of the GIT and bronchi are slight, although
spasms of the ureters, bladder and uterus sometimes occur
Opiates also exert complex immunosuppressant effects. The immune system is
depressed by long-term opiate abuse, leading to increased susceptibility to infections
Narcotic analgesics (Opioid Analgesics),
Uses & Side Effects
 USES:
 Analgesia. Severe, constant pain is usually relieved with opioid analgesics with high
intrinsic activity. Example: morphine
 In anesthesia. The opioids such as fentanyl are frequently used as premedicant drugs
before anesthesia and surgery because of their sedative, anxiolytic, and analgesic
properties. They are also used intraoperatively both as adjuncts to other anesthetic
agents and, in high doses, as a primary component of the anesthetic regimen
 Cough suppression. Example: codeine
 Diarrhoea: Example: diphenoxylate
 SIDE EFFECTS
Morphine and related opioids produce a wide spectrum of unwanted effects, including:
respiratory depression,
nausea, vomiting, constipation, increased pressure in the biliary tract
urinary retention
dizziness, mental clouding, dysphoria
pruritus
Increased sensitivity to pain after analgesia has worn off also may occur
Narcotic analgesics (Opioid Analgesics),
Tolerance & Dependence
 Tolerance to opiates (i.e. an increase in the dose needed to produce a given
pharmacological effect) develops within a few days. To reproduce the original response, a
larger dose must be administered. Tolerance includes analgesia, emesis, euphoria and
respiratory depression, but affects the constipating and pupil-constricting actions much
less
 Physical dependence refers to a state in which withdrawal of the drug causes adverse
physiological effects, i.e. the abstinence syndrome. These phenomena occur to some
degree whenever opiates are administered for more than a few days. Weak, long-acting μreceptor agonists such as methadone may be used to relieve withdrawal symptoms
 These phenomena must not be confused with addiction, in which physical dependence is
much more pronounced and psychological dependence (or 'craving') is the main driving
force. Addiction is rare in patients receiving opiates to control pain
 Certain opioid analgesics, such as codeine, pentazocine, buprenorphine and tramadol, are
much less likely to cause physical or psychological dependence