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ANALGESTICS NARCOTIC
OPIOIDS
Naturally occurring opioid compounds are found in plants (e.g. morphine) and produced in the
body (endogenous opioids), where they are widely distributed throughout the central nervous
system (CNS).
CLASSIFICATION OF OPIOIDS
Traditional - based upon analgesic potency
Origin of drug - i.e. naturally occurring or manufactured
Function - their action at the opioid receptor.
In the traditional classification, the ‘strong’ group includes drugs that are pure agonists, whereas
intermediate group includes partial agonists
Traditional
Origin
Function
Strong
Naturally occurring
Pure agonists
morphine
pethidine
fentanyl
alfentanil
remifentanil
sufentanil
morphine
codeine
papavarine
thebaine
morphine
fentanyl
alfentanil
remifentanil sufentanil
intermediate
Semisynthetic
diamorphine
Partial agonist
buprenorphine
buprenorphine
pentazocine
butorphanol
nalbuphine
dihydrocodeine
buprenorphine
Agonists-antagonists
pentazocine nalbuphine
nalorphine
Weak
Synthetic
Phenylpyperidines:
codeine
pethidine, fentanyl, alfentanil,
sufentanil Diphenylpropylamines:
methadone,
Pure Antagonists naloxone
naltrexone
Pharmacological action of opioid agonist
Central nervous system
Analgesia
Most effective in relieving dull, continuous and poorly localised pain arising from deeper
structures, for example the gut. Less effective against superficial and sharp pain.
Neuropathic pain can be very resistant, but patients may report that pain is still present, but
the intensity is decreased and it no longer bothers them as much.
Sedation
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Drowsiness, feeling of heaviness and difficulty in concentrating are common.
Sleep may occur with relief of pain, although they are not true hypnotics.
Euphoria and dysphoria
Morphine and other opioids cause a sense of contentment and well being (euphoria). If
there is no pain, morphine may cause restlessness and agitation (dysphoria).
Hallucinations
These are more common with KOP agonists, but morphine and other MOP agonists may
also cause hallucinations.
Tolerance and dependence
Tolerance is the decrease in effect seen despite maintaining a given concentration of a drug.
The mechanism is not fully understood but could involve down regulation of opioid
receptors or decreased production of endogenous opioids.
Dependence exists when the sudden withdrawn of an opioid, after repeated use over a
prolonged period, results in various physical and psychological signs. These include;
restlessness, irritability, increased salivation, lacrimation and sweating, muscle cramps,
vomiting and diarrhsoea.
Cardiovascular system
Mild bradycardia
Common as a result of decreased sympathetic drive and a direct effect on the sino-atrial (SA)
node.
Peripheral vasodilatation
Caused by histamine release and reduced sympathetic drive may result in a slight fall in blood
pressure that may be significant in hypovolaemic patients.
Respiratory system
Respiratory depression
• Mediated via MOP receptors at the respiratory centres in the brainstem.
Respiratory rate falls more than the tidal volume and the sensitivity of the brain stem to carbon
dioxide is reduced. Its response to hypoxia is less affected but if hypoxic stimulus is removed by
supplemental oxygen then respiratory depression may be augmented..
Cough suppression
• Codeine suppresses coughing to a degree similar to morphine, buthas lesser analgesic activity.
Morphine and diamorphine are used in paroxysmal nocturnal dyspnoea, as they produce sedation,
reduce preload and depress abnormal respiratory drive.
Gastrointestinal System
• Stimulation of the chemoreceptor trigger zone causes nausea and vomiting.
Smooth muscle tone is increased but motility is decreased resulting in delayed absorption,
increased pressure in the biliary system (spasm of sphincter of Oddi) and constipation.
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Endocrine System
The release of ACTH, prolactin and gonadotrophic hormone isinhibited. Secretion of ADH is
increased.
Ocular effects
MOP and KOP receptors in Edinger-Westphal nucleus of occulomotor nerve are stimulated by
opioids resulting in constriction of the pupils (meiosis).
Histamine release and itching
Some opioids cause histamine release from mast cells resulting in urticaria, itching,
bronchospasm and hypotension.
• Itching occurs most often after intrathecal opioids and is more pronounced on the face, nose and
torso.
• The mechanism is centrally mediated and may be reversed by naloxone.
Muscle rigidity
Large doses of opioids may occasionally produce generalized muscle rigidity especially of
thoracic wall and interfere with ventilation.
Immunity
• The immune system is depressed after long-term opioid abuse.
Effects on pregnancy and neonates
All opioids cross the placenta and if given during labour, can cause neonatal respiratory
depression.
Chronic use by the mother may cause physical dependence in utero and lead to a withdrawal
reaction in the neonate at birth that can be life threatening.
• There are no known teratogenic effects.
Describe the mode of action of opioids
Opioids produce their actions at a cellular level by activating opioid receptors. These
receptors are distributed throughout the central nervous system (CNS) with high
concentrations in the nuclei of tractus solitarius, peri-aqueductal grey area (PAG), cerebral
cortex, thalamus and the substantia gelatinosa (SG) of the spinal cord.
They have also been found on peripheral afferent nerve terminals and many other organs.
The efficacy of centrally applied opioids is well recognized, but when applied peripherally,
for example in post-traumatic and inflammatory states,their actions are less reliable.
Opioid receptors are coupled with inhibitory G-proteins and their activation has a number
of actions including: closing of voltage sensitive calcium channels; stimulation of
potassium efflux leading to hyperpolarization and reduced cyclicadenosine
monophosphate production.
Overall, the effect is a reduction in neuronal cell excitability that in turn results in reduced
transmission of nociceptiveimpulses.
Pure opioid agonists (morphine, diamorphine, pethidine and fentanyl) bind to opioid
receptors avidly and demonstrate high intrinsic activity at the cellular level as described
above. Partial opioid agonists (buprenorphine, pentazocine) bind to opioid receptors, but
produce a sub-maximal effect compared to pure agonists and so have less intrinsic activity
associated with receptor binding.
By case study show the paharmacokinetic of some opioids drugs
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Morphine
Morphine is a naturally occurring phenanthrene derivative. It is the standard drug against which
all other opioids are compared.
Dose
Morphine can be given orally, intramuscularly (IM), intravenously (IV), subcutaneously
(SC), rectally, epidurally and intrathecally.
The intramuscular dose is 0.1-0.2mg.kg-1, time to peak effect is 30-60 minutes and
duration of action is 3-4 hours. Intravenous administration should be titrated to effect
(usually 1-2mg boluses), but the total dose is similar.
The onset of action is slightly more rapid with following IV administration, as the main
factor responsible for its latency is low lipid solubility and slowpenetration of blood brain
barrier.
Morphine may be given epidurally at 10% and intrathecally at 1% of the parenteral dose.
Pharmacokinetics
Morphine is extensively metabolized by the gut wall and the liver to morphine-3-glucuronide
(M3G) (70%), morphine-6 glucuronide (M6G) (10%) and to sulphate conjugates. M6G is 10-
20 times more potent than morphine and is normally excreted in urine.
It accumulates in renal failure and accounts for increased sensitivity to morphine.
Neonates are more sensitive than adults to morphine due to reduced hepatic conjugating
capacity.In the elderly, owing to reduced volume of distribution, peak plasma level of morphine is
higher compared to younger patient.
Effects
The main effects are mediated through MOP receptors. It is a potent analgesic with good
sedative and anxiolytic properties.
It may cause euphoria, dysphoria and hallucination. It produces respiratory depression and
cough suppression.
It has minimal effect on cardiovascular system and may produce bradycardia and
hypotension. Nausea and vomiting are common side-effects. Histamine release may lead
to rash, itching and bronchospasm (in susceptible patients). Meiosis is common.Tolerance
and dependence may develop.
Codeine
Codeine is a natural opioid and one of the principal alkaloids of opium. It has very low affinity for
opioid receptors.
Dose
Can be given orally and IM. The dose for an adult is 30-60mg by either route and can be
repeated at 6 hour intervals, if required.
Varying doses of codeine (8-30mg) are commonly incorporated with NSAIDs in
compounds employed in the treatment of mild to moderate pain.
Codeine is also used in antitussive and antidiarrhoeal preparations.
Pharmacokinetics
Oral bioavailability of codeine is 50%. About 10% is metabolized to morphine and the rest is
metabolized to inactive conjugated compounds.
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Metabolism to morphine depends on an isoform of cytochrome p450, which exhibits
polymorphism, thus poor metabolizers
Effects
It causes little euphoria and has low abuse potential. Codeine is less sedative and less likely to
cause respiratory depression than morphine. It may cause disorientation and excitement.
• Constipation is common side effect.
• Dihydrocodeine is a semi-synthetic derivative of codeine with similar pharmacologic effects.
• Oxycodone is more effective, but has higher abuse potential.
Diamorphine (heroin)
A semi-synthetic opioid, the diacetylated analogue of morphine. It is 1.5-2.0 times more
potent than morphine.
It is a pro-drug and is converted to the active components of acetylmorphine and morphine
by esterases in the liver, plasma and central nervous system.
Dose
Diamorphine can also be given by the same routes as morphine in approximately half the dose.
Due to its higher lipid solubility, it is less likely than morphine to cause delayed respiratory
depression when used epidurally or intrathecally.
It can be administered as hydrochloride salt by IM or SC infusion in a smaller volume of solution
than an equivalent dose of morphine. This is an important consideration for patients with terminal
malignant disease who may require large doses of opioid for pain relief.
Pharmacokinetics
• Diamorphine is 200 times more lipid soluble than morphine and, therefore, passes more rapidly
across the blood-brain barrier into the CNS where it is converted to morphine. Therefore, it has
more analgesic potency and a more rapid onset of action than morphine.
• Because of the extensive first pass metabolism, it has low bioavailability.
Effects
It shares common opioid effects with morphine. It is associated with an increased tendency to
cause euphoria and dependency.
• May cause less nausea and vomiting than morphine

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ANALGESTICS –NARCOTIC OPIOIDS Naturally occurring opioid compounds are found in plants (e.g. morphine) and produced in the body (endogenous opioids), where they are widely distributed throughout the central nervous system (CNS). CLASSIFICATION OF OPIOIDS Traditional - based upon analgesic potency Origin of drug - i.e. naturally occurring or manufactured Function - their action at the opioid receptor. In the traditional classification, the ‘strong’ group includes drugs that are pure agonists, whereas intermediate group includes partial agonists Traditional Strong morphine pethidine fentanyl alfentanil remifentanil sufentanil intermediate buprenorphine pentazocine butorphanol nalbuphine Weak codeine Origin Naturally occurring morphine codeine papavarine thebaine Function Pure agonists morphine fentanyl alfentanil remifentanil sufentanil Semisynthetic diamorphine dihydrocodeine buprenorphine Partial agonist buprenorphine Synthetic Phenylpyperidines: pethidine, fentanyl, alfentanil, sufentanil Diphenylpropylamines: methadone, Agonists-antagonists pentazocine nalbuphine nalorphine Pure Antagonists naloxone naltrexone Pharmacological action of opioid agonist Central nervous system Analgesia • Most effective in relieving dull, continuous and poorly localised pain arising from deeper structures, for example the gut. Less effective against superficial and sharp pain. • Neuropathic pain can be very resistant, but patients may report that pain is still present, but the intensity is decreased and it no longer bothers them as much. Sedation • Drowsiness, feeling of heaviness and difficulty in concentrating are common. • Sleep may occur with relief of pain, although they are not true hypnotics. Euphoria and dysphoria • Morphine and other opioids cause a sense of contentment and well being (euphoria). If there is no pain, morphine may cause restlessness and agitation (dysphoria). Hallucinations • These are more common with KOP agonists, but morphine and other MOP agonists may also cause hallucinations. Tolerance and dependence • Tolerance is the decrease in effect seen despite maintaining a given concentration of a drug. The mechanism is not fully understood but could involve down regulation of opioid receptors or decreased production of endogenous opioids. • Dependence exists when the sudden withdrawn of an opioid, after repeated use over a prolonged period, results in various physical and psychological signs. These include; restlessness, irritability, increased salivation, lacrimation and sweating, muscle cramps, vomiting and diarrhsoea. Cardiovascular system Mild bradycardia • Common as a result of decreased sympathetic drive and a direct effect on the sino-atrial (SA) node. Peripheral vasodilatation • Caused by histamine release and reduced sympathetic drive may result in a slight fall in blood pressure that may be significant in hypovolaemic patients. Respiratory system Respiratory depression • Mediated via MOP receptors at the respiratory centres in the brainstem. • Respiratory rate falls more than the tidal volume and the sensitivity of the brain stem to carbon dioxide is reduced. Its response to hypoxia is less affected but if hypoxic stimulus is removed by supplemental oxygen then respiratory depression may be augmented.. Cough suppression • Codeine suppresses coughing to a degree similar to morphine, buthas lesser analgesic activity. • Morphine and diamorphine are used in paroxysmal nocturnal dyspnoea, as they produce sedation, reduce preload and depress abnormal respiratory drive. Gastrointestinal System • Stimulation of the chemoreceptor trigger zone causes nausea and vomiting. • Smooth muscle tone is increased but motility is decreased resulting in delayed absorption, increased pressure in the biliary system (spasm of sphincter of Oddi) and constipation. Endocrine System • The release of ACTH, prolactin and gonadotrophic hormone isinhibited. Secretion of ADH is increased. Ocular effects • MOP and KOP receptors in Edinger-Westphal nucleus of occulomotor nerve are stimulated by opioids resulting in constriction of the pupils (meiosis). Histamine release and itching • Some opioids cause histamine release from mast cells resulting in urticaria, itching, bronchospasm and hypotension. • Itching occurs most often after intrathecal opioids and is more pronounced on the face, nose and torso. • The mechanism is centrally mediated and may be reversed by naloxone. Muscle rigidity • Large doses of opioids may occasionally produce generalized muscle rigidity especially of thoracic wall and interfere with ventilation. Immunity • The immune system is depressed after long-term opioid abuse. Effects on pregnancy and neonates • All opioids cross the placenta and if given during labour, can cause neonatal respiratory depression. • Chronic use by the mother may cause physical dependence in utero and lead to a withdrawal reaction in the neonate at birth that can be life threatening. • There are no known teratogenic effects. Describe the mode of action of opioids ● Opioids produce their actions at a cellular level by activating opioid receptors. These receptors are distributed throughout the central nervous system (CNS) with high concentrations in the nuclei of tractus solitarius, peri-aqueductal grey area (PAG), cerebral cortex, thalamus and the substantia gelatinosa (SG) of the spinal cord. ● They have also been found on peripheral afferent nerve terminals and many other organs. The efficacy of centrally applied opioids is well recognized, but when applied peripherally, for example in post-traumatic and inflammatory states,their actions are less reliable. ● Opioid receptors are coupled with inhibitory G-proteins and their activation has a number of actions including: closing of voltage sensitive calcium channels; stimulation of potassium efflux leading to hyperpolarization and reduced cyclicadenosine monophosphate production. ● Overall, the effect is a reduction in neuronal cell excitability that in turn results in reduced transmission of nociceptiveimpulses. ● Pure opioid agonists (morphine, diamorphine, pethidine and fentanyl) bind to opioid receptors avidly and demonstrate high intrinsic activity at the cellular level as described above. Partial opioid agonists (buprenorphine, pentazocine) bind to opioid receptors, but produce a sub-maximal effect compared to pure agonists and so have less intrinsic activity associated with receptor binding. By case study show the paharmacokinetic of some opioids drugs Morphine Morphine is a naturally occurring phenanthrene derivative. It is the standard drug against which all other opioids are compared. Dose ● Morphine can be given orally, intramuscularly (IM), intravenously (IV), subcutaneously (SC), rectally, epidurally and intrathecally. ● The intramuscular dose is 0.1-0.2mg.kg-1, time to peak effect is 30-60 minutes and duration of action is 3-4 hours. Intravenous administration should be titrated to effect (usually 1-2mg boluses), but the total dose is similar. ● The onset of action is slightly more rapid with following IV administration, as the main factor responsible for its latency is low lipid solubility and slowpenetration of blood brain barrier. ● Morphine may be given epidurally at 10% and intrathecally at 1% of the parenteral dose. Pharmacokinetics • Morphine is extensively metabolized by the gut wall and the liver to morphine-3-glucuronide (M3G) (70%), morphine-6 glucuronide (M6G) (10%) and to sulphate conjugates. M6G is 1020 times more potent than morphine and is normally excreted in urine. • It accumulates in renal failure and accounts for increased sensitivity to morphine. Neonates are more sensitive than adults to morphine due to reduced hepatic conjugating capacity.In the elderly, owing to reduced volume of distribution, peak plasma level of morphine is higher compared to younger patient. Effects • The main effects are mediated through MOP receptors. It is a potent analgesic with good sedative and anxiolytic properties. • It may cause euphoria, dysphoria and hallucination. It produces respiratory depression and cough suppression. • It has minimal effect on cardiovascular system and may produce bradycardia and hypotension. Nausea and vomiting are common side-effects. Histamine release may lead to rash, itching and bronchospasm (in susceptible patients). Meiosis is common.Tolerance and dependence may develop. Codeine Codeine is a natural opioid and one of the principal alkaloids of opium. It has very low affinity for opioid receptors. Dose • Can be given orally and IM. The dose for an adult is 30-60mg by either route and can be repeated at 6 hour intervals, if required. • Varying doses of codeine (8-30mg) are commonly incorporated with NSAIDs in compounds employed in the treatment of mild to moderate pain. • Codeine is also used in antitussive and antidiarrhoeal preparations. Pharmacokinetics • Oral bioavailability of codeine is 50%. About 10% is metabolized to morphine and the rest is metabolized to inactive conjugated compounds. • Metabolism to morphine depends on an isoform of cytochrome p450, which exhibits polymorphism, thus poor metabolizers Effects • It causes little euphoria and has low abuse potential. Codeine is less sedative and less likely to cause respiratory depression than morphine. It may cause disorientation and excitement. • Constipation is common side effect. • Dihydrocodeine is a semi-synthetic derivative of codeine with similar pharmacologic effects. • Oxycodone is more effective, but has higher abuse potential. Diamorphine (heroin) • A semi-synthetic opioid, the diacetylated analogue of morphine. It is 1.5-2.0 times more potent than morphine. • It is a pro-drug and is converted to the active components of acetylmorphine and morphine by esterases in the liver, plasma and central nervous system. Dose • Diamorphine can also be given by the same routes as morphine in approximately half the dose. Due to its higher lipid solubility, it is less likely than morphine to cause delayed respiratory depression when used epidurally or intrathecally. • It can be administered as hydrochloride salt by IM or SC infusion in a smaller volume of solution than an equivalent dose of morphine. This is an important consideration for patients with terminal malignant disease who may require large doses of opioid for pain relief. Pharmacokinetics • Diamorphine is 200 times more lipid soluble than morphine and, therefore, passes more rapidly across the blood-brain barrier into the CNS where it is converted to morphine. Therefore, it has more analgesic potency and a more rapid onset of action than morphine. • Because of the extensive first pass metabolism, it has low bioavailability. Effects • It shares common opioid effects with morphine. It is associated with an increased tendency to cause euphoria and dependency. • May cause less nausea and vomiting than morphine Name: Description: ...
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