Opiates Pharma. Dr. Ali
Opioid Pharmacology
1-Opium – a mixture of alkaloids from Papaver somniferum
2-An opiate is a naturally occurring alkaloid, i.e., morphine or codeine
3-An opioid is any natural or synthetic compound, which has morphine-like properties.
Opioid Classification based on intrinsic activity
- Agonists (morphine, fentanyl)
- Pure antagonists (naloxone, naltrexone)
- Mixed agonist-antagonists (pentazocin, nalbuphine, butorphanol)
Receptors: Mu (μ), Kappa (κ), Delta (δ) and Sigma (σ) opioid receptors
Mu (μ):
-found primarily in the brainstem and medial thalamus.
responsible for supraspinal analgesia, respiratory depression, euphoria, sedation,
decreased gastrointestinal motility, and physical dependence.
Subtypes include Mu1 and Mu2,
Mu1 related to analgesia, euphoria, and serenity,
Mu2 is related to respiratory depression, pruritus, prolactin release, dependence,
anorexia, and sedation.
Kappa (κ):
-found in the limbic and other diencephalic areas, brain stem, and spinal cord
responsible for spinal analgesia, miosis, sedation, dyspnea, dependence, dysphoria, and
respiratory depression.
Delta (δ):
dysphoria, and stress-induced depression.
located largely in the brain
responsible for psychomimetic and dysphoric effects.
Sigma (σ):
responsible for psychomimetic effects, They are no longer considered opioid receptors
Endogenous Opioid Peptides
1. Enkephalins Relatively selective Delta (δ) receptors.-Widely distributed in CNS; - Act
like morphine to modulate neurotransmitter release.- Found with catecholamines in
sympathetic terminals and adrenal.
2. Endorphins It binds preferentially to μ receptors; Localized primarily in pituitary and
hypothalamus.
3. Dynorphins a potent and highly selective agonist at κ receptors; - Similar distribution
to the enkephalins.
- Opioid peptides function as neurotransmitters or neuromodulators.
- Modulate pain transmission in the cord and alter acetylcholine release in the
myenteric plexus.
- Play fundamental roles in hormonal secretion, thermoregulation, and cardiovascular
control.
Opioid Agonists – Pharmacodynamics
The opioid-like peptides inhibit synaptic transmission by binding to opioid receptors on
the presynaptic membrane and the post-synaptic membrane of the synapse. On the pre-
synaptic membrane they inhibit the opening of the calcium channels and so prevent the
release of the neurotransmitter that sends the signal to the receiving neuron. On the
post-synaptic membrane, the opioid-like peptides bind to opiate receptors and make the
membrane less responsive to stimulation by neurotransmitters. Morphine and other
opioid drugs are similar in molecular structure to the opioid-like peptides so they bind to
the same opioid receptors and produce the same effect – inhibition of the pain
transmission across the synapse
General Clinical Properties:
Acute: Analgesia; Miosis; Respiratory Depression; Nausea and vomiting; Sedation;
Skeletal muscle hypertonus; Euphoria; Constipation; Vasodilatation; Urinary retention;
Bradycardia; Biliary Spasm; Cough suppression
Chronic: Tolerance; Physical Dependence
- All of the clinically-used μ opioid agonists produce these effects.
- The few qualitative differences between drugs (e.g. histamine release) usually do not
involve specific opioid receptor mechanisms.
- Opioids differ greatly in physicochemical properties as well as speed of onset and
duration of action, so clinical selection is frequently based on pharmacokinetic
considerations.
Mechanisms:
a. Analgesia and Mood
Processing of pain information is inhibited by a direct spinal effect at the dorsal horn.
Probably involves presynaptic inhibition of the release of tachykinins like substance P.
Rostrad transmission of pain signals decreased by activation of descending inhibitory
pathways in the brainstem.
Emotional response to pain altered by opioid actions on the limbic cortex.
Opioids may act at receptors located peripherally on sensory neurons. Possibly
important in painful conditions accompanied by tissue inflammation.
Clinical characteristics:
Selective relief of pain at doses which do not produce hypnosis or impair sensation.
Typically, patients report that pain is still present, but the intensity is decreased and it no
longer bothers them as much.
Mood elevation, sometimes frank euphoria can occur. Sense of well-being and cloudy
detachment thought to be an important reason for opioid abuse.
Some types of pain more responsive to opioids than others. More effect in prolonged,
burning pain than sharp pain of an incision. Neuropathic pain (e.g. pain of nerve root
compression) can be very resistant.
b. Sedation-Hypnosis
- Drowsiness, feelings of heaviness, and difficulty concentrating are common.
- Sleep may occur with relief of pain, although these drugs are not hypnotics. Most likely
to occur in elderly or debilitated patients and in those taking other CNS depressants
(EtOH, benzodiazepines).
c. CNS Toxicity
- Dysphoria and agitation occur infrequently (incidence higher with meperidine and
codeine).
- Seizures can be produced by meperidine—major metabolite, normeperidine, is a
convulsant.
- Opioids generally avoided in head injury or when elevated intracranial pressure (ICP) is
suspected.
1. ↓ ventilation can ↑ PaCO2 and raise ICP further.
2. Pupil effects may mask changing neurologic signs.
d. Respiratory Depression
Mechanism: - Direct effects on respiratory centers in the medulla. - Dose-related
depression of ventilatory response to hypercarbia and hypoxia. This shifts CO2 response
curve to the right. - May involve a distinct subset of μ2 receptors.
Clinical Characteristics:
With usual analgesic doses, arterial O2 saturation often decreases.
Drive to breathe may be abnormal despite an apparently normal respiratory rate and
state of consciousness.
Effects are dose related. First CO2 and hypoxic response are depressed, then respiratory
rate slows. Very large doses may cause irregular or periodic breathing and eventually
apnea.
Trouble most likely to occur with pre-existing pathology (such as hypothyroidism,
pulmonary or CNS disease) or previous drug administration (alcohol, general anesthetics,
benzodiazepines).
Sleep depresses the response to CO2 and potentiates the opioid effect.
Respiratory depression is the major toxicity of opioids and nearly always the cause of
death from overdose.
Equi-analgesic doses of all opioids produce equivalent amounts of respiratory
depression. There is no convincing evidence than any analgesic is more or less dangerous
than morphine in this regard.
Both analgesia and respiratory depression are reduced by administration of an opioid
antagonist or by the development of tolerance. important clinical implications:
1. Tolerant individuals who require large amounts of opioid for relief of pain are not at
proportionately increased risk for respiratory depression
2. Respiratory depression is difficult to reverse without reversing some analgesia.
d-Cough suppression:
Depression of cough centers in the medulla (and possibly, the periphery).
Different molecular mechanism than analgesia or respiratory depression— cough
suppressed by dextro-isomers of opioids (e.g. dextromethorphan), compounds which
have no analgesic activity.
e- Pupillary Constriction:
Stimulation of Edinger-Westphal (parasympathetic) nucleus of the oculomotor nerve to
produce miosis.
Pinpoint pupil is a pathognomonic sign of opioid overdose.
Antagonized by naloxone, atropine or ganglionic blockers.
f-Nausea and vomiting:
Direct stimulation of the chemoreceptor trigger zone (CTZ) in the area postrema on the
floor of the fourth ventricle. This activates the vomiting center proper
Emetic effects markedly potentiated by stimulation of the vestibular apparatus, so
ambulatory patients are much more likely to vomit than those lying quietly.
- In animals (and man?), very high doses can depress the vomiting center
g-Muscle Rigidity
- Large i.v. doses can cause generalized stiffness of skeletal muscle. Thought due to μ-
mediated increase in striatal dopamine synthesis and inhibition of striatal GABA release.
- Most common with fentanyl and congeners.
- May play a role in some overdose fatalities.
4- Cardiovascular effects:
Decrease in central sympathetic tone causes vasodilation and orthostatic
hypotension.
Effects on both capacitance and resistance vessels.
Bradycardia by stimulating central vagal nuclei
Little or no myocardial depression.
5- Histamine release:
Morphine, codeine, meperidine cause non-immunologic displacement of histamine
from tissue mast cells.
Occasionally redness, hives, itching near injection site. Rarely, hypotension,
generalized flushing.
Not an allergy—true allergic responses to opioids are very rare.
Facial itching and warmth are common after opioids—probably a dysesthesia which
has nothing to do with histamine.
6- Smooth muscle effect:
a. Intestine and Stomach
- Spasm of smooth muscle all along the GI tract. Both small and large bowel become
hypertonic, but rhythmic propulsive activity is diminished. Delay in intestinal transit time
and spasm of the anal sphincter cause constipation.
- Delayed gastric emptying. Important because it may slow absorption of oral
medications.
- Mechanism involves both CNS effects and peripheral actions on opioid receptors in the
enteric plexus. Smooth muscle effects of morphine > meperidine > agonist-antagonist
opioids.
Chronic administration of opioids frequently necessitates the administration of laxatives
and stool softeners to treat constipation. Recent evidence that poorly-absorbed
quaternary opioid antagonists are also effective in reversing this local effect.
Constipating effect is used therapeutically for treatment of diarrhea. Diphenoxylate (in
Lomotil) and loperamide (Imodium) are poorly-absorbed opioids that do not produce
central effects.
b. Biliary System
- Contraction of smooth muscle along the biliary tree and spasm of the sphincter of Oddi.
- Can precipitate biliary colic on rare occasions.
- Effect antagonized by naloxone and partially reversed by glucagon, nitroglycerin, or
atropine.
c. Urinary Tract
- Increase contractions of the ureter and tone of the urinary sphincter, but decrease
force of detrusor muscle contraction. Decreased attention to full bladder. Can cause
urinary retention.
- Probably both central and peripheral mechanisms involved.
7. Effects on Pregnancy and the Neonate
- All cross the placenta.
No teratogenic effects, but chronic use may cause physical dependence in utero.
Neonatal withdrawal after delivery can be life-threatening.
Opioids given during labor can cause respiratory depression in baby.
8. Tolerance
-Reduction in effect with repeated dosing (or higher dose to produce same effect). First
indication usually decreased duration of analgesia, then decreased intensity.
- Cross-tolerance to other opioids.
- Mechanism not known precisely. Involves adaptive response of adenylyl cyclase and/or
G protein coupling. Not a pharmacokinetic effect.
-Develops most rapidly to depressant effects like analgesia, respiratory depression,
euphoria, but much less tolerance to stimulatory effects like constipation or miosis. This
has some important clinical consequences:
1. Heroin addicts or methadone maintenance patients may have little euphoria from high
doses but continue to experience constipation and miosis.
2. Terminal cancer patients and others requiring high doses for analgesia are also tolerant
to respiratory depression (cf. p. 6), but they frequently require treatment for
constipation.
9. Physical Dependence
-Adaptation which produces stereotyped withdrawal syndrome (abstinence) when drug is
stopped. Symptoms stop when small dose of opioid is given.
- Giving antagonist (naloxone) to physically dependent person causes rapid onset of more
severe precipitated abstinence.
- Withdrawal symptoms include runny nose, vomiting, diarrhea, gooseflesh, mydriasis,
shaking chills, drug seeking behavior.
- Physical dependence not the same as psychological dependence or addiction. Mild
physical dependence may be common.
Opioids agonists:
1-Morphine and related opioids:
Morphine:
Morphine is the standard opioid to which others are compared and remains a valuable
drug for the treatment of acute, severe pain. Rapid absorption from GIT, wide
distribution, The analgesic effect is greater when the drug is administered IM or IV
compare with oral route and rapid clearance from plasma. Peak effect after IV bolus is 15
min. Duration of action is between 2 and 3 h. Both liver and kidney function are
responsible for morphine elimination. The liver mainly metabolizes it. One of the
principal metabolites morphine-6-glucuronide, it is also a potent opioid agonist and may
accumulate and induced toxicity ( opioids depression) in renal failure. Polar metabolites
cleared by kidney.
Effects: Analgesia, vomiting, respiratory depression, miosis,, orthostatic hypotension
(vasomotor medullary depression), Constipation (↓ peristalsis), ↓ pancreatic and biliary
secretion, constrict the sphincter of Oddi (↑biliary pressure), ↑ detrusor muscle tone (
→ felling of urgency), bronchospasm (↑ histamine release and vagal stimulation) and
pruritis (↑ histamine release)
Uses : Relief of severe pain ( MI, terminal illness, surgery, obstetric procediures), To
facilitate mechanical ventilation, acute left ventricular failure- by relieving anxiety and
producing vasodilatation
Contraindications: Airway obstruction and pain caused by biliary colic
Administration
IV bolus: 2.5 mg every 15 min as required, IV infusion rate: 1–5 mg/h dilute in 5%
glucose or 0.9% saline
Adverse effects: Respiratory depression and apnoea, hypotension and tachycardia,
nausea and vomiting, delayed gastric emptying, reduce intestinal mobility, biliary spasm,
constipation, urinary retention, histamine release, tolerance, pulmonary oedema.
Codeine
It can be taken from opium or synthesized by methylation of morphine. Codeine has a
low affinity for the µ and k opioid receptors, 1/20 of the analgesic activity of morphine. It
has a high oral/ parenteral potency ratio so when given orally , it is 60% as potent as
when injected IM. It is useful as an antitussive and for the treatment of diarrhoea. side-
effects. Respiratory depression is seldom a problem. This explains its traditional use to
provide analgesia for head-injured and neurosurgical patients.
Doses: 60 mg , of it 10% undergoes demethylation to morphine – this possibly
contributing to the analgesic effect.
Uses : Mild to moderate pain, Diarrhoea and excessive ileostomy output and Antitussive.
Codeine has antitussive effects, is especially useful in relieving painful cough. It also
exerts a drying action on the respiratory mucosa that may be useful (e.g., in
bronchorrhea). At doses used for cough suppression, codeine has minimal respiratory
depressant effects. Nausea, vomiting, constipation, tolerance to antitussive as well as
analgesic effects, and physical dependence can occur, but potential for abuse is low.
Contraindications: Airway obstruction
Administration: Orally 30–60 mg 4–6 hourly (the analgesic effect of 30 mg codeine
orally= 600 mg aspirin), IM 30–60 mg 4–6 hourly
Adverse effects: drowsiness, constipation, nausea and vomiting and respiratory
depression (less GIT side effects and respiratory depression than morphine). Less
addiction liability and less withdrawal than morphine
Causions: Enhanced sedative and respiratory depression from interaction with:
benzodiazepines, Antidepressants, anti-psychotics, MAOI (hypertension, hyperpyrexia,
convulsions and coma), Head injury and neurosurgical patients (may exacerbate ↑ ICP as
a result of ↑ PaCO2).
Heroin:
It is diacetylated morphine, with more rapid onset and shorter duration than morphine,
but with greater analgesic effect 3 mg heroin= 10 mg morphine, a drug of abuse and not
used clinically.
2-Meperidine and related congeners:
Meperidine:
Synthetic opiods, as analgesic it is 1/8 as potent as morphine(100 mg meperidine= 15
mg morphine).
Rapid absorption by all rotes and it is better absorbed orally, wide distribution, and rapid
clearance from plasma. Clearance mainly by hepatic biotransformation (48-56% first
pass). Metabolized by N-demethylation to normeperidine, oxidation to meperidinic acid
or normeperidinic acid. Normeperidine is a CNS stimulant and can produce convulsions in
man.Metabolite has T½ of 8-12 hr so significant amounts may accumulate. Metabolites
excreted in urine. Toxicity most likely with high doses in renal failure. Cause histsamine
release and broncospasm, cause respiratory depression and possess addiction liability,
withdrawal effects less severe than morphine. Possess weak atropine like activity cause
medriasis, has no GIT and antitussive activity. In IV injection , toxicity increased. Repeated
IM injection causes tissue irritation.
Fentanyl
Congener of meperidine, 80 times the analgesic and the respiratory suppressant effect
of morphine, when combined with droperidol , it causes dissociative anesthesia, its
principle use in anesthesia
Rapid absorption, wide distribution, moderately rapid hepatic clearance, More than 60%
first-pass metabolism to inactive metabolites. Extremely lipophilic. Rapidly crosses BBB
and other membrane barriers so effects parallel changes in plasma concentrations (rapid
onset, within 1–2 min after IV injection and a peak effect within 4–5 min, duration of
action after a single bolus is 20 min.). More effective than morphine in maintaining
hemodynamic stability. High dose caused muscle rigidity.
Dose: For sedation: IV infusion: 1–5 microgram/kg/h , During anaesthesia IV bolus: 1–3
microgram/kg with spontaneous ventilation, 5–10 microgram/kg with intermittent
positive pressure ventilation, Up to 100 microgram/kg for cardiac surgery
Adverse effects: Respiratory depression and apnoea, Bradycardia and hypotension,
Nausea and vomiting, Delayed gastric emptying, Reduce intestinal mobility, Biliary spasm,
Constipation, Urinary retention, Chest wall rigidity (may interfere with ventilation),
Muscular rigidity and hypotension more common after high dosage
Alfentanil
Synthetic opioids, with more rapid onset. It is 30 times more potent than morphine and
its duration is shorter than that of fentanyl.
The maximum effect occurs about 1 min after IV injection. Duration of action following
an IV bolus is between 5 and 10 min. Its distribution volume and lipophilicity are lower
than fentanyl. It is ideal for infusion and may be the agent of choice in renal failure. The
context sensitive half-life may be prolonged following IV infusion. In patients with hepatic
failure the elimination half-life may be markedly increased and a prolonged duration of
action may be seen. Uses: Patients receiving short-term
ventilation; Contraindications: Airway obstruction and Concomitant use of MAOI.
Administration : IV bolus: 500 mcg every 10 min as necessary, IV infusion rate: 1–5 mg/h
(up to 1 mcg/kg/min).
Don’t use alfentanil: In combination with an opioid partial agonist, e.g. buprenorphine
(antagonizes opioid effects).
Adverse effects: Respiratory depression and apnoea, Bradycardia, Nausea and vomiting,
Delayed gastric emptying, Reduce intestinal mobility, Biliary spasm, Constipation, Urinary
retention, Chest wall rigidity (may interfere with ventilation)
Diphenoxylate:
It is derivative of meperidine, it causes few morphine subjective effects, has no addiction
laiability. Mainly use for treatment of diarrhea, combined with atropine (Lomotil,
Entrostop)
3-Methadone related congeners:
Methadone:
It is synthetic diphenylheptane. It has very similar actions to morphine, but more
effective orally,it is less sedating and longer acting. Its main use is by mouth to replace
morphine heroin or diamorphine when these drugs are being with-rawn in the treatment
of drug dependence. The duration of analgesic of methadone is equal to that of
morphine although the half life is much more which can be resulted in accumulated
toxicity. Well absorbed orally , metabolized in liver and excreted in urine and bile.
Methadone given once daily under supervision is preferable to leaving addicts. The object
is to reduce craving for opioids and minimize withdrawal effects by occupying opioid
receptors. Methadone is also becoming more widely used in the treatment of chronic or
terminal pain. Adverse effect the same as morphine, both tolerance and physical
dependence
Propoxyphene:
It is structural analogue of methadone, with a spectrum of activity (especially analgesia)
similar to that of codeine.prepared as water soluble hydrochloride, it is absorbed rapidly,
metabolized to N- demethylated metabolites which slowly excreted in urine. Abuse
comparable to that of codeine, Physical dependence and tolerance occurs when used in
high doses for long period.
4- Non opioids antitussive:
Dextromethorphan:
A congener of the narcotic analgesic levorphanol, has no significant analgesic or sedative
properties, does not depress respiration in usual doses, and is nonaddictive. No evidence
of tolerance has been found during long-term use. Extremely high doses may depress
respiration.
Opioid Agonist-Antagonists
1. Developed in search for less abusable potent analgesics.
2. All have analgesic (agonist) properties as well as ability to antagonize morphine effects
3. Two basic mechanisms:
- Partial agonists at μ receptor. Buprenorphine has high affinity, but limited efficacy at μ
receptor. Given alone, it has morphine-like effects. Competes effectively with agonists
like morphine and may reduce effect.
- Agonists/Partial agonists at κ receptor. Nalorphine, pentazocine, nalbuphine,
butorphanol act as κ agonists (probably κ3) to produce analgesia. Also act as competitive
antagonists at μ receptors (high affinity but no efficacy at this receptor).
4. Clinical properties:
-Potent analgesics effective in moderate to severe pain.
-Relatively limited toxicity (respiratory dep., smooth muscle)
-Decreased abuse potential, but also decreased patient acceptance (mood elevation may
be clinically important!).
-Occasional dysphoria or hallucination with κ agonists
-Antagonist properties mean they can precipitate withdrawal in patients already
receiving chronic treatment with opioid agonists.
5. Neither agonist vs. antagonist potency nor μ/κ selectivity seem to predict clinical utility
or patient acceptance.
Opioid Antagonists
1. Naloxone
- Pure, competitive antagonist at μ, κ, and δ receptors (highest affinity at μ). Given alone,
almost no effect. Some behavioral effects in animals.
- Rapidly reverses opioid overdose, but effect short due to redistribution.
Patient may become renarcotized.
2. Naltrexone
-Used orally in high doses to treat detoxified heroin addicts (blocks euphoria
from injected heroin).
-Effects primarily from active metabolite, 6-β-naltrexol.