Transcript OPIATE ANALGESICS AND ANTAGONISTS

Pain ,opiate analgesics and
antagonists
Dr. Israa
Mechanism of pain and nociception
• Polymodal nociceptors are the main type of
peripheral sensory neuron that responds to
noxious stimuli; the majority are nonmyelinated C fibers whose endings respond to
thermal, mechanical and chemical stimuli.
• Chemical stimuli causing pain includes
bradykinin, protons, ATP and vanilloids (e.g.
Capsaicin)
• Stimuli to these receptors (agonist) open cation
channel s and causing membrane depolarization
and AP initiation .
• Theses receptors are sensitized by prostaglandins
which explain the analgesic effect of NSAIDs.
• Nociceptive fibers terminate in the superficial
fibers of the dorsal horn, forming synaptic
connection with transmission neurons running to
the thalamus
• Transmission in the dorsal horn is subjective to
various modulatory influence, constituting the
“gate control mechanism”
• Descending pathways from the midbrain and
brain stem exert strong inhibitory effect on
dorsal horn transmission.
• The descending inhibition is mediated mainly
by enkephalin, 5-HT from NRM(neuclus raphi
magnus) and noradrenaline which is released
from the locus coeruleus .
• Opioids analgesics causes analgesia partly by
inhibiting transmission in the dorsal horn,
partly by activating the descending pathways,
partly by inhibiting excitation of the sensory
nerve terminals in the periphery
• C-fiber activity facilitates transmission through
the dorsal horn
through substance P
receptors and NMDA receptors.
OPIOID ANALGESICS
(NARCOTIC ANALGESICS)
• Analgesia: Relief of pain without loss of
consciousness.
• Opium: Natural extract from Poppy plant used for
social and medicinal purpose for thousands of
years to produce euphoria, analgesia, sleep and to
prevent diarrhea
• Opioid drugs: natural + synthetic morphine-like
drugs.
Opioids analgesics and antagonists
Strong agonists includes:
– Alfentanil
– Fentanyl
– Heroin
– Mepridine
– Methadone
– Morphine
– Oxycodone
– Remifentanil
– Sufentanil.
Moderate agonists
includes:
– Codeine
– Propoxyphene.
Mixed Agonists and
Antagonists
• Pentazocine
• Nalbuphine
• Butorphanol
• Buprenorphine
Opioid Antagonists
• Naloxone
• Naltrexone
• Nalmephine
Opioid receptors
• The opioid agonists act at specific receptor sites to
produce their pharmacological effects.
• Opioid Receptors are:
– μ (μ1, μ 2)
– қ (қ1, қ2, қ3)
– δ (δ1, δ2)
• They are for endogenous opioid-like substances:(which
also stimulate opioid receptors)
– [Met]enkephalin: Tyr-Gly-Gly-Phe-Met
– [Leu]enkephalin: Tyr-Gly-Gly-Phe-Leu
– Beta Endorphin: a 31 amino acid peptide with
[Met]enkephalin at N-terminal sequence
– Dynorphin: a 17 amino acid peptide with
[Leu]enkephalin at N-terminal sequence
Endogenous Opioid Peptides
(Opiopeptins)
Families
Precursors
Peptides
Proenkephalins
(also known as
proenkephalin A)
Met-enkephalin
Leu-enkephalin
Endorphins
Pro-opiomelonocortin
(POMC)
MSH*
ACTH*
β-Lipoprotein*
β-Endorphin
Dynorphins
Prodynorphin
(also known as
proenkephalin B)
Dynorphin A Dynorphin B
α-Neoendorphin
Β-Neoendorphin
Enkephalins
* Non-opioid peptides
Opioid Receptors and their Prototypic
Ligands
Receptor type
Representative Ligands
Endogenous
Exogenous
Mu (μ)
(μ1, μ2)
Β-endorphin
Morphine
Delta (δ)
(δ1, δ2)
Met-enkephalin
Etorphine
Kappa (κ)
(κ1, κ2, κ3)
Dynorphin A
Ethyl-keto-cycla-zocine
Action and selectivity of some opioids (and opioid antagonists) at various opioid receptors
Drug
Receptor type
Mu - μ
Kappa - κ
+++
+
Delta - δ
Agonists
Morphine
Codeine
+
Methadone
+++
Meperidine
+++
Fentanyl
+++
Sufentanyl
+++
+
Buprenorphine
PA
Antagonist (−)
Pentazocine
PA
++
+
+
Partial and Mixed Agonists
Antagonists
Nalaxone and Naltrexone
Antagonist (−−−)
Antagonist (−−)
Antagonist (−)
Endogenous Peptides
Met-enkephalin
++
+++
Beta-endorphin
+++
+++
Dynorphin A
+
+++
+
• Three genes have been identified which code
for opioid peptides
• Beta endorphin and ACTH
• Enkephalins
• Dynorphins
• These neuropeptides are released by stress
and appear to modulate the release of other
neurotransmitters.
Mechanism of Action of opioids
• Morphine binds opioid receptors and thus
impairs the normal sensory pathways through:
– Blockade of calcium channels which leads to
decreased release of substance P and
glutamate from the 1st neuron of the sensory
pathway (in substantia gelatinosa in spinal
cord).
– Decreased c-AMP which leads to opening of
K-channels and hyperpolarization of the 2nd
neuron of the sensory pathway.
Mechanism of Action of Opioids
A. Effects due to μB. Effects due to қreceptor stimulation:
receptor stimulation:
• Supraspinal, spinal &
• Spinal and peripheral
peripheral analgesia
analgesia,
• Euphoria
• Dysphoria
• Respiratory depression
• Sedation
• Miosis
• Respiratory
depression (less)
• Decreased GIT
motility,
• Miosis (less)
• Sedation
• Decrease GIT motility
• Physical dependence.
• Physical dependence
C. Effects due to δ-receptor stimulation:
• Spinal analgesia
• Respiratory depression
• Decrease GIT motility .
• They are not true opioid receptors only
some opioids react with them .
I. Morphine
• Effective orally, but is much less effective than
when given parenterally due to first-pass
metabolism in the liver.
• Metabolism involves glucuronide formation, the
product of which is excreted in the urine.
A. Effects of morphine
1. Central Nervous System Effects
• Morphine has mixed depressant and stimulatory
actions on the CNS.
- Depressant effects predominate in man.
- Excitatory effects predominate in cats and
horses.
a) Analgesia:
– Drowsiness is common
– Continuous dull pain relieved more
effectively than sharp intermittent pain
– Most patients indicate that they can still feel
the pain, but that it no longer bothers them
– Morphine is an agonist at μ and қ opioid
receptors.
b) Euphoria and sedation
– It is mainly due to activation of μ-receptor
c) Emesis
– Morphine directly stimulates the
chemoreceptor trigger zone, usually transient
and disappear with repeated administration .
d) Antianxiety
e) Miosis (pinpoint pupil).
– It is due to stimulation of the EdengerWestphal nucleus of the oculomotor nerve .
f) Cough reflex is inhibited:
– This action ,surprisingly, does not correlate
closely with analgesic and respiratory
depressant effect of opiates, and its
mechanism of action at receptor level is
unclear
– Chemical modification (Codiene and
Pholcodiene ) the antitussive effect can occur
at sub- analgesic dose.
g) Respiration depression:
– Due to a direct effect on the brain stem
respiratory center.
– Death from narcotic overdose is nearly
always due to respiratory arrest.
– It occur at therapeutic doses but not
accompanied
with
cardiac
center
depression in contrast to other CNS
depressant like general anesthetic agents.
h) Other effects:
– Morphine is a basic drug causes the release
of histamine causes the body to feel warm
and
the
face,
nose
to
itch
,bronchoconstriction and hypotension .
– It also abolishes hunger
– It dilate the cerebral vessels and increase
intracranial pressure
2. Cardiovascular Effects
• Postural orthostatic hypotension due primarily
to decreased V.M.C. activity leading to
peripheral vasodilation, which may be also
due in part to histamine release.
• In congestive heart failure, morphine
decreases the left ventricular workload and
myocardial oxygen demand.
3. Endocrine Effects
• Increases prolactin secretion
• Increases vasopressin (ADH) secretion (oliguria).
• Decreases pituitary gonadotropin (LH & FSH)
secretion.
• Decreases stress induced ACTH secretion.
4. Gastrointestinal Effects
• It decrease the motility and increase the tone
of the intestinal circular muscle and the tone
of the anal sphincter , it also causes
contraction of the gallbladder and constriction
of the biliary sphincter
• Constipation (tolerance does not develop to
this effect).
• Diphenoxylate and Loperamide can be used in
the treatment of diarrhea.
• They decrease GIT motility and peristalsis
5. Genitourinary Effects
• Morphine prolong the second stage of labor
by decreasing the strength, duration and
frequency of uterine contraction
• Inhibit urinary bladder voiding reflex
(sometimes catheterization may be required
in some cases )
B. Adverse Reactions
• Generally direct extensions of their pharmacological
actions.
– Respiratory depression, apnea
– Nausea and vomiting
– Dizziness, orthostatic hypotension, edema
– Mental clouding, drowsiness
– Constipation, ileus
– Biliary spasm (colic)
– Dry mouth
– Urine retention, urinary hesitancy
– Hypersensitivity reactions (contact dermatitis,
urticaria)
– Immunosuppression (recurrent infections)
C. Precautions
– Respiratory depression, particularly in the newborn
and patients with COPD
– Orthostatic hypotension
– Histamine release (asthma)
– Drug interactions (with other CNS depressants)
– Tolerance and cross tolerance to other opioids
– Benign prostatic hyperplasia(may precipitate urine
retention
– Dependence (psychological & physical)
– Liver disease(accumulation of the drug)
– Increase intracranial pressure and head injury (it
enhances cerebral ischemia)
D. Therapeutic uses:
- Analgesia: myocardial infarction, terminal
cancer, surgery, obstetrical procedures
- Dyspnea due to pulmonary edema
- Severe diarrhea.
II. Other Opioid (Narcotic) Analgesics
A. Heroin (diacetyl morphine)
– μ- agonist
– Heroin is more lipid soluble than morphine
and about 2½ times more potent
– It enters the CNS more readily
– It is a schedule I drug and is not used
clinically, but it is a drug of abuse.
B. Codeine
– From opium or synthesized by methylation of
morphine
– Has a much better oral /parenteral absorption ratio
than morphine.
– Effective for mild to moderate pain, cough, diarrhea.
– Metabolized in part to morphine by O-demethylation.
– μ- receptor agonist.
– Has a more potent histamine-releasing action than
morphine.
– Dependence liability of codeine is less than that of
morphine, .
– It is 1/12 as potent as morphine
C. Dextromethorphan:
– Excellent oral antitussive
– No analgesic effect
– No GI effects
– No respiratory depression
D. Meperidine (Pethidine)
– Produces analgesia, sedation,
respiratory depression.
euphoria
and
– Less potent than morphine, 80-100 mg meperidine
equals 10 mg morphine.
– Shorter duration of action than morphine (2-4 hrs).
– Meperidine has greater excitatory activity than does
morphine and toxicity may lead to convulsions.
– Meperidine appears to have weak atropine-like
activity.
– It does not constrict the pupils to the same extent
as morphine.
– Does not cause as much constipation as morphine
– Purely synthetic μ- agonist
– Not an effective antitussive agent.
– less effect in uterine contraction commonly employed
in obstetrics also causes less urine retention
Adverse reactions to Meperidine
– Respiratory depression
– Tremors
– Delirium and possible convulsions
– Dry mouth
– Severe reaction if given with MAOI, consists of
excitement, hyperthermia and convulsions; it is due to
accumulation of pethidine(norpethidine) metabolite
but the details are still unclear.
E. Fentanyl
– μ- agonist, related chemically to meperidine.
– Approximately 80 times more potent than
morphine, main use in anesthesia .
– Duration of action very short (t1/2 = 20 min).
– Can be given IM, IV, transdemally or via
patient controlled infusion system may be
given intrathecally
– Often used during cardiac surgery because of
its negligible effect on the myocardial
contractility
F. Sufentanil
– A synthetic opioid related to fentanyl.
– About 7 times more potent than fentanyl.
– Has a slightly more rapid onset of action
than fentanyl.
G. Methadone
– Pharmacology and analgesic potency
similar to morphine; μ- receptor agonist.
– Very effective following oral administration.
– Longer duration of action than morphine
due to plasma protein binding (t1/2
approximately 25 hrs).
– Used in methadone maintenance programs
for treatment of opioid addicts and for
opiate withdrawal syndrome(it reduces the
physical abstinence syndrome)make it
possible to wean the addict from opioids.
H. Propoxyphene
– A methadone analog.
– Used orally to relieve mild to moderate pain,
it is weak analgesic ;often combined with
Paracetamol .
– Has a low addiction potential
– The most common adverse effects are:
dizziness, drowsiness, and nausea and
vomiting.
– CNS depression is additive with other CNS
depressants (alcohol and sedatives).
– can cause cardio- toxicity and pulmonary
edema which can not reversed by naloxone
III. Mixed Narcotic Agonists/Antagonists
• These drugs produce analgesia, but have a lower
potential for abuse and do not produce as much
respiratory depression.
A. Pentazocine
– қ- agonist (analgesia) and μ-antagonist (less
respiratory depression).
– Orally, it has about the same analgesic
potency as codeine.
– Adverse reactions to Pentazocine: Nausea,
vomiting, dizziness, dysphoria, nightmares
and visual hallucinations.
– Rarely used nowadays
B. Nalbuphine
– Resembles pentazocine pharmacologically.
– Like morphine, nalbuphine reduces
myocardial oxygen demand. May be of
value following acute myocardial infarction
due to both its analgesic properties and
reduced myocardial oxygen demand.
– Most frequent side effect is sedation.
– Less
propensity
to
produce
psychotomimetic side effects
C. Butorphanol
– Resembles pentazocine pharmacologically.
– 3.5 to 7 times more potent than morphine.
– Not available for oral administration
– They exhibit ceiling of respiratory depression
effect
D. Buprenorphine
– A partial agonist at μ-receptor.
– 200 times more potent than morphine.
– Low potential abuse, but can precipitate
withdrawal in addicts
– In naive persons it acts like morphine
– Major use is office-based detoxification of
opioids
– Causes less sedation, respiratory depression
and hypotension even in high doses.
IV. Opiate Antagonists
Opiate antagonists have no agonist properties.
They are utilized to reverse opiate induced
respiratory depression and to prevent drug abuse.
A. Naloxone (Narcan)
– Pure opiate antagonist at all opioid receptors
– Given parenterally -Short duration of action
(1-4 h)
– Can precipitate withdrawal in addicts.
B. Naltrexone
– Oral pure opioid antagonist
– Long duration of action
– Contraindicated in liver disease
– Used in late stages of opioid addiction
treatment ( also in treatment of alcoholism).
C. Nalmephine
– Long-acting parenteral opioid antagonist.
Antitussives
Cough Center
medulla
Chemical & mechanical
Stimuli
Afferents
EFFerents
Respiratory muscles
Sensory receptors in upper respiratory tract
Antitussives
• Antitussives: against cough
• Coughing is a protective reflex
• Antitussives depress cough center, therefore
depress the cough reflex.
• Antitussives should not be used in productive
cough.
Antitussives include:
1. Opioids:
– Codeine, dextromethorphan, hydrocodone,
hydromorphone.
– They are opioid agonists against dry cough.
– They are of low abuse potential.
– Side effects include: drowsiness and
constipatiopn.
2. Non-opioids:
– E.g. butamirate citrate which depress the
cough center.
3. Peripherally acting antitussives:
– These prevent irritation of sensory receptors
in the upper respiratory tract.
4. Local anesthetics
– also depress the cough center. They include:
a) demulcents: liquorice, honey
b) local anesthetics: benzonatate
THANK YOU
•
•
•
•
•
REFRENCES:
RANG AND DALE
LIPPINCOTTOS
LANGE
TABLES FROM DR.KUKAB SLIDES