OPIOID ANALGESICS AND

ANTAGONISTS
By : Asep Sukohar
Departement of Pharmacology
Medical School Lampung University

OPIOIDS are natural or synthetic compounds

produce morphine like effects
Opiates are drugs obtained from the juice of opium
poppy
Action : Binding to specific reseptors in the CNS
effect that mimic the action of endogenous pepetide
neurotransmitters (= opiopeptines) e.g. enkephalins
and endorphin
Many other effects
Primary use Relief intense pain and its anxiety
Euphoric properties DRUG ABUSE

OPIOID RESEPTORS
1. On the membranes of certain cells in the CNS
2. On nerve terminals in the periphery
3. On the cells of the GIT

The terms of the reseptors :

Mu, kappa, delta and sigma each exhibits a
different specificity
Mu and kappa analgesics properties

Enkephalins more selectively interact with

delta receptors in the periphery
Sigma receptors less specific can also bind
non opioid agents (hallucinogen)
Sigma is responsible for the
associated effects with opioids e.I
hallucination and dysphoria
Naloxone is an antagonist to mu, kappa,
delata but not to sigma

All opioid receptors :

1. Coupled to inhibitory G protein
2. Inhibit adenylyl cyclase
3. Associated with ion channels to
increase K+ efflux hyperpolarization
or reduce Ca++ influx impeding

Opioid agonists and antagonists

are :
1. STRONG AGONISTS : morphine, meperidine,
methadone, fentanyl-sufentanil,heroin
2. MODERATE AGONISTS : propoxyphen,
codeine
3. MIXED AGONISTS-ANTAGONISTS :
pentazocine, buprenorphine
4. ANTAGONISTS : naloxone, naltrexone

Actions of agonists and antagonists at opioid

receptors
Mor,Her,Cod,Fent

Pentazocine

Mainly at mu recept.

Agonist at kappa
Partial antagonist at mu

+
Mu

Kappa

Sigma

Antagonists act at mu, kappa, sigma receptors

Action of drugs :
At Mu receptors : 1. Suprapinal analgesia
2. Respiratory depression
3. Euphoria / sedation
4. Physical dependence
5. Decreased GIT motility
6. Pupil constriction

Kappa receptors :
1. Spinal analgesia
2. Sedation/dysphoria
3. Pupil constriction
Sigma receptors :
1. Dysphoria
2. Hallucination
3. Psychomimetic effects
4. Pupil dilatation

Distribution of opioid receptors :

1. Brainstem : Resp., cough, nausea, vomit, BP, pupil,
stomach secretions
2. Medial thalamus : deep pain that is poorly localized
and emotionnaly influenced
3. Spinal cord on substantia gelatinosa : sensory
information, painful afferent stimuli decrease
4. Hypothalamus : affect neuroendocrine secretion

Distribution of opioid receptors (cont.)

5. Limbic system :concentrate in amygdala,

influence emotional behaviour
6. PeripherY : inhibit Ca++ dependent release of
excitatory pro inflammatory substance (e.g
Subtance P) from these nerve endings
7. Immuno cells : the role has not been determined

Morphine
Crude opium contains major analgesic morphine
and lower concentration of codein
Both have high affinity to Mu, varying to Kappa
and Delta and low to Sigma receptors
The prototype agonist

Mechanism of action :
Interacting with opioid receptors in CNS and GIT :

Hyperpolarization of nerve cells

Inhibition of nerve firing

Presynaptic inhibition of Transmitter release

Acts at Mu receptor in substantia gelatinosa

Spinal Cord

Mechanism of action (cont.)

Inhibits the release of any excitatory trnsmitters

from nerve terminals carrying nociceptive
(painful) stimuli

ACTION of morphine
1. Analgesia result of raising treshold at SC
level and altering the brains perception of
pain (aware the presence of pain but the
sensation is not unpleasant)

All addicts pinpoint pupil

specific

Emesis caused by stimulating the CTZ

(chemoreceotor trigger zone) ; this symptom is not
unpleasant
GIT : mophine relief diarrhea and dysentery
smoot muscle : motility

, tone

Billiary tract Pressure

Anal sphincter tone

constipation

Cardiovascular, very high dose gives effects

hypotension, bradycardia

2. Respiration : reduction of sensitivity of neurons in

Resp. center to CO2 respiaratory depression (with
ordinary dose). Higher dose cause respiratory cease, if
dose more higher (OD) death.
3. Depression of cough reflex. Morphine and codein
are antitussive. The receptor is defferent than those
involved in analgesia.
4. Miosis result from stimuli of Mu and Kappa
receptors. Morphine excites the Edinger-Westfal of
acculomotor nerve enhanced stimuli of
parasympathic nerve to the eyes.

Respiratory depression + CO2 retention

cerebral vessels dilates pressure of CSF
Morphine is contraindicated in severe brain injury
Histamine release : urticaria, sweating,
vasodilatation, bronchodilatation (Asthmatics is
CI)
Hormonal actions :
Inhibits releas of GTHR, CTRH
Decreases the concentration of LH, FSH,
ACTH, FSH, beta endorphine

Decreases Testosteron and Cortison

Increases Prolactin and GH
Increase ADH urinary retention
THERAPEUTIC USES
As an analgesia. When pain is present and needed
sleep, morphine is supplements to benzodiazepin
to induce sleeping.
Antidiarrhea
Relief of cough. More widely used : codein or
dextromethorpan

Pharmacokinetics :
Adm. : Morfin usually not be given orally
IM,SC,IV. Codein orally
Distrib. : Morfin to allbody tissues and cross into
the fetus. Morfin is yhe least lipophilic, cross the
BBB in a very small amount : Fentanyl and Heroin
are fat soluble rush euphoria.
Fate : Transformed to glucuronides Morfine-6glucuronide very potent analgesics.
Excretion : Urine >>, a small amount into bile
DOA of morfine is 4 6 hours in native individuals

ADVERSE EFFECTS
Severe respiratory depression

Vomiting, dysphoria, allergy

Increase cranial pressure
Ischemia of cerebral and spinal
In prostate hypertrophy urine retention
In adrenal insuff. And myxedem extended
and increased effects

Tolerance and Physical Dependence

Repeated use tolerance to Resp. depression,
analgesic, euphoric, sedative effects of morphine,
not to pupil-constriction and constipating effects.
Physical and psychological dependence more
readily with morphine.
Withdrawl is an unbearable symptoms of
autonomic system and psychological responses

DRUG INTERACTIONS
The depressant effect of morphine is enhanced
by phenothiazines, MAOI, tricyclic
antidepressants.
Amphetamine low dose and Hydroxyzine
Increase analgesic effect

MEPERIDINE
A synthetic opioid
Binds particularly kappa receptors
Causes respiratory depression
Orally no significant Cardiovascular
action
IV peripheral resistence decrease,
peripheral blood flow increase cardiac rate
increase

Pupil : Midriasis because of an atropin-like

activity
Use for any types of severe pain
Not use for diarrhea and cough
Less increase urinary retention
PO or IM potent analgesics
DOA : 2 4 hours, excreted in urine
Preferred for analgesia during labor

Large dose :Tremors, muscle twiches, rarely

convulsion,pupil dilates and hyperactive reflexes
Given post-op. severe hypotension
Combined with major neuroleptics increased
depression
Combined with MAOI convulsion and
hyperthermia
Dependence can ocure but use for substitute in
addict with morphine and heroin
Cross tolerance with other opioids

Methadone : Orally : can substitute the injected

opioid, can control withdrawl from heroin and
morphine. DOA is longer than morphine
Fentanyl : Potent analgesics 80 times than
morphine. Combined with droperidol
dissociative anaesthesia. Sufentanil a related
drug is more potent analgsics
Heroin : an acethylation of morphine, 3 times more
potent. Fat soluble BBB PE :exagerrated
euphoria

Moderate antagonist
Propoxyphen : Combined with aspirin or
acetaminophen. SE : as morphin but weaker
Combined with alcohol and sedative causes CNS
depression death by resp. depress. And
cardiotoxicity; Toxic dose : Like morphin =some
patients cardiotoxic and pulmo edema

Codein : A higher oral efficacy much less potent

analgesics, combination with aspirin or
acteminophen;
In non prescriptioned cough preparation used
dextromethorphan

Mixed agonist and antagonists

Pentazocine and Buprenophine
Antagonist : Naloxone and Naltrexone