OPIOID ANALGESICS AND ANTAGONISTSBy : Asep SukoharDepartement of PharmacologyMedical School Lampung University

OPIOIDS are natural or synthetic compounds produce morphine like effectsOpiates are drugs obtained from the juice of opium poppyAction : Binding to specific reseptors in the CNS effect that mimic the action of endogenous pepetide neurotransmitters (= opiopeptines) e.g. enkephalins and endorphinMany other effectsPrimary use Relief intense pain and its anxietyEuphoric 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 specificityMu and kappa analgesics properties

Enkephalins more selectively interact with delta receptors in the peripherySigma receptors less specific can also bind non opioid agents (hallucinogen) Sigma is responsible for the associated effects with opioids e.I hallucination and dysphoriaNaloxone 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 neuronal firing and transmitter release

Opioid agonists and antagonists are :STRONG AGONISTS : morphine, meperidine, methadone, fentanyl-sufentanil,heroinMODERATE AGONISTS : propoxyphen, codeineMIXED AGONISTS-ANTAGONISTS : pentazocine, buprenorphineANTAGONISTS : naloxone, naltrexone

Actions of agonists and antagonists at opioid receptorsMor,Her,Cod,Fent PentazocineMainly 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 :

Brainstem : Resp., cough, nausea, vomit, BP, pupil, stomach secretionsMedial thalamus : deep pain that is poorly localized and emotionnaly influencedSpinal cord on substantia gelatinosa : sensory information, painful afferent stimuli decreaseHypothalamus : 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 codeinBoth have high affinity to Mu, varying to Kappa and Delta and low to Sigma receptorsThe 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 Decrease substance P in SC

Mechanism of action (cont.)Inhibits the release of any excitatory trnsmitters from nerve terminals carrying nociceptive (painful) stimuli

ACTION of morphineAnalgesia 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 specificEmesis caused by stimulating the CTZ (chemoreceotor trigger zone) ; this symptom is not unpleasantGIT : mophine relief diarrhea and dysentery smoot muscle : motility , toneBilliary tract Pressure Anal sphincter tone constipationCardiovascular, 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 CSFMorphine is contraindicated in severe brain injuryHistamine 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 USESAs an analgesia. When pain is present and needed sleep, morphine is supplements to benzodiazepin to induce sleeping.AntidiarrheaRelief of cough. More widely used : codein or dextromethorpan

Pharmacokinetics : Adm. : Morfin usually not be given orally IM,SC,IV. Codein orallyDistrib. : 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-6-glucuronide very potent analgesics.Excretion : Urine >>, a small amount into bileDOA of morfine is 4 6 hours in native individuals

ADVERSE EFFECTS Severe respiratory depressionVomiting, dysphoria, allergyIncrease cranial pressure Ischemia of cerebral and spinalIn prostate hypertrophy urine retentionIn adrenal insuff. And myxedem extended and increased effects

Tolerance and Physical DependenceRepeated 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 INTERACTIONSThe 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 activityUse for any types of severe painNot use for diarrhea and coughLess increase urinary retentionPO or IM potent analgesicsDOA : 2 4 hours, excreted in urinePreferred for analgesia during labor

Large dose :Tremors, muscle twiches, rarely convulsion,pupil dilates and hyperactive reflexesGiven post-op. severe hypotensionCombined with major neuroleptics increased depressionCombined with MAOI convulsion and hyperthermiaDependence can ocure but use for substitute in addict with morphine and heroinCross tolerance with other opioids

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

Moderate antagonistPropoxyphen : Combined with aspirin or acetaminophen. SE : as morphin but weakerCombined 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 BuprenophineAntagonist : Naloxone and Naltrexone