• Pure agonist: has affinity for binding plusefficacy• Pure antagonist: affinity for binding but noefficacy• Mixed agonist: antagonist produces anagonist effect at one receptor and antagonistat other• Partial agonist: has affinity for binding but lowefficacy.
Opioid receptors• In 1973 a graduate student Candance pertused radioactive morphine to evaluate thelocation of site of action of morphine, and hefound that drug attaches to very specificareas of brain dubbed as opioid receptors
Opioid receptors• There are opioid receptors within the CNS aswell as throughout the peripheral tissues.These receptors are normally stimulated byendogenous peptides(endorphins,enkephalins and dynorphins)
Opioid Receptors• Mu: µ• Kappa: К• Delta: δ
Functions of opiod receptors• Mu (µ): supraspinal and spinal analgesia,sedation, inhibition of respiration, slowgastrointestinal transit, modulation of hormoneand neurotransmitter release• Kppa (К): supraspinal and spinal analgesia,psychotomimetic effects, slowed gastrointestinaltransit• Delta (δ): supraspinal and spinal analgesia,modulation of hormone and neurotransmitterrelease
Functions of opiod receptors• All these receptors possess strong affinity forendogeneous opioid peptides e.g endorphins,enkephalins, and dynorphins
Organ system effects of morphine andits surrogates• 1)CNS: due to the affinity for µ receptors, theyproduce analgesia, euphoria, sedation, andrespiratory depression and tolerance occur withrepeated use.• a) analgesia: opioid analgesics are unique toreduce both aspects (sensory and affective) ofpain.• b) euphoria: intravenous drug users usuallyexperience pleasant floating sensations with lessanxiety ad distress
• c) sedation: induce sleep particularly in elderlyas well as with combination of other CNSdepressing agents like sedatives & hypnotics• d) respiratory depression: all opioids producerespiratory depression by inhibiting brain stemrespiratory mechanism and depressed responseto CO2 challenge.• e) cough suppression: suppresses cough reflex inthis respect codeine is most effective
• f) miosis: constriction of pupils have beenseen with all opioid agonists• g) truncal rigidity: intensification of tone inlarge trunk muscles have been noted withnumber of opioids, may be due to spinalaction of these drugs.• h) nausea & vomiting: opioid analgesics canactivate chemoreceptors and produce nauseaand vomiting.
• i) temperature: homeostatic regulation ofbody temperature is mediated in part b actionof the action of endogenous peptides in thebrain.• 2)Peripheral effects:• a)CVS: no significant effect observed on cvswith the exception of meperidine which mayproduce tachycardia.
• b)G.I.T: in large intestine peristaltic wavesdiminished and causes constipation, more opioidsare successfully used for the treatment of thediarrhea (loperamide).• c) biliary tract: opiods contract biliary smoothmuscles which can result in biliary colic.• d) renal: opioids depress renal function, µ opioidshave anti-diuretic action. Ureteral and bladdertone increased due to opioids administration
• e) uterus: peripheral and central actions ofopioids reduce uterine contractions andprolong labor.• f) neuroendocrine: opioids increase therelease of ADH, prolactin and somatostatinbut inhibit the release of luteinizing hormone.• g) pruritus: opioids induced pruritus andurticaria more prominently by parenteral use.
Clinical uses of opioid analgesics• Analgesia: severe pain associated with canceror other terminal illnesses may be treatedsuccessfully. Opioids are often used inobstetric labor.• Pulmonary edema: morphine can beparticularly useful in treating painfulmyocardial ischemia with pulmonary edema• Cough: on lower doses cough suppressioneffect can be obtained.
• Diarrhea: synthetic surrogates diphenoxylateor loperamide are available to control non-infecteous diarrhea.• Applications in anesthesia: opioids are used incardiovascular and other high risk surgeries, inwhich primary goal is to minimizecardiovascular depression.
Mechanism of action• Activation of peripheral nociceptive fibrescauses release of substance P an other painsignaling neurotransmitters from nerve ofterminals in the dorsal horn of spinal cord.• Release of pain signaling neurotransmitters isregulated by endogenous endorphins or byexogenous opioid agonists by acting pre-synaptically to inhibit substance P releasecausing analgesia.
• Involves changes in transmembrane ionconductance• Increase potassium conductance• In-activation of calcium channels
Adverse effects• Severe respiratory depression can occur andmay result in death. Other effects includevomiting, dyphoria, histamine enhancedhypotensive effects, increased intracranialpressure, cerebral and spinal ischemia. Careshould be taken while prescribing morphine inCLD, CRF.
Tolerance and dependence• Repeated use produce tolerance to analgesic,euphoric, respiratory and sedative effects ofmorphine. Physical and psychologicaldependence readily occur with morphine andother agonists. Withdrawal effects includerhinorrhea, lacrimation, yawning,hyperventilation, hyperthermia, mydriasis,muscular aches and vomiting.
Meperidine• A synthetic opioid structurally unrelated tomorphine.• Mechanism of action: binds to µ and Кreceptors.• Clinical uses: indicated for acute nature ofpain, not recommended for long term use• Adverse effects: large doses can cause anxiety,tremor, muscle twitches.
Methadone• A synthetic opioid orally effective induces lesseuphoria and longer duration of action.• Mechanism of action: acts on µ and NMDAreceptors.• Clinical uses: used as analgesic in neurogenicpain, controlled withdrawal in morphine andheroin abusers.• Adverse effects: withdrawal effects ,but lesstoxic than morphine.
Fentanyl• A synthetic opioid and 100 times more potentthan morphine use in anesthesia. The drug hasrapid short duration (15-30 mnts). Administeredby i.v route but oral mucosal preparations andtransdermal patches also available. This is oftenused in cardiac surgery due to its negligibleeffects on myocardial contractility.• Adverse effects: are those of µ receptor agonists
Heroin• Also called diacetylmorphine three foldincreased in potency than morphine. Due toits greater solubility it cross BBB more rapidlythan morphine causing more euphoria. It hasno accepted medical use in USA, but it is usedin other countries in severe cancer pain.• Heroin users experience more severewithdrawal symptoms than morphine
Pakistani heroin addict
Moderate agonist: Codeine• The analgesic potency of codeine is much lessthan the morphine, however it shows goodanti-tussive activity at doses that do notcauses analgesia. Codeine is often used incombinations with aspirin and acetaminophen
Mixed agonist-antagonist & partialagonist• Mixed agonist-antagonist: shows agonisticactivity and are used to relieve pain.• Pentazocine: it acts as agonist on К receptorsand weak agonist at µ and δ receptors.Pentazocine promotes analgesia activatingreceptors in spinal cord. It can precipitatewithdrawal symptoms in morphine users.Tolerance and dependence develops withrepeated use.
Buprenorphine• A partial agonist acting on the µ receptors, itsmajor usage is in opiate detoxification,because it has less severe and shorterduration of withdrawal symptoms comparedto methadone. It causes little sedation,respiratory depression and hypotension evenat higher doses. Adverse effects arerespiratory depression which do not easilyreverse with NALOXONE .
Antagonists• Opioid antagonists bind with high affinity toopioid receptors but fail to activate response• Naloxone: naloxone antagonise µ, К, and δreceptors. It has 10 fold higher affinity to µthan for К receptors. It reverses the coma andrespiratory overdose of opioids within 30seconds of i.v injection of naloxone .
Naltrexone• It has similar action like naloxone but longerduration of action than naloxone. A singleoral dose of naltrexone blocks the effect ofinjected heroin up to 48 hrs. Naltrexone maycause hepatotoxicity.