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MIT HST 151 - Opioid Pharmacology

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Opioid Pharmacology HST-151 1 Definitions 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. Hundreds of opioid alkaloids and peptides have been synthesized, but all clinically available opioid analgesics are alkaloids. Structure-Activity Relationships 1. Most opioid analgesics are related to morphine (see figure). 2. Distinctive features of morphine include 5 rings, 3- and 6-hydroxyl groups (phenolic and alcoholic), piperidine ring with an N-methyl group, and a quaternary carbon at position 13. Morphine is optically active, and only the levorotatory isomer is an analgesic. O N-CH3 HO OH N-CH3 COOC2H5 MORPHINE MEPERIDINE 3. Simple modifications of morphine make active analgesics • Codeine is morphine O-methylated at position 3. • Heroin is morphine O-acetylated at positions 3 and 6. 4. Replacing the N-methyl with something larger (allyl, cyclopropyl, cyclobutyl) usually produces a compound with opioid antagonist properties. N-allyl substitution of morphine and oxymorphone produces the antagonists nalorphine and naloxone, respectively. 5. Morphine may be modified extensively but still have agonist activity. Meperidine (Demerol) is a synthetic opioid with only fragments of the morphine structure (see figure above). Opioid Classification 1. Based on intrinsic activity • Agonists (morphine, fentanyl) • Pure antagonists (naloxone, naltrexone) • Mixed agonist-antagonists (nalbuphine, butorphanol) 2. Based on interaction with µ, κ, or δ opioid receptor subtypes Harvard-MIT Division of Health Sciences and Technology HST.151: Principles of Pharmocology Instructor: Dr. Carl RosowHST-151 2 • All three receptors have been cloned, and knockout mice created. • Each receptor thought to have 2-3 (or more) subtypes, but no distinct gene products have been identified. All belong to the superfamily of G-protein coupled receptors. • Most opioid analgesics are relatively selective µ opioid agonists. The various µ effects are discussed below. • A few analgesics (pentazocine, nalbuphine, butorphanol) are κ agonists, although they are not highly selective. Experimental selective κ drugs produce analgesia, but also unique effects like diuresis and dysphoria. • The selective δ agonists are mainly peptides. Receptor may function permissively with µ receptor (allosteric interaction?). Endogenous Opioid Peptides 1. Enkephalins include several compounds derived from a large proenkephalin molecule (also called proenkephalin A). • Most important compounds are pentapeptides, methionine- and leucine-enkephalin. Relatively selective δ ligands. • Widely distributed in CNS • Act like morphine to modulate neurotransmitter release (see p. 3) • Found with catecholamines in sympathetic terminals and adrenal. 2. Endorphins (chiefly β-endorphin) are derived from the large precursor molecule pro-opiomelanocortin (POMC). • POMC also the precursor for ACTH and MSH, which are found together with β-endorphin. • β-endorphin is a 31 amino acid peptide which has analgesic activity in man and animals. It binds preferentially to µ receptors. • Localized primarily in pituitary and hypothalamus. 3. Dynorphins are derived from a prodynorphin molecule (also called proenkephalin B). • Dynorphin A is a 17 amino-acid peptide which is a potent and highly selective agonist at κ receptors. • Similar distribution to the enkephalins. 4. Opioid peptides are located in places which allow them to function as neurotransmitters or neuromodulators. 5. Probably modulate pain transmission in the cord and alter acetylcholine release in the myenteric plexus. 6. Postulated to play fundamental roles in areas as diverse as hormonal secretion, thermoregulation, and cardiovascular control.HST-151 3 Opioid Agonists -- Pharmacodynamics 1. General Mechanisms • Opioids inhibit adenylyl cyclase via interaction with Gi/G0. • Hyperpolarize postsynaptic neurons by increasing outward K+ currents • Act presynaptically to block Ca++ uptake and consequently inhibit neurotransmitter release. Opioids have been shown to inhibit the release of many neurotransmitters, including substance P, acetylcholine, norepinephrine, glutamate, and serotonin. • Opioids produce highly specific depressant and stimulant effects by acting at discrete CNS sites. For example, morphine stimulates the vagal nuclei in the medulla while depressing respiratory centers only a few millimeters away. • The mechanism for neuronal stimulation is often the depression of an inhibitory interneuron .HST-151 4 2. General Clinical Properties Acute and Chronic Effects of Opioids 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. 3. CNS Effects a. Analgesia and MoodHST-151 5 Mechanisms: • 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


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