Opioid analgesics and antagonists

Definitions Opiate a drug derived from alkaloids of poppy plant Opioid the class of drugs that include opiates , opiopeptins, and all synthetic and semisynthetic drugs that mimic the actions of the opiates Opiopeptins endogenous peptides synthesised by the nerve cells and adrenal medullary cells and interact with opioid receptors Opium obtained from the poppy Papaver sominiferum first undisputed reference to "poppy juice" is found in the writings of Theophrastus in the third century B.C. opium derived from the Greek word for "juice" opium contains more than 20 alkaloids morphine, codeine, thebaine, papaverine 1803, Sertrner isolated a pure active alkaline substance from opium, which he named morphine, after Morpheus, the Greek god of dreams isolation of other alkaloids soon followed codeine in 1832 and papaverine in 1848 natural opium alkaloids thebaine not an analgesic precursor of several semisynthetic opioid agonists (etorphine) and antagonist naloxone papaverine not an analgesic vasodilatory property lead to the development of verapamil Classification (by occurrence) natural alkaloids of opium phenanthrenes (morphine, codeine, thebaine) benzylisoquinolines (papaverine, noscapine) semi-synthetic derivatives diacetylmorphine (heroin) hydromorphone, oxymorphone hydrocodone, oxycodone synthetic derivatives phenylpiperidines (pethidine, fentanyl, alfentanil, sufentanyl) benzmorphans (pentazocine, phenazocine, cyclazocine) propioanilides (methadone) morphinans (levorphanol) Classification (by action) opioid full agonist a drug that activates some or all opioid receptor subtypes and does not block any e.g. morphine opioid partial agonist a drug that can activate an opioid receptor to effect a submaximal response even when it is bound to all the receptors, e.g. codeine opioid mixed agonist-antagonist a drug that activates some opioid receptor subtypes and blocks other subtypes, e.g. nalbuphine opioid antagonists a drug that blocks some or all opioid receptor subtypes e.g. naloxone

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Partial agonist the slope of the dose-response curve is less than that of a full agonist maximal response below that obtainable by a full agonist (lower intrinsic activity) partial agonists may displace full agonists from binding sites and are able to antagonise the effects of large doses of full agonists concentration-effect of adding a partial agonist

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Structure activity agonists and antagonists have complex structures, usually with a number of optical isomers, of which only the l-isomer is most active minor molecular alterations may drastically change the action of the compounds Phenanthrene structure "T-shape" a tertiary, positively charged basic nitrogen a quaternary carbon, C13 in morphine, separated from the basic N17 by an ethane (-CH2-CH2-) chain, attached to a phenyl group (phenol, ketone) presence of an aromatic ring, centre is 0.455 nm from N atom replacement of the methyl group at N17 of piperidine ring with larger groups results in agents with partial agonist or antagonist properties allyl (-CH2-CH=CH2) substitution morphine to nalorphine oxymorphone to naloxone levorphanol to levallorphan methylcyclopropane in buprenorphine methylcyclobutane in nalbuphine methyl substitution at the phenolic hydroxyl group at C3 reduces susceptibility to first-pass hepatic metabolism of the molecule by glucuronide conjugation at this position reduces the intrinsic activity morphine to codeine oxymorphone to oxycodone acetylation of both C3 and C6 hydroxyl groups of morphine yields lipid soluble heroin penetrates blood brain barrier faster than morphine heroin is metabolised in the brain to monoacetylmorphine and morphine Phenylpiperidines substitution of methyl group at N17 yields opioids of varying potencies

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Opioid receptors 3 major types of receptors identified, , , & serpentine G protein-coupled receptors, coupled to Gq inhibit adenylyl cyclase subtypes 1, 2, 1, 2, 3 & 1, 2 OP1 (), OP2 (), OP3 () on the basis of these receptors, drugs can be divided into agonists, partial agonists, agonist-antagonists and antagonists; however, whether an antagonist behaves as an inverse agonist or neutral antagonist also appears to be dependent upon the state of the receptor, following agonist treatment many neutral antagonists and weak partial agonists act as inverse agonists activation of receptors increases K+ conductance, hyperpolarising central neurons and primary afferents supraspinal and spinal analgesia, sedation, respiratory depression, slow gastrointestinal transit, modulation of neurotransmitter and hormone release, euphoria, miosis activation of receptors closes Ca++ channels, evoking an inhibitory postsynaptic potential supraspinal and spinal analgesia, modulation of neurotransmitter and hormone release activation of receptors closes Ca++ channels, evoking inhibitory postsynaptic potential supraspinal and spinal analgesia, diuresis, sedation, dysphoria, miosis Endogenous opioid peptides 3 principal precursor proteins of endogenous opioid peptides present at brain sites that have been implicated in pain modulation, adrenal medullar and neural plexuses of intestines: preproopiomelanocortin (POMC), preproenkephalin, preprodynorphin giving rise to 3 families of peptides Endorphins (, ) - -END, -END & -END Enkephalins (, ) - met-ENK & leu-ENK Dynorphins (, ) - DYN-A, B, - & neodynorphin Distribution of opioid receptors limbic system amygdaloid & septal nuclei thalamus medial thalamic nuclei, ventral caudal thalamus hypothalamus basal, medial, and arcuate regions pituitary gland brain-stem periaqueductal gray area, midline reticular formation in the midbrain, area postrema (CTZ), rostral ventral medulla, periventricular grey areas in the medulla, locus ceruleus, nucleus ambiguus spinal cord primary afferents, dorsal horn, spinothalamic tract, laminae I, II & IV of the spinal cord (substantia gelatinosa) retina

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miosis

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mediated by parasympathetic pathways, caused by stimulation of the Edinger-Westphal nucleus by most and receptor agonists pinpoint pupils being pathognomic of opioid overdose truncal rigidity, results from action at supraspinal level, characterized by increasing muscle tone progressing to severe stiffness, particularly in the thoracic and abdominal muscles appears to be a higher incidence with large boluses and rapid infusions the elderly concomitant use of N2O with alfentanil can be decreased with priming with one-eighth to one-sixth dose of the intended intubating dose of nondepolarising muscle relaxant Neuroendocrine effects generally decrease the responsiveness of the hypothalamus, probably through the effects of endogenous opioid peptides on the thalamus, causing decreased body temperature decreased release of gonadotropin releasing hormone results in decreased secretion of FSH, LH, ACTH & -END stimulates the release of antidiuretic hormone, growth hormone, prolactin, somatotropin Cerebral blood flow the opioids generally produce a modest (10-15%) decrease in cerebral oxygen consumption and intracranial pressures except when hypercapnia develops as a result of respiratory depression no differences on intracranial pressure changes were found between patients with preserved and impaired autoregulation morphine 1-3 mg/kg + 70% N2O insignificant changes in CBF and CMRO2 fentanyl 100 g/kg + 70% N2O dose related decreases in, CBF - to a maximum of 50% CMRO2 - to a maximum of 35% similar changes seen with sufentanil and alfentanil all of these agents decrease formation of cerebrospinal fluid while not affecting reabsorption Cardiovascular effects peripheral vascular dilation centrally mediated reduction in sympathetic tone , reversible by naloxone depression of the baroreceptor reflexes , with postural hypotension in subjects seated or standing vagal induced bradycardia release of histamine splanchnic sequestration of blood indirect, hypercapnoea mediated vasodilatation

the action of morphine at the receptor may evoke the release of endogenous opioid peptides that additionally act at and receptors in OA and RA, END and ENK are expressed by macrophage-like (CD68(+)) and fibroblast-like (CD68(-)) cells within synovial lining layers; and macrophages/monocytes, lymphocytes and plasma cells in sublining layers in joint trauma, END and ENK are expressed by granulocytes in the sublining layers Pharmacodynamic effects Effects on the central nervous system analgesia euphoria some patients experience dysphoria, a disquieted state characterised by restlessness and a feeling of malaise sedation respiratory depression tolerance with repeated use cough suppression nausea and vomiting direct stimulation of the chemoreceptor trigger zone in the area postrema of the medulla also stimulated by apomorphine, a dopaminergic agonist may be treated with phenothiazines which posses a dominant dopamineblocking action vestibular component, up to 15-40% of ambulatory patients affected

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bradycardia the nucleus ambiguus is an area containing cardiac vagal neurons, from which originates most of the parasympathetic control regulating heart rate and cardiac function it contains receptors, hence all receptor agonists (except intravenous administration of pethidine) decrease heart rate centrally mediated reduction in sympathetic tone depression of the baroreceptor reflexes increased risk of bradycardia / asystole on induction of anaesthesia laryngoscopy (vagal stimulation) concomitant use of benzodiazepines, Ca++-channel blocker, or -adrenergic blockers, muscle relaxants without vagolytic properties (vecuronium), muscle relaxants with vagotonic properties (succinylcholine) rapid administration of the opioid Respiratory depression dose dependent decreased brainstem sensitivity to CO2, decreased slope of the CO2-ventilation response curve increased apnoeic threshold decrease hypoxic drive to respiration carotid body chemoreception is virtually abolished reduced activities of pontine & medullary centres involved in rhythmic respiration hypoxic pulmonary vasoconstriction not affected delayed respiratory depression has been reported with most of the opioids (morphine, pethidine, fentanyl, alfentanil, and sufentanyl), exact cause is unclear, possibly due to secondary plasma drug peaks as a result of sequestration of drug in the stomach (approximately 20% of fentanyl) large peripheral storage compartments (skeletal muscle) supplemental analgesics and other medications lack of nociceptive stimulation Gastrointestinal effects opioid receptors exist in high density in gastrointestinal tract, effects mediated through opioid action on local enteric nervous system and central nervous system stomach motility decrease but tone may increase decreased gastric secretion of hydrochloric acid small intestine resting tone is increased, periodic spasms, peristaltic waves decreased decreased peristaltic waves in large intestines resulting in constipation Effect on the biliary tract constrict biliary smooth muscle, may result in biliary colic sphincter of Oddi may constrict resulting in reflux of biliary and pancreatic secretions and elevated serum amylase and lipase concentrations

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Effects on the genitourinary tract renal function is depressed decreased renal blood flow increased ureteric and bladder tone, increased sphincter tone may precipitate urine retention Other effects uterus reduction in uterine tone due to peripheral and central effects skin flushing and warming of the skin, perspiration and itching probably due to central effects and histamine release immune system modulate lymphocyte proliferation, antibody production, and chemotaxis Effects of increasing age marked and widespread reduction in and receptor densities with age dose requirements decrease in elderly Tolerance with frequently repeated administration of opioids, there is a gradual loss in effectiveness, to achieve the initial response, a larger dose must be administered along with tolerance, physical dependence occur minimal cross-tolerance between different receptor groups physical dependence the occurrence of the characteristic withdrawal or abstinence syndrome when the drug is stopped or an antagonist is administered Mechanisms reduction in the number of receptors by internalisation of GPCR and by reduced synthesis reduction in the function of receptors uncoupling of the receptor and second messenger system change in the receptors ability to associate with Gi/o coupling proteins, increased amount of G proteins, and an up-regulated cAMP system changes in second messenger systems related to Ca++ flux, adenylyl cyclase inhibition, and protein phosphorylation chronic exposure and tolerance to opioids is associated with an elevation of intracellular Ca++ phosphokinase C-mediated Degree of tolerance

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Context-sensitive half-time context refers to the length of the infusion context sensitive half-time refers to the time for plasma concentration to decrease by 50% after terminating an intravenous infusion designed to maintain a constant plasma concentration the offset of action of a drug is a function of the elimination half-life the rate of equilibration between plasma and effector site the method of administration and duration of infusion

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Pharmacokinetics

Absorption well absorbed from the following sites skin (transdermal), subcutaneous, intramuscular, mucosal surface, gastrointestinal tract bioavailability decreased by glucuronidation of C3 and C6 hydroxyl groups in the liver codeine and oxycodone have high oral:parenteral potency ratios because they are partially protected from conjugation by a methyl group on the aromatic hydroxyl group at C3 Distribution bind to plasma protein (-acid glycoprotein) with varying affinity morphine 20-45% bound; fentanyl 80% bound they then rapidly leave the blood and localise in highest concentrations in tissues that are highly perfused such as brain, lungs, liver, kidneys, spleen skeletal muscle serves as the main reservoir for opioids because of the greater bulk accumulation in fatty tissue becomes important after frequent high dose administration of highly lipophilic opioids that are slowly metabolised access through blood brain barrier greatest difficulty with amphoteric agents: opioids with acidic group (phenolic hydroxyl at C3) and basic group (N17 amine) e.g. morphine more readily with opioids in which aromatic hydroxyl at C3 is substituted e.g. heroin, codeine

Metabolism major portion of opioids converted to polar metabolites, which are then excreted by the kidneys conjugation opioids with free hydroxyl groups are conjugated with glucuronic acid, e.g. morphine, levorphanol morphine-6-glucuronide possesses analgesic potency that may be greater than that of morphine itself, accumulation of this compound in renal failure ester hydrolysis heroin, remifentanil hydrolysed by tissue esterases heroin (diacetylmorphine) is hydrolysed to monoacetylmorphine and finally to morphine, which is then conjugated with glucuronic acid N-demethylation pethidine N-demethylated to norpethidine, accumulation of norpethidine may occur in renal failure, may cause seizures, especially in children oxidation primary mechanism for phenylpiperidine opioids Excretion polar metabolites excreted mainly in the urine morphine-6-glucuronie norpethidine small amounts of unchanged drug may also be found in the urine glucuronide conjugates are found in the bile enterohepatic circulation a small portion of the excretory process Remifentanil member of 4-amilidopiperidine group fentanyl derivative with ester linkage m.w. of 412.9 daltons pure agonist does not have a chiral centre, exists only in one form potency similar to fentanyl, 15-30 times more potent than alfentanil presence of a methyl ester in the N-acyl moiety undergoes widespread extrahepatic metabolism by blood and nonspecific esterases that are nonstaurable poor substrate for plasma cholinesterase, hence not affected by deficiency of enzyme not affected by anticholinesterases such as neostigmine adverse effects rarely due to its pharmacokinetic profile administration by intravenous infusion, onset 1-2 minutes distribution extremely lipid soluble Vdss 0.3-0.4 L/kg tcontext 3 minutes, consistent with whatever the duration of infusion

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metabolism ester linkage broken down by plasma and tissue esterases to inactive carboxylic acid derivative, which is excreted in urine potency of metabolite only 0.1-0.3% of remifentanil metabolite t 1.5-2 hours safe for use in both liver and renal failure Cl 40-60 ml/min/kg, t 12-21 minutes duration of action <5 minutes since metabolism is rapid, accumulation is unlikely with repeated bolus doses or infusion cardiovascular effects decrease in blood pressure and heart rate in excess of 20%, unrelated to dose hypotension not associated with histamine release central nervous system analgesia and sedation at age 40 years, MAC of isoflurane reduced by 50% at target plasma concentration of 1.2 ng/ml more marked in elderly patients a ceiling effect was observed at 32 ng/ml and MAC was not reduced to zero nausea, vomiting rarely respiratory depression dose-dependent increase in respiratory depression spontaneous ventilation possible at a rate of 0.05 g/kg/min muscle rigidity dose and rate dependent 8% incidence following bolus 1 g/kg and infusion at 0.5 g/kg/min preparation formulated in glycine, an inhibitory neurotransmitter, thus should not be administered epidurally or intrathecally disadvantage too short acting, no postoperative analgesia if infusion is stopped at the end of surgery difficulty in titrating infusion rate without causing respiratory depression dosing guidelines

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weak but selective receptor agonist M1 metabolite of tramadol, produced by liver O-demethylation, shows a higher affinity for opioid receptors than the parent drug inhibits noradrenaline and serotonin reuptake, making a significant contribution to the analgesic action by blocking nociceptive impulses at the spinal level. increasing noradrenaline and serotonin concentrations causing enhancement of serotoninergic and noradrenergic pathways adverse effects, and nausea in particular, are dosedependent reduction of this dose during the first days of treatment is an important factor in improving tolerability. other adverse effects are generally similar to those of opioids, although they are usually less severe, and can include respiratory depression, dysphoria, sedation, and constipation. available as oral, IM, IV preparations toxicity dependence and withdrawal syndromes, seizures and rarely anaphylactoid reactions

Perfect opioid produces intense analgesia with high potency minimal side effects continuing into the postoperative period respiratory depression, nausea and vomiting, drug dependence short duration of action such that the drug can be administered by intravenous infusion its effect can be rapidly increased or decreased by altering the rate of administration recovery is rapid , valuable in day surgery Naloxone morphine derivative with bulky derivatives at N17 position high affinity for receptor low affinity at other receptors, but can be reverse agonist at and sites poor efficacy when given by mouth duration of action 1-2 h when given by injection after a single dose, a severely depressed patient may relapse into coma after 1-2 h metabolism chiefly by glucuronide conjugation, like other opioid agonists with hydroxyl groups no tolerance to the antagonistic action antagonistic action is seen within 1-3 minutes of administration usual dose 0.1-0.4 mg intravenously, repeated as necessary

Tramadol a synthetic 4-phenyl-piperidine analogue of codeine. central-acting analgesic with a low affinity for opioid receptors