Opioid Agonists and Antagonists PDF

OPIOID AGONISTS AND ANTAGONISTS JORGE L HERNANDEZ, DNAP, CRNA UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS SCHOOL OF NURSING Opium Poppy - Papaver Somniferum • Source of 20 distinct alkaloids • Written mention up to 300 BC • 1803 Morphine • 1832 Codeine • 1848 Papaverine • Opioids are unique...

OPIOID AGONISTS AND ANTAGONISTS JORGE L HERNANDEZ, DNAP, CRNA UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS SCHOOL OF NURSING Opium Poppy - Papaver Somniferum • Source of 20 distinct alkaloids • Written mention up to 300 BC • 1803 Morphine • 1832 Codeine • 1848 Papaverine • Opioids are unique in producing analgesia without loss of touch, proprioception, or consciousness. Opium Poppy - Papaver Somniferum Chemical Structure of Opium Alkaloids v Can be divided in two (2) distinct classes v The three rings of phenanthrene are composed of 14 carbon atoms. Minimal analgesic activity v The fourth piperidine ring includes a tertiary amine nitrogen which is present in most opioid agonists. v At pH7.4 the tertiary amine is highly ionized (water soluble). Lack analgesic activity Opium Poppy - Papaver Somniferum Semisynthetic Opioids Ø Simple modification of the morphine molecule yields many derivative compounds with differing properties. Ø Codeine –substitution of methyl group for hydroxyl group on carbon 3 (naturally occurring) Ø Heroin – substitution of acetyl group on carbon 3 and 6. Ø Hydromorphone – carbonyl group instead of hydroxyl at carbon 6 and lacks doble bond between 7 and 8. Ø Thebaine (naturally occurring). Opium Poppy - Papaver Somniferum Synthetic Opioids Ø Contain phenantrene nucleus of morphine but are manufactured by synthesis rather than chemical modification of morphine. Ø Widely used to supplement general anesthesia or primary anesthetic in very high doses. Ø Major pharmacodynamic differences between these drugs in potency, rate of equilibration and site of drug effect. Opium Poppy - Papaver Somniferum Opioid Receptors (𝝁, 𝜹, 𝜿) 𝝁 − 𝑶𝒑𝒊𝒐𝒊𝒅 𝑹𝒆𝒄𝒆𝒑𝒕𝒐𝒓𝒔 Ø Belong to superfamily of seven transmembrane segment guanine (G-protein coupled receptors). Ø Supraspnial and spinal anesthesia. Ø Brain – opioid receptors primarily found in periaqueductal gray, locus ceruleus, and the rostral ventral medulla. Ø 𝜇1 − Analgesia Ø 𝜇2 − Hypoventilation & physical dependance Ø Spinal Cord – found in both interneurons and primary afferent neurons in the dorsal horn. 𝜿 − 𝑹𝒆𝒄𝒆𝒑𝒕𝒐𝒓𝒔 Ø Sensory neurons and immune cells – receptors can be found outside the CNS (intraarticular morphine provides analgesia after knee surgery) Ø Dysphoria and diuresis. Ø Less effective for high-intensity pain. Ø Opioid agonists-antagonists often act on Kappa Opium Poppy - Papaver Somniferum 𝜹 − 𝑹𝒆𝒄𝒆𝒑𝒕𝒐𝒓𝒔 Ø Respond to endogenous ligands known as enkephalins and may serve to modulate 𝜇 receptors. Ø Endorphins inhibit release of excitatory neurotransmitters from nerve terminals carrying nociceptive impulses. Endogenous Pain-Modulating Mechanisms Ø Opioid receptors function as endogenous pain suppression system. Ø Opioid receptors present in areas of the brain: periaqueductal gray, locus ceruleus, and rostral ventral medulla Ø Opioid receptors present in the spinal cord: substansia gelatinosa Perception Integration Response Common Opioid Side Effects Cardiovascular System Ø Unlikely to cause direct myocardial depression or hypotension in the supine normovolemic patient. Ø Ortostatic hypotension is observed which reflect blockage of sympathetic compensatory mechanisms. Ø Venous pooling is observed which leads to decreased venous return and CO. Ø Drug induced bradycardia and histamine release can also decrease BP Increase activity over vagal nerves & direct depression of SA node. Common Opioid Side Effects Cardiovascular System Ventilation Ø Morphine does not sensitize the heart to catecholamines and/or dysrhythmias (barring hypercarbia or hypoxemia from ventilatory depression). Ø Opioid induced depression is characterized by decreased responsiveness of ventilatory centers to CO2 and displacement of the CO2 response curve to the right. Ø Synergistic effect of opioids with inhaled anesthetics and/or benzodiazepines can precipitate a decrease in CO & systemic BP. Ø Opioids have been recognized to play a role in protecting the myocardium from ischemia (𝜎 − 𝑟𝑒𝑐𝑒𝑝𝑡𝑜𝑟𝑠 𝑎𝑟𝑒 𝑏𝑒𝑙𝑖𝑒𝑣𝑒𝑑 𝑡𝑜 𝑏𝑒 𝑖𝑛𝑣𝑜𝑙𝑣𝑒𝑑) Ø Interfere with pontine and medullary ventilatory centers that regulate rhythm = prolonged pauses and periodic breathing. Ø High doses may result in apnea and death. Ø Factors that aggravate advanced age and/or occurrence of natural sleep. Ø Pain from surgery counteracts depression of ventilation. Common Opioid Side Effects Cough Suppression Ø Opioids depress cough by effects on the medullary cough centers. Ø Greater effect occurs with opioids that have bulky substitutions on carbon #3 (Codeine). Central Nervous System • In the absence of hypoventilation, opioids decrease CBF & possibly ICP. • Use with caution: ü ü ü Effects on wakefulness Production of miosis Depression of ventilation Ø EEG’s show no evidence of seizure activity. Ø Skeletal muscle rigidity and/or myoclonus (thoracic & abdominal muscles) can occur. Prominent w. Fentanyl and can compromise ventilation (chest wall rigidity). Ø Miosis due to excitatory action of opioids on the autonomic nervous system (Edinger Westphal nucleus of oculomotor nerve). ü Can be antagonized by atropine ü Hypoxemia can still produce mydriasis Common Opioid Side Effects Biliary Tract Gastrointestinal Tract Ø Opioids can cause spasm of biliary smooth muscle (sphincter of Oddi spasm). § Spasm of GI tract smooth muscle: ü Constipation ü Biliary colic ü Delayed gastric emptying Ø Naloxone relieves the pain of sphincter spasm but not angina. § Decreased peristalsis of small and large bowel. Ø Nitroglycerin relieves both types of pain. § Ø Glucagon, 2 mg IV, also reverses opioid-induced spasm. Enhances tone of pyloric sphincter, ileocecal valve and anal sphincter. § Chronic preoperative administration – consider delayed gastric emptying. Ø Can produce epigastric distress or biliary colic (can be confused with angina pectoris). Common Opioid Side Effects Nausea & Vomiting Ø Direct stimulation of the chemoreceptor trigger zone in the floor of the fourth ventricle. Ø Reflects on the role of opioid agonists as dopamine agonists at DA receptors. Ø Increasing of GI secretions and delayed passage of intestinal content towards the colon can contribute as well. Genitourinary System Ø Increase the tone and peristaltic activity of the ureter. Atropine reverses effects. Ø Urinary urgency by augmentation of detrusor muscle tone and sphincter tone = Urgency feeling! Cutaneous Changes • Cutaneous vessels dilate with flushing of face, neck and upper chest. Partly related to histamine release. Placental Transfer • Readily transported across the placenta. • Depression of the neonate can occur. (Morphine>Meperidine>Fentanyl) • Chronic use by the mother can cause dependance in the fetus with withdrawal symptoms if naloxone is administered (life-threatening) Common Opioid Side Effects Drug Interactions Ø Ventilatory depressant effects of some opioids may be exaggerated by amphetamines, MAO inhibitors and tricyclic antidepressants. Hormonal Changes Ø Prolonged opioid use may influence the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis, leading to endocrine and immune effects. Pharmacodynamic Tolerance & Physical Dependence Ø Cross-tolerance occur amongst all opioids. Ø Tolerance can occur w/o physical dependence but not the other way around. Ø Takes 2-3 weeks & acute tolerance can develop faster. Ø TRIAD = miosis, hypoventilation and coma. Ø Tolerance develops to analgesia, euphoria, sedation, depression of ventilation & emetic effects but not on miosis and bowel motility. Ø Treat with mechanical ventilation and naloxone (Intranasal, IM or IV) Ø Physical dependence does not occur with antagonist and is less likely with opioid agonist-antagonists. Overdose Common Opioid Side Effects Pharmacodynamic Tolerance & Physical Dependence Ø If physical dependence is present, discontinuation produces withdrawal abstinence syndrome: Yawning, diaphoresis, lacrimation, or coryza, insomnia and restlessness. Ø Abdominal cramps, nausea, vomiting, and diarrhea reach peak in 72 hrs. and decline over the next 7-10 days. Ø Tolerance is lost during withdrawal Ø Mechanisms proposed: 1. Desensitization by downregulation 2. Upregulation of cAMP system Ø Long-term pharmacodynamic tolerance associated with activation of NMDA receptors (hence effectivity of Ketamine). Opioid Agonists “The most notable feature of the clinical use of opioids is the extraordinary variation in dose requirements for pain management.” Opioid Agonists Morphine (Greek for “god of dreams”) Morphine Pharmacokinetics Ø Prototype agonist to which all other opioids are compared. Ø Peak effect at 15 to 30 min. and duration of about 4 hours . Ø Analgesia, euphoria, sedation, and diminished ability to concentrate. Ø Delayed transit of morphine across brain blood barrier Ø Nausea, feeling of body warmth, heaviness of the extremities, dry mouth and pruritus (cutaneous area around the nose). Ø Analgesia and ventilatory effects may not be evident at first. Ø Increase threshold of pain and/or perception. Ø Continuous dull pain is better treated than sharp intermittent pain. Ø Analgesia is better when administered before painful stimulus. Ø Reasons for poor penetration of morphine into the CNS 1. 2. 3. 4. Relatively poor lipid solubility High degree of ionization Protein binding Rapid conjugation with glucuronic acid Opioid Agonists Pharmacokinetics Ø Cerebrospinal fluid (CSF) concentrations following intravenous administration of morphine decay more slowly than plasma concentrations. The end-tidal CO2 concentration (PETCO2) remains increased despite a decreasing plasma concentration of morphine. Ø Morphine does accumulate rapidly in the kidneys, liver, and skeletal muscle. Ø Unlike Fentanyl, morphine does not undergo significant first-pass uptake into the lungs. Opioid Agonists Morphine Metabolism Ø Conjugation with glucuronic acid in hepatic and extrahepatic sites, especially the kidneys. o o 75% to 85% morphine-3-glucuronide 5% to 10% 6-glucuronide Principally eliminated by urine Pharmacologically Inactive • Produces analgesia and depression of ventilation. • Duration of action greater than morphine. • Possible that is responsible for the majority of analgesic activity. • Potency is 650x morphine. • Elimination may be impaired in patients with renal failure. • MAOI’s impair formation of glucuronide conjugates which may contribute to exaggerated morphine effects. Opioid Agonists Morphine Elimination Half-Time Ø Initial decrease in plasma concentration is due to metabolism (only small fraction of unchanged drug in urine). Ø Plasma morphine concentrations are greater in the elderly. Ø There is decreased clearance in the first 4 days of life of the neonate. Ø Patients with renal failure exhibit higher plasma and CSF concentrations. Ø Breast milk shows - unlikely that significant amounts of morphine will be transferred to the neonate in patient receiving PCA morphine. Opioid Agonists Meperidine (Synthesized in 1939) Metabolism Ø Shares structural features that are present in local anesthetics: Ø Extensive hepatic metabolism (90%). • Tertiary amines • Ester group • Lipophilic phenyl group Blocks sodium channels when intratechal. Ø Demethylation to normeperidine and hydrolysis to meperidinic acid. Ø Structurally, like atropine and has mild atropinelike antispasmodic effect on smooth muscle. Ø Urinary excretion is primary elimination route (pH dependent). Ø 1/10 as potent as morphine Ø Normeperidine has elimination half life of 15 hrs. (35 hrs. if renal failure). Ø DoA is 2 – 4 hrs. Ø Extensive hepatic firs-pass limits oral presentation (80%) Ø Normepedire is half as active as meperidine but acts as a CNS stimulant (seizures, myoclonus, & delirium can occur). Opioid Agonists Meperidine Elimination Half-Time Ø 3 – 5 hrs. with clearance primarily dependent on hepatic metabolism. Ø 60% is bound to plasma proteins which is decreased in elderly patients (increases sensitivity). Clinical Use Ø Clinical use has declined greatly in recent years Side Effects Ø Same as for morphine . Ø + Atropine like increase in HR (different from morphine). Ø + Potential for seizures and delirium Ø + Not used in high doses because significant negative cardiac inotropic effect plus histamine release (unique for this drug). Ø Only opioid considered adequate for surgery when administered intrathecally. Ø Serotonin syndrome (autonomic instability w. HTN, tachycardia, diaphoresis, hyperthermia, confusion, agitation and hyperreflexia) Ø Effective in suppressing postoperative shivering, attribute to 𝜅 𝑟𝑒𝑐𝑒𝑝𝑡𝑜𝑟𝑠 & 𝛼2 (meperidine 25 mg IV). Ø Avoid administering to patients on MAOI’s Ø Mydriasis & dry mouth (atropine like). Ø Transient neurologic syndrome after intrathecal administration Opioid Agonists Fentanyl (phenylpiperidine-derivative) Ø 75– 125 times more potent than morphine Ø Faster onset and shorter duration of action than morphine (greater lipid solubility). Ø Plasma concentration correlate well with CSF concentration. Ø Lungs also serve as large inactive storage site (estimated 75% of initial dose of fentanyl). Ø Plays important role in determining pharmacokinetic profile of fentanyl Ø Progressive saturation occurs with continuous infusions or repeated administration. Rapid redistribution = short DoA Opioid Agonists Fentanyl Metabolism Ø Extensively metabolized by N-demethylation to: § Norfentanyl Hydroxyproprionyl-fentanyl § Hydroxyproprionyl-norfentanyl § Ø The pharmacologic activity of fentanyl metabolites is believed to be minimal. Ø Less than 10% of fentanyl is excreted unchanged in the urine. Elimination Half-Time o Elimination half-time is longer than that for morphine. o longer elimination half-time reflects a larger Vd (greater lipid solubility). o Elimination half-time increased with age presumably from decreased hepatic clearance and decreased protein binding (79%-87%). o Half-time not affected in cirrhosis patients. Opioid Agonists Fentanyl Context Sensitive Half-time Ø As the duration of continuous infusion of fentanyl increases beyond about 2 hours, the contextsensitive half-time of this opioid becomes greater than sufentanil. Ø Reflects saturation of inactive tissue sites with fentanyl during prolonged infusions and return of the opioid from peripheral compartments to the plasma. Opioid Agonists Fentanyl Clinical Uses Ø Fentanyl is administered clinically in a wide range of doses. Ø Fentanyl may be administered as a transmucosal preparation. Ø Large doses of fentanyl as the sole anesthetic have the advantage of stable hemodynamics due principally to: Ø Transdermal fentanyl preparations delivering 75 to 100 μg/hour . 1. Lack of direct myocardial depressant effects. 2. Absence of histamine release. Suppression of the stress responses to surgery. 3. Ø Evidence of opioid overdose has been observed when an upper body warming blanket was placed intraoperatively and came into contact with the fentanyl patch. Opioid Agonists Fentanyl Side Effects Seizure Activity Ø Side effects of fentanyl resemble those described for morphine. Ø No evidence of EEG activity that sugests seizures. Ø Persistent or recurrent depression of ventilation due to fentanyl is a potential postoperative problem. Ø Opioids might produce a form of myoclonus secondary to depression of inhibitory neurons that would produce a clinical picture of seizure activity in the absence of EEG change Cardiovascular Effects Ø Unlike morphine, fentanyl, even in large doses (50 μg/kg IV), does not evoke the release of histamine Ø Bradycardia is more prominent with fentanyl than morphine and may lead to occasional decreases in blood pressure and cardiac output. SSEP’s Ø Fentanyl in doses exceeding 30 μg/kg IV produces changes in somatosensory-evoked potentials that, although detectable, do not interfere with the use and interpretation of this monitor during anesthesia. Opioid Agonists Fentanyl Intracranial Pressure Ø Administration of fentanyl and sufentanil to head injury patients has been associated with modest increases (6-9 mm Hg) in ICP despite maintenance of an unchanged PaCO2. Drug Interactions Ø Analgesic concentrations of fentanyl greatly potentiate the effects of benzodiazepines and decrease the dose requirements of propofol. Opioid Agonists Sufentanil (1974) Ø 5 to 10 x the potency of fentanyl Ø Ø Greater affinity of sufentanil for opioid receptors. High lipid solubility allows rapid penetration of brain blood barrier Ø Onset of CNS effects (6.2 minutes) Pharmacokinetics Ø Rapid redistribution to inactive tissues terminates effect. Ø Sufentanil undergoes significant first-pass pulmonary uptake (60%). Ø Greater protein binding of sufentanil (92.5%) compared to fentanyl contributes to smaller Vd Ø Binds to 𝛼1 – acid glycoprotein (increased after surgery). Ø Elimination half-time of sufentanil is intermediate between that of fentanyl and alfentanil. Ø Sufentanil has a similar elimination half-time in patients with or without cirrhosis of the liver. Ø The Vd and elimination half-time is increased in obese patients (reflects high lipid solubility). Opioid Agonists Sufentanil Metabolism Ø Rapidly metabolized by N-dealkylation at the piperidine nitrogen and by O-demethylation. Ø Pharmacologically inactive metabolites. 10% of sufentanil activity Ø Extensive hepatic extraction ratio (sensitive to flow). Ø Production of weakly active metabolite suggest the importance of adequate renal function. Context Sensitive Half-Time Ø Less than that for alfentanil for continuous infusions of up to 8 hours (larger Vd). Ø More favorable recovery profile over alfentanil when used over long period of time. Opioid Agonists Sufentanil Clinical Uses Ø 18.9 μg/kg IV, results in more rapid induction of anesthesia, earlier emergence from anesthesia, and earlier tracheal extubation. Ø Sufentanil causes a decrease in cerebral metabolic oxygen requirements and cerebral blood flow is also decreased or unchanged (as with other opioids). Ø Bradycardia produced by sufentanil may be sufficient to decrease cardiac output. Ø As observed with fentanyl, delayed depression of ventilation has also been described after the administration of sufentanil. Ø Use of large doses of opioids, including sufentanil or fentanyl, to produce IV induction of anesthesia may result in rigidity of chest and abdominal musculature. Opioid Agonists Alfentanil (1976) Ø 1/5 to 1/10 the potency and 1/3 the duration of fentanyl. Ø Unique advantage over fentanyl and sufentanil is faster onset (effect site equlibrium of 1.4 min). Pharmacokinetics Ø Short elimination half-time compared with fentanyl and sufentanil . Ø Cirrhosis of the liver, but not cholestatic disease, prolongs the elimination half-time of alfentanil. Ø Renal failure does not alter the clearance or elimination half-time of alfentanil. Ø rapid effect-site equilibration characteristic of alfentanil is a result of the low pKa of this opioid such that nearly 90% of the drug exists in the nonionized form at physiologic pH Opioid Agonists Alfentanil Pharmacokinetics Ø Short elimination half-time compared with fentanyl and sufentanil . Ø Cirrhosis of the liver, but not cholestatic disease, prolongs the elimination half-time of alfentanil. Ø Renal failure does not alter the clearance or elimination half-time of alfentanil. Ø Rapid effect-site equilibration characteristic of alfentanil is a result of the low pKa of this opioid such that nearly 90% of the drug exists in the nonionized form at physiologic pH Ø Useful when an opioid is required to blunt the response to a single, brief stimulus such as tracheal intubation or performance of a retrobulbar block. Ø Vd of alfentanil is 4 to 6 times smaller than that of fentanyl (lower lipid solubility and higher protein binding). Ø Higher non-ionized fraction allows for faster cross of BBB. Bound to 𝛼1 – acid glycoprotein. Opioid Agonists Alfentanil Metabolism Ø Metabolized predominantly by two independent pathways: piperidine N-dealkylation to noralfentanil and amide N-dealkylation to N-phenylpropionamide. Ø Efficient metabolism with 96% of alfentanil metabolized within 60 minutes of administration. Ø Wide interindividual variability in alfentanil pharmacokinetics (presents difficulty with reliable infusion regimens). Ø 10-fold interindividual variability in alfentanil systemic clearance, presumably reflecting variability in hepatic intrinsic clearance. Context-Sensitive Half-Time Ø Context-sensitive half-time of alfentanil is actually longer than that of sufentanil for infusions up to 8 hours in duration (reflects larger Vd of sufentanil). Opioid Agonists Alfentanil Clinical Uses Ø Has a rapid onset and offset of intense analgesia reflecting its very prompt effect-site equilibration. Ø Alfentanil is used to provide analgesia when the noxious stimulation is acute but transient. Ø Alfentanil increases biliary tract pressures similarly to fentanyl. Opioid Agonists Remifentanil Ø Selective μ-opioid agonist with an analgesic potency similar to that of fentanyl (15-20 times as potent as alfentanil) and a blood–brain equilibration (effect-site equilibration) time similar to that of alfentanil. Ø Structurally unique because of its ester linkage (susceptible to hydrolysis by nonspecific plasma and tissue esterases to inactive metabolites). Ø This unique pathway of metabolism leads to: 1. Brief action 2. Precise and rapidly titrable effect 3. Lack of accumulation 4. Rapid recovery after administration Opioid Agonists Remifentanil Pharmacokinetics Ø Pharmacokinetics of remifentanil is characterized by small Vd, rapid clearance, and low interindividual variability compared to other IV anesthetic drugs. Ø Dosing regimens should be based on ideal (lean) body mass rather than total body weight. Ø Context-sensitive half-time) of the remifentanil plasma concentration will be nearly independent of the infusion duration. Ø The rapid effect-site equilibration means that a remifentanil infusion rate will promptly approach steady state in the plasma and its effect site (steady state within 10 minutes). Opioid Agonists Remifentanil Metabolism Ø Remifentanil is unique among the opioids in undergoing metabolism by nonspecific plasma and tissue esterases to inactive metabolites. Ø Likely that remifentanil’s pharmacokinetics will be unchanged by renal or hepatic failure because esterase metabolism is usually preserved in these states. Ø Esterase metabolism appears to be a very well-preserved metabolic system with little variability between individuals, which contributes to the predictability of drug effect associated with the infusion of remifentanil. Ø Remifentanil does not appear to be a substrate for butyrylcholinesterases (pseudocholinesterase), and thus, its clearance should not be affected by cholinesterase deficiency or anticholinergics. Opioid Agonists Remifentanil Context-Sensitive Half-Time Ø Context-sensitive half-time for remifentanil is independent of the duration of infusion and is estimated to be about 4 minutes. Ø In contrast, the context-sensitive half-times for sufentanil, alfentanil, and fentanyl are longer and depend significantly on the duration of the infusion. Clinical Uses Ø Prompt onset and short duration of action make remifentanil a useful selection for suppression of the transient sympathetic nervous system response to direct laryngoscopy and tracheal intubation in at-risk patient. Ø Remifentanil could be used for long operations, when a quick recovery time is desired (neurologic assessment, wake-up test) but at a significantly higher cost than other opioids. Ø The spinal or epidural administration of remifentanil is not recommended, as the safety of the vehicle (glycine, which acts as an inhibitory neurotransmitter) or opioid has not been determined. Opioid Agonists Remifentanil Side Effects Ø Advantage of remifentanil possessing a short recovery period may be considered a disadvantage if the infusion is stopped suddenly, whether it be deliberate or accidental. Ø Nausea and vomiting, depression of ventilation, and mild decreases in systemic blood pressure and heart rate may accompany the administration of remifentanil. Ø Histamine release does not accompany the administration of remifentanil. ICP and intraocular pressure are not changed by remifentanil. Ø High-dose remifentanil decreases cerebral blood flow and cerebral metabolic oxygen requirements Hyperalgesia Ø Initial reports suggested that intraoperative remifentanil infusion produces acute opioid tolerance and hyperalgesia. Ø NMDA receptor antagonists such as ketamine and magnesium may be helpful.