Chapter 7 Notes PHARM PDF

Stoelting Chapter 7: Review Notes 1 Introduction to Opioids 1. Origin - The word “opium” originates from the Greek word opion, meaning “poppy juice”. - The opium poppy, *Papaver somniferum*, is the source of 20 unique alkaloids. 2. Historical Reference - Medicinal use of poppy juice has been docum...

Stoelting Chapter 7: Review Notes 1 Introduction to Opioids 1. Origin - The word “opium” originates from the Greek word opion, meaning “poppy juice”. - The opium poppy, *Papaver somniferum*, is the source of 20 unique alkaloids. 2. Historical Reference - Medicinal use of poppy juice has been documented since at least 300 BC, with potential religious uses predating this. 3. Terminology and Drugs - Drugs derived from opium are termed opiates. - Morphine, the most renowned opiate, was isolated in 1803. - Codeine was discovered in 1832, and papaverine in 1848. - While morphine can be synthesized, deriving it from opium is more straightforward. - The word "narcotic" comes from the Greek word for "stupor" and is traditionally linked to potent analgesics similar to morphine with the potential for causing physical dependence. 4. Opioids - The creation of synthetic drugs possessing morphine-like attributes ushered in the term opioid. - Opioids are defined as exogenous substances, both natural and synthetic, that specifically bind to certain opioid receptor subpopulations and manifest some agonist (similar to morphine) effects. - Unique characteristic: Opioids can produce analgesia without compromising touch, proprioception, or consciousness. 5. Classification - Opioids can be broadly classified into: - Opioid agonists - Opioid agonist-antagonists - Opioid antagonists. Opioids, derived from the opium poppy, have been used for millennia for their analgesic properties. Their unique ability to provide pain relief without a loss of touch, proprioception, or consciousness makes them indispensable in modern medicine, particularly in perioperative care and pain management. By: VA, September 2023 Stoelting Chapter 7: Review Notes 2 Chemical Structure of Opium Alkaloids 1. Two Main Classes - Phenanthrenes - Benzylisoquinolines 2. Phenanthrene Alkaloids - Present in opium are morphine, codeine, and thebaine. - Characterized by a core structure with three rings made up of 14 carbon atoms. - Most opioid agonists also contain a fourth piperidine ring which houses a tertiary amine nitrogen. - At a pH of 7.4, the tertiary amine nitrogen is highly ionized, giving the molecule its water solubility. 3. Benzylisoquinoline Alkaloids - The main ones present in opium are papaverine and noscapine. - Notably, these lack analgesic activity. 4. Chirality - Opium alkaloids are chiral molecules, meaning they can exist in different spatial arrangements that are mirror images of each other. - The levorotatory (left-rotating) isomers of these molecules are the ones biologically active at the opioid receptors. The chemical structures of opium alkaloids determine their pharmacological properties. The phenanthrene alkaloids, which include well-known substances like morphine and codeine, are responsible for the analgesic effects of opium, whereas the benzylisoquinoline alkaloids, like By: VA, September 2023 Stoelting Chapter 7: Review Notes 3 papaverine and noscapine, lack such activity. The molecular structure, particularly the highly ionized tertiary amine nitrogen at physiological pH, ensures their water solubility. Only the levorotatory isomers of these molecules exhibit biological activity at opioid receptors. Semisynthetic Opioids 1. Modification 1. Derivative compounds can be produced through simple modifications of the morphine molecule. 2. Examples - Methylmorphine (codeine): Results from substituting a hydroxyl group on carbon 3 with a methyl group. - Diacetylmorphine (heroin): Produced by the substitution of acetyl groups on carbons 3 and 6. - Hydromorphone: Contains a carbonyl group at position 6, and doesn't have the double bond between carbons 7 and 8. - Thebaine: Has negligible analgesic activity but is a precursor to etorphine, an extremely potent analgesic. Synthetic Opioids 1. Origin - They retain the phenanthrene nucleus of morphine but are made entirely by synthesis rather than modification of natural morphine. 2. - Groups of Synthetic Opioids Morphine derivatives: e.g., levorphanol Methadone derivatives Benzomorphan derivatives: e.g., pentazocine Phenylpiperidine derivatives: e.g., meperidine, fentanyl 3. Characteristics - These synthetic opioids share similarities in molecular weights (236-326) and pKs with amide local anesthetics. By: VA, September 2023 Stoelting Chapter 7: Review Notes 4 4. Popular Synthetic Opioids - Fentanyl, sufentanil, alfentanil, and remifentanil are used widely in anesthesia. - The main differences between them lie in potency and the rate at which they reach the site of action (biophase). The development and classification of opioids can be understood through the distinctions between semisynthetic and synthetic types. Semisynthetic opioids emerge from direct modifications to the morphine molecule, while synthetic opioids, although related in structure to morphine, are completely manufactured. The latter category encompasses a range of drugs, some of which are widely used in anesthesia and differ in terms of potency and speed of action. By: VA, September 2023 Stoelting Chapter 7: Review Notes 5 Opioid Receptors 1. Types - Classified into three subtypes: μ, δ, and κ receptors. 2. - Naming Origin μ: Derived from morphine κ: Derived from ketocyclazocine δ: Named due to its isolation from mouse vas deferens 3. Structure and Family - Opioid receptors belong to a superfamily of seven transmembrane-segment guanine (G) protein–coupled receptors. - This family also includes other receptors like muscarinic, adrenergic, and somatostatin receptors. 4. Molecular Biology - These receptors have been successfully cloned, and their amino acid sequences have been determined. - For the μ-receptor: Only one gene is responsible, but it gives rise to six distinct μ receptors. By: VA, September 2023 Stoelting Chapter 7: Review Notes 6 Location and Functions of Opioid Receptors 1. Brain Locations - Found mainly in the periaqueductal gray, locus ceruleus, and the rostral ventral medulla. 2. Spinal Cord - Present on interneurons and primary afferent neurons in the dorsal horn. - Direct application of opioid agonists can produce intense analgesia. 3. Outside CNS - Found on sensory neurons and immune cells. - Intraarticular morphine can produce analgesia post knee surgery through action on peripheral nerves. - Immune cells at inflammation sites secrete opioid peptides for local analgesia. 4. μ-Opioid Receptors - Account for supraspinal and spinal analgesia. - μ1 and μ2 subtypes speculated for distinct effects. - Cloning suggests no clear distinction between μ1 and μ2. - Activity modulated by β-arrestins. 5. κ Receptors - Inhibition of neurotransmitter release. - Less respiratory depression compared to μ-receptor but can cause dysphoria and diuresis. - κ-mediated analgesia might be less potent for high-intensity pain. 6. δ Receptors - Respond to enkephalins. - Modulate μ receptors' activity. - μ- and δ-opioid receptors can heteromerize, leading to distinct receptor pharmacology. 7. σ Receptors - Not true opioid receptors. - Found extensively in the CNS and peripheral tissues. - Involved in diverse cellular functions like metabolic regulation and mitochondrial metabolism. Endogenous Pain-Modulating Mechanisms 1. Purpose of Endogenous System - Opioid receptors and endogenous opioid agonists act as an innate pain suppression system. - Once pain is perceived, there's a survival benefit to having mechanisms to attenuate this perception. 2. Opioid Receptor Locations - Brain areas: periaqueductal gray, locus ceruleus, and the rostral ventral medulla. - Spinal cord: substantia gelatinosa. - These locations are pivotal for pain perception, integration, and response. By: VA, September 2023 Stoelting Chapter 7: Review Notes 7 3. Function of Endorphins - Believed to inhibit the release of excitatory neurotransmitters from pain-carrying nerve terminals. - Causes neurons to hyperpolarize, suppressing spontaneous discharges and evoked responses. 4. Mechanisms of Analgesia - Electrical stimulation of specific brain sites or mechanical stimulation (e.g., acupuncture) likely triggers endorphin release. - The analgesic effect of placebos may also be linked to endorphin release. 5. Endogenous Opioids and Pain - Prolonged pain and stress induce the release of endogenous opioids in various brain regions. - Activation of μ-opioid receptors is linked to decreased sensory and emotional aspects of pain, with distinct neural pathways involved. Influence of Treatment Expectancy on Analgesic Efficacy 1. Role of Expectancy - A study revealed that an individual's expectation about a treatment can significantly influence its effect. 2. Effects on Remifentanil - Positive treatment expectancy doubled the analgesic benefits of remifentanil. - In contrast, negative treatment expectancy completely negated remifentanil's analgesic properties. 3. Neural Corroborations - The subjective effects of expectancy were validated by observable changes in brain activity related to pain intensity. 4. Brain Regions Involved**: - Positive expectancy effects were linked to the activation of the endogenous pain modulatory system. By: VA, September 2023 Stoelting Chapter 7: Review Notes 8 - Negative expectancy effects were associated with activity in the hippocampus. 5. Conclusion from the Study - Both subjective feelings and objective brain mechanisms support the idea that an individual's expectation about a drug's outcome critically affects its therapeutic efficacy. - Different regulatory brain mechanisms are activated depending on the type of expectancy (positive or negative). Common Opioids Side Effects - An ideal opioid agonist targets receptors for analgesia without affecting receptors linked to side effects. All opioids have similar side effects, differing mainly in intensity. Morphine is commonly used as a reference to understand these side effects. Cardiovascular System and Morphine - - - - - - - - Direct Myocardial Depression: - Morphine, even in high doses, is unlikely to cause direct myocardial depression or hypotension in supine and Normovolemic patients. Orthostatic Hypotension: - Morphine can cause orthostatic hypotension when patients change from supine to standing due to decreased sympathetic nervous system tone and subsequent venous pooling. Bradycardia & Histamine Release - Morphine can cause decreased blood pressure due to bradycardia (from increased vagal nerve activity) or histamine release. Histamine Release Limitations - Limiting morphine infusion rates, positioning the patient appropriately, and optimizing fluid volume can reduce the chances of histamine release. Fentanyl Comparison - Unlike morphine, fentanyl doesn't release histamine when infused. Cardiac Sensitivity - Morphine does not increase cardiac sensitivity to catecholamines unless there's hypercarbia or arterial hypoxemia from ventilatory depression. Tachycardia & Hypertension - If they occur during anesthesia with morphine, they're not due to the opioid but are responses to surgical pain. Anesthesia Combination - Combining opioids with inhaled/IV anesthetics can cause cardiovascular depression. Also, combining an opioid with a benzodiazepine might reduce systemic vascular resistance and blood pressure. Myocardium Protection - Opioids are believed to protect the myocardium from ischemia, largely via σ and κ receptors. By: VA, September 2023 Stoelting Chapter 7: Review Notes - 9 σ Receptors - Though once linked with opioids, σ receptors now are seen to play roles in cell signaling, metabolic regulation, and are not true opioid receptors. Ventilation and Opioids Ventilatory Depression - Opioids cause ventilatory depression, leading to decreased sensitivity to carbon dioxide, resulting in increased arterial partial pressure of CO2. This shifts the carbon dioxide response curve to the right. Breathing Rhythm: - Opioids affect pontine and medullary ventilatory centers that regulate breathing rhythm, leading to prolonged pauses between breaths and periodic breathing. Mechanism - Opioids might reduce sensitivity to carbon dioxide by decreasing acetylcholine release in the medullary ventilatory center during hypercarbia. Cellular Level - β-arrestin may mediate opioid-induced ventilatory depression, suggesting the potential use of "biased ligands" at opioid receptors to reduce this adverse effect. Duration & Magnitude - Ventilatory depression from opioids is rapid, persists for hours, and is demonstrated by reduced responses to carbon dioxide. High opioid doses can lead to apnea, but patients can still initiate a breath when prompted. Cause of Death - Death from an opioid overdose is typically due to ventilatory depression. Clinical Manifestations - Clinically, opioids decrease the frequency of breathing, often compensated with increased tidal volume. However, this compensation is incomplete, leading to increases in PaCO2. Influencing Factors - Factors like advanced age, natural sleep, and surgical pain can influence the magnitude and duration of opioid-induced ventilatory depression. Ciliary Activity - Opioids depress ciliary activity in airways in a dose-dependent manner. Airway Resistance - Opioids can increase airway resistance due to direct effects on bronchial smooth muscle and indirectly due to histamine release (from certain opioids). By: VA, September 2023 Stoelting Chapter 7: Review Notes 10 Cough Suppression and CNS Effects of Opioids Cough Suppression Mechanism - Opioids suppress cough through their impact on the medullary cough centers, separate from their effects on ventilation. Codeine - Opioids like codeine, with bulky substitutions at the number 3 carbon position, show the most significant cough suppression. Dextrorotatory Isomers - These, such as dextromethorphan, suppress cough without causing analgesia or ventilatory depression but have potential for abuse. Central Nervous System (CNS) - - - - - Cerebral Blood Flow - Opioids decrease cerebral blood flow and may reduce intracranial pressure (ICP) unless hypoventilation occurs. Use in Head Injury - Caution is needed due to opioids' effects on wakefulness, miosis production, and potential for increased ICP if PaCO2 rises. Head injuries can also enhance sensitivity to opioids due to compromised blood-brain barrier. EEG Changes - Morphine induces sleep-like EEG changes, shifting from rapid α waves to slower δ waves. No evidence of seizure activity is seen even after large doses. Muscle Effects - Rapid IV administration of large opioid doses can cause skeletal muscle rigidity. Clonic muscle activity during opioid use might look like grand mal seizures, but without EEG evidence of seizures. Rigidity might relate to opioid receptor actions and involve interactions with dopaminergic and γ-aminobutyric acid-responsive neurons. Miosis - Opioids cause miosis due to their excitatory effects on the Edinger-Westphal nucleus of the oculomotor nerve. Morphine's miotic effects show limited tolerance and can be counteracted by atropine. Severe arterial hypoxemia in the presence of morphine might lead to mydriasis. By: VA, September 2023 Stoelting Chapter 7: Review Notes 11 Rigidity and Sedation Effects of Opioids Rigidity - - - - - - Cause - Rapid IV administration of large doses of opioids, especially fentanyl and its derivatives. Effect - Can lead to generalized skeletal muscle rigidity, often severe enough to hinder manual ventilation. Primary Affected Area - Commonly referred to as “chest wall” rigidity, but the main resistance to ventilation is due to laryngeal musculature contraction. Mechanism - Opioid-induced muscle tone increase is likely due to the inhibition of striatal γaminobutyric acid release and heightened dopamine production. Incidence - With a moderate dose of sufentanil, the occurrence of ventilation difficulties is reported between 84% and 100%. Treatment - Options include muscle relaxation via neuromuscular-blocking drugs or opioid antagonism using naloxone. Sedation - - - - Onset - Postoperative titration of morphine often leads to sedation, which can precede the beginning of analgesia. Titration Recommendation - Morphine should be titrated with short intervals between boluses (5-7 minutes) to evaluate its clinical impact. Incidence - Up to 60% of patients may experience sedation during morphine titration, making it a prevalent reason to cease morphine titration for postoperative pain relief. Misconception - The belief that pains relief equates to sleep onset isn't always correct. Morphineinduced sedation shouldn't be viewed as an indicator of suitable analgesia during IV morphine titration. Effects of Opioids on the Biliary Tract Biliary Smooth Muscle Spasm - Cause: Opioids. By: VA, September 2023 Stoelting Chapter 7: Review Notes 12 - Effect: Results in increased biliary pressure, possibly leading to epigastric distress or biliary colic. This pain can sometimes be mistaken for angina pectoris. Relief Methods - Naloxone: - Relieves pain caused by biliary spasm, but not pain due to myocardial ischemia. - Nitroglycerin - Can relieve pain resulting from either biliary spasm or myocardial ischemia. Comparison of Opioids on Bile Duct Pressure - Fentanyl → Increases common bile duct pressure by 99% above predrug levels. Morphine → 53% increase. Meperidine→ 61% increase. Pentazocine → 15% increase. Surgery Implications - Opioid-induced spasm of the sphincter of Oddi might appear in radiological imaging as a sharp constriction at the end of the common bile duct. This can be mistaken for a bile duct stone. - For accurate interpretation of cholangiograms, it might be necessary to counteract the opioid-induced biliary spasm with naloxone. Alternative Treatment - Glucagon (2 mg IV) also reverses the spasm without negating the analgesic effects of the opioid. - However, not all patients receiving opioids experience this spasm. For instance, with fentanyl (when used as a supplement to inhale anesthetics), the incidence is about 3%. Effects on Pancreatic Ducts - - Opioid-induced contraction of the pancreatic ducts' smooth muscles might be the reason for observed increases in plasma concentrations of amylase and lipase after morphine administration. These increases can potentially complicate the diagnosis, especially when acute pancreatitis is a consideration. Effects of Opioids on the Gastrointestinal Tract 1. Smooth Muscle Spasm - Opioids Implicated i. Morphine, meperidine, and fentanyl. - Effects By: VA, September 2023 Stoelting Chapter 7: Review Notes - 13 i. These opioids can cause spasms of the gastrointestinal (GI) smooth muscles. Resulting Side Effects i. This can lead to constipation, biliary colic, and delayed gastric emptying. 2. Effects on Intestinal Contractions and Sphincters - Decreased Peristaltic Contractions - Morphine reduces the propulsive peristaltic contractions of both small and large intestines. - Enhanced Sphincter Tone - Morphine increases the tone of the pyloric sphincter, ileocecal valve, and anal sphincter. - Outcome - Due to the delayed movement of intestinal contents through the colon, there's more absorption of water leading to constipation. 3. Constipation - Chronic Opioid Therapy i. Constipation is a frequent issue with opioid treatment and can be particularly challenging for patients on chronic opioid therapy because there's minimal tolerance development to this side effect. - Historical Perspective i. Historically, opium was used as a remedy for diarrhea before its analgesic properties became popular. 4. Increased Biliary Pressure - Mechanism i. This occurs when the gallbladder contracts against a sphincter of Oddi that is either closed or narrowed. - Impact i. This can result in biliary colic. 5. Delayed Gastric Emptying - Effect i. Opioids can increase the tone at the gastroduodenal junction, causing a delay in the passage of gastric contents into the proximal duodenum. - Implications i. Preoperative medication containing opioids might slow gastric emptying, which could elevate the risk of aspiration or postpone the absorption of oral medications. 6. Reversal of Opioid-Induced GI Effects - Method i. Many of the GI effects induced by opioids can be counteracted or even prevented by using a peripheral-acting opioid antagonist. By: VA, September 2023 Stoelting Chapter 7: Review Notes 14 Nausea and Vomiting Induced by Opioids Cause - Direct stimulation of the chemoreceptor trigger zone in the fourth ventricle's floor. Role of Dopamine - Opioid agonists act as partial dopamine agonists at receptors in the chemoreceptor trigger zone. Example - Apomorphine, a strong emetic, is highly potent at dopamine receptors among opioids. - **Mechanism**: - The stimulation of dopamine receptors is a probable cause for opioid-induced nausea and vomiting. Supporting Evidence - The antiemetic efficacy of butyrophenones and phenothiazines. Additional Effects of Morphine - Increases gastrointestinal secretions. - Delays the movement of intestinal contents towards the colon. Observation - Nausea and vomiting are less common in recumbent patients given morphine. Implication - A vestibular component might play a role in opioid-induced nausea and vomiting. Genitourinary System Effects of Morphine Ureter - Morphine enhances the tone and peristaltic activity. - These effects can be reversed with anticholinergic drugs like atropine. Urination - Morphine causes urinary urgency by increasing detrusor muscle tone. - Enhances the tone of the urinary sphincter, making voiding difficult. Antidiuresis - In animals, morphine induces antidiuresis due to the release of arginine vasopressin hormone (antidiuretic hormone). In humans: - Morphine doesn't prompt the release of this hormone when administered without painful surgical stimulation. - When given with adequate intravascular fluid volume, urine output remains unchanged. By: VA, September 2023 Stoelting Chapter 7: Review Notes Cutaneous Changes due to Morphine Vasodilation - Morphine causes dilation of cutaneous blood vessels. - This leads to flushing and warmth of the skin, especially in the face, neck, and upper chest. Histamine Release - Partly responsible for the above-mentioned vasodilation. - Likely causes urticaria and erythema observed at the morphine injection site. - Probably responsible for conjunctival erythema and pruritus. Allergic Reaction - Localized skin changes due to histamine release, especially along the vein where morphine is injected, do not indicate an allergy. Placental Transfer of Opioids Placental Transport - Opioids are easily transferred across the placenta. Neonatal Depression - Opioid administration to the mother during labor can depress the neonate. - Effects on neonates are variable. - Morphine may result in greater neonatal depression than meperidine. - Fentanyl, unless given in large doses, does not significantly depress the neonate. Physical Dependence - Chronic maternal opioid use can lead to fetal dependence. Risks with Naloxone - If the neonate is physically dependent due to maternal opioid use, administration of naloxone can trigger a severe neonatal withdrawal syndrome. Drug Interactions with Opioids Enhanced Ventilatory Depressant Effects - Amphetamines, phenothiazines, monoamine oxidase inhibitors, and tricyclic antidepressants can intensify the ventilatory depressant effects of some opioids. Specific Interaction with Monoamine Oxidase Inhibitors - Patients on monoamine oxidase inhibitors may show amplified CNS depression and hyperpyrexia when given an opioid agonist, notably meperidine. Hormonal Changes due to Prolonged Opioid Therapy Influence on Major Axes**: By: VA, September 2023 15 Stoelting Chapter 7: Review Notes - 16 Opioids can impact the hypothalamic-pituitary-adrenal axis and the hypothalamicpituitary-gonadal axis, leading to potential endocrine and immune consequences. Effects on Cortisol - Morphine may result in a continuous decline in plasma cortisol levels. Modulation of Hormone Release - Opioids affect the release of several hormones: - Increase → Prolactin levels go up. - Decrease → There's a reduction in luteinizing hormone, follicle-stimulating hormone, testosterone, and estrogen levels. Opioid Overdose Primary Symptom - The primary sign of opioid overdose is respiratory depression. This is evident by slow breathing, which can advance to a state of not breathing at all (apnea). Pupillary Response: - Pupils are typically small and symmetric (miotic). If there's severe lack of oxygen in the blood (arterial hypoxemia), the pupils dilate (mydriasis). Muscular Response - Muscles become limp (flaccid) and there can be obstruction in the upper airway. Pulmonary Edema - Fluid accumulates in the lungs, but the cause is not clearly understood. Other Severe Symptoms - If arterial hypoxemia continues, it can lead to low blood pressure (hypotension) and seizures. Diagnostic Triad - Three major symptoms hint at opioid overdose: small pupils (miosis), slow or no breathing (hypoventilation), and unconsciousness (coma). Treatment - Immediate treatment includes mechanically assisting the patient's breathing with oxygen and providing an opioid antagonist like naloxone. Concerns with Treatment - Using an opioid antagonist can cause sudden withdrawal symptoms in patients who are dependent on opioids. By: VA, September 2023 Stoelting Chapter 7: Review Notes 17 Availability of Naloxone - With the rise in opioid overdose deaths, having easy access to naloxone, whether via nasal spray or intramuscular injection, outside of hospitals is crucial. Naloxone as a Rescue Drug - Patients on high doses of opioids should be prescribed naloxone as an emergency measure. Ultra-potent Opioids - Extremely large doses of naloxone may be required for overdoses from very potent opioids, such as carfentanil. Provocation of coughing - - Preinduction administration of opioids like fentanyl, sufentanil, or alfentanil can sometimes trigger reflex coughing. The exact cause of this coughing is not well understood but may involve an imbalance in sympathetic and vagal innervation of the airways and/or stimulation of irritant receptors. Morphine and hydromorphone do not typically induce this coughing reaction. Pharmacodynamic Tolerance and Physical Dependence - - - Pharmacodynamic tolerance and physical dependence are common outcomes of repeated opioid agonist administration. Cross-tolerance develops between all opioids, but it is incomplete, as evidenced by the reduced doses needed with opioid rotation. Tolerance can develop without physical dependence, but the opposite does not typically occur. Tolerance is the need for increased doses of an opioid agonist to achieve the same effect previously achieved with a lower dose. It usually takes 2 to 3 weeks to develop with morphine but can occur more quickly with highly potent opioids. Tolerance develops to various effects of opioids, including analgesia, euphoria, sedation, depression of ventilation, and emetic effects, but not to miosis (pupil constriction) and bowel motility effects. Physical dependence on opioids typically takes about 25 days to develop, with some degree of physical dependence occurring after only 48 hours of continuous use. When physical dependence is established, discontinuation of the opioid agonist results in withdrawal symptoms, which can include yawning, diaphoresis, lacrimation, coryza, insomnia, restlessness, abdominal cramps, nausea, vomiting, and diarrhea. By: VA, September 2023 Stoelting Chapter 7: Review Notes 18 - Tolerance to the opioid is rapidly lost during withdrawal, and the withdrawal syndrome can be terminated with a modest dose of opioid agonist, with the required dose decreasing over time. - Pharmacodynamic tolerance to opioids is associated with neurologic changes that occur after long-term exposure to the drugs. One classic explanation for tolerance involves changes at the receptor level, including receptor desensitization. Opioid receptors on cell membranes become desensitized, leading to reduced transcription and a decrease in the absolute number of receptors (downregulation). Another proposed mechanism for tolerance is upregulation of the cyclic adenosine monophosphate (cAMP) system. Opioids acutely inhibit the functional activity of cAMP pathways, but long-term exposure leads to a gradual recovery of cAMP pathways, resulting in tolerance. Increased cAMP synthesis may also be responsible for physical dependence and withdrawal symptoms. Upregulation of cAMP has been demonstrated in the locus ceruleus of the brain, and drugs like clonidine can help suppress withdrawal signs in individuals physically dependent on opioids. Enzyme induction is not responsible for tolerance because it does not lead to an increase in the metabolism rate of opioid agonists. Long-term pharmacodynamic tolerance, characterized by opioid insensitivity, can persist for months or years and likely involves persistent neural adaptation. N-methyl-D-aspartate (NMDA) glutamate receptors play a crucial role in opioid tolerance and increased pain sensitivity. Prolonged opioid exposure activates NMDA receptors through second messenger mechanisms and downregulates spinal glutamate transporters, leading to high synaptic concentrations of glutamate and NMDA receptor activation, which contribute to opioid tolerance and abnormal pain sensitivity. Treatment with small doses of ketamine, an NMDA receptor antagonist, can abolish acute opioid tolerance, supporting the role of NMDA receptors in opioid tolerance. - - - - - By: VA, September 2023 Stoelting Chapter 7: Review Notes 19 Opioid Agonist - Opioid agonists encompass a range of drugs such as morphine, meperidine, fentanyl, sufentanil, alfentanil, and remifentanil. One significant aspect of using opioids in clinical practice is the remarkable variability in dose requirements for pain management among individuals. This variability highlights that standard doses of opioids can lead to either insufficient pain relief or excessive opioid effects. Opioid rotation, or switching to a different opioid, may be considered when increasing the dose of the current opioid does not effectively manage pain. Morphine - Morphine, discovered in 1806 and named after the Greek god of dreams, is the prototype opioid agonist, serving as a reference point for comparing other opioids. In humans, morphine induces various effects, including analgesia (pain relief), euphoria, sedation, and reduced ability to concentrate. Morphine use may also lead to sensations such as nausea, warmth, heaviness in the extremities, dry mouth, and itching, especially around the nose. While morphine does not eliminate the cause of pain, it increases the pain threshold and alters the perception of painful stimuli, making them less painful. Morphine is more effective at relieving continuous, dull pain compared to sharp, intermittent pain. The analgesic effects of morphine are most pronounced when administered before the onset of a painful stimulus. Pharmacokinetics - - - Morphine is well absorbed after intramuscular (IM) administration, typically taking 15 to 30 minutes for onset and 45 to 90 minutes for peak effect. Its clinical duration of action is approximately 4 hours. When administered orally for chronic pain, morphine's absorption from the gastrointestinal tract may be limited. In the perioperative period, morphine is commonly given intravenously (IV), ensuring predictable and rapid onset. IV-administered morphine has a delayed peak effect (equilibration time between blood and brain) of about 15 to 30 minutes, in contrast to opioids like fentanyl and alfentanil. Inhaled morphine from a nebulizer can alleviate dyspnea associated with lung cancer and pleural effusion by affecting afferent nerve pathways in the airways. However, it may lead to significant ventilation depression. The onset and duration of analgesic effects for morphine are similar whether administered IV or inhaled through a pulmonary drug delivery system that produces a fine aerosol. By: VA, September 2023 Stoelting Chapter 7: Review Notes - - - - - - 20 Plasma concentrations of morphine after rapid IV injections do not closely correlate with its pharmacologic effects, mainly due to the delay in the drug's transit across the bloodbrain barrier. Cerebrospinal fluid (CSF) concentrations of morphine peak about 15 to 30 minutes after IV injection and decline more slowly than plasma concentrations. As a result, the analgesic and ventilatory depressant effects of morphine may not be immediately evident after IV administration and persist despite decreasing plasma concentrations. Moderate analgesia typically requires maintaining plasma morphine concentrations of at least 0.05 μg/mL. Only a small fraction of administered morphine gains access to the central nervous system (CNS), estimated at <0.1% at the time of peak plasma concentrations. Reasons for poor penetration of morphine into the CNS include its relatively poor lipid solubility, high degree of ionization at physiologic pH, protein binding, and rapid conjugation with glucuronic acid. Alkalinization of the blood, such as through hyperventilation, can increase the nonionized fraction of morphine, enhancing its passage into the CNS. However, respiratory acidosis, which decreases the nonionized fraction of morphine, results in higher plasma and brain concentrations of morphine compared to normocarbia. Carbon dioxide-induced increases in cerebral blood flow appear to play a more critical role in delivering morphine to the brain than the fraction of the drug existing in either the ionized or nonionized form. Morphine accumulates rapidly in the kidneys, liver, and skeletal muscles, but it does not undergo significant first-pass uptake into the lungs, unlike fentanyl. Metabolism - Morphine is primarily metabolized through conjugation with glucuronic acid, occurring in hepatic and extrahepatic sites, particularly the kidneys. By: VA, September 2023 Stoelting Chapter 7: Review Notes - - - - - - - 21 Approximately 75% to 85% of a morphine dose is metabolized to morphine-3glucuronide, and 5% to 10% to morphine-6-glucuronide, with a ratio of 9:1 between them. Morphine-3-glucuronide is rapidly detectable in the plasma within 1 minute after IV injection and becomes almost 10 times more concentrated than unchanged morphine within 90 minutes. A minor fraction (about 5%) of morphine is demethylated to normorphine, and there may also be some formation of codeine (methylmorphine). Metabolites of morphine are primarily eliminated in the urine, with only 7% to 10% undergoing biliary excretion. Morphine-3-glucuronide is pharmacologically inactive, while morphine-6-glucuronide produces analgesia and respiratory depression through its agonist actions at μ-opioid receptors. Morphine-6-glucuronide has a longer duration of action than morphine, and it is suggested that a significant portion of the analgesic activity attributed to morphine may be due to morphine-6-glucuronide, especially with prolonged morphine administration. Renal metabolism contributes significantly to the total metabolism of morphine, which explains why systemic clearance of morphine is not reduced in patients with hepatic cirrhosis or during the anhepatic phase of liver transplantation. Patients with renal failure may experience impaired elimination of morphine glucuronides, leading to metabolite accumulation and unexpected respiratory depressant effects even with small doses of opioids. The administration of morphine to patients on monoamine oxidase inhibitors can lead to exaggerated effects due to impaired formation of glucuronide conjugates. Elimination Half-Time - - - After IV administration of morphine, the elimination half-time of morphine-3glucuronide is somewhat longer than that of morphine itself. Morphine clearance is reduced, and its elimination half-time is prolonged in neonates, especially during the first 4 days of life, which makes them more sensitive to the respiratory depressant effects of morphine. Elderly individuals have higher plasma morphine concentrations compared to young adults. Patients with renal failure exhibit higher plasma and cerebrospinal fluid (CSF) concentrations of morphine and its metabolites due to a smaller volume of distribution (Vd). There is a potential for the accumulation of morphine-6-glucuronide in such patients, necessitating caution when administering morphine. Colostrum of parturient receiving patient-controlled analgesia (PCA) with morphine contains low concentrations of morphine, making it unlikely that significant amounts of the drug will be transferred to breast-fed neonates. By: VA, September 2023 Stoelting Chapter 7: Review Notes 22 Sex - - Sex can influence opioid analgesia, but the impact varies based on multiple factors, including the specific opioid being used. Morphine tends to have greater analgesic potency and a slower offset in women compared to men. This difference may contribute to higher postoperative opioid consumption in men. Morphine can also cause more significant respiratory depression in women. The clinical significance of these sex-related differences in opioid response can vary depending on factors such as individual pain perception, opioid side effects, and sensitivity to opioids. Thus, the impact may be context-dependent. Side effects - The side effects associated with morphine are typical of other opioid agonists, but their occurrence and severity may differ between opioids. Meperidine - Meperidine (or pethidine) is a synthetic opioid agonist that acts on μ- and κ-opioid receptors. It shares structural similarities with local anesthetics and has been used for intrathecal anesthesia. Meperidine has a chemical structure like atropine and exhibits mild antispasmodic effects on smooth muscle. Pharmacokinetics - Meperidine is approximately one-tenth as potent as morphine. Its duration of action is shorter, typically lasting 2 to 4 hours. Meperidine is absorbed from the gastrointestinal tract, but extensive first-pass hepatic metabolism (up to 80%) limits its oral use. Metabolism - Hepatic metabolism of meperidine is extensive, with around 90% of the drug initially undergoing demethylation to normeperidine and hydrolysis to meperidinic acid. Normeperidine subsequently undergoes hydrolysis to normeperidinic acid. Urinary excretion is the primary elimination route and is pH dependent. Acidification of the urine can enhance meperidine elimination. Normeperidine has an elimination half-time of 15 hours (35 hours in patients with renal failure) and can be detected in urine for up to 3 days after meperidine administration. Normeperidine is approximately half as active as meperidine as an analgesic and can lead to CNS stimulation and toxicity, including myoclonus and seizures, especially in cases of prolonged meperidine administration or impaired renal function. By: VA, September 2023 Stoelting Chapter 7: Review Notes 23 Elimination Half-Time - The elimination half-time of meperidine is 3 to 5 hours. Clearance of meperidine primarily depends on hepatic metabolism. Large doses of meperidine can saturate enzyme systems but do not significantly alter elimination half-time. Approximately 60% of meperidine is bound to plasma proteins. Elderly patients may exhibit decreased plasma protein binding of meperidine, leading to increased concentrations of free drug and apparent increased sensitivity to the opioid. Alcoholics may develop increased tolerance to meperidine and other opioids, likely due to an increased volume of distribution (Vd), resulting in lower plasma concentrations of meperidine for a given dose. Clinical Uses Meperidine - Meperidine is considered adequate for surgery when administered intrathecally. The clinical use of meperidine has declined in recent years. IM injections of meperidine for postoperative analgesia can result in highly variable peak plasma concentrations and time to reach peak concentrations among patients. The minimum analgesic plasma concentration of meperidine varies among patients, with small concentration differences determining the level of pain relief. A plasma meperidine concentration of 0.7 μg/mL is expected to provide postoperative analgesia in about 95% of patients. Normeperidine toxicity has been observed in patients receiving meperidine for PCA (patient-controlled analgesia), making it an unfavorable choice for PCA. Meperidine may be effective in suppressing postoperative shivering, likely due to its activity at κ receptors and α2-adrenergic receptors. Clonidine is more effective than meperidine in reducing postoperative shivering. Meperidine is not suitable for the treatment of diarrhea or as a cough suppressant. High doses of meperidine are not recommended due to negative cardiac inotropic effects and histamine release in some patients. Fentanyl - Fentanyl is a synthetic opioid agonist derived from phenylpiperidine and is structurally related to meperidine. It is significantly more potent than morphine, with analgesic potency ranging from 75 to 125 times greater. Fentanyl was first synthesized in 1960 by Janssen Pharmaceutica and is available as the citrate salt under the trade name Sublimaze. By: VA, September 2023 Stoelting Chapter 7: Review Notes 24 Pharmacokinetics- Fentanyl - - - - Fentanyl has a more rapid onset and shorter duration of action than morphine when administered as a single IV dose. This rapid onset is due to the greater lipid solubility of fentanyl, which allows it to pass more easily through the blood-brain barrier, and the shorter effect-site equilibration time between blood and the brain. Fentanyl's shorter duration of action is attributed to its rapid redistribution to inactive tissue sites, such as fat, skeletal muscles, and the lungs. The lungs act as a significant storage site for fentanyl, with about 75% of the initial dose being taken up by the lungs. When multiple IV doses of fentanyl are administered or continuous infusion is used, these inactive tissue sites can become saturated, leading to a slower decrease in plasma concentration and prolonged analgesia and respiratory depression. Cardiopulmonary bypass has minimal effects on the pharmacokinetics of fentanyl, despite the changes in physiology associated with bypass surgery. Metabolism Fentanyl - - - Fentanyl is extensively metabolized in the body by a process called N-demethylation, leading to the formation of several metabolites, including norfentanyl, hydroxyproprionyl-fentanyl, and hydroxyproprionylnorfentanyl. Norfentanyl is the principal metabolite of fentanyl in humans and is structurally like normeperidine, a metabolite of meperidine. Norfentanyl is excreted by the kidneys and can be detected in the urine for up to 72 hours after a single IV dose of fentanyl. Only a small fraction (less than 10%) of fentanyl is excreted unchanged in the urine. The pharmacologic activity of fentanyl metabolites is believed to be minimal, and they are not considered major contributors to fentanyl's effects. Fentanyl is a substrate for hepatic P-450 enzymes, particularly CYP3A, and is susceptible to drug interactions that can affect its metabolism, although it is less susceptible to such interactions compared to drugs like alfentanil. Drug interactions can result from interference with enzyme activity, potentially leading to altered fentanyl levels in the body. Elimination Half-Time Fentanyl - Despite the clinical impression that fentanyl has a short duration of action, its elimination half-time is longer than that of morphine. The longer elimination half-time of fentanyl is primarily due to its larger volume of distribution (Vd), while the clearance of both opioids is similar. Fentanyl's larger Vd results from its greater lipid solubility, allowing it to rapidly distribute from the plasma to highly vascular tissues such as the brain, lungs, and heart. More than 80% of the injected dose leaves the plasma in less than 5 minutes. By: VA, September 2023 Stoelting Chapter 7: Review Notes - - 25 The plasma concentrations of fentanyl are maintained by slow reuptake from inactive tissue sites, contributing to the persistence of its effects. In elderly patients, the prolonged elimination half-time of fentanyl is primarily attributed to decreased clearance, with Vd remaining unchanged compared to younger adults. This suggests that a given dose of fentanyl will be effective for a longer period in elderly patients. Hepatic cirrhosis does not significantly prolong the elimination half-time of fentanyl, which is different from what is observed in elderly patients. Context-Sensitive Half-Time- Fentanyl - Context-sensitive half-time (CSHT) of fentanyl increases after about 2 hours of continuous infusion. The CSHT of fentanyl becomes longer than sufentanil. This phenomenon is due to the saturation of inactive tissue sites with fentanyl during prolonged infusions. Fentanyl returns from peripheral compartments to the plasma. The tissue reservoir of fentanyl replaces the drug eliminated by hepatic metabolism. This slows down the rate of decrease in plasma fentanyl concentration when the infusion is stopped. Cardiopulmonary Bypass- Fentanyl - All opioids exhibit a decrease in plasma concentration when cardiopulmonary bypass is initiated. Fentanyl experiences a significant decrease due to a portion of the drug adhering to the cardiopulmonary bypass circuit. Opioids with a larger volume of distribution (Vd), such as sufentanil and alfentanil, may offer more stable plasma concentrations during bypass. Cardiopulmonary bypass can prolong the elimination of fentanyl and alfentanil. Clinical uses of fentanyl - - Fentanyl is administered in a wide range of doses, from low doses (1-2 μg/kg IV) for analgesia to larger doses as an adjuvant to inhaled anesthetics to blunt circulatory responses during intubation or changes in surgical stimulation. Timing of IV fentanyl injections should consider the effect-site equilibration time, which is prolonged compared to other opioids like alfentanil and remifentanil. Administering fentanyl before painful surgical stimulation can reduce the subsequent postoperative opioid requirements for analgesia. Large doses of fentanyl (50-150 μg/kg IV) can be used for surgical anesthesia, offering hemodynamic stability, lack of myocardial depression, and suppression of stress responses. By: VA, September 2023 Stoelting Chapter 7: Review Notes 26 - Intrathecal fentanyl (maximal benefit at 25 μg) provides rapid, profound analgesia for early labor with minimal side effects. - Transmucosal fentanyl preparations can be used for preoperative sedation and induction of anesthesia, but they may lead to decreases in breathing frequency, arterial oxygenation, and increased postoperative nausea and vomiting, especially in children. - Transdermal fentanyl patches are used for extended pain management but may lead to acute toxic delirium in some cases, particularly in patients with chronic pain and renal failure. Caution should be exercised in using fentanyl, especially when considering its dosing, route of administration, and potential side effects. Side effects of fentanyl - - The side effects of fentanyl are similar to those of morphine. Persistent or recurrent depression of ventilation is a potential postoperative issue with fentanyl. Secondary peaks in plasma fentanyl concentrations have been observed and may be due to various factors, including sequestration of fentanyl in acidic gastric fluid (ion trapping) or washout of opioid from the lungs during the postoperative period. Monitoring and managing the respiratory effects of fentanyl are crucial to prevent and address potential complications. Cardiovascular effects of fentanyl - Fentanyl, even in large doses, does not release histamine, reducing the likelihood of venous dilatation and hypotension. Fentanyl can depress carotid sinus baroreceptor reflex control of heart rate, especially in neonates, making changes in blood pressure important to monitor. Bradycardia is more prominent with fentanyl compared to morphine and can occasionally lead to decreases in blood pressure and cardiac output. Careful monitoring of cardiovascular parameters is essential during fentanyl anesthesia, particularly in neonates. Seizure activity related to fentanyl and similar opioids - Seizure-like activity can follow rapid IV administration of opioids such as fentanyl, sufentanil, and alfentanil. Distinguishing opioid-induced skeletal muscle rigidity or myoclonus from true seizure activity can be challenging, especially without EEG evidence. High plasma concentrations of opioids may not necessarily result in EEG evidence of seizure activity. Opioids can potentially produce myoclonus due to the depression of inhibitory neurons, leading to clinical symptoms resembling seizures even in the absence of EEG changes. By: VA, September 2023 Stoelting Chapter 7: Review Notes 27 Important information about the effects of fentanyl on somatosensory-evoked potentials and electroencephalogram: - Fentanyl doses exceeding 30 μg/kg IV can produce changes in somatosensory-evoked potentials. These changes, although detectable, do not typically interfere with the use and interpretation of somatosensory-evoked potential monitoring during anesthesia. Opioids like fentanyl can reduce skeletal muscle movement without significantly affecting the EEG. Movement in response to surgical skin incision (used to measure minimum alveolar concentration) primarily reflects a drug's ability to dampen noxious reflexes and may not be the best indicator for assessing consciousness or loss of consciousness. The effect of fentanyl and sufentanil on intracranial pressure (ICP): - - Administration of fentanyl and sufentanil to head injury patients can lead to modest increases (approximately 6-9 mm Hg) in ICP. These increases in ICP are usually accompanied by decreases in mean arterial pressure and cerebral perfusion pressure. Preventing changes in mean arterial pressure during sufentanil administration can mitigate the increases in ICP, suggesting that the autoregulatory response to decreased blood pressure may contribute to this effect. Opioid-induced increases in ICP are observed regardless of the status of cerebral autoregulation, indicating that other mechanisms may also be involved in this response. Drug interactions involving fentanyl: - Analgesic concentrations of fentanyl can greatly enhance the effects of benzodiazepines and reduce the dose needed for propofol. This opioid-benzodiazepine combination exhibits significant synergy in inducing hypnosis and suppressing ventilation, which must be carefully considered in clinical settings to balance patient comfort and potential adverse effects. Sufentanil - Sufentanil is a thienyl analogue of fentanyl, synthesized in 1974. It is 5 to 10 times more potent than fentanyl in terms of analgesic potency. Sufentanil has a greater affinity for opioid receptors compared to fentanyl. Its EC50 (the plasma concentration required for 50% of the maximum EEG slowing) is 12 times more potent than fentanyl. Accidental intrathecal injection of a large dose of sufentanil can lead to transient skeletal muscle spasm, suggesting an irritant effect. By: VA, September 2023 Stoelting Chapter 7: Review Notes 28 pharmacokinetics of sufentanil: - Sufentanil has an elimination half-time intermediate between fentanyl and alfentanil. Cirrhosis of the liver does not significantly affect the elimination half-time of sufentanil. Elderly patients may experience a prolonged elimination half-time when receiving sufentanil for abdominal aortic surgery. Obesity can increase the volume of distribution (Vd) and elimination half-time of sufentanil. Sufentanil has high lipid solubility, allowing for rapid penetration of the blood-brain barrier and quick onset of CNS effects. It undergoes significant first-pass pulmonary uptake, similar to fentanyl. Sufentanil has extensive protein binding (92.5%), with α1-acid glycoprotein being a major contributor. Neonates and infants have lower levels of α1-acid glycoprotein, leading to increased free fraction and enhanced effects of sufentanil compared to older children and adults. Metabolism of sufentanil: - Sufentanil undergoes rapid metabolism through N-dealkylation at the piperidine nitrogen and O-demethylation. The N-dealkylation products are pharmacologically inactive, while desmethyl sufentanil, a metabolite, retains about 10% of the activity of sufentanil. Less than 1% of an administered dose of sufentanil is excreted unchanged in urine. Sufentanil's high lipid solubility leads to maximal renal tubular reabsorption of the free drug and enhanced access to hepatic microsomal enzymes. Extensive hepatic extraction makes the clearance of sufentanil sensitive to changes in hepatic blood flow but not to alterations in the drug-metabolizing capacity of the liver. Sufentanil metabolites are excreted in both urine and feces, with approximately 30% appearing as conjugates. Normal renal function is likely important for the clearance of sufentanil, as impaired renal function can lead to prolonged depression of ventilation and increased plasma concentrations of sufentanil. Context-sensitive half-time of sufentanil: - The context-sensitive half-time of sufentanil is shorter than that of alfentanil for continuous infusions lasting up to 8 hours. This shorter context-sensitive half-time can be attributed in part to the large volume of distribution (Vd) of sufentanil compared to alfentanil. After discontinuing a sufentanil infusion, the decrease in plasma drug concentration is accelerated due to both metabolism and continued redistribution of sufentanil into peripheral tissue compartments. By: VA, September 2023 Stoelting Chapter 7: Review Notes - 29 Sufentanil may offer a more favorable recovery profile when used over an extended period, making it suitable for longer-lasting procedures. In contrast, alfentanil has a pharmacokinetic advantage in treating brief and transient noxious stimuli because its short effect-site equilibration time allows for rapid drug access to the brain and easier titration. Clinical uses of sufentanil: - A single dose of sufentanil (0.1 to 0.4 μg/kg IV) provides a longer duration of analgesia and less depression of ventilation compared to a similar dose of fentanyl (1-4 μg/kg IV). - Sufentanil, given at large doses (18.9 μg/kg IV), leads to quicker induction of anesthesia, earlier emergence from anesthesia, and faster tracheal extubation compared to large doses of morphine or fentanyl. - Sufentanil, like fentanyl, reduces cerebral metabolic oxygen requirements and may either decrease or leave unchanged cerebral blood flow. - Sufentanil can induce bradycardia that may reduce cardiac output. - Delayed depression of ventilation can occur after sufentanil administration. - While large doses of sufentanil or fentanyl generally have minimal hemodynamic effects in patients with good left ventricular function, they may not reliably prevent systemic blood pressure and hormonal (catecholamine) responses to painful stimuli, such as median sternotomy. - Large doses of opioids like sufentanil or fentanyl used for IV induction of anesthesia can cause skeletal muscle rigidity, making positive airway pressure ventilation challenging. This rigidity may reflect upper airway obstruction and can often be resolved with tracheal intubation. Alfentanil - Alfentanil is an analogue of fentanyl, less potent (one-fifth to one-tenth) and with a shorter duration of action (one-third of fentanyl). It was first synthesized in 1976. Alfentanil has a unique advantage compared to fentanyl and sufentanil in that it has a more rapid onset of action, with an effect-site equilibration time of 1.4 minutes, compared to 6.8 minutes for fentanyl and 6.2 minutes for sufentanil, after IV administration. By: VA, September 2023 Stoelting Chapter 7: Review Notes 30 Pharmacokinetics of Alfentanil: - - Alfentanil has a shorter elimination half-time compared to fentanyl and sufentanil. Cirrhosis of the liver, but not cholestatic disease, can prolong the elimination half-time of alfentanil. Renal failure does not significantly alter the clearance or elimination half-time of alfentanil. The elimination half-time of alfentanil is shorter in children (4-8 years old) than in adults due to a smaller volume of distribution in younger patients. Alfentanil's rapid effect-site equilibration is due to its low pKa, which results in nearly 90% of the drug existing in the nonionized form at physiologic pH, facilitating its quick passage across the blood-brain barrier. Alfentanil has a smaller volume of distribution compared to fentanyl, primarily due to lower lipid solubility and higher protein binding. Protein binding of alfentanil is mainly to α1-acid glycoprotein, and this binding is not significantly affected by liver disease. The shorter elimination half-time of alfentanil in children may be attributed to a lower percentage of adipose tissue in this population. Metabolism of Alfentanil: - - - - Alfentanil undergoes hepatic metabolism through two main pathways: piperidine Ndealkylation to noralfentanil and amide N-dealkylation to N-phenylpropionamide. The major metabolite of alfentanil found in urine is noralfentanil, and less than 0.5% of an administered dose is excreted unchanged. Hepatic metabolism of alfentanil is highly efficient, with approximately 96% of the drug being cleared from the plasma within 60 minutes of administration. The wide interindividual variability in alfentanil pharmacokinetics poses challenges in developing reliable infusion regimens to achieve and maintain specific plasma concentrations. The primary factor contributing to this variability is the 10-fold interindividual difference in systemic clearance of alfentanil, which is likely related to variations in hepatic intrinsic clearance. Population variability in the activity of the hepatic enzyme P-450 3A4 (CYP3A4), responsible for alfentanil metabolism and clearance, is believed to underlie the interindividual differences in disposition. Alfentanil clearance is significantly influenced by CYP3A activity, making it a sensitive indicator and probe for CYP3A activity. By: VA, September 2023 Stoelting Chapter 7: Review Notes - 31 Erythromycin has the potential to inhibit the metabolism of alfentanil, leading to a prolonged opioid effect. Context-sensitive half-time of Alfentanil: - - - The context-sensitive half-time of alfentanil is longer than that of sufentanil for infusions up to 8 hours in duration. This phenomenon is partly explained by the large volume of distribution (Vd) of sufentanil. After discontinuation of a continuous infusion of sufentanil, the decrease in plasma drug concentration is influenced by both metabolism and continued redistribution of the drug into peripheral compartments. In contrast, the Vd of alfentanil equilibrates rapidly, which means that peripheral distribution of the drug away from the plasma is not a significant contributor to the decrease in plasma concentration after discontinuation of the alfentanil infusion. Despite the short elimination half-time of alfentanil, it may not necessarily be a superior choice to sufentanil for ambulatory sedation techniques, especially when considering context-sensitive effects during prolonged infusions. Clinical uses of alfentanil: - Alfentanil has a rapid onset and offset of intense analgesia due to its prompt effect-site equilibration. It is commonly used to provide analgesia for acute but transient noxious stimuli, such as laryngoscopy, tracheal intubation, and retrobulbar blocks. Administration of alfentanil s