Drug Interactions

Educational Objectives

The goal of this program is to improve awareness and understanding of drug interactions. After hearing and assimilating this program, the clinician will be better able to:

1. Evaluate the pharmacokinetics of induction and inhibition of the 5 clinically relevant isozymes of cytochrome P450.
2. Identify the effects of induction or inhibition of cytochrome P450 isozymes on the metabolism of the various classes of anesthetic medications.
3. Recognize the effects of induction of the cytochrome P450 isozyme CYP2E1 on acetaminophen metabolism.
4. Assess the effects of tolerance and cross-tolerance among opioids and between opioids and stimulants.
5. Choose an appropriate anesthesia strategy for a patient with enzyme deficiencies, eg, with a cholinesterase deficiency.

Summary

Pharmacokinetic Drug Interactions (DIs)

6 mechanisms: induction (one drug causes an increase in the metabolism of another by increasing the number of enzyme molecules); inhibition (one drug causes a decrease in the metabolism of the other drug); displacement (one drug displaces another from its binding site, thereby increasing the concentration and effect of the active form of the drug; not common in clinical practice); inhibition of the renal excretion of another drug (not common); interaction (drugs interact chemically, causing inactivation of the drug); and inhibition of the gastrointestinal (GI) absorption of one drug by another (but very few anesthetic medications are given orally)

Induction and inhibition of drug metabolism: there are ≈5 clinically relevant isozymes of cytochrome P450 (CYP), CYP1A2, CYP2B6, CYP2D6, CYP2E1, CYP3A4; CYP1A2 is inhibited by ciprofloxacin and fluvoxamine and is induced by the polycyclic aromatic hydrocarbons found in cigarette smoke and the char of barbecued meat; CYP2B6 is inhibited by the antifungal agent voriconazole and related drugs, and is induced by medications that include anticonvulsants (carbamazepine, phenytoin, phenobarbital), antimicrobials (rifampin), and multiple drugs used to treat HIV infection; CYP2D6 has the greatest interindividual variability; among individuals of Western European descent, ≈10% have no functional enzyme at all, in contrast, people whose ancestry is from the Arabian Peninsula often have extra copies of the 2D6 gene and are considered ultrarapid metabolizers of drugs that are substrates for CYP2D6; important inhibitors of CYP2D6 include the antidepressant bupropion and multiple selective serotonin reuptake inhibitor (SSRI) antidepressants; CYP2E1 is induced by ethanol and isoniazid (the drug most commonly used to treat tuberculosis); CYP3A4 is the most important isozyme of CYP in terms of the number of medications that are substrates; important inhibitors of CYP3A4 include the antiemetic drug aprepitant, the macrolide antibiotics clarithromycin and erythromycin, the antifungal agents fluconazole and itraconazole, the protease inhibitors used to treat HIV infection, and grapefruit juice; people who drink a large amount of grapefruit juice often have clinically relevant DIs resulting in inhibition of drug metabolism via the CYP3A4 isozyme; important inducers of CYP3A4 include anticonvulsants in the barbiturate class, carbamazepine, phenytoin, the antimicrobial agent rifampin, and the over-the-counter herb St. John's wort (the most important herb in terms of DIs overall)

Classes of Anesthetic Medications

Muscle relaxants: those in the benzylisoquinoline class, cisatracurium and atracurium, are metabolized by multiple esterases and are therefore involved in few (if any) clinically relevant DIs; in contrast, the steroidal muscle relaxants vecuronium and rocuronium are metabolized by CYP3A4 and are involved in numerous clinically relevant DIs; CYP3A4 inhibitors often cause a potentiation of the muscle-relaxant effect; in contrast, CYP3A4 inducers often cause a very short duration action of rocuronium and vecuronium; the depolarizing muscle relaxant succinylcholine is metabolized by pseudocholinesterase; this enzyme may be inhibited by echothiophate, a drug used topically for glaucoma that is primarily a cholinesterase inhibitor but that also inhibits pseudocholinesterase; patients using echothiophate topically often experience systemic inhibition of pseudocholinesterase, resulting in a marked prolongation of the activity of succinylcholine

Hypnotic agents: the hypnotics used in anesthesia (barbiturates, propofol, ketamine, and etomidate) have their effects terminated primarily by redistribution, so they are not involved in clinically relevant DIs; barbiturates are broad-spectrum inducers of multiple isozymes of CYP and therefore cause numerous DIs with other medications that are metabolized by CYP; ketamine is metabolized by multiple isozymes of CYP, and therefore the induction or inhibition of any one of these isozymes does not produce clinically relevant DIs; etomidate is an inhibitor of an important mitochondrial enzyme that is not involved in drug metabolism, but it is the enzyme that catalyzes the final step in the biosynthesis of cortisol; therefor, even a single induction dose of etomidate suppresses cortisol synthesis for about 8 to 12 hr; in most patients, this suppression is not thought to be clinically harmful; new etomidate analogs that do not cause long-term suppression of cortisol synthesis are being investigated

Benzodiazepines: like the hypnotic drugs, diazepam and midazolam have their effects terminated primarily by redistribution, and metabolism is generally not important in terminating their effects when the drugs are given as a single bolus or as a few boluses; however, when midazolam is given by continuous infusion, drug metabolism does play a role; midazolam is a substrate of CYP3A4, and when it is given by continuous infusion, if the patient is also receiving a CYP3A4 inhibitor, the drug’s sedating effect will be potentiated; if the patient is receiving an inducer of CYP3A4, the drug’s effect will be less

Opioids

Morphine: metabolized primarily by glucuronosyltransferase, an enzyme that is subject to being induced by barbiturates; the duration of action of morphine may be decreased in patients on a long-term barbiturate

Codeine: a prodrug that has to be metabolized to morphine by CYP2D6 in order to be active as an analgesic; because of huge interindividual variability in underlying and inherent CYP2D6 activities, ≈10% of patients of Western European descent do not derive a meaningful amount of analgesia from codeine, whereas patients with ancestry in the Arabian Peninsula may manifest an ultrarapid metabolizing pattern resulting in an exaggerated effect from even a small dose of codeine

Fentanyl and remifentanil: fentanyl is highly lipid soluble, and when given in the usual doses by bolus injection, its effect is terminated by redistribution; in contrast, when a patient is given a fentanyl infusion or patch, metabolism becomes important in determining the ultimate disposition of the drug; fentanyl is a substrate for CYP3A4, so patients receiving a continuous infusion or using a patch may experience an exaggerated or a lesser effect from the expected dose of fentanyl if they are simultaneously being given an inhibitor or an inducer of CYP3A4; remifentanil is metabolized by tissue esterases, primarily in skeletal muscle, that are also inhibited by echothiophate, so a patient using topical echothiophate may experience a longer than expected effect from the usually short-acting remifentanil

Methadone: one of the few medications that is metabolized by CYP2B6; patients taking methadone long-term may experience a potentiating DI if they are also taking a CYP2B6 inhibitor such as an antifungal agent (eg, voriconazole); conversely, they may experience a lesser than expected effect from methadone when taking a CYP2B6 inducer; these include anticonvulsant drugs (carbamazepine, phenytoin, phenobarbital), rifampin, and many of the antiretroviral drugs used to treat HIV)

Tramadol: a substrate for CYP3A4 that is subject to DI when CYP3A4 inhibitors or inducers are given concurrently; since tramadol also has serotonin reuptake inhibiting activity, an excessive concentration of tramadol due to inhibition of CYP3A4 may not only be manifested as an exaggerated opioid effect, it may also predispose the patient to serotonin syndrome

Inhalational agents: isoflurane and desflurane are negligibly metabolized and therefore participate in no clinically relevant DIs; in contrast, sevoflurane is extensively metabolized by CYP2E1, which is induced by ethanol and isoniazid; patients do not need to drink ethanol to excess to experience a clinically significant induction effect; a person who has an alcoholic drink every day or two may have significantly increased CYP2E1 activity; there are no important DIs with sevoflurane in terms of its metabolism

Acetaminophen: when taken in usual doses, acetaminophen is metabolized primarily to glucuronide or sulfate (≈95% of its metabolism proceeds via these pathways); ≈5% proceeds via hydroxylation of the nitrogen in the molecule that is catalyzed by CYP2E1; this reaction forms the metabolite N-acetyl-p-benzoquinone imine (NAPQI); NAPQI is ordinarily scavenged by glutathione, rendering it nontoxic; however, when the liver's supply of glutathione is exhausted, the NAPQI may react covalently with critical macromolecules in the cell, resulting in cell death; CYP2E1 is induced by ethanol and isoniazid; a patient who has taken either of these substances and is experiencing induction of CYP2E1 will form a greater than usual percentage of NAPQI, resulting in glutathione depletion and death of hepatocytes; the usual recommendation for most patients taking acetaminophen for chronic pain is to limit their daily dose to 4 gm; a patient experiencing induction of CYP2E1 should probably limit themselves to 3 gm per day; accidental overdose of acetaminophen is a major public health problem, as it is now one of the leading causes of hepatic failure leading to transplantation

Local anesthetics: lidocaine is metabolized by CYP2D6 and CYP3A4; a clinically significant DI is unlikely to occur with lidocaine metabolism because both isozymes would need to be simultaneously inhibited; in contrast, ropivacaine is primarily metabolized by CYP1A2, which is inhibited strongly by ciprofloxacin and fluvoxamine (either could lead to a toxic concentration of ropivacaine); the antiemetic agent aprepitant is a strong inhibitor of CYP3A4; its use may result in toxic concentrations of medications that are metabolized by CYP3A4 if they are given by continuous infusion or in multiple repeated bolus doses; these medications include l-fentanyl, fentanyl, midazolam, and tramadol

Pharmacodynamic Interactions

Types: include one drug inducing tolerance to itself or cross-tolerance to another drug in its class or a similar class; 2 drugs may also have additive or synergistic effects when given simultaneously; one medication might be a pharmacologic antagonist of another

Tolerance: the molecular mechanism of most drugs capable of producing the general anesthetic state involves potentiating the activity of the neurotransmitter gamma aminobutyric acid (GABA); medications that potentiate GABA include benzodiazepines, barbiturates, propofol, etomidate, and the volatile agents; ethanol also may act by potentiation of GABA, as well as by producing other effects; tolerance develops with chronic use of all the mentioned medications, and cross-tolerance exists

Tolerance to opioids: occurs when they are administered over a long period of time; the first indication is often a decrease in the duration of analgesia after each dose, but eventually the intensity of the effect declines as well; tolerance may be overcome by an increase in the dose of the opioid; some patients develop profound tolerance and require huge doses to produce analgesia; tolerance involves a simultaneous development of cross-tolerance to other opioid agonists; tolerance develops primarily to depressant effects (eg, analgesia, ventilatory depression, euphoria); less tolerance develops to the stimulant effects of opioids (eg, constipation, pupillary constriction)

Cross-tolerance: cross-tolerance among opioids is often incomplete; when a patient is changed from one opioid analgesic to another at a supposedly equipotent dose, a greater opioid effect than expected may occur; when changing opioids, it is therefore prudent to start at a dose less than the predicted equipotent dose and then evaluate the magnitude of the effect produced by the new drug; the stimulants used to treat attention-deficit/hyperactivity disorder (eg, methylphenidate, amphetamine) have been shown to reverse the general anesthetic state in rats anesthetized with propofol or a volatile agent; although no studies in humans have been performed, it seems prudent to advise patients taking stimulant medications to avoid them on the day of surgery; anticipate the possible need for higher doses or concentrations of anesthetic drugs for patients presenting for unscheduled surgery

Pharmacogenetic Entities

Cholinesterase deficiency: plasma cholinesterase is an enzyme found in the circulation that has no known physiologic role; deficiency comes to light when patients are given succinylcholine and its duration is much longer than expected; physiologic reasons for a decrease in activity include liver disease (leading to decreased protein synthesis) and pregnancy; ≈96% of the population has 2 normal genes for plasma cholinesterase, ≈4% is heterozygous (these individuals have a mild prolongation in the duration of succinylcholine that may not come to medical attention); ≈1 person in 2500 is homozygous for 2 abnormal genes; these patients are essentially unable to metabolize succinylcholine, so its duration is terminated by renal excretion of the unchanged molecule (half-life is ≈30 min); the clinical duration of succinylcholine in these patients is typically ≈2 hr rather than a few minutes; if it appears that succinylcholine is manifesting an unexpectedly long duration of action, the patient should remain under anesthesia and be monitored until recovery, usually 2 to 3 hr with normal renal function

Porphyria: porphyrias result from an enzyme deficiency in the biosynthetic pathway of heme; when a patient receives a medication that induces the first enzyme in this pathway, aminolevulinic acid synthase, delta-aminolevulinic acid accumulates and causes neurotoxicity; all barbiturates and etomidate are contraindicated; among the injectable benzodiazepines, lorazepam in small doses is likely the safest; other commonly used anesthetic drugs are probably safe, including propofol, short-acting muscle relaxants (eg, succinylcholine, rocuronium, cisatracurium), opioids, local anesthetics, volatile anesthetics, and antiemetics

Glucose-6-phosphate dehydrogenase (G6PD) deficiency: this is the most common enzyme deficiency in humans; persons deficient in G6PD may suffer red cell hemolysis when administered certain medications; men are affected far more commonly than women; prevalent in Black people from sub-Saharan Africa and in people from all sides of the Mediterranean; in the United States, ≈10% of males of black African descent are affected; none of the most commonly used anesthetic drugs needs to be withheld in these patients

Readings

Anzenbacherova E et al. Interaction of rocuronium with human liver cytochromes P450. J Pharmacol Sci. 2015;127(2):190-195. doi:10.1016/j.jphs.2014.12.006; Ferrari A et al. Methadone--metabolism, pharmacokinetics and interactions. Pharmacol Res. 2004;50(6):551-559. doi:10.1016/j.phrs.2004.05.002; Kalsi SS et al. Does cytochrome P450 liver isoenzyme induction increase the risk of liver toxicity after paracetamol overdose?. Open Access Emerg Med. 2011;3:69-76. Published 2011 Oct 13. doi:10.2147/OAEM.S24962; Kaufman SE et al. Prolonged neuromuscular paralysis following rapid-sequence intubation with succinylcholine. Ann Pharmacother. 2011;45(4):e21. doi:10.1345/aph.1P753; Kharasch ED. Biotransformation of sevoflurane. Anesth Analg. 1995;81(6 Suppl):S27-S38. doi:10.1097/00000539-199512001-00005; Mustajoki P, Heinonen J. General anesthesia in "inducible" porphyrias. Anesthesiology. 1980;53(1):15-20. doi:10.1097/00000542-198007000-00004; Olkkola KT, Ahonen J. Midazolam and other benzodiazepines. Handb Exp Pharmacol. 2008;(182):335-360. doi:10.1007/978-3-540-74806-9_16; Pelkonen O et al. Inhibition and induction of human cytochrome P450 enzymes: current status. Arch Toxicol. 2008;82(10):667-715. doi:10.1007/s00204-008-0332-8; Zanger UM et al. Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry. Naunyn Schmiedebergs Arch Pharmacol. 2004;369(1):23-37. doi:10.1007/s00210-003-0832-2.

Disclosures

In adherence to ACCME Standards for Commercial Support, Audio Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, members of the faculty and planning committee reported nothing to disclose.

Acknowledgements

Dr. Dershwitz was recorded exclusively for Audio Digest, using virtual teleconference software, in compliance with current social-distancing guidelines during the COVID-19 pandemic. Audio Digest thanks Dr. Dershwitz for his cooperation in the production of this program.

CME/CE INFO

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Lecture ID:

AN632901

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.