Drug Interactions PDF

66 c h a p t e r Important Drug Interactions & heir...

66 c h a p t e r Important Drug Interactions & heir T Mechanisms John. orn, harmD, F R H P CCP One of the factors that can alter the response to drugs is the con- the sequence of drug administration. The most important factor current administration of other drugs. There are several mecha- that can mitigate the risk of patient harm is recognition by the nisms by which drugs may interact, but most can be categorized prescriber of a potential interaction followed by appropriate action. as pharmacokinetic (absorption, distribution, metabolism, excre- tion), pharmacodynamic (additive, synergistic, or antagonistic effects), or combined interactions. The general principles of phar- Pharmacokinetic echanisms macokinetics are discussed in Chapters 3 and 4; the general prin- M ciples of pharmacodynamics in Chapter 2. The gastrointestinal absorption of drugs may be affected by con- Botanical medications (“herbals”) may interact with each other current use of other agents that (1) have a large surface area upon or with conventional drugs. Unfortunately, botanicals are much which the drug can be adsorbed, (2) bind or chelate, (3) alter gastric less well studied than other drugs, so information about their pH, (4) alter gastrointestinal motility, or (5) affect transport pro- interactions is scanty. Pharmacodynamic herbal interactions are teins such as P-glycoprotein and organic anion transporters. One described in Chapter 64. Pharmacokinetic interactions that have must distinguish between effects on absorption rate and effects on been documented (eg, St. John’s wort) are listed in Table 66–1. extent of absorption. A reduction in only the absorption rate of a Knowledge of the mechanism by which a given drug interaction drug is seldom clinically important, whereas a reduction in the occurs is often clinically useful, since the mechanism may influence extent of absorption is clinically important if it results in subthera- both the time course and the methods of circumventing the inter- peutic serum concentrations. action. Some important drug interactions occur as a result of two The mechanisms by which drug interactions alter drug distri- or more mechanisms. bution include (1) competition for plasma protein binding, (2) displacement from tissue binding sites, and (3) alterations in local tissue barriers, eg, P-glycoprotein inhibition in the blood-brain PREDICTABILITY OF DRUG barrier. Although competition for plasma protein binding can INTERACTIONS increase the free concentration (and thus the effect) of the dis- placed drug in plasma, the increase will be transient owing to a The designations listed in Table 66–1 are used here to estimate the compensatory increase in drug disposition. The clinical impor- predictability of the drug interactions. These estimates are intended tance of protein binding displacement has been overemphasized; to indicate simply whether or not the interaction will occur, and current evidence suggests that such interactions are unlikely to they do not always mean that the interaction is likely to produce result in adverse effects. Displacement from tissue binding sites an adverse effect. Whether or not the interaction occurs (precipi- would tend to transiently increase the blood concentration of the tant drug produces a measurable change in the object drug) and displaced drug. produces an adverse effect depends on both patient- and drug- The metabolism of drugs can be stimulated or inhibited by con- specific factors. Patient factors can include intrinsic drug clearance, current therapy, and the importance of the effect varies from negligible genetics, gender, concurrent diseases, and diet. Drug-specific fac- to dramatic. Drug metabolism primarily occurs in the liver and the wall tors include dose, route of administration, drug formulation, and of the small intestine, but other sites include plasma, lung, and kidney. 1118 https://kat.cr/user/Blink99/ Katzung-Ch66_p1118-1132.indd 1118 24/10/14 11:19 PM  CHAPTER 66 Important Drug Interactions & Their Mechanisms     1119 TABLE 66–1 Important drug interactions. Drug or Drug Group Properties Promoting Drug Interaction Clinically Documented Interactions Alcohol Chronic alcoholism results in enzyme induction. Acetaminophen: [NE] Increased formation of hepatotoxic Acute alcoholic intoxication tends to inhibit drug acetaminophen metabolites (in chronic alcoholics). metabolism (whether person is alcoholic or not). Acitretin: [P] Increased conversion of acitretin to etretinate (teratogenic). Severe alcohol-induced hepatic dysfunction may inhibit ability to metabolize drugs. Disulfiram-like Anticoagulants, oral: [NE] Increased hypoprothrombinemic effect reaction in the presence of certain drugs. with acute alcohol intoxication. Additive central nervous system depression with Central nervous system depressants: [HP] Additive or synergistic other central nervous system depressants. central nervous system depression. Insulin: [NE] Acute alcohol intake may increase hypoglycemic effect of insulin (especially in fasting patients). Drugs that may produce a disulfiram-like reaction: Cephalosporins: [NP] Disulfiram-like reactions are noted with cefamandole, cefoperazone, cefotetan, and moxalactam. Chloral hydrate: [NP] Mechanism not established. Disulfiram: [HP] Inhibited aldehyde dehydrogenase. Metronidazole: [NP] Mechanism not established. Sulfonylureas: [NE] Chlorpropamide is most likely to produce a disulfiram-like reaction; acute alcohol intake may increase hypoglycemic effect (especially in fasting patients). Allopurinol Inhibits hepatic drug-metabolizing enzymes. Anticoagulants, oral: [NP] Increased hypoprothrombinemic effect. Febuxostat (another drug used in gout) will also Azathioprine: [P] Decreased azathioprine detoxification resulting in inhibit the metabolism of azathioprine and increased azathioprine toxicity. mercaptopurine. Mercaptopurine: [P] Decreased mercaptopurine metabolism resulting in increased mercaptopurine toxicity. Antacids Antacids may adsorb drugs in gastrointestinal Atazanavir: [P] Decreased absorption of atazanavir (requires acid for tract, thus reducing absorption. Antacids tend to absorption). speed gastric emptying, thus delivering drugs to Dasatinib: [P] Decreased absorption of dasatinib. absorbing sites in the intestine more quickly. Some antacids (eg, magnesium hydroxide Digoxin: [NP] Decreased gastrointestinal absorption of digoxin. with aluminum hydroxide) alkalinize the urine Indinavir: [P] Decreased absorption of indinavir (requires acid for somewhat, thus altering excretion of drugs absorption). sensitive to urinary pH. Iron: [P] Decreased gastrointestinal absorption of iron with calcium-containing antacids. Itraconazole: [P] Reduced gastrointestinal absorption of itraconazole due to increased pH (itraconazole requires acid for dissolution). Ketoconazole: [P] Reduced gastrointestinal absorption of ketoconazole due to increased pH (ketoconazole requires acid for dissolution). Quinolones: [HP] Decreased gastrointestinal absorption of ciprofloxa- cin, norfloxacin, and enoxacin (and probably other quinolones). Rosuvastatin: [P] Decreased absorption of rosuvastatin. Salicylates: [P] Increased renal clearance of salicylates due to increased urine pH; occurs only with large doses of salicylates. Sodium polystyrene sulfonate: [NE] Binds antacid cation in gut, resulting in metabolic alkalosis. Tetracyclines: [HP] Decreased gastrointestinal absorption of tetracyclines. Thyroxine: [NP] Reduced gastrointestinal absorption of thyroxine. Anticoagulants, oral Warfarin, apixaban, dabigatran, rivaroxaban Drugs that may increase anticoagulant effect: elimination inducible. Susceptible to inhibition Acetaminophen: [NE] Impaired synthesis of clotting factors. of CYP2C9 (warfarin), CYP3A4 (apixaban, rivaroxaban), and P-glycoprotein (apixaban, Amiodarone: [P] Inhibited anticoagulant metabolism. dabigatran, rivaroxaban). Warfarin highly bound Anabolic steroids: [P] Altered clotting factor disposition? to plasma proteins. Anticoagulation response Chloramphenicol: [NE] Decreased dicumarol metabolism altered by drugs that affect clotting factor (probably also warfarin). synthesis or catabolism. E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. (continued) Katzung-Ch66_p1118-1132.indd 1119 24/10/14 11:19 PM  1120 S ion X Special Topics      ect BL 66–1 mportant drug interactions. ( ontinued) TA E I C Drug or Drug Group Properties Promoting Drug nteraction linically Documented nteractions I C I nticoagulants, oral imetidine: [HP] Decreased warfarin metabolism. A C (cont.) lofibrate: [P] Mechanism not established. C lopidogrel: [NP] Decreased warfarin metabolism and inhibits platelet C function. Danazol: [NE] Impaired synthesis of clotting factors? Dextrothyroxine: [P] Enhanced clotting factor catabolism? Disulfiram: [P] Decreased warfarin metabolism. favirenz: [NP] Decreased warfarin metabolism. E rythromycin: [NP] Probably inhibits anticoagulant metabolism. E Fluconazole: [P] Decreased warfarin metabolism. Fluoxetine: [P] Decreased warfarin metabolism. Gemfibrozil: [NE] Mechanism not established. etoconazole: [P] Decreased apixaban, dabigatran, rivaroxaban K elimination. Lovastatin: [NP] Decreased warfarin metabolism. etronidazole: [P] Decreased warfarin metabolism. M iconazole: [NE] Decreased warfarin metabolism. M onsteroidal anti-inflammatory drugs ( Ds): [P] Inhibition of N NSAI platelet function, gastric erosions; some agents increase hypoprothrom- binemic response (unlikely with diclofenac, ibuprofen, or naproxen). Propafenone: [NE] Probably decreases anticoagulant metabolism. Quinidine: [NP] Additive hypoprothrombinemia. itonavir: [P] Decreased apixaban, dabigatran, rivaroxaban elimination. R alicylates: [HP] Platelet inhibition with aspirin but not with other S salicylates; [P] large doses have hypoprothrombinemic effect. imvastatin: [NP] Decreased warfarin metabolism. S ulfinpyrazone: [NE] Inhibited warfarin metabolism. S ulfonamides: [NE] Inhibited warfarin metabolism. S hyroid hormones: [P] Enhanced clotting factor catabolism. T rimethoprim-sulfamethoxazole: [P] Decreased warfarin metabolism. T Verapamil: [P] Decreased apixaban, dabigatran, rivaroxaban elimination. Voriconazole: [NP] Decreased warfarin metabolism. See also Alcohol; Allopurinol. Drugs that may decrease anticoagulant effect: minoglutethimide: [P] Increased metabolism of anticoagulant. A Barbiturates: [P] Increased metabolism of anticoagulant. Bosentan: [P] Increased metabolism of anticoagulant. arbamazepine: [P] Increased elimination of anticoagulant. C holestyramine: [P] Reduced absorption of anticoagulant. C Glutethimide: [P] Increased metabolism of anticoagulant. afcillin: [NE] Increased metabolism of anticoagulant. N Phenytoin: [NE] Increased metabolism of anticoagulant.; Anticoagulant effect may increase transiently at start of phenytoin therapy due to protein-binding displacement of warfarin. Primidone: [P] Increased metabolism of anticoagulant. ifabutin: [P] Increased elimination of anticoagulant. R ifampin: [P] Increased elimination of anticoagulant. R t. John’s wort: [NE] Increased elimination of anticoagulant. S Effects of anticoagulants on other drugs: ypoglycemics, oral: [P] Dicumarol inhibits hepatic metabolism of H tolbutamide and chlorpropamide. Phenytoin: [P] Dicumarol inhibits metabolism of phenytoin. E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. (continued) https://kat.cr/user/Blink99/ Katzung-Ch66_p1118-1132.indd 1120 24/10/14 11:19 PM  CHAPTER 66 Important Drug Interactions & Their Mechanisms     1121 TABLE 66–1 Important drug interactions. (Continued) Drug or Drug Group Properties Promoting Drug Interaction Clinically Documented Interactions Antidepressants, Inhibition of amine uptake into postganglionic Amiodarone: [P] Decreased antidepressant metabolism. tricyclic and adrenergic neuron. Antimuscarinic effects may Barbiturates: [P] Increased antidepressant metabolism. heterocyclic be additive with other antimuscarinic drugs. Metabolism inducible. Susceptible to inhibition Bupropion: [NE] Decreased antidepressant metabolism. of metabolism via CYP2D6, CYP3A4, and other Carbamazepine: [NP] Enhanced metabolism of antidepressants. CYP450 enzymes. Cimetidine: [P] Decreased antidepressant metabolism. Clonidine: [P] Decreased clonidine antihypertensive effect. Guanadrel: [P] Decreased uptake of guanadrel into sites of action. Guanethidine: [P] Decreased uptake of guanethidine into sites of action. Haloperidol: [P] Decreased antidepressant metabolism. Monoamine oxidase inhibitors (MAOIs): [NP] Some cases of excitation, hyperpyrexia, mania, and convulsions, especially with serotonergic antidepressants such as clomipramine and imipramine, but many patients have received combination without ill effects. Quinidine: [NP] Decreased antidepressant metabolism. Rifampin: [P] Increased antidepressant metabolism. Selective serotonin reuptake inhibitors (SSRIs): [P] Fluoxetine and paroxetine inhibit CYP2D6 and decrease metabolism of antidepressants metabolized by this enzyme (eg, desipramine). Citalopram, sertraline, and fluvoxamine are only weak inhibitors of CYP2D6, but fluvoxamine inhibits CYP1A2 and CYP3A4 and thus can inhibit the metabolism of antidepressants metabolized by these enzymes. Sympathomimetics: [P] Increased pressor response to norepinephrine, epinephrine, and phenylephrine. Terbinafine: [P] Decreased antidepressant metabolism. Azole antifungals Inhibition of CYP3A4 (itraconazole = Antivirals: [P] Decreased metabolism of amprenavir, atazanavir, ketoconazole > posaconazole > voriconazole darunavir, delavirdine, indinavir, lopinavir, nelfinavir, ritonavir, > fluconazole). Inhibition of CYP2C9 (flucon- saquinavir. azole, voriconazole). Inhibition of P-glycoprotein Barbiturates: [P] Increased metabolism of itraconazole, ketoconazole, (itraconazole, ketoconazole, posaconazole). voriconazole. Susceptible to enzyme inducers (itraconazole, ketoconazole, voriconazole). Gastrointestinal Benzodiazepines: [P] Decreased metabolism of alprazolam, midazolam, absorption pH-dependent (itraconazole, triazolam. ketoconazole, posaconazole). Calcium channel blockers: [P] Decreased calcium channel blocker metabolism. Carbamazepine: [P] Decreased carbamazepine metabolism. Potential increased metabolism of azole antifungal. Cisapride: [NP] Decreased metabolism of cisapride; possible ventricular arrhythmias. Colchicine: [P] Decreased metabolism and transport of colchicine. Cyclosporine: [P] Decreased elimination of cyclosporine. Digoxin: [NE] Increased plasma concentrations of digoxin with itraconazole, posaconazole, and ketoconazole. Ergot alkaloids: [P] Decreased metabolism of ergot alkaloids. H2-receptor antagonists: [NE] Decreased absorption of itraconazole, ketoconazole, and posaconazole. HMG-CoA reductase inhibitors: [HP] Decreased metabolism of lovastatin, simvastatin, and, to a lesser extent, atorvastatin. Opioid analgesics: [P] Decreased elimination of alfentanil, fentanyl, methadone, oxycodone, sufentanil. Quinidine: [P] Decreased metabolism of quinidine. Phenytoin: [P] Decreased metabolism of phenytoin with fluconazole and probably voriconazole. (continued) Katzung-Ch66_p1118-1132.indd 1121 24/10/14 11:19 PM  1122 S ion X Special Topics      ect BL 66–1 mportant drug interactions. ( ontinued) TA E I C Drug or Drug Group Properties Promoting Drug nteraction linically Documented nteractions I C I zole antifungals Phosphodiesterase inhibitors: [P] Decreased metabolism of A (cont.) phosphodiesterase inhibitor. Pimozide: [NE] Decreased pimozide metabolism. Proton pump inhibitors (PP s): [P] Decreased absorption of I itraconazole, ketoconazole, and posaconazole. ifabutin: [P] Decreased rifabutin metabolism. Increased metabolism R of itraconazole, ketoconazole, and voriconazole. ifampin: [P] Increased metabolism of itraconazole, ketoconazole, R and voriconazole. irolimus: [P] Decreased elimination of sirolimus. S acrolimus: [P] Decreased elimination of tacrolimus. T See also Antacids; Anticoagulants, oral. Barbiturates Induction of hepatic microsomal drug Beta-adrenoceptor blockers: [P] Increased β-blocker metabolism. metabolizing enzymes and P-glycoprotein. alcium channel blockers: [P] Increased calcium channel blocker Additive central nervous system depression with C metabolism. other central nervous system depressants. entral nervous system depressants: [HP] Additive central nervous C system depression. orticosteroids: [P] Increased corticosteroid metabolism. C C yclosporine: [NE] Increased cyclosporine metabolism. Delavirdine: [P] Increased delavirdine metabolism. Doxycycline: [P] Increased doxycycline metabolism. strogens: [P] Increased estrogen metabolism. E ethadone: [NE] Increased methadone metabolism. M Phenothiazine: [P] Increased phenothiazine metabolism. Protease inhibitors: [NE] Increased protease inhibitor metabolism. Quinidine: [P] Increased quinidine metabolism. irolimus: [NE] Increased sirolimus metabolism. S acrolimus: [NE] Increased tacrolimus metabolism. T heophylline: [NE] Increased theophylline metabolism; reduced T theophylline effect. Valproic acid: [P] Decreased phenobarbital metabolism. See also Anticoagulants, oral; Antidepressants, tricyclic. Beta-adrenoceptor Beta-blockade (especially with nonselective Drugs that may increase b-blocker effect: blockers agents such as propranolol) alters response to miodarone: [P] Decreased metabolism of beta-blockers metabolized sympathomimetics with β-agonist activity (eg, A by CYP2D6 (timolol, propranolol, metoprolol, carvedilol). Enhanced epinephrine, albuterol). Beta blockers that effects on myocardial conduction. undergo extensive first-pass metabolism may be imetidine: [P] Decreased metabolism of β blockers that are cleared affected by drugs capable of altering this process. C primarily by the liver, eg, propranolol. Less effect (if any) on those Beta blockers may reduce hepatic blood flow. cleared by the kidneys, eg, atenolol, nadolol. Diphenhydramine: [P] Decreased metabolism of beta-blockers metabolized by CYP2D6 (timolol, propranolol, metoprolol, carvedilol). elective serotonin reuptake inhibitors ( s): [P] Fluoxetine and S SSRI paroxetine inhibit CYP2D6 and increase concentrations of timolol, propranolol, metoprolol, carvedilol, and nebivolol. erbinafine: [P] Decreased metabolism of beta-blockers metabolized T by CYP2D6 (timolol, propranolol, metoprolol, carvedilol). Drugs that may decrease b-blocker effect: onsteroidal anti-inflammatory drugs ( Ds): [P] Indomethacin N NSAI reduces antihypertensive response; other prostaglandin inhibitors probably also interact. Effects of b blockers on other drugs: lonidine: [NE] Hypertensive reaction if clonidine is withdrawn while C patient is taking propranolol. E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. (continued) https://kat.cr/user/Blink99/ Katzung-Ch66_p1118-1132.indd 1122 24/10/14 11:19 PM  CHAPTER 66 Important Drug Interactions & Their Mechanisms     1123 TABLE 66–1 Important drug interactions. (Continued) Drug or Drug Group Properties Promoting Drug Interaction Clinically Documented Interactions Beta-adrenoceptor Insulin: [P] Inhibition of glucose recovery from hypoglycemia; blockers (cont.) inhibition of symptoms of hypoglycemia (except sweating); increased blood pressure during hypoglycemia. Prazosin: [P] Increased hypotensive response to first dose of prazosin. Sympathomimetics: [P] Increased pressor response to epinephrine (and possibly other sympathomimetics); this is more likely to occur with nonselective β blockers. See also Barbiturates; Theophylline. Bile acid-binding Resins may bind with orally administered drugs Acetaminophen: [NE] Decreased gastrointestinal absorption of resins in gastrointestinal tract. Resins may bind in gas- acetaminophen. trointestinal tract with drugs that undergo Digitalis glycosides: [NE] Decreased gastrointestinal absorption of enterohepatic circulation, even if the latter are digitoxin (possibly also digoxin). given parenterally. Furosemide: [P] Decreased gastrointestinal absorption of furosemide. Methotrexate: [NE] Reduced gastrointestinal absorption of methotrexate. Mycophenolate: [P] Reduced gastrointestinal absorption of mycophenolate. Thiazide diuretics: [P] Reduced gastrointestinal absorption of thiazides. Thyroid hormones: [P] Reduced thyroid absorption. See also Anticoagulants, oral. Calcium channel Verapamil, diltiazem, and perhaps nicardipine Atazanavir: [NE] Decreased metabolism of calcium channel blockers. blockers inhibit hepatic drug-metabolizing enzymes and Carbamazepine: [P] Decreased carbamazepine metabolism with P-glycoprotein. Metabolism (via CYP3A4) of diltiazem and verapamil; possible increase in calcium channel blocker diltiazem, felodipine, nicardipine, nifedipine, metabolism. verapamil, and probably other calcium channel blockers subject to induction and inhibition. Cimetidine: [NP] Decreased metabolism of calcium channel blockers. Clarithromycin: [P] Decreased metabolism of calcium channel blockers. Colchicine: [P] Decreased colchicine metabolism and transport with diltiazem and verapamil. Conivaptan: [P] Decreased metabolism of calcium channel blockers. Cyclosporine: [P] Decreased cyclosporine elimination with diltiazem, nicardipine, verapamil. Erythromycin: [P] Decreased metabolism of calcium channel blockers. Phenytoin: [P] Increased metabolism of calcium channel blockers. Rifampin: [P] Increased metabolism of calcium channel blockers. Sirolimus: [P] Decreased sirolimus elimination with diltiazem, nicardipine, verapamil. Tacrolimus: [P] Decreased tacrolimus elimination with diltiazem, nicardipine, verapamil. See also Azole antifungals; Barbiturates; Theophylline; Digitalis glycosides. Carbamazepine Induction of hepatic microsomal drug Atazanavir: [NE] Decreased metabolism of carbamazepine. metabolizing enzymes and P-glycoprotein. Cimetidine: [P] Decreased carbamazepine metabolism. Susceptible to inhibition of metabolism, primarily by CYP3A4. Clarithromycin: [P] Decreased carbamazepine metabolism. Corticosteroids: [P] Increased corticosteroid metabolism. Cyclosporine: [P] Increased cyclosporine metabolism and possible decreased carbamazepine metabolism. Danazol: [P] Decreased carbamazepine metabolism. Doxycycline: [P] Increased doxycycline metabolism. Erythromycin: [NE] Decreased carbamazepine metabolism. Fluvoxamine: [NE] Decreased carbamazepine metabolism. Estrogens: [P] Increased estrogen metabolism. (continued) Katzung-Ch66_p1118-1132.indd 1123 24/10/14 11:19 PM  1124 S ion X Special Topics      ect BL 66–1 mportant drug interactions. ( ontinued) TA E I C Drug or Drug Group Properties Promoting Drug nteraction linically Documented nteractions I C I arbamazepine aloperidol: [P] Increased haloperidol metabolism. C H (cont.) soniazid: [P] Decreased carbamazepine metabolism. I efazodone: [NE] Decreased carbamazepine metabolism. N Propoxyphene: [HP] Decreased carbamazepine metabolism and possible increased propoxyphene metabolism. ifampin: [P] Increased carbamazepine metabolism. R elective serotonin reuptake inhibitors ( s): [NE] Fluoxetine and S SSRI fluvoxamine decrease carbamazepine metabolism. irolimus: [P] Increased sirolimus metabolism. S t. John’s wort: [P] Increased carbamazepine metabolism. S acrolimus: [P] Increased tacrolimus metabolism. T heophylline: [NE] Increased theophylline metabolism. T See also Anticoagulants, oral; Antidepressants, tricyclic; Azole antifungals; Calcium channel blockers. hloramphenicol Inhibits hepatic drug-metabolizing enzymes. Phenytoin: [P] Decreased phenytoin metabolism. C ulfonylurea hypoglycemics: [P] Decreased sulfonylurea metabolism. S See also Anticoagulants, oral. imetidine Inhibits hepatic microsomal drug-metabolizing A tazanavir: [NP] Decreased absorption of atazanavir (requires acid for C enzymes. (Ranitidine, famotidine, and nizatidine absorption; other H2 blockers and proton pump inhibitors would be do not.) May inhibit the renal tubular secretion expected to have the same effect). of weak bases. Benzodiazepines: [P] Decreased metabolism of alprazolam, chlordiazepoxide, diazepam, halazepam, prazepam, and clorazepate but not oxazepam, lorazepam, or temazepam. armustine: [NE] Increased bone marrow suppression. C Dofetilide: Decreased renal excretion of dofetilide. ndinavir: [NP] Decreased absorption of indinavir (requires acid for I absorption; other H2 blockers and proton pump inhibitors would be expected to have the same effect). Lidocaine: [P] Decreased metabolism of lidocaine; increased serum lidocaine concentrations. Phenytoin: [NE] Decreased phenytoin metabolism; increased serum phenytoin concentrations. Procainamide: [P] Decreased renal excretion of procainamide; increased serum procainamide concentrations. Quinidine: [P] Decreased metabolism of quinidine; increased serum quinidine concentrations. heophylline: [P] Decreased theophylline metabolism; increased T plasma theophylline concentrations. See also Anticoagulants, oral; Antidepressants, tricyclic; Azole antifungals; β-adrenoceptor blockers; Calcium channel blockers; Carbamazepine. isapride Susceptible to inhibition of metabolism by tazanavir: [NE] Decreased metabolism of cisapride; possible C A CYP3A4 inhibitors. High cisapride serum concen- ventricular arrhythmia. trations can result in ventricular arrhythmias. larithromycin: [P] Decreased metabolism of cisapride; possible C ventricular arrhythmia. yclosporine: [NE] Decreased metabolism of cisapride; possible C ventricular arrhythmia. rythromycin: [P] Decreased metabolism of cisapride; possible E ventricular arrhythmia. efazodone: [NP] Possibly decreased metabolism of cisapride by N CYP3A4; possible ventricular arrhythmia. itonavir: [E] Decreased metabolism of cisapride; possible ventricular R arrhythmia. E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. (continued) https://kat.cr/user/Blink99/ Katzung-Ch66_p1118-1132.indd 1124 24/10/14 11:19 PM  CHAPTER 66 Important Drug Interactions & Their Mechanisms     1125 TABLE 66–1 Important drug interactions. (Continued) Drug or Drug Group Properties Promoting Drug Interaction Clinically Documented Interactions Cisapride (cont.) Selective serotonin reuptake inhibitors (SSRIs): [NP] Fluvoxamine inhibits CYP3A4 and probably decreases cisapride metabolism; possi- ble ventricular arrhythmia. See also Azole antifungals. Colchicine Susceptible to inhibition of CYP3A4 metabolism Amiodarone: [NP] Decreased colchicine metabolism and transport. and P-glycoprotein transport. Amprenavir: [P] Decreased colchicine metabolism. Boceprevir: [P] Decreased metabolism of colchicine. Carbamazepine: [P] Increased metabolism of colchicine. Clarithromycin: [P] Decreased colchicine metabolism and transport. Conivaptan: [P] Decreased metabolism of colchicine. Cyclosporine: [P] Decreased colchicine metabolism and transport. Diltiazem: [P] Decreased colchicine elimination. Dronedarone: [NE] Decreased colchicine transport. Erythromycin: [P] Decreased colchicine metabolism and transport. Fluconazole: [P] Decreased colchicine elimination. Imatinib: [P] Decreased colchicine elimination. Nefazodone: [NE] Decreased colchicine metabolism. Posaconazole: [P] Decreased colchicine elimination. Rifampin: [P] Increased colchicine metabolism. Ritonavir: [P] Decreased colchicine metabolism. Verapamil: [P] Decreased colchicine elimination. See also Azole antifungals, Calcium channel blockers. Cyclosporine Metabolism inducible. Susceptible to inhibition Aminoglycosides: [NE] Possible additive nephrotoxicity. of elimination by CYP3A4 and P-glycoprotein. Amphotericin B: [NE] Possible additive nephrotoxicity. (Tacrolimus and sirolimus appear to have similar interactions.) Drugs that may increase cyclosporine effect: Amiodarone: [P] Decreased cyclosporine elimination. Amprenavir: [P] Decreased cyclosporine elimination. Androgens: [NE] Increased serum cyclosporine. Atazanavir: [NE] Decreased metabolism of cyclosporine. Clarithromycin: [P] Decreased cyclosporine elimination. Erythromycin: [NP] Decreased cyclosporine elimination. Indinavir: [P] Decreased cyclosporine elimination. Lovastatin: [NP] Decreased metabolism of lovastatin. Myopathy and rhabdomyolysis noted in patients taking lovastatin and cyclosporine. Nefazodone: [P] Decreased cyclosporine metabolism. Quinupristin: [P] Decreased cyclosporine metabolism. Ritonavir: [P] Decreased cyclosporine elimination. Simvastatin: [NP] Decreased metabolism of simvastatin. Myopathy and rhabdomyolysis noted in patients taking simvastatin and cyclosporine. Drugs that may decrease cyclosporine effect: Barbiturates: [P] Increased cyclosporine elimination. Bosentan: [P] Increased cyclosporine elimination. Carbamazepine: [P] Increased cyclosporine elimination. Efavirenz: [P] Increased cyclosporine metabolism. Phenytoin: [P] Increased cyclosporine metabolism. Rifabutin: [NP] Increased cyclosporine metabolism. Rifampin: [P] Increased cyclosporine elimination. St. John’s wort: [NP] Increased cyclosporine elimination. See also Azole antifungals; Barbiturates; Calcium channel blockers. (continued) Katzung-Ch66_p1118-1132.indd 1125 24/10/14 11:19 PM  1126 S ion X Special Topics      ect BL 66–1 mportant drug interactions. ( ontinued) TA E I C Drug or Drug Group Properties Promoting Drug nteraction linically Documented nteractions I C I Digitalis glycosides Digoxin susceptible to alteration of Drugs that may increase digitalis effect: gastrointestinal absorption. Renal and nonrenal miodarone: [P] Increased digoxin plasma concentrations. excretion of digoxin susceptible to inhibition. A zithromycin: [NP] Increased plasma concentration of digoxin. Digitalis toxicity may be increased by drug- A induced electrolyte imbalance (eg, hypokalemia). larithromycin: [P] Increased plasma concentration of digoxin. C yclosporine: [P] Increased digoxin plasma concentrations. C Diltiazem: [P] Increased digoxin plasma concentration and additive AV conduction effects. rythromycin: [NP] Increased plasma concentration of digoxin. E Potassium-depleting drugs: [P] Increases likelihood of digitalis toxicity. Propafenone: [P] Increases digoxin plasma concentrations. Quinidine: [HP] Increased digoxin plasma concentrations; displaces digoxin from tissue binding sites. itonavir: [P] Increases digoxin plasma concentrations. R pironolactone: [NE] Increased digoxin plasma concentrations. S Verapamil: [P] Increased digoxin plasma concentrations and additive AV conduction effects. See also Azole antifungals. Drugs that may decrease digitalis effect: aolin-pectin: [P] Decreased gastrointestinal digoxin absorption. K ifampin: [NE] Increased metabolism of digitoxin and elimination of R digoxin. ulfasalazine: [NE] Decreased gastrointestinal digoxin absorption. S See also Antacids; Bile acid-binding resins. Disulfiram Inhibits CYP2C9. Inhibits aldehyde Benzodiazepines: [P] Decreased metabolism of chlordiazepoxide and dehydrogenase. diazepam but not lorazepam and oxazepam. etronidazole: [NE] Confusion and psychoses reported in patients M receiving this combination; mechanisms unknown. Phenytoin: [P] Decreased phenytoin metabolism. See also Alcohol; Anticoagulants, oral. strogens Metabolism inducible. Enterohepatic circulation mpicillin: [NP] Interruption of enterohepatic circulation of estrogen; E A of estrogen may be interrupted by alteration in possible reduction in oral contraceptive efficacy. Some other oral bowel flora (eg, due to antibiotics). antibiotics may have a similar effect. Bosentan: [NP] Enzyme induction leading to reduced estrogen effect. orticosteroids: [P] Decreased metabolism of corticosteroids leading C to increased corticosteroid effect. Griseofulvin: [NE] Increased estrogen metabolism, possible reduction in oral contraceptive efficacy. Phenytoin: [P] Increased estrogen metabolism; possible reduction in oral contraceptive efficacy. Primidone: [P] Increased estrogen metabolism; possible reduction in oral contraceptive efficacy. ifabutin: [P] Increased estrogen metabolism; possible reduction in R oral contraceptive efficacy. ifampin: [P] Increased estrogen metabolism; possible reduction in R oral contraceptive efficacy. t. John’s wort: [P] Increased estrogen metabolism; possible S reduction in oral contraceptive efficacy. See also Barbiturates; Carbamazepine. G- o reductase Lovastatin, simvastatin, and, to a lesser extent, miodarone: [NP] Decreased statin metabolism. A HM C A inhibitors atorvastatin are susceptible to CYP3A4 inhibi- tazanavir: [NP] Decreased statin metabolism. tors; lovastatin, simvastatin, and, to a lesser A Boceprevir: [P] Decreased statin metabolism. extent, atorvastatin are susceptible to CYP3A4 inducers; increased risk of additive myopathy risk Bosentan: [P] Increased statin metabolism. with other drugs that can cause myopathy. arbamazepine: [P] Increased statin metabolism. C E, Expected; HP, Highly predictable. Interaction occurs in almost all patients receiving the interacting combination; P, Predictable. Interaction occurs in most patients receiving the combination; NP, Not predictable. Interaction occurs only in some patients receiving the combination; NE, Not established. Insufficient data available on which to base estimate of predictability. (continued) https://kat.cr/user/Blink99/ Katzung-Ch66_p1118-1132.indd 1126 24/10/14 11:19 PM  CHAPTER 66 Important Drug Interactions & Their Mechanisms     1127 TABLE 66–1 Important drug interactions. (Continued) Drug or Drug Group Properties Promoting Drug Interaction Clinically Documented Interactions HMG-CoA reductase Clarithromycin: [P] Decreased statin metabolism. inhibitors (cont.) Clofibrate: [NP] Increased risk of myopathy. Cyclosporine: [P] Decreased statin metabolism. Delavirdine: [P] Decreased statin metabolism. Diltiazem: [NE] Decreased statin metabolism. Erythromycin: [P] Decreased statin metabolism. Gemfibrozil: [NP] Increased plasma lovastatin and simvastatin and increase the risk of myopathy. Imatinib: [P] Decreased statin metabolism. Indinavir: [NE] Decreased statin metabolism. Nefazodone: [NE] Decreased statin metabolism. Phenytoin: [P] Increased statin metabolism. Rifampin: [P] Increased statin metabolism. Ritonavir: [NE] Decreased statin metabolism. St. John’s wort: [NP] Increased statin metabolism. Verapamil: [NE] Decreased statin metabolism. See also Azole antifungals; Cyclosporine. Iron Binds with drugs in gastrointestinal tract, Methyldopa: [NE] Decreased methyldopa absorption. reducing absorption. Mycophenolate: [P] Decreased mycophenolate absorption. Quinolones: [P] Decreased absorption of ciprofloxacin and other quinolones. Tetracyclines: [P] Decreased absorption of tetracyclines; decreased efficacy of iron. Thyroid hormones: [P] Decreased thyroxine absorption. See also Antacids. Levodopa Levodopa degraded in gut prior to reaching Clonidine: [NE] Inhibited antiparkinsonism effect. sites of absorption. Agents that alter Monoamine oxidase inhibitors (MAOIs): [P] Hypertensive reaction gastrointestinal motility may alter degree of (carbidopa prevents the interaction). intraluminal degradation. Anti-parkinsonism effect of levodopa susceptible to inhibition by Papaverine: [NE] Inhibited antiparkinsonism effect. other drugs. Phenothiazines: [P] Inhibited antiparkinsonism effect. Phenytoin: [NE] Inhibited antiparkinsonism effect. Pyridoxine: [P] Inhibited antiparkinsonism effect (carbidopa prevents the interaction). See also Antimuscarinics. Lithium Renal lithium excretion sensitive to changes in ACE inhibitors (ACEIs): [NE] Probably reduce renal clearance of lithium; sodium balance. (Sodium depletion tends to increase lithium effect. cause lithium retention.) Susceptible to drugs Angiotensin II receptor blockers (ARBs): [NE] Probably reduce renal enhancing central nervous system lithium clearance of lithium; increase lithium effect. toxicity. Diuretics (especially thiazides): [P] Decreased excretion of lithium; furosemide may be less likely to produce this effect than thiazide diuretics. Haloperidol: [NP] Occasional cases of neurotoxicity in manic patients, especially with large doses of one or both drugs. Methyldopa: [NE] Increased likelihood of central nervous system lithium toxicity. Nonsteroidal anti-inflammatory drugs (NSAIDs): [NE] Reduced renal lithium excretion (except sulindac and salicylates). Theophylline: [P] Increased renal excretion of lithium; reduced lithium effect. (continued) Katzung-Ch66_p1118-1132.indd 1127 24/10/14 11:19 PM  1128 S ion X Special Topics      ect BL 66–1 mportant drug interactions. ( ontinued) TA E I C Drug or Drug Group Properties Promoting Drug nteraction linically Documented nteractions