Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 61. Drug Interactions

Drug Interactions: Introduction

Drug interactions occur when one drug modifies the actions of another drug in the body. Drug interactions can result from pharmacokinetic alterations, pharmacodynamic changes, or a combination of both. Interactions between drugs in vitro (eg, precipitation when mixed in solutions for intravenous administration) are usually classified as drug incompatibilities, not drug interactions.

Although hundreds of drug interactions have been documented, relatively few are of enough clinical significance to constitute a contraindication to simultaneous use or to require a change in dosage. Some of these are listed in Table 61-1. In patients taking many drugs, however, the likelihood of significant drug interactions is increased. Elderly patients have a high incidence of drug interactions because they often have age-related changes in drug clearance and commonly take multiple medications.

TABLE 61-1 Some important drug interactions.

Drug Causing the Interaction Examples of Drugs Affected Comments Alcohol CNS depressants Additive CNS depression, sedation, ataxia, increased risk of accidents Acetaminophen Increased formation of hepatotoxic metabolites of acetaminophen Antacids Digoxin, iron supplements, fluoroquinolones, ketoconazole, tetracyclines, thyroxine Decreased gut absorption due either to reaction with the affected drug or due to reduced acidity Antihistamines (H1 blockers)

Antimuscarinics, sedatives Additive effects with the drugs affected Antimuscarinic drugs Drugs absorbed from the small intestine Slowed onset of effect because stomach emptying is delayed Barbiturates, especially phenobarbital Azoles, calcium channel blockers, cyclosporine, propranolol, protease inhibitors, quinidine, steroids, warfarin, and many other drugs metabolized in the liver Increased clearance of the affected drugs due to enzyme induction, possibly leading to decreases in drug effectiveness Beta blockers Insulin Masking of symptoms of hypoglycemia Prazosin Increased first-dose syncope Bile acid-binding resins Acetaminophen, digitalis, thiazides, thyroxine Reduced absorption of the affected drug Carbamazepine Cyclosporine, doxycycline, estrogen, haloperidol, theophylline, warfarin Reduced effect of other drugs because of induction of metabolism Cimetidine Benzodiazepines, lidocaine, phenytoin, propranolol, quinidine, theophylline, warfarin Risk of toxicity due to inhibition of metabolism Disulfiram, metronidazole, certain cephalosporins Ethanol Increased hangover effect due to inhibition of aldehyde dehydrogenase Erythromycin Carbamazepine, cisapride, quinidine, sildenafil, SSRIs Risk of toxicity due to inhibition of metabolism Furanocoumarins (grapefruit juice) Alprazolam, atorvastatin, cyclosporine, midazolam Risk of toxicity due to inhibition of metabolism Ketoconazole and other azoles Benzodiazepines, cisapride cyclosporine, fluoxetine, lovastatin, omeprazole, quinidine, tolbutamide, warfarin Risk of toxicity due to inhibition of metabolism MAO inhibitors Catecholamine releasers (amphetamine, ephedrine) Increased norepinephrine in sympathetic nerve endings released by the interacting drugs Tyramine-containing foods and beverages Hypertensive crisis NSAIDs Anticoagulants Increased bleeding tendency because of reduced platelet aggregation Angiotensin-converting enzyme (ACE) inhibitors Decreased antihypertensive efficacy of ACE inhibitor Loop diuretics, thiazides Reduced diuretic efficacy Phenytoin Doxycycline, methadone, quinidine, steroids, verapamil Reduced effect of other drugs because of induction of metabolism Rifampin Azole antifungal drugs, corticosteroids, methadone, sulfonylureas Reduced effect of other drugs because of induction of metabolism Ritonavir Benzodiazepines, cyclosporine, diltiazem, HMG-CoA reductase inhibitors, lidocaine, metoprolol, other HIV protease inhibitors, , SSRIs Risk of toxicity due to inhibition of metabolism Salicylates Corticosteroids Additive toxicity to gastric mucosa Heparin, warfarin Increased bleeding tendency Methotrexate Decreased clearance, causing greater methotrexate toxicity Sulfinpyrazone, probenecid Decreased uricosuric effect Selective serotonin reuptake inhibitors (SSRIs) Monoamine oxidase (MAO) inhibitors, meperidine, tricyclic antidepressants, St. John's wort Serotonin syndrome (hypertension, tachycardia, muscle rigidity, hyperthermia, seizures) Thiazides Digitalis Increased risk of digitalis toxicity because thiazides diminish potassium stores Lithium Increased plasma levels of lithium due to decreased total body water Warfarin Amiodarone, cimetidine, erythromycin, fluconazole, lovastatin, metronidazole Increased anticoagulant effect via inhibition of warfarin metabolism Aspirin, NSAIDs, quinidine, thyroxine Increased anticoagulant effects via pharmacodynamic mechanisms Barbiturates, carbamazepine, phenytoin, rifabutin, rifampin, St. John's wort Decreased anticoagulant effect due to increased clearance of warfarin via induction of hepatic metabolism

High-Yield Terms to Learn

Additive effects The effect of 2 drugs given together is equal to the sum of the responses to the same doses given separately Antagonism The effect of 2 drugs given together is less than the sum of the responses to the same doses given separately Pharmacodynamic interaction A change in the pharmacodynamics of 1 drug caused by the interacting drug (eg, additive action of 2 drugs having similar effects) Pharmacokinetic interaction A change in the pharmacokinetics of 1 drug caused by the interacting drug (eg, an inducer of hepatic enzymes) Synergism The effect of 2 drugs given together is greater than the sum of the 2 responses when they are given separately

Pharmacokinetic Interactions

Interactions Based on Absorption

Absorption from the gastrointestinal tract may be influenced by agents that bind drugs (eg, resins, antacids, calcium-containing foods), by agents that increase or decrease gastrointestinal motility (eg, metoclopramide or antimuscarinics, respectively), and by drugs that alter the P-glycoprotein and organic anion transporters in the intestine. Concomitant use of antacids, which increase gastric pH, can decrease gastrointestinal absorption of digoxin, ketoconazole, quinolone antibiotics, and tetracyclines. Compounds in grapefruit juice and some drugs inhibit the P-glycoprotein drug transporter in the intestinal epithelium and may increase the net absorption of drugs that are normally expelled by the transporter. Absorption from subcutaneous sites can be slowed predictably by vasoconstrictors given simultaneously (eg, local anesthetics and epinephrine) and by cardiac depressants that decrease tissue perfusion (eg,  blockers).

Interactions Based on Distribution and Binding

Distribution of a drug can be altered by other drugs that compete for binding sites on plasma proteins. For example, antibacterial sulfonamides can displace methotrexate, phenytoin, sulfonylureas, and warfarin from binding sites on albumin. However, it is difficult to document many clinically significant interactions of this type, and they seem to be the exception rather than the rule. Changes in drug distribution can occur if one agent alters the size of the physical compartment in which another drug distributes. For example, diuretics, by reducing total body water, can increase plasma levels of aminoglycosides and lithium, possibly enhancing drug toxicities.

Interactions Based on Metabolic Clearance

Drug interactions of this type are well documented and have considerable clinical significance. The metabolism of many drugs can be increased by other agents that induce hepatic drug-metabolizing enzymes, especially cytochrome P450 isozymes. Induction of drug-metabolizing enzymes occurs predictably with the chronic administration of barbiturates, carbamazepine, ethanol, phenytoin, or rifampin.Conversely, the metabolism of some drugs may be decreased by other drugs that inhibit drug-metabolizing enzymes. Such inhibitors of drug-metabolizing enzymes include cimetidine, disulfiram, erythromycin, furanocoumarins (in grapefruit juice), ketoconazole, quinidine, ritonavir, and sulfonamides. The CYP3A4 isozyme of cytochrome P450, the dominant form in the human liver, is particularly sensitive to such inhibitory actions.

Drugs that reduce hepatic blood flow (eg, propranolol ) may reduce the clearance of other drugs metabolized in the liver, especially those subject to flow-limited hepatic clearance such as morphine and verapamil.

A modified form of an interaction based on metabolic clearance results from the ability of some drugs to increase the stores of endogenous substances by blocking their metabolism. These endogenous compounds may subsequently be released by other exogenous drugs, resulting in an unexpected action. The best-documented reaction of this type is the sensitization of patients taking MAO inhibitors to indirectly acting sympathomimetics (eg, amphetamine, phenylpropanolamine). Such patients may suffer a severe hypertensive reaction in response to ordinary doses of cold remedies, decongestants, and appetite suppressants.

D. Interactions Based on Renal Function

Excretion of drugs by the kidney can be changed by drugs that reduce renal blood flow (eg,  blockers) or inhibit specific renal transport mechanisms (eg, the action of aspirin on uric acid secretion in the proximal tubule). Drugs that alter urinary pH can alter the ionization state of drugs that are weak acids or weak bases, leading to changes in renal tubular reabsorption.

Skill Keeper: Warfarin

(See Chapter 34)

When describing pharmacokinetic drug interactions, the anticoagulant warfarin inevitably springs to mind. This is because warfarin has such a narrow therapeutic window and because its metabolism depends on CYP450 activity. How does this important anticoagulant work, how is its action monitored, and if a drug interaction leads to an excessive effect, how is its action reversed? The Skill Keeper Answer appears at the end of the chapter.

Pharmacodynamic Interactions

Interactions Based on Opposing Actions or Effects

Antagonism, the simplest type of drug interaction, is often predictable. For example, antagonism of the bronchodilating effects of 2-adrenoceptor activators used in asthma is to be anticipated if a  blocker is given for another condition. Likewise, the action of a catecholamine on heart rate (via -adrenoceptor activation) is antagonized by an inhibitor of acetylcholinesterase that acts through ACh (via muscarinic receptors). Antagonism by mixed agonist-antagonist drugs (eg, pentazocine) or by partial agonists (eg, pindolol) is not as easily predicted but should be expected when such drugs are used with pure agonists. Some drug antagonisms do not appear to be based on receptor interactions. For example, nonsteroidal anti-inflammatory drugs (NSAIDs) may decrease the antihypertensive action of angiotensin-converting enzyme (ACE) inhibitors by reducing renal elimination of sodium.

Interactions Based on Additive Effects

Additive interaction describes the algebraic summing of the effects of 2 drugs. The 2 drugs may or may not act on the same receptor to produce such effects. The combination of tricyclic antidepressants with diphenhydramine or promethazine predictably causes excessive atropine-like effects because all these drugs have significant muscarinic receptor-blocking actions. Tricyclic antidepressants may increase the pressor responses to sympathomimetics by interference with amine transporter systems.

One of the most common and important drug interactions is the additive depression of CNS function caused by concomitant administration of sedatives, hypnotics, and opioids with each other or associated with the consumption of ethanol. Similarly, the patient with moderate to severe hypertension maintained on one drug is at risk of excessive lowering of blood pressure if another drug with a different site of action is added at high dosage. Additive effects of anticoagulant drugs can lead to bleeding complications. In the case of warfarin, the potential for such adverse effects is enhanced by aspirin (via an antiplatelet action), thrombolytics (via plasminogen activation), and the thyroid hormones (via enhanced clotting factor catabolism).

Supra-additive interactions and potentiation appear to be much less common than antagonism and the simple additive interactions described previously. Supra-additive (synergistic) interaction is said to occur when the result of interaction is greater than the sum of the drugs used alone; the best example is the therapeutic synergism of certain antibiotic combinations such as sulfonamides and dihydrofolic acid reductase inhibitors such as trimethoprim. Potentiation is said to occur when a drug's effect is increased by another agent that has no such effect. The best example of this type of interaction is the therapeutic interaction of -lactamase inhibitors such as clavulanic acid with -lactamase-susceptible penicillins.

Interactions of Herbal Medications with Other Drugs

Because of the marked increase in use of herbal medications, more interactions of these agents with purified drugs are being reported. Some of the reported or suspected interactions are listed in Table 61-2. Several herbals listed are known to enhance the actions of anticoagulants. Many other herbs, or edible plants, also contain compounds with anticoagulant or antiplatelet potential, including anise, arnica, capsicum, celery, chamomile, clove, feverfew, garlic, ginger, horseradish, meadowsweet, onion, passion flower, turmeric, and wild lettuce.

TABLE 61-2 Selected interactions of herbals with other drugs.

Herbal Medication Other Drugs Interaction Dong quai Warfarin Increased anticoagulant effect of warfarin; bleeding Garlic, ginkgo Anticoagulants, antiplatelet agents Increased risk of bleeding Ginseng Antidepressants Increased antidepressant effect, mania Kava Sedative-hypnotics Additive sedation Liquorice root Aldosterone, antihypertensive drugs Liquorice root extract (not candy) increases salt retention; hypertension Ma huang, other ephedra preparations Sympathomimetics Ephedrine in ma huang is additive with other sympathomimetics; hypertension, stroke St. John's wort Oral contraceptives, cyclosporine digoxin, HIV protease inhibitors, warfarin Increased metabolism of drug, decreased efficacy Antidepressants Increased antidepressant effect; serotonin syndrome with selective serotonin reuptake inhibitors

Skill Keeper Answer: Warfarin

(See Chapter 34)

Warfarin inhibits coagulation by interfering with the vitamin K-dependent post-translational modification of several clotting factors (prothrombin and factors VII, IX and X) and the anticoagulant proteins C and S. Without this post-translational modification, these proteins are inactive. Because warfarin inhibits the synthesis of coagulation factors and not the function of preformed factors, it has a relatively slow onset and offset of activity. The anticoagulant effect of warfarin is monitored by the prothrombin time (PT) test. Excessive anticoagulation can be reversed by administration of vitamin K or by transfusion with fresh or frozen plasma, which contains functional clotting factors.

Checklist

When you complete this chapter, you should be able to:

 Describe the primary pharmacokinetic mechanisms that underlie drug interactions.

Describe how the pharmacodynamic characteristics of different drugs administered concomitantly may lead to additive, synergistic, or antagonistic effects.

Identify specific drug interactions that involve (1) alcohol, (2) antacids, (3) cimetidine, (4) ketoconazole, (5) NSAIDs, (6) phenytoin, (7) rifampin, and (8) warfarin.

 List specific drug interactions that can occur in the management of HIV patients.

 Identify specific drug interactions that involve commonly used herbals.



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