Chapter 61: Drug Interactions

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 commonly take multiple medications and they often have age-related changes in drug clearance.

A. 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, β blockers).

B. 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.

C. 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 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, sulfonamides, and many others. 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, β 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.

When describing pharmacokinetic drug interactions, the anticoagulant warfarin inevitably springs to mind (See Chapter 34). This is because warfarin has such a narrow therapeutic window and because its metabolism depends on cytochrome P450 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.

A. 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 β₂-adrenoceptor activators used in asthma is to be anticipated if a β blocker is given for another condition. Likewise, the action of a catecholamine on heart rate (via β-adrenoceptor activation) is antagonized by an inhibitor of acetylcholinesterase that acts through acetylcholine (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.

B. 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 β-lactamase inhibitors such as clavulanic acid with β-lactamase-susceptible penicillins.

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.

1. A 55-year-old patient currently receiving a drug for a psychiatric condition is to be started on diuretic therapy for mild heart failure. Consideration should be given to the fact that thiazides are known to reduce the excretion of which of the following?

   • (A) Diazepam

   • (B) Fluoxetine

   • (C) Imipramine

   • (D) Lithium

   • (E) Trifluoperazine

2. A hypertensive patient has been using nifedipine for some time without untoward effects. If he experiences a rapidly developing enhancement of the antihypertensive effect of the drug, it is most likely due to which of the following?

   • (A) Concomitant use of antacids

   • (B) Foods containing tyramine

   • (C) Furanocoumarins in grapefruit juice

   • (D) Induction of drug metabolism

   • (E) Over-the-counter decongestants

3. A patient suffering from a depressive disorder is being treated with imipramine. If he uses diphenhydramine for allergic rhinitis, a drug interaction is likely to occur because

   • (A) Both drugs block muscarinic receptors

   • (B) Both drugs block reuptake of norepinephrine released from sympathetic nerve endings

   • (C) Diphenhydramine inhibits imipramine metabolism

   • (D) Imipramine inhibits the metabolism of diphenhydramine

   • (E) The drugs compete with each other for renal elimination

4. If phenelzine is administered to a patient taking fluoxetine, which of the following is most likely to occur?

   • (A) A decrease in the plasma levels of fluoxetine

   • (B) Antagonism of the antidepressant action of fluoxetine

   • (C) Agitation, muscle rigidity, hyperthermia, seizures

   • (D) Decreased metabolism of fluoxetine

   • (E) Priapism

5. AJ is a 45-year-old homeless man participating in a drug rehabilitation program that supplies daily methadone. AJ reports that he needs more methadone to avoid withdrawal, since he started treatment for his tuberculosis. Which of the following drugs might have caused this scenario?

   • (A) Ciprofloxacin

   • (B) Cyclosporine

   • (C) Erythromycin

   • (D) Rifampin

   • (E) Tetracycline

6. A 43-year-old woman with type 2 diabetes and hypertension visits your clinic. Her current blood pressure (measured 3 times) is not at target: 155/98 mm Hg, despite the fact that she is taking hydrochlorothiazide and captopril. The antihypertensive effects of captopril can be antagonized (reduced) by which of the following?

   • (A) Angiotensin II receptor blockers

   • (B) Loop diuretics

   • (C) NSAIDs

   • (D) Sulfonylurea hypoglycemics

   • (E) Pioglitazone

7. Which drug has resulted in severe hematotoxicity when administered to a patient being treated with azathioprine?

   • (A) Allopurinol

   • (B) Cholestyramine

   • (C) Digoxin

   • (D) Lithium

   • (E) Theophylline

   Questions 8–10. The following section consists of a list of lettered options followed by several numbered items. For each numbered item, select the ONE option that is most closely associated with it.

   • (A) Allopurinol

   • (B) Carbamazepine

   • (C) Cholestyramine

   • (D) Cimetidine

   • (E) Clarithromycin

   • (F) Cyclosporine

   • (G) Digoxin

   • (H) Erythromycin

   • (I) Fluoxetine

   • (J) Ibuprofen

   • (K) Lovastatin

   • (L) Phenelzine

   • (M) Rifampin

   • (N) Ritonavir

   • (O) Theophylline

8. In patients with HIV infection, the inhibitory action of this agent on drug metabolism has clinical value.

9. This drug enhances the toxicity of methotrexate by decreasing its renal clearance.

10. Concomitant use of St. John’s wort is reported to increase the effectiveness of this drug.

1. Thiazides reduce the clearance of lithium by about 25%. They do not alter the clearance of the other agents listed. The answer is D.

2. Compounds in grapefruit juice can increase the rate and extent of bioavailability of several dihydropyridine calcium channel blockers, including felodipine and nifedipine. This interaction may be due to inhibition of the metabolism of the dihydropyridines by intestinal wall CYP3A4 or inhibition of the P-glycoprotein transporter in the same location. The answer is C.

3. This is a good example of an additive drug interaction resulting from 2 drugs acting on the same type of receptor. Most tricyclic antidepressants, phenothiazines, and older antihistaminic drugs (those available without prescription) are blockers of muscarinic receptors. Used concomitantly, any pair of these agents will demonstrate a predictable increase in atropine-like adverse effects. The answer is A.

4. The drug interaction between the inhibitors of monoamine oxidase used for depression and the drugs that selectively block serotonin reuptake (SSRIs) is called the serotonin syndrome. In the case of phenelzine and fluoxetine, the interaction has resulted in a fatal outcome. Key interventions include control of hyperthermia and seizures. The answer is C.

5. Rifampin is an effective inducer of hepatic P450 isozymes. Cyclosporine and tetracycline have no significant effects on drug metabolism. Ciprofloxacin and erythromycin are inhibitors of drug metabolism. The answer is D.

6. NSAIDs interfere with the antihypertensive action of angiotensin-converting enzyme inhibitors; the other drugs listed enhance the blood pressure-lowering effects of captopril and other members of the “pril” drug family. Pioglitazone is a hypoglycemic drug used in patients with type 2 diabetes mellitus and has no significant effect on blood pressure. The answer is C.

7. Azathioprine is converted to mercaptopurine, which is responsible for both its immunosuppressant action and its hematotoxicity. Allopurinol inhibits xanthine oxidase, the enzyme that metabolizes mercaptopurine. The answer is A.

8. Ritonavir inhibits the metabolism of other HIV protease inhibitors and is used in low-dose combinations with indinavir or lopinavir. The answer is N.

9. Several NSAIDs, including aspirin, ibuprofen, and piroxicam, increase serum levels of methotrexate by interfering with its renal clearance. The adverse effects of methotrexate, including its hematotoxicity, are predictably increased. The answer is J.

10. Concomitant use of St. John’s wort enhances the effects of selective serotonin reuptake inhibitors. Note that enhancement is not always positive and too much serotonin is harmful (serotonin syndrome). In contrast, the herb decreases the effectiveness of other drugs (including cyclosporine, estrogens, and protease inhibitors) via its induction of drug-metabolizing enzymes. The answer is I.

Warfarin inhibits coagulation by interfering with the vitamin K-dependent post-translational modification of several clotting factors (prothrombin (factor II) and factors VII, IX, and X, mnemonic “1972”) and the anticoagulant proteins C and S (See Chapter 34). 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.

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.