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Chapter 66: Important Drug Interactions & Their Mechanisms

John R. Horn

INTRODUCTION

One of the factors that can alter the response to drugs is the concurrent administration of other drugs. There are several mechanisms by which drugs may interact, but most can be categorized as pharmacokinetic (absorption, distribution, metabolism, excretion), pharmacodynamic (additive, synergistic, or antagonistic effects), or combined interactions. The general principles of pharmacokinetics are discussed in Chapters 3 and 4; the general principles of pharmacodynamics are discussed in Chapter 2.

Botanical medications (“herbals”) may interact with each other or with conventional drugs. Unfortunately, botanicals are much less well studied than other drugs, so information about their interactions is scanty. Pharmacodynamic herbal interactions are described in Chapter 64. Pharmacokinetic interactions that have been documented (eg, St. John’s wort) are listed in Table 66–1.

TABLE 66–1Important drug interactions.
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TABLE 66–1 Important drug interactions.
Drug or Drug Group Properties Promoting Drug Interaction Clinically Documented Interactions
Acid-reducing agents Antacids may adsorb drugs in gastrointestinal tract, thus reducing absorption. Some antacids (eg, magnesium hydroxide with aluminum hydroxide) alkalinize the urine somewhat, thus altering excretion of drugs sensitive to urinary pH. H2-antagonists and proton-pump inhibitors can alter the absorption of drugs requiring gastric acidity for dissolution.

Antivirals: [P] Decreased absorption of antivirals that require acid for dissolution including atazanavir, fosamprenavir, indinavir, nelfinavir, rilpivirine.

Azole antifungals: [P] Reduced gastrointestinal absorption of itraconazole, ketoconazole, and posaconazole due to increased gastric pH.

Digoxin: [NP] Decreased gastrointestinal absorption of digoxin.

Iron: [P] Decreased gastrointestinal absorption of iron with calcium-containing antacids.

Kinase inhibitors: [P] Reduced gastrointestinal absorption of bosutinib, dabrafenib, dasatinib, erlotinib, idelalisib, and lapatinib due to increased gastric pH.

Quinolones: [HP] Decreased gastrointestinal absorption of ciprofloxacin, 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.

Tetracyclines: [HP] Decreased gastrointestinal absorption of tetracyclines.

Thyroxine: [NP] Reduced gastrointestinal absorption of thyroxine.
Alcohol Chronic alcoholism results in enzyme induction. Acute alcoholic intoxication tends to inhibit drug metabolism (whether person is alcoholic or not). Severe alcohol-induced hepatic dysfunction may inhibit ability to metabolize drugs. Disulfiram-like reaction in the presence of certain drugs. Additive central nervous system depression with other central nervous system depressants.

Acetaminophen: [NE] Increased formation of hepatotoxic acetaminophen metabolites (in chronic alcoholics).

Acitretin: [P] Increased conversion of acitretin to etretinate (teratogenic).

Anticoagulants, oral: [NE] Increased hypoprothrombinemic effect with acute alcohol intoxication.

Central nervous system depressants: [HP] Additive or synergistic 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 ...

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