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Although pharmacokinetic interactions occur as a result of alterations in drug absorption, distribution, metabolism, or elimination, the effects on drug metabolism are the most clinically significant. A commonly seen absorption interac- tion occurs when fluoroquinolones are administered con- comitantly with antacids, causing decreased quinolone bioavailability. Similarly, enteral feeding should be withheld 2 hours before and after the administration of oral phenytoin formulations because of the decreased and delayed absorp- tion of phenytoin that occurs.

Drug interactions owing to altered distribution also may occur. When two drugs compete for binding sites on plasma proteins or tissues, the unbound or free serum concentration of one or both drugs may increase. Although this theoreti- cally may increase a drug’s effect, the enhanced pharmaco- logic effect is usually transient because more unbound drug is now available for elimination by the liver and kidney. Thus the clinical significance of protein-binding displacement interactions is minimal unless there is concomitant hepatic or renal disease. However, warfarin and phenytoin may be transiently displaced by a number of drugs.

Pharmacokinetic drug interactions are frequently due to altered metabolism involving the cytochrome P450 (CYP) enzyme system, which is largely responsible for oxidative metabolism of drugs by the liver. These enzymes are a super- family of microsomal drug-metabolizing enzymes that degrade endogenous substances, chemicals, toxins, and med- ications. The primary ones responsible for drug metabolism are CYP3A4, CYP2D6, CYP1A2, and CYP2C. Examples of commonly used drugs that are inducers and inhibitors of CYP are shown in Table 4–6.The most potent drugs likely to be encountered are phenobarbital, phenytoin, and rifampin, with subsequently more rapid metabolism and lower serum levels for cimetidine, phenytoin, theophylline, warfarin, cor- ticosteroids, and quinidine. Cigarette smoking and chronic ethanol use also increase CYP activity. This explains why alcoholics may require surprisingly high doses of sedatives (eg, diazepam and midazolam) or analgesics. CYP induction does not occur immediately, but usually takes at least several days. Therefore, effects of CYP may be immediate (eg, in a

Drug Affected CYP Inducer/Inhibitor Effect

Benzodiazepines (alprazolam) Inhibitor

Azole antifungal (fluconazole, itracona zole, ketoconazole)

Increased benzodiazepine concentration

Cyclosporine Inducer

Rifampin, rifabutin, phenobarbital, phenytoin

Inhibitor

Erythromycin, azole antifungal

Decreased cyclosporine levels

Increased cyclosporine levels

Theophylline Inhibitor

Fluoroquinolone Inducer Cigarette smoking

Increased theophylline levels Decreased theophylline levels

Warfarin Inducer

Phenobarbital Inhibitor Cimetidine

Decreased warfarin levels Increased warfarin levels Table 4–6. Examples of cytochrome P450 (CYP) induction or inhibition by drugs.

chronic smoker) or delayed (eg, after starting a potential CYP inducer in the hospital). Drugs that inhibit CYP systems may behave differently than those that are inducers because the former can act immediately on CYP. The most common CYP inhibitors in the ICU are allopurinol, amiodarone, cimetidine, erythromycin, and fluconazole.

The importance of CYP induction and inhibition depend on the therapeutic indices of the drugs whose metabolism are affected. The narrower the therapeutic window (level providing therapeutic effect compared with the level result- ing in toxic effect), the greater is the likelihood that a CYP inhibitor will lead to toxicity or an inducer will cause sub- therapeutic levels.

Adverse Effects & Drug Toxicities

Drugs may adversely affect all organ systems, but the kidney, liver, heart, CNS, and vascular system are most frequently affected. In critically ill patients with multiple medical prob- lems, it can be quite difficult to isolate drug toxicity as the sole cause of organ failure. Some drug toxicities are dose- dependent, so attention to dosing and elimination is impor- tant, as well as to drug interactions that may increase drug levels (eg, inhibition of cytochrome P450 enzymes). Other adverse effects are allergic and depend on the host response and prior exposure. For some adverse effects, the patient may be more susceptible for genetic or other reasons (long QT syndrome).

Nephrotoxicity

The most common causes of drug-induced nephrotoxicity are listed in Table 4–7.Nephrotoxicity in critically ill patients may be due to drug-induced causes or to hypoperfusion. Because the mortality rate for ICU patients with acute renal failure approaches 80%, efforts should be directed at remov- ing all potential causes of nephrotoxicity. Adequate fluid resuscitation and maintenance of renal perfusion are of paramount importance for preventing prerenal acute renal failure. Appropriate intravascular volume status and pre- treatment with N-acetylcysteine or sodium bicarbonate decrease the risk of nephrotoxicity from radiocontrast agents.

Despite adequate preventive measures, up to 20% of all cases of acute renal failure may be associated with drug toxi- city. Drug-induced toxicity may take the form of acute tubu- lar necrosis, interstitial nephritis, or glomerulonephritis. Of those drugs associated with acute tubular necrosis, the most notable are the aminoglycosides and amphotericin B. With once-daily dosing of aminoglycosides (5–7 mg/kg per day) and proper therapeutic drug monitoring, the incidence of acute tubular necrosis is reduced significantly. Novel ampho- tericin B formulations as well as the increased use of other antifungals (eg, azoles and echinocandins) reduce the risk of nephrotoxicity. Interstitial nephritis and glomerulonephritis

are due to hypersensitivity reactions or immune-complex formation. The most common drugs leading to interstitial nephritis are antibiotics, even though the most likely culprit, methicillin, is no longer used.

Hepatotoxicity

While a number of drugs have been associated with altered liver function tests, these changes are usually reversible on discontinuation of the offending agent. Since acute hepatic injury is classified according to morphology, drug-induced hepatic injury may cause either direct hepatocellular necro- sis, cholestasis, or a mixed presentation of both (Table 4–8).

Some drug combinations such as rifampin and isoniazid, amoxicillin and clavulanic acid, and trimethoprim and sul- famethoxazole also may increase the possibility of hepato- toxic reactions. This may occur because one agent alters the metabolism of the other, leading to the production of toxic metabolites. Phenytoin induces both hepatic necrosis and cholestasis in association, producing an immune response manifested by a rash, eosinophilia, atypical lymphocytosis, and serum IgG antibodies against phenytoin.

An increasingly important source of drug-induced hepa- totoxicty is the use of herbal drugs. These may not be disclosed

Acute tubular necrosis

Acyclovir Aminoglycosides Amphotercin B Iodinated contrast dyes Foscarnet Pentamidine Interstitial nephritis Allopurinol Cimetidine Furosemide Methicillin Phenytoin Rifampin Thiazides Trimethoprim-sulfamethoxazole Vancomycin Glomerulonephritis ACE inhibitors Gold salts Hydralazine Penicillamine Rifampin Renal hemodynamics ACE inhibitors Cyclosporine NSAIDs Tacrolimus

by patients without specific questioning. Toxicity may be hepatocellular or cholestatic in nature. Some herbs may inhibit or induce the CYP system (eg, St. John’s wart induces CYP3A4, reducing concentrations of cyclosporine A), and several herbal drugs affect metabolism of warfarin.