Pharmacodynamics

In the case of antibiotic chemotherapy, the ideal phar-macodynamic response is usually no pharmacodynamic response; the pharmacological target is not normal human cells but rather a parasite, a virus-infected human cell, or a cancerous cell. The less selective the chemotherapeutic drug, the greater the severity of adverse effects. Cancer chemotherapy is often severely toxic, even life threatening. Suppression of a viral infection, such as occurs in the treatment of HIV with antiviral drugs, is often complicated by serious drug-associated toxicity, such as hepatotoxicity or bone marrow suppression.

Compared with other pharmacological agents, antibacterial chemotherapeutic drugs are remarkably safe. Toxicity is common mainly in patients who are given inappropriately high doses or who develop high drug levels because of decreased drug clearance. Most antibiotics are renally cleared, so renal failure is a common cause of diminished antibiotic drug clearance.

The adverse reactions associated with the use of antibacterial chemotherapy include allergic reactions, toxic reactions resulting from inappropriately high drug doses, interactions with other drugs, reactions related to alterations in normal body flora, and idiosyncratic reactions. Several types of allergic responses occur, including immediate hypersensitivity reactions (hives, anaphylaxis), delayed sensitivity reactions (interstitial nephritis), and hapten-mediated serum sickness.Allergic cross-reactions to structurally related antibiotics can occur. Although an alternative non-cross-reacting antibiotic is generally preferred, desensitization protocols are available for situations in which there is no good alternative.

There is heterogeneity in human populations for the hepatic microsomal cytochrome P450 enzyme (see Chapter 4). Possession of an unfavorable phenotype may place a patient at risk for drug toxicity. For exam ple, some patients who are slow acetylators of isoniazid may develop peripheral neuropathy with standard-dose isoniazid therapy.

Toxicity is most likely in tissues that interact with the drug. For example, gentamicin is polycationic and binds to anionic phospholipids in the cell membranes of renal proximal tubular cells, where it inhibits phospho-lipases and damages intracellular organelles.

Some adverse reactions are unrelated to either allergy or overdose; these are termed idiosyncratic. For instance, sulfonamides may precipitate acute hemolysis in some people having a glucose-6-phosphate dehydro-genase deficiency.

Many antibiotics alter the enteric microbial flora, particularly if high concentrations reach the colon. Antibiotic-sensitive bacteria are suppressed or killed, thereby removing their inhibitory effects on potentially pathogenic organisms. Overgrowth of pathogenic microbes can then occur. Unlike anaerobes, Clostridium difficile is resistant to clindamycin and some (3-lactams. Use of such an antibiotic permits the proliferation of C. difficile, which then elaborates its toxin in high concentration. This toxin can cause pseudomembranous colitis, which can be fatal if not recognized and treated.

The effectiveness of chemotherapy is enhanced by adequate immune function; however, some antibiotics suppress immune function. For example, tetracyclines can decrease leukocyte chemotaxis and complement activation. Rifampin decreases the number of T lymphocytes and depresses cutaneous hypersensitivity. Antibiotics such as the sulfonamides may induce granu-locytopenia or bone marrow aplasia. These effects are not well understood but may be due to enteric bacterial metabolic byproducts of these antibiotics.

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