Chapter 005. Principles of Clinical Pharmacology (Part 13)

Epidemiology Patients receive, on average, 10 different drugs during each hospitalization. The sicker the patient, the more drugs are given, and there is a corresponding increase in the likelihood of adverse drug reactions. When 15 drugs are given, the probability is 40%. Retrospective analyses of ambulatory patients have revealed adverse drug effects in 20%. Serious adverse reactions are also well recognized with "herbal" remedies and OTC compounds: examples include kava-associated hepatotoxicity, L-tryptophan-associatedeosinophilia-myalgia, and phenylpropanolamine-associated stroke, each of which has caused fatalities. ...
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Chapter 005. Principles of Clinical Pharmacology (Part 13) Chapter 005. Principles of Clinical Pharmacology (Part 13) Epidemiology Patients receive, on average, 10 different drugs during each hospitalization.The sicker the patient, the more drugs are given, and there is a correspondingincrease in the likelihood of adverse drug reactions. When 15 drugs are given, the probability is >40%. Retrospective analyses ofambulatory patients have revealed adverse drug effects in 20%. Serious adversereactions are also well recognized with herbal remedies and OTC compounds:examples include kava-associated hepatotoxicity, L-tryptophan-associatedeosinophilia-myalgia, and phenylpropanolamine-associated stroke, each of whichhas caused fatalities. A small group of widely used drugs accounts for a disproportionate numberof reactions. Aspirin and other NSAIDs, analgesics, digoxin, anticoagulants,diuretics, antimicrobials, glucocorticoids, antineoplastics, and hypoglycemicagents account for 90% of reactions, although the drugs involved differ betweenambulatory and hospitalized patients. Toxicity Unrelated to a Drugs Primary Pharmacologic Activity Cytotoxic Reactions Drugs or more commonly reactive metabolites generated by CYPs cancovalently bind to tissue macromolecules (such as proteins or DNA) to causetissue toxicity. Because of the reactive nature of these metabolites, covalentbinding often occurs close to the site of production, typically the liver. The most common cause of drug-induced hepatotoxicity is acetaminophenoverdosage. Normally, reactive metabolites are detoxified by combining withhepatic glutathione. When glutathione becomes exhausted, the metabolites bindinstead to hepatic protein, with resultant hepatocyte damage. The hepatic necrosisproduced by the ingestion of acetaminophen can be prevented or attenuated by theadministration of substances such as N-acetylcysteine that reduce the binding ofelectrophilic metabolites to hepatic proteins. The risk of acetaminophen-relatedhepatic necrosis is increased in patients receiving drugs such as phenobarbital orphenytoin that increase the rate of drug metabolism or ethanol that exhaustglutathione stores. Such toxicity has even occurred with therapeutic dosages, sopatients at risk through these mechanisms should be warned. Immunologic Mechanisms Most pharmacologic agents are small molecules with low molecularweights (occasionally causing lupus erythematosus. Drug-induced pure red cell aplasia(Chap. 102) is due to an immune-based drug reaction. Red cell formation in bonemarrow cultures can be inhibited by phenytoin and purified IgG obtained from apatient with pure red cell aplasia associated with phenytoin. Serum sickness (Chap. 311) results from the deposition of circulating drug-antibody complexes on endothelial surfaces. Complement activation occurs,chemotactic factors are generated locally, and an inflammatory response developsat the site of complex entrapment. Arthralgias, urticaria, lymphadenopathy,glomerulonephritis, or cerebritis may result. Foreign proteins (vaccines,streptokinase, therapeutic antibodies) and antibiotics are common causes. Manydrugs, particularly antimicrobial agents, ACE inhibitors, and aspirin, can elicitanaphylaxis with production of IgE, which binds to mast cell membranes. Contactwith a drug antigen initiates a series of biochemical events in the mast cell andresults in the release of mediators that can produce the characteristic urticaria,wheezing, flushing, rhinorrhea, and (occasionally) hypotension. Drugs may also elicit cell-mediated immune responses. Topicallyadministered substances may interact with sulfhydryl or amino groups in the skinand react with sensitized lymphocytes to produce the rash characteristic of contactdermatitis. Other types of rashes may also result from the interaction of serumfactors, drugs, and sensitized lymphocytes.