The first-pass hepatic metabolism of a number of important therapeutic agents is inconsistent with traditional models that assume that the hepatic extraction ratio of a drug is constant in each individual (independent of the concentration of drug in the hepatic sinusoidal blood and also independent of the history of exposure to the drug). In this review, the authors examine the first-pass metabolism of five "problematic drugs" (propranolol, lidocaine, propafenone, verapamil, and nitroglycerin). Each of these compounds has unique facets to its hepatic clearance and pharmacokinetics as well as striking similarities. Selected aspects of first-pass metabolism are reviewed, and a theory that may explain some of the unusual behavior of the four lipophilic bases (propranolol, lidocaine, propafenone, and verapamil) is presented. Finally, the unusual and variable clearance of nitroglycerin is discussed.
This chapter reviews the drugs currently available in the United States that exert their therapeutic effects through actions on α‐ and β‐adrenoceptors and biosynthesis, release, and processing of the neurotransmitter norepinephrine. Included in the review are drugs acting as selective and nonselective agonists and antagonists at both α‐ and β‐adrenoceptors, as well as drugs that interfere with norepinephrine biosynthesis and release. Therapeutic categories include antihypertensives, bronchodilators, antiglaucoma agents, vasopressors, and nasal decongestants. Structure‐activity relationships are reviewed as are the structure and function of various adrenoceptors. Briefly covered is the metabolism of representative drugs in each structural class as well as recent developments in approaches to new drugs in the areas of selective α
1A
‐antagonists for treatment of prostatic hypertrophy and selective β
3
‐agonists for treatment of obesity and diabetes.
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