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Chapter 005. Principles of Clinical Pharmacology (Part 3)

Clinical Implications of Altered Bioavailability Some drugs undergo near-complete presystemic metabolism and thus cannot be administered orally. Nitroglycerin cannot be used orally because it is completely extracted prior to reaching the systemic circulation. The drug is therefore used by the sublingual or transdermal routes, which bypass presystemic metabolism. Some drugs with very extensive presystemic metabolism can still be administered by the oral route, using much higher doses than those required intravenously. Thus, a typical intravenous dose of verapamil is 1–5 mg, compared to the usual single oral dose of 40–120 mg. Administration of low-dose aspirin can result in exposure of. | Chapter 005. Principles of Clinical Pharmacology Part 3 Clinical Implications of Altered Bioavailability Some drugs undergo near-complete presystemic metabolism and thus cannot be administered orally. Nitroglycerin cannot be used orally because it is completely extracted prior to reaching the systemic circulation. The drug is therefore used by the sublingual or transdermal routes which bypass presystemic metabolism. Some drugs with very extensive presystemic metabolism can still be administered by the oral route using much higher doses than those required intravenously. Thus a typical intravenous dose of verapamil is 1-5 mg compared to the usual single oral dose of 40-120 mg. Administration of low-dose aspirin can result in exposure of cyclooxygenase in platelets in the portal vein to the drug but systemic sparing because of first-pass aspirin deacylation in the liver. This is an example of presystemic metabolism being exploited to therapeutic advantage. Distribution and Elimination Most pharmacokinetic processes are first-order i.e. the rate of the process depends on the amount of drug present. Clinically important exceptions are discussed below see Principles of Dose Selection . In the simplest pharmacokinetic model Fig. 5-2 a drug bolus is administered instantaneously to a central compartment from which drug elimination occurs as a first-order process. The first-order nature of drug elimination leads directly to the relationship describing drug concentration C at any time t following the bolus where Vc is the volume of the compartment into which drug is delivered and 11 2 is elimination half-life. As a consequence of this relationship a plot of the logarithm of concentration vs time is a straight line Fig. 5-2A inset . Half-life is the time required for 50 of a first-order process to be complete. Thus 50 of drug elimination is accomplished after one drug-elimination half-life 75 after two 87.5 after three etc. In practice first-order processes such as .