Chapter 005. Principles of Clinical Pharmacology (Part 5)

Adjusting Drug Dosages While elimination half-life determines the time required to achieve steadystate plasma concentrations (Css), the magnitude of that steady state is determined by clearance (Cl) and dose alone. For a drug administered as an intravenous infusion, this relationship isWhen drug is administered orally, the average plasma concentration within a dosing interval (Cavg,ss) replaces Css, and bioavailability (F) must be included: Genetic variants, drug interactions, or diseases that reduce the activity of drug-metabolizing enzymes or excretory mechanisms may lead to decreased clearance and hence a requirement for downward dose adjustment to avoidtoxicity. Conversely, some drug interactions and genetic...
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Chapter 005. Principles of Clinical Pharmacology (Part 5) Chapter 005. Principles of Clinical Pharmacology (Part 5) Adjusting Drug Dosages While elimination half-life determines the time required to achieve steady-state plasma concentrations (Css), the magnitude of that steady state is determinedby clearance (Cl) and dose alone. For a drug administered as an intravenousinfusion, this relationship is When drug is administered orally, the average plasma concentration withina dosing interval (Cavg,ss) replaces Css, and bioavailability (F) must be included: Genetic variants, drug interactions, or diseases that reduce the activity ofdrug-metabolizing enzymes or excretory mechanisms may lead to decreasedclearance and hence a requirement for downward dose adjustment to avoidtoxicity. Conversely, some drug interactions and genetic variants increase CYPexpression, and hence increased drug dosage may be necessary to maintain atherapeutic effect. The Concept of High-Risk Pharmacokinetics When drugs utilize a single pathway exclusively for elimination, anycondition that inhibits that pathway (be it disease-related, genetic, or due to a druginteraction) can lead to dramatic changes in drug concentrations and thus increasethe risk of concentration-related drug toxicity. For example, administration ofdrugs that inhibit P-glycoprotein reduces digoxin clearance, since P-glycoproteinis the major mediator of digoxin elimination; the risk of digoxin toxicity is highwith this drug interaction unless digoxin dosages are reduced. Conversely, whendrugs undergo elimination by multiple drug metabolizing or excretory pathways,absence of one pathway (due to a genetic variant or drug interaction) is much lesslikely to have a large impact on drug concentrations or drug actions. Active Drug Metabolites From an evolutionary point of view, drug metabolism probably developedas a defense against noxious xenobiotics (foreign substances, e.g., from plants) towhich our ancestors inadvertently exposed themselves. The organization of thedrug uptake and efflux pumps and the location of drug metabolism in the intestineand liver prior to drug entry to the systemic circulation (Fig. 5-3) support this ideaof a primitive protective function. However, drug metabolites are not necessarily pharmacologically inactive.Metabolites may produce effects similar to, overlapping with, or distinct fromthose of the parent drug. For example, N-acetylprocainamide (NAPA) is a majormetabolite of the antiarrhythmic procainamide. While it exerts antiarrhythmiceffects, its electrophysiologic properties differ from those of the parent drug.Indeed, NAPA accumulation is the usual explanation for marked QT prolongationand torsades des pointes ventricular tachycardia (Chap. 226) during therapy withprocainamide. Thus, the common laboratory practice of adding procainamide toNAPA concentrations to estimate a total therapeutic effect is inappropriate. Prodrugs are inactive compounds that require metabolism to generate activemetabolites that mediate the drug effects. Examples include many angiotensin-converting enzyme (ACE) inhibitors, the angiotensin receptor blocker losartan, theantineoplastic irinotecan, and the analgesic codeine (whose active metabolitemorphine probably underlies the opioid effect during codeine administration).Drug metabolism has also been implicated in bioactivation of procarcinogens andin generation of reactive metabolites that mediate certain adverse drug effects(e.g., acetaminophen hepatotoxicity, discussed below). Principles of Pharmacodynamics Once a drug accesses a molecular site of action, it alters the function of thatmolecular target, with the ultimate result of a drug effect that the patient orphysician can perceive. For drugs used in the urgent treatment of acute symptoms,little or no delay is anticipated (or desired) between the drug-target interaction andthe development of a clinical effect. Examples of such acute situations includevascular thrombosis, shock, malignant hypertension, or status epilepticus. For many conditions, however, the indication for therapy is less urgent, anda delay between the interaction of a drug with its pharmacologic target(s) and aclinical effect is common. Pharmacokinetic mechanisms that can contribute tosuch a delay include uptake into peripheral compartments or accumulation ofactive metabolites. Commonly, the clinical effect develops as a downstreamconsequence of the initial molecular effect the drug produces. Thus, administrationof a proton-pump inhibitor or an H2-receptor blocker produces an immediateincrease in gastric pH but ulcer healing that is delayed. Cancer chemotherapyinevitably produces delayed therapeutic effects, often long after drug isundetectable in plasma and tissue. Translation of a molecular drug action to aclinical effect can thus be highly complex and dependent on the details of thepathologic state being treated. These complexities have made pharmacodynamicsand its variability less amenable than pharmacokinetics to rigorous mathematicalanalysis. Nevertheless, some clinically important principles can be elucidated. A drug effect often depends on the presence of underlyingpathophysiology. Thus, a drug may produce no action or a different spectrum ofactions in unaffected individuals compared to patients. Further, concomitantdisease can complicate interpretation of response to drug therapy, especiallyadverse effects. For example, high doses of anticonvulsants such as phenytoin maycause neurologic symptoms, which may be confused with the underlyingneurologic disease. Similarly, increasing dyspnea in a pa ...