Pharmacodynamic Interactions

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Combinations of drugs often are employed to therapeutic advantage when their beneficial effects are additive or synergistic or because therapeutic effects can be achieved with fewer drug-specific adverse effects by using submaximal doses of drugs in concert. Combination therapy often constitutes optimal treatment for many conditions, including heart failure (see Chapter 33), hypertension (see Chapter 32), and cancer (see Chapter 51). This section addresses pharmacodynamic interactions that produce adverse effects.

Nitrovasodilators (see Chapter 31) produce vasodilation by NO-dependent elevation of cyclic GMP in vascular smooth muscle. The pharmacologic effects of sildenafil, tadalafil, and vardenafil result from inhibition of the type 5 cyclic nucleotide phosphodiesterase (PDE5) that hydrolyzes cyclic GMP to 5'GMP in the vasculature. Thus, coadministration of an NO donor (e.g., nitroglycerin) with a PDE5 inhibitor can cause potentially catastrophic hypotension.

The oral anticoagulant warfarin has a narrow margin between therapeutic inhibition of clot formation and bleeding complications and is subject to several important drug interactions (see Chapter 54). Nonsteroidal anti-inflammatory drugs cause gastric and duodenal ulcers (see Chapter 36), and their concurrent administration with warfarin increases the risk of GI bleeding almost fourfold compared with warfarin alone. By inhibiting platelet aggregation, aspirin increases the incidence of bleeding in warfarin-treated patients. Finally, antibiotics that alter the intestinal flora reduce the bacterial synthesis of vitamin K, thereby enhancing the effect of warfarin.

A subset of nonsteroidal anti-inflammatory drugs, including indomethacin, ibuprofen, piroxi-cam, and the cyclooxygenase (COX)-2 inhibitors, can antagonize antihypertensive therapy, especially with regimens employing angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, and b adrenergic receptor antagonists. The effect on arterial pressure ranges from trivial to severe. In contrast, aspirin and sulindac produce little, if any, elevation of blood pressure when used concurrently with these antihypertensive drugs.

Antiarrhythmic drugs that block potassium channels, such as sotalol and quinidine, can cause the polymorphic ventricular tachycardia known as torsades de pointes (see Chapter 34). The abnormal repolarization that leads to polymorphic ventricular tachycardia is potentiated by hypokalemia, and diuretics that produce potassium loss increase the risk of this drug-induced arrhythmia.

AGE AS A DETERMINANT OF RESPONSE TO DRUGS Most drugs are evaluated in young and middle-aged adults, and data on their use in children and the elderly are sparse. At the extremes of age, drug pharmacokinetics and pharmacodynamics can be altered, possibly requiring substantial alteration in the dose or dosing regimen to safely produce the desired clinical effect.

Children Drug disposition in childhood does not vary linearly with either body weight or body surface area, and there are no reliable, broadly applicable formulas for converting drug doses used in adults to those that are safe and effective in children. An important generality is that phar-macokinetic variability is likely to be greatest at times of physiological change (e.g., the newborn or premature baby or at puberty) such that dosing adjustment, often aided by drug monitoring for drugs with narrow therapeutic indices, becomes critical for safe, effective therapeutics.

Most drug-metabolizing enzymes are expressed at low levels at birth, followed by an isozyme-specific postnatal induction. CYP2E1 and CYP2D6 appear in the first day, followed within 1 week by CYP3A4 and the CYP2C subfamily. CYP2A1 is not expressed until 1-3 months after birth. Some glucuronidation pathways are decreased in the newborn, and an inability of newborns to glu-curonidate chloramphenicol was responsible for the "gray baby syndrome" (see Chapter 46). When adjusted for body weight or surface area, hepatic drug metabolism in children after the neonatal period often exceeds that of adults. Studies using caffeine as a model substrate illustrate the developmental changes in CYP1A2 that occur during childhood (Figure 5-2). The mechanisms regulating such developmental changes are uncertain, and other pathways of drug metabolism probably mature with different patterns.

Renal elimination of drugs also is reduced in the neonatal period. Neonates at term have markedly reduced GFR (2-4 mL/min/1.73 m2), and prematurity reduces renal function even further. As a result, neonatal dosing regimens for a number of drugs (e.g., aminoglycosides) must be

Term 1 Year Puberty Adult

FIGURE 5-2 Developmental changes in CYP1A2 activity, assessed as caffeine clearance.

Term 1 Year Puberty Adult

FIGURE 5-2 Developmental changes in CYP1A2 activity, assessed as caffeine clearance.

reduced to avoid toxic drug accumulation. GFR (corrected for body surface area) increases progressively to adult levels by 8-12 months of age. Dosing guidelines for children—where they exist—are drug- and age-specific.

Drug pharmacodynamics in children also may differ from those in adults. Antihistamines and barbiturates that generally sedate adults may be excitatory in children. The enhanced sensitivity to the sedating effects of propofol in children has led to the administration of excessive doses that produced myocardial failure, metabolic acidosis, and multiorgan failure. Unique features of childhood development also may provide special vulnerabilities to drug toxicity; for example, tetracyclines can permanently stain developing teeth, and glucocorticoids can attenuate linear growth of bones.

The Elderly As adults age, gradual changes in pharmacokinetics and pharmacodynamics increase the interindividual variability of doses required for a given effect. Pharmacokinetic changes result from changes in body composition and the function of drug-eliminating organs. The reduction in lean body mass, serum albumin, and total-body water, coupled with the increase in percentage of body fat, alters drug distribution in a manner dependent on lipid solubility and protein binding. The clearance of many drugs is reduced in the elderly. Renal function variably declines to ~50% of that in young adults. Hepatic blood flow and drug metabolism also are reduced in the elderly but vary considerably. In general, the activities of hepatic CYPs are reduced, but conjugation mechanisms are relatively preserved. Frequently, the elimination half-lives of drugs are increased as a consequence of larger apparent volumes of distribution of lipid-soluble drugs and/or reductions in the renal or metabolic clearance.

Changes in pharmacodynamics are important factors in treating the elderly. Drugs that depress the CNS produce increased effects at any given plasma concentration due to age-related pharma-cokinetic changes, physiological changes, and loss of homeostatic resilience, resulting in increased sensitivity to unwanted effects of drugs (e.g., hypotension from psychotropic medications and hemorrhage from anticoagulants).

The number of elderly in developed nations is increasing rapidly. These individuals have more illnesses than younger people and consume a disproportionate share of prescription and over-the-counter drugs; they also are a population in whom drug use is especially likely to be marred by serious adverse effects and drug interactions. They therefore should receive drugs only when absolutely necessary for well-defined indications and at the lowest effective doses. Appropriate monitoring of drug levels and frequent reviews of the patient's drug history, with discontinuation of those drugs that did not achieve the desired end point or are no longer required, would greatly improve the health of the elderly.

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