Pharmacodynamics

The time course and effect of drugs on cellular and organ function.

In the elderly, the effects of similar drug concentrations at the site of action may be larger or smaller than those in younger persons (see Table 6-3). The difference may be due to changes in drug-receptor interaction, in postreceptor events, or in adaptive homeostatic responses; among frail patients, the difference is often due to organ pathology.

Increased sensitivity due to aging must be considered when drugs that can have serious adverse effects are used. These drugs include morphine, pentazocine, warfarin, angiotensin-converting enzyme inhibitors, diazepam (especially given parenterally), and levodopa. Some drugs whose effects are reduced with normal aging (eg, tolbutamide, glyburide, -blockers) should also be used with caution in elderly patients because serious dose-related toxicity can occur and signs of toxicity may be delayed.

Stimulation of receptors increases intracellular cyclic adenosine monophosphate (cAMP). This activates a protein kinase, an enzyme that phosphorylates proteins, leading to altered cellular function. In elderly persons, the cAMP response to agonists is decreased in human lymphocytes and cardiac tissue, apparently due to reduced binding affinity of agonists for the receptor and to changes in postreceptor response.

Desensitization is not responsible. Up-regulation of receptors in the heart and lymphocytes after -blockade is unaltered by aging. These changes, however, are tissue-specific and differ in other tissues (eg, adipocytes). Thus, the chronotropic response to bolus administration of the agonist isoproterenol (isoprenaline) becomes blunted with age. However, sensitivity to isoproterenol is reduced in both the young and old by nonselective -blockers (eg, propranolol). The effect of propranolol may be due to blockade of receptors in the peripheral vasculature or in the heart. However, the heart rate response to isoproterenol bolus dosing is largely due to baroreflex responses of vagal withdrawal and sympathetic activation rather than to the direct effect of receptor activation. Thus, the blunted chronotropic response in the elderly is largely abolished by autonomic blockade by atropine and clonidine, which block the component of the chronotropic response due to baroreceptor reflex activation secondary to isoproterenol-induced vasodilatation. This effect shows that evaluation of drug responses must consider counterregulatory mechanisms.

With age, central nervous system sedation by benzodiazepines is increased. This increase is clinically important. For effective and safe acute sedation, the dose of midazolam should be decreased by 30% in elderly patients because of pharmacodynamic changes with age. The effect of oral triazolam is also increased, but this increase is due to increased drug levels rather than to increased sensitivity. Similar pharmacokinetic and pharmacodynamic considerations apply to long-acting benzodiazepines such as chlordiazepoxide, diazepam, and flurazepam, all of which undergo oxidation to active metabolites that accumulate with chronic dosing and have a prolonged effect. The renal response to furosemide or dopamine is reduced. However, while the acute bronchodilator responses to albuterol (a ₂ agonist) are reduced with age in normal subjects, the responses to albuterol or ipratropium (a muscarinic antagonist) are unaltered with age in patients with asthma or chronic obstructive pulmonary disease.