Age-Related Pharmacological Changes

Age-Related Pharmacological Changes

Aging produces both pharmacokinetic (the relationship between drug dose and plasmaconcentration) and pharmacodynamic (the rela-tionship between plasma concentration and clinical effect) changes. Disease-related changes and wide variations among individuals in similar populations prevent generalizations.

A progressive decrease in muscle mass and increase in body fat (particularly in older women) results in decreased total body water. The reduced volume of distribution for water-soluble drugs can lead to greater plasma concentrations; conversely, an increased volume of distribution for lipid-soluble drugs could theoretically reduce their plasma con-centration. Any change in volume of distribution sufficient to significantly change concentrations will influence the elimination time. Because renal and hepatic functions decline with age, reductions in clearance prolong the duration of action of many drugs.

Distribution and elimination are also affected by altered plasma protein binding. Albumin, which binds acidic drugs (eg, barbiturates, benzodiaze-pines, opioid agonists), typically decreases with age. α₁-Acid glycoprotein, which binds basic drugs (eg,local anesthetics), is increased.

The principal pharmacodynamic change asso-ciated with aging is a reduced anesthetic require-ment, represented by a reduced MAC. Careful titration of anesthetic agents helps to avoid adverse side effects and unexpected, prolonged duration; short-acting agents, such as propofol, desflurane, remifentanil, and succinylcholine, may be particu-larly useful in elderly patients. Drugs that are not significantly dependent on hepatic or renal function or blood flow, such as atracurium or cisatracurium, are useful.

INHALATIONAL ANESTHETICS

The MAC for inhalational agents is reduced by 4% per decade of age over 40 years. Onset of action is faster if cardiac output is depressed, whereas it is delayed if there is a significant ven-tilation/perfusion abnormality. Recovery from anesthesia with a volatile anesthetic may be pro-longed because of an increased volume of dis-tribution (increased body fat) and decreased pulmonary gas exchange. Decreased hepatic func-tion is of less importance, even for halothane. Agents that are rapidly eliminated (eg, desflurane) are good choices for speeding emergence in the elderly patient.

NONVOLATILE ANESTHETIC AGENTS

In general, elderly patients display a lower dose requirement for propofol, etomidate,barbiturates, opioids, and benzodiazepines. The typical octogenarian will require a smaller induction dose of propofol than that required by a 20-year-old patient.

Although propofol may be close to an ideal induction agent in elderly patients because of its rapid elimination, it is more likely to cause apnea and hypotension than in younger patients. Both pharmacokinetic and pharmacodynamic fac-tors are responsible for this enhanced sensitivity. Elderly patients require nearly 50% lower blood

levels of propofol for anesthesia than do younger patients. Moreover, both the rapidly equilibrating peripheral compartment and systemic clearance for propofol are significantly reduced in elderly patients. The initial volume of distribution for etomidate significantly decreases with aging: lower doses are required to achieve the same electroen-cephalographic endpoint in elderly patients (com-pared with young patients).

Enhanced sensitivity to fentanyl, alfentanil, and sufentanil is primarily pharmacodynamic. Pharmacokinetics for these opioids are not signifi-cantly affected by age. Dose requirements for the same EEG endpoint using fentanyl and alfentanil are 50% lower in elderly patients. In contrast, the volume of the central compartment and clearance are reduced for remifentanil; thus, both phar-macodynamic and pharmacokinetic factors are important.

Use of sedative and antinausea agents with anti-cholinergic and antidopaminergic properties may produce adverse effects in patients with Parkinson’s disease.

Aging increases the volume of distribution for all benzodiazepines, which effectively prolongs their elimination half-lives. Enhanced pharmacodynamic sensitivity to benzodiazepines is also observed. Midazolam requirements are generally 50% less in elderly patients, and its elimination half-life is pro-longed by about 50%.

MUSCLE RELAXANTS

The response to succinylcholine and other neuro-muscular blockers is unaltered by aging. Decreased cardiac output and slow muscle blood flow, however, may cause up to a 2-fold prolongation in the onset of neuromuscular blockade in elderly patients. Recov-ery from nondepolarizing muscle relaxants that depend on renal excretion (eg, pancuronium) may be delayed due to decreased drug clearance. Like-wise, decreased hepatic excretion from a loss of liver mass prolongs the elimination half-life and duration of action of rocuronium and vecuronium. The phar-macological profile of atracurium is not significantly affected by age.