Patient Physiology

Age

Total-body water is decreased in the elderly. One pharmacokinetic result is a reduced initial mixing volume. This smaller central volume of distribution leads to higher peak concentrations after a bolus or during the early part of an infusion. A decreased central volume of distribution partly accounts for the increased sensitivity of elderly patients to many anesthetic drugs (see Chapter 60 and Chapter 62 ).

Aging is also associated with decreased lean body mass and increased body fat. Because the lipid content of elderly patients is higher than that of young patients, elderly patients have more potential for lipophilic drugs to accumulate in peripheral volumes of distribution, leading to increased duration of effect for many anesthetic drugs.

Liver volume, liver blood flow, and hepatic metabolic capacity decrease with advancing age. These changes in hepatic physiology account for the decreased clearance of opioids, hypnotics, benzodiazepines, and muscle relaxants, and they contribute to the increased sensitivity of elderly subjects to anesthetic drugs.

Age only modestly reduces cardiac output in the absence of hypertension, coronary artery disease, valvular heart disease, or other cardiovascular pathology. Advancing age can be expected to modestly reduce intercompartmental clearance for anesthetic drugs. The effect of decreased intercompartmental clearance is to increase initial plasma concentrations during drug administration. After termination of drug administration, the role of decreased intercompartmental clearance is complex. In general, plasma concentrations decrease more rapidly after long infusions when intercompartmental clearance is decreased.

Albumin and α₁ -acid glycoprotein are the primary sites of protein binding. Albumin concentration decreases with advancing age, hepatic disease, and malnutrition. In contrast, α₁ -acid glycoprotein concentration increases with advancing age and acute disease. The effects of age and disease on protein binding depend on which protein binds the drug. For example, because diazepam primarily binds to albumin, the free fraction of diazepam increases in elderly patients. This may partly explain the increased sensitivity in elderly subjects. In contrast, lidocaine binds

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Although important age-related pharmacokinetic differences have been investigated in detail, there is a paucity of data addressing pharmacodynamic differences between age groups. Overall, the presence or absence of age-related pharmacodynamic differences appears to depend on the drug. For example, antiepileptic agents and digoxin have been examined in adults and children, and the effective plasma concentration is the same. This finding suggests that no age-related differences in pharmacodynamic responses occur for these two types of drugs. However, many drugs with CNS effects (e.g., thiopental,^[25] midazolam, ^[26] opioids,^{[27] [28]} propofol^[29] ) appear to be intrinsically more potent in the elderly, and this change in potency has been quantitated with pharmacodynamic models. Understanding the biologic basis of increased sensitivity in the elderly to anesthetic and perioperative drugs is an area of active investigation by many researchers.

Disease States

Various diseases contribute to variation in drug response. Although diseases frequently result in pharmacokinetic variations (e.g., decreased liver perfusion in heart failure or decreased elimination in renal failure), pharmacodynamic variation is also observed. Diseases such as diabetes, thyroid disease, adrenal disease, myasthenia gravis, and hypertension alter receptor function and therefore represent pharmacodynamic effects. Some diseases directly affect drug receptors. For example, in patients with myasthenia gravis, antibodies to the postsynaptic nicotinic acetylcholine receptor effectively decrease the number of receptors present. Muscle weakness characterizes the disease. As a result, these patients are exquisitely sensitive to muscle relaxants, which act through the nicotinic acetylcholine receptor. Clinically, the dose of muscle relaxant must be decreased or eliminated in this patient population.