pharmacokinetics in elderly

Pharmacokinetics (see Pharmacokinetics) is best defined as what the body does to the drug; it includes absorption, distribution across body compartments, metabolism, and excretion.

With aging, the metabolism and excretion of many drugs decrease, requiring that doses of some drugs be adjusted. Toxicity may develop slowly because levels of chronically used drugs tend to increase for about 5 to 6 half-lives. For example, certain benzodiazepines (diazepam

, flurazepam

, chlordiazepoxide

) have half-lives of up to 96 h in many elderly
patients; signs of toxicity may not appear until days or weeks after therapy is started.

Absorption: Despite an age-related decrease in small-bowel surface area, slowed gastric emptying, and an increase in gastric pH, changes in drug absorption tend to be clinically inconsequential for most drugs.

Distribution: With aging, body fat generally increases, and total body water decreases. Increased fat increases the volume of distribution for highly lipophilic drugs (eg, diazepam

)
and may increase their elimination half-lives.

Serum albumin decreases and α1-acid glycoprotein increases with age, but the clinical effect of these changes on serum drug binding is unclear. In patients with an acute disorder or undernutrition, rapid reductions in serum albumin may enhance drug effects because serum levels of unbound drug may increase (eg, with phenytoin

or warfarin

).

Hepatic metabolism: Overall hepatic metabolism of many drugs through the cytochrome P-450 enzyme system decreases with age. For drugs with decreased hepatic metabolism (see Table 1: Drug Therapy in the Elderly: Effect of Aging on Drug Metabolism* and Elimination), clearance typically decreases 30 to 40%. Theoretically, maintenance drug doses should be decreased by this percentage; however, rate of drug metabolism varies greatly from person to person, and individual titration is required.

Hepatic clearance of drugs with multistage metabolism (nonsynthetic and synthetic reactions) is more likely to be prolonged in the elderly (see Pharmacokinetics: Drug Metabolism). Usually, age does not greatly affect clearance of drugs that are metabolized by conjugation, typically with glucuronic acid.

Renal elimination: After age 30, creatinine clearance decreases an average of 8 mL/min/1.73 m2/decade; however, the age-related decrease varies substantially from person to person. Serum creatinine levels often remain within normal limits despite a decrease in GFR because the elderly generally have less muscle mass and thus produce less creatinine. Decreases in tubular function parallel those in glomerular function.

These changes decrease renal elimination of some drugs (see Table 1: Drug Therapy in the Elderly: Effect of Aging on Drug Metabolism* and Elimination). Clinical implications depend on the extent that renal elimination contributes to total systemic elimination and on the drug’s therapeutic index (ratio of maximum tolerated dose to minimum effective dose). Creatinine clearance (measured or estimated using computer programs or a formula, such as Cockcroft-Gault—see Approach to the Genitourinary Patient: Creatinine clearance) is used to guide drug dosing. Because renal function is dynamic, maintenance doses of drugs should be adjusted when patients become ill or dehydrated or have recently recovered from dehydration.

Table 1

Effect of Aging on Drug Metabolism* and Elimination

Class or Category
Decreased Hepatic Metabolism
Decreased Renal Elimination

Analgesics and anti-inflammatory drugs
Dextropropoxyphene

Ibuprofen

Meperidine

Morphine

Naproxen

Antibiotics

Amikacin

Ciprofloxacin

Gentamicin

Nitrofurantoin

Streptomycin

Tobramycin

Cardiovascular drugs
Amlodipine

Diltiazem

Lidocaine

Nifedipine

Propranolol

Quinidine

Theophylline

Verapamil

N-Acetylprocainamide

Captopril

Digoxin

Enalapril

Lisinopril

Procainamide

Quinapril

Diuretics

Amiloride

Furosemide

Hydrochlorothiazide

Triamterene

Psychoactive drugs
Alprazolam

Chlordiazepoxide

Desipramine

Diazepam

Imipramine

Nortriptyline

Trazodone

Triazolam


Risperidone

Others
Levodopa
Amantadine

Chlorpropamide

Cimetidine

Glyburide

Lithium

Metoclopramide

Ranitidine

*When aging’s effect on hepatic metabolism of a drug is controversial, effects reported in the majority of studies are listed.
†The effect occurs in men but not in wome

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