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Pharmacokinetics in the Elderly

by J. Mark Ruscin, PharmD, Sunny A. Linnebur, PharmD, FCCP, BCPS, CGP

Pharmacokinetics (see also Pharmacokinetics) is best defined as what the body does to the drug; it includes

  • Absorption

  • Distribution across body compartments

  • Metabolism

  • Excretion

With aging, there are changes in all these areas; some changes are more clinically relevant. 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 increase for 5 to 6 half-lives, until a steady state is achieved. For example, certain benzodiazepines (diazepam, flurazepam, chlordiazepoxide) have half-lives of up to 96 h in 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. One exception is Ca carbonate, which requires an acidic environment for optimal absorption. Age-related increases in gastric pH decrease Ca absorption and increase the risk of constipation. Thus, elderly patients should use a Ca salt (eg, Ca citrate) that dissolves more easily in a less acidic environment. Another example of altered absorption is early release of enteric-coated dosage forms with increased gastric pH.

Distribution

With age, body fat generally increases and total body water decreases. Increased fat increases the volume of distribution for highly lipophilic drugs (eg, diazepam, chlordiazepoxide) 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 malnutrition, rapid reductions in serum albumin may enhance drug effects because serum levels of unbound (free) drug may increase (only unbound drug has a pharmacologic effect). Phenytoin and warfarin are drugs with a high risk of toxic effects when serum albumin level decreases.

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 Effect of Aging on Metabolism* and Elimination of Some Drugs), 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 dose adjustment is required.

Hepatic clearance of drugs metabolized by phase I reactions (oxidation, reduction, hydrolysis—see Drug Metabolism) is more likely to be prolonged in the elderly. Usually, age does not greatly affect clearance of drugs that are metabolized by conjugation (phase II reactions).

First-pass metabolism (metabolism, typically hepatic, that occurs before a drug reaches systemic circulation) is also affected by aging, decreasing by about 1%/yr after age 40. Thus, for a given oral dose, the elderly may have higher circulating drug levels. Important examples of drugs with a high risk of toxic effects include nitrates, propranolol, phenobarbital, and nifedipine.

Renal elimination

One of the most important pharmacokinetic changes associated with aging is decreased renal elimination of drugs. After age 30, creatinine clearance decreases an average of 8 mL/min/1.73 m 2 /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 are generally less physically active than younger adults and thus produce less creatinine. Maintenance of normal serum creatinine levels can mislead clinicians who assume those levels reflect normal kidney function. Decreases in tubular function with age parallel those in glomerular function.

These changes decrease renal elimination of many drugs (see Effect of Aging on Metabolism* and Elimination of Some Drugs). 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 Creatinine clearance) is used to guide drug dosing. The daily dose of drugs that rely heavily on renal elimination should be lower and/or the frequency of dosing should be decreased. Because renal function is dynamic, maintenance doses of drugs may need adjustment when patients become ill or dehydrated or have recently recovered from dehydration.

Effect of Aging on Metabolism* and Elimination of Some Drugs

Class or Category

Decreased Hepatic Metabolism

Decreased Renal Elimination

Analgesics and anti-inflammatory drugs

Ibuprofen

Meperidine

Morphine

Naproxen

Meperidine

Morphine

Oxycodone

Antibiotics

Amikacin

Ciprofloxacin

Gentamicin

Levofloxacin

Nitrofurantoin

Streptomycin

Tobramycin

Cardiovascular drugs

Amlodipine

Diltiazem

Lidocaine

Nifedipine

Propranolol

Quinidine

Theophylline

Verapamil

Warfarin

N -Acetylprocainamide

Apixaban

Captopril

Dabigatran

Digoxin

Enalapril

Enoxaparin

Heparin

Lisinopril

Procainamide

Quinapril

Rivaroxaban

Diuretics

Amiloride

Furosemide

Hydrochlorothiazide

Triamterene

Psychoactive drugs

Alprazolam

Chlordiazepoxide

Desipramine

Diazepam

Imipramine

Nortriptyline

Trazodone

Triazolam

Risperidone

Others

Levodopa

Amantadine

Chlorpropamide

Cimetidine

Exenatide

Gabapentin

Glyburide

Lithium

Metoclopramide

Ranitidine

Sitagliptin

*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 women.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • No US brand name
  • LIBRIUM
  • VALIUM
  • COUMADIN
  • DILANTIN
  • ADALAT CC, PROCARDIA
  • INDERAL
  • FURADANTIN, MACROBID, MACRODANTIN
  • ELIQUIS
  • OXYCONTIN
  • NEURONTIN
  • DYRENIUM
  • XANAX
  • DIABINESE
  • REGLAN
  • LASIX
  • ADVIL, MOTRIN IB
  • LANOXIN
  • LOVENOX
  • MICROZIDE
  • OLEPTRO
  • HALCION
  • GENOPTIC
  • DIABETA, GLYNASE
  • MIDAMOR
  • IQUIX, LEVAQUIN, QUIXIN
  • AVENTYL
  • RISPERDAL
  • CARDIZEM, CARTIA XT, DILACOR XR
  • ALEVE, NAPROSYN
  • DEMEROL
  • ACCUPRIL
  • BYETTA
  • CALAN
  • CILOXAN, CIPRO
  • TOFRANIL
  • XYLOCAINE
  • PANHEPRIN
  • DURAMORPH PF, MS CONTIN
  • TAGAMET
  • TOBI, TOBREX
  • CAPOTEN
  • NORVASC
  • VASOTEC
  • JANUVIA
  • NORPRAMIN
  • ELIXOPHYLLIN
  • XARELTO
  • PRINIVIL, ZESTRIL
  • LITHOBID
  • ZANTAC

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