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Pharmacokinetics in Older Adults

By

J. Mark Ruscin

, PharmD, FCCP, BCPS, Southern Illinois University Edwardsville School of Pharmacy;


Sunny A. Linnebur

, PharmD, BCPS, BCGP, University of Colorado Anschutz Medical Campus

Last full review/revision Dec 2018| Content last modified Dec 2018
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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 decreased. Toxicity may develop slowly because concentrations of chronically used drugs increase for 5 to 6 half-lives, until a steady state is achieved. For example, certain benzodiazepines (diazepam, flurazepam, chlordiazepoxide), or their active metabolites, have half-lives of up to 96 h in older 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 clinically relevant exception is calcium carbonate, which requires an acidic environment for optimal absorption. Thus, increases in gastric pH—which may be age-related (such as with atrophic gastritis) or drug-related (such as with proton pump inhibitors)—can decrease calcium absorption and increase the risk of constipation. Thus, older adults should use a calcium salt (eg, calcium citrate) that dissolves more easily in a less acidic environment. Another example of altered absorption with increased gastric pH is early release of enteric-coated dosage forms (eg, enteric-coated aspirin, enteric-coated erythromycin), increasing the risk of GI adverse effects.

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 alpha 1-acid glycoprotein increases with age, but the clinical effect of these changes on serum drug binding varies with different drugs. In patients with an acute disorder or malnutrition, rapid reductions in serum albumin may enhance drug effects because serum concentrations of unbound (free) drug may increase. Phenytoin and warfarin are examples of drugs with a higher risk of toxic effects when the 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 table 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 dose adjustments should be individualized.

Hepatic clearance of drugs metabolized by phase I reactions (oxidation, reduction, hydrolysis—see table Common Substances That Interact With Cytochrome P-450 Enzymes) is more likely to be prolonged in older adults. Usually, age does not greatly affect clearance of drugs that are metabolized by conjugation and glucuronidation (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, older adults may have higher circulating drug concentrations. Important examples of drugs with a high risk of toxic effects include nitrates, propranolol, phenobarbital, and nifedipine.

Other factors can also influence hepatic metabolism of drugs being taken, including smoking, decreased hepatic blood flow in patients with heart failure, and taking drugs that induce or inhibit cytochrome P-450 metabolic enzymes.

Renal elimination

One of the most important pharmacokinetic changes associated with aging is decreased renal elimination of drugs. After age 40, 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 older adults 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 table 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 Evaluation of the Renal Patient: Creatinine clearance) is used to guide dosing for most drugs eliminated by the kidneys. 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.

Table
icon

Effect of Aging on Metabolism* and Elimination of Some Drugs

Class or Category

Decreased Hepatic Metabolism

Decreased Renal Elimination

Analgesics and anti-inflammatory drugs

Diclofenac

Ibuprofen

Meperidine

Morphine

Naproxen

Meperidine

Morphine

Oxycodone

Antidiabetic drugs

Canagliflozin

Chlorpropamide

Dapagliflozin

Empagliflozin

Ertugliflozin

Exenatide

Glimepiride

Glyburide

Lixisenatide

Metformin

Sitagliptim

Antimicrobial agents

Amikacin

Ciprofloxacin

Gentamicin

Levofloxacin

Nitrofurantoin

Streptomycin

Tobramycin

Trimethoprim

Cardiovascular drugs

Amlodipine

Diltiazem

Lidocaine

Nifedipine

Propranolol

Quinidine

Theophylline

Verapamil

Warfarin

N-Acetylprocainamide

Apixaban

Captopril

Dabigatran

Digoxin

Dofetilide

Edoxaban

Enalapril

Enoxaparin

Heparin

Lisinopril

Procainamide

Quinapril

Rivaroxaban

Diuretics

Amiloride

Furosemide

Hydrochlorothiazide

Spironolactone

Triamterene

Psychoactive drugs

Alprazolam

Chlordiazepoxide

Desipramine

Diazepam

Imipramine

Nortriptyline

Trazodone

Triazolam

Brexpiprazole

Lurasidone

Paliperidone

Risperidone

Others

Levodopa

Amantadine

Cimetidine

Gabapentin

Lithium

Metoclopramide

Oseltamivir

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 women.

Drugs Mentioned In This Article

Drug Name Select Trade
MICROZIDE
LIBRIUM
DIABINESE
ALDACTONE
REGLAN
FURADANTIN, MACROBID, MACRODANTIN
FARXIGA
CILOXAN, CIPRO
INVOKANA
Ertugliflozin
JARDIANCE
No US brand name
AVENTYL
REXULTI
IQUIX, LEVAQUIN, QUIXIN
Lixisenatide
INVEGA
ERY-TAB, ERYTHROCIN
ELIXOPHYLLIN
DYRENIUM
NORPRAMIN
XARELTO
AMARYL
INDERAL
RISPERDAL
TAMIFLU
PRINIVIL, ZESTRIL
NORVASC
TOBI, TOBREX
LASIX
LATUDA
TOFRANIL
ADALAT CC, PROCARDIA
GENOPTIC
LOVENOX
TIKOSYN
XANAX
ZANTAC
DEMEROL
NEURONTIN
CATAFLAM, VOLTAREN
TAGAMET
CALAN
ADVIL, MOTRIN IB
CAPOTEN
OLEPTRO
GLUCOPHAGE
XYLOCAINE
MIDAMOR
ACCUPRIL
HALCION
DILANTIN
CARDIZEM, CARTIA XT, DILACOR XR
VASOTEC
OXYCONTIN
BYETTA
DIABETA, GLYNASE
COUMADIN
VALIUM
ALEVE, NAPROSYN
DURAMORPH PF, MS CONTIN
SAVAYSA
Levodopa
ELIQUIS
PANHEPRIN
LANOXIN
LITHOBID
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