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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, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado

Medically Reviewed Jul 2021 | Modified Sep 2022
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Topic Resources
  • 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 hours 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 gastrointestinal adverse effects. Age-related slowing of gastrointestinal motility or use of anticholinergic drugs can prolong movement of drugs through the stomach to the small intestine. For drugs absorbed in the upper small intestine, such as acetaminophen, slowed gastrointestinal motility can delay the absorption and onset of action and reduce peak drug concentrations and pharmacologic 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 meaningfully 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 highly protein-bound 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 Effect of Aging on Metabolism* and Elimination of Some Drugs 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 Common Substances That Interact With Cytochrome P-450 Enzymes 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%/year after age 40. Thus, for a given oral dose, older adults may have higher circulating drug concentrations. Important examples of drugs with a higher risk of toxic effects because of age-related reductions in first-pass metabolism 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, glomerular filtration rate (GFR) decreases an average of 8 mL/min/1.73 m2/decade (0.1 mL/sec/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 glomerular filtration rate (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 to 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 Effect of Aging on Metabolism* and Elimination of Some Drugs 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 Creatinine clearance In patients with renal disorders, symptoms and signs may be nonspecific, absent until the disorder is severe, or both. Findings can be local (eg, reflecting kidney inflammation or mass), result... read more 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

Drugs Mentioned In This Article

Drug Name Select Trade
Diastat, Dizac, Valium, VALTOCO
Dalmane
Librium
AcidFree, Alka-Mints, Alka-Seltzer, Alka-Seltzer Heartburn Relief, Alkets , Antacid Fast Dissolve, Calcarb 600, Calci-Chew , Calci-Mix , Calcium Antacid, Cal-Gest , Caltrate, Maalox, Maalox Antacid Barrier, Maalox Quick Dissolve, Mylanta Children's, Nephro-Calci , Pepto-Bismol Children's, Rolaids Extra Strength, Titralac, Titralac Extra Strength, Tums, Tums Chewy Bites , Tums Cool Relief, Tums E-X, Tums Freshers, Tums Kids, Tums Lasting Effects, Tums Smooth Dissolve, Tums Smoothies, Tums Ultra
Calcitrate
Anacin Adult Low Strength, Aspergum, Aspir-Low, Aspirtab , Aspir-Trin , Bayer Advanced Aspirin, Bayer Aspirin, Bayer Aspirin Extra Strength, Bayer Aspirin Plus, Bayer Aspirin Regimen, Bayer Children's Aspirin, Bayer Extra Strength, Bayer Extra Strength Plus, Bayer Genuine Aspirin, Bayer Low Dose Aspirin Regimen, Bayer Womens Aspirin , BeneHealth Aspirin, Bufferin, Bufferin Extra Strength, Bufferin Low Dose, DURLAZA, Easprin , Ecotrin, Ecotrin Low Strength, Genacote, Halfprin, MiniPrin, St. Joseph Adult Low Strength, St. Joseph Aspirin, VAZALORE, Zero Order Release Aspirin, ZORprin
A/T/S, Akne-mycin, E.E.S., Emcin Clear , EMGEL, E-Mycin, ERYC, Erycette, Eryderm , Erygel, Erymax, EryPed, Ery-Tab, Erythra Derm , Erythrocin, Erythrocin Lactobionate, Erythrocin Stearate, Ilosone, Ilotycin, My-E, PCE, PCE Dispertab , Romycin, Staticin, T-Stat
7T Gummy ES, Acephen, Aceta, Actamin, Adult Pain Relief, Anacin Aspirin Free, Apra, Children's Acetaminophen, Children's Pain & Fever , Comtrex Sore Throat Relief, ED-APAP, ElixSure Fever/Pain, Feverall, Genapap, Genebs, Goody's Back & Body Pain, Infantaire, Infants' Acetaminophen, LIQUID PAIN RELIEF, Little Fevers, Little Remedies Infant Fever + Pain Reliever, Mapap, Mapap Arthritis Pain, Mapap Infants, Mapap Junior, M-PAP, Nortemp, Ofirmev, Pain & Fever , Pain and Fever , PAIN RELIEF , PAIN RELIEF Extra Strength, Panadol, PediaCare Children's Fever Reducer/Pain Reliever, PediaCare Children's Smooth Metls Fever Reducer/Pain Reliever, PediaCare Infant's Fever Reducer/Pain Reliever, Pediaphen, PHARBETOL, Plus PHARMA, Q-Pap, Q-Pap Extra Strength, Silapap, Triaminic Fever Reducer and Pain Reliever, Triaminic Infant Fever Reducer and Pain Reliever, Tylenol, Tylenol 8 Hour, Tylenol 8 Hour Arthritis Pain, Tylenol 8 Hour Muscle Aches & Pain, Tylenol Arthritis Pain, Tylenol Children's, Tylenol Children's Pain+Fever, Tylenol CrushableTablet, Tylenol Extra Strength, Tylenol Infants', Tylenol Infants Pain + Fever, Tylenol Junior Strength, Tylenol Pain + Fever, Tylenol Regular Strength, Tylenol Sore Throat, XS No Aspirin, XS Pain Reliever
Albuked , Albumarc, Albuminar, Albuminex, AlbuRx , Albutein, Buminate, Flexbumin, Kedbumin, Macrotec, Plasbumin, Plasbumin-20
Dilantin, Dilantin Infatabs, Dilantin-125, Phenytek
Coumadin, Jantoven
HEMANGEOL, Inderal, Inderal LA, Inderal XL, InnoPran XL
Luminal
Adalat, Adalat CC, Afeditab CR, Nifediac CC, Nifedical XL, Procardia, Procardia XL
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