Geriatric Pharmacology

Why Aging Matters for Medications

By age 65, the average American takes five or more prescription medications. By age 75, that number rises to seven or more for many people. This accumulation of medications is not a coincidence — it reflects the accumulation of chronic conditions that come with age: hypertension, diabetes, heart disease, arthritis, depression, osteoporosis, and others.

At the same time, the aging body processes medications less efficiently. Organ function declines. Body composition shifts. The brain becomes more sensitive to certain drug effects. The net result is that older adults are two to three times more likely to experience adverse drug reactions than younger adults — even when taking the same drugs at the same doses.

Understanding how aging changes pharmacology is foundational to safe prescribing and medication management in older adults.

Pharmacokinetic Changes With Age

Pharmacokinetics — how the body absorbs, distributes, metabolizes, and eliminates drugs — changes in predictable ways with aging.

Absorption Changes

Gastric acid secretion decreases with age, raising stomach pH. This affects drugs that require an acidic environment for dissolution and absorption. Gastric emptying slows, which can delay peak drug concentrations. Intestinal motility decreases, potentially prolonging exposure time for extended-release formulations. Blood flow to the gut decreases, slowing absorption of some drugs.

For most drugs, these absorption changes are modest and do not require dose adjustments. However, they do mean that peak drug levels may be reached later and vary more widely than in younger adults.

Distribution Changes

Aging brings significant changes to body composition. The proportion of body fat increases, while lean muscle mass and total body water decrease. These shifts have important pharmacokinetic consequences:

• Fat-soluble drugs (e.g., diazepam, many lipid-soluble anesthetics) distribute into a larger fat compartment, increasing their volume of distributionVolume of Distribution

  A theoretical volume that relates the total amount of drug in the body to its plasma concentration. A large Vd indicates the drug distributes extensively into tissues, while a small Vd suggests the dr

  and prolonging their half-lifeHalf-Life

  The time required for the plasma concentration of a drug to decrease by 50%. Half-life determines how often a medication needs to be dosed — drugs with shorter half-lives require more frequent dosing

  . A single dose of diazepam in an 80-year-old may produce effects lasting far longer than the same dose in a 30-year-old.
• Water-soluble drugs (e.g., lithium, digoxin) distribute into a smaller water compartment, producing higher plasma concentrations at the same dose.
• Albumin levels may decline with illness or malnutrition in older adults, reducing protein bindingProtein Binding

  The reversible binding of drugs to plasma proteins (primarily albumin). Only the unbound (free) fraction of a drug is pharmacologically active. Highly protein-bound drugs can be displaced by other dru

  for some drugs (particularly warfarin and phenytoin) and increasing the free (active) fraction.

Metabolism Changes

Liver size and blood flow to the liver decrease by 20–40% with age. The activity of first-pass metabolism and phase I metabolic reactions (oxidation, reduction, hydrolysis — primarily CYP450 enzymes) decreases, while phase II reactions (glucuronidation, sulfation) are relatively preserved. This means drugs that are heavily metabolized before reaching systemic circulation may achieve higher blood levels in older adults.

Renal Elimination Changes

Renal function declines with age even in the absence of disease. Glomerular filtration rate (GFR) decreases by roughly 1% per year after age 40. By age 80, many people have GFR values 40–50% lower than young adults — yet their serum creatinine may appear normal because they also have less muscle mass producing creatinine. Serum creatinine is therefore an unreliable measure of kidney function in older adults; equations like the Cockcroft-Gault formula (which accounts for age, weight, and sex) are needed to estimate actual renal function.

Drugs primarily eliminated by the kidneys — including many antibiotics, antidiabetics, and digoxin — accumulate to higher levels in older adults with declining renal function. Dose reductions or extended dosing intervals are often required.

Pharmacodynamic Changes With Age

Beyond pharmacokinetics, aging also changes pharmacodynamics — how drug receptors and target tissues respond to a given drug concentration. Older adults often show heightened sensitivity to drugs acting on the central nervous system. A benzodiazepine at a blood level that produces mild sedation in a young adult can cause confusion, falls, and respiratory depression in a 75-year-old. Similarly, older adults are more sensitive to anticholinergic drug effects (dry mouth, constipation, urinary retention, confusion) and to orthostatic hypotension from blood pressure medications.

This heightened sensitivity means that even when drug levels are in the "normal" range for adults, older patients may experience effects — both beneficial and harmful — at lower concentrations.

polypharmacyPolypharmacy

The concurrent use of multiple medications by a patient, typically defined as five or more drugs. Polypharmacy increases the risk of drug interactions, adverse effects, medication errors, and poor adh

-the-many-drug-problem">Polypharmacy: The Many-Drug Problem

Polypharmacy — typically defined as taking five or more medications simultaneously — is nearly universal in older adults with multiple chronic conditions. The risks of polypharmacy are real:

• Drug-drug interactions multiply rapidly with each added medication. With five drugs, there are 10 possible two-drug interaction pairs. With ten drugs, there are 45.
• Each additional drug introduces additional side effect risks.
• Complex regimens are harder to adhere to, leading to inconsistent drug levels.
• Drugs may be prescribed to manage side effects of other drugs ("prescribing cascade"), adding complexity without addressing root causes.

Approximately one-third of hospital admissions in older adults are related to adverse drug events, many of which are preventable.

The Beers Criteria

The American Geriatrics Society (AGS) publishes the Beers Criteria — a list of medications that are potentially inappropriate for use in older adults due to elevated risk of harm relative to benefit. The list is updated regularly and is widely used by clinicians to review medication regimens.

Categories in the Beers Criteria include: - Drugs to avoid in most older adults (e.g., most benzodiazepines, many antihistamines, certain muscle relaxants) - Drugs to avoid in older adults with certain conditions (e.g., NSAIDs in people with heart failure or chronic kidney disease) - Drugs to use with caution (e.g., certain antidepressants and anticoagulants) - Drug-drug interactions to avoid

The Beers Criteria is a tool for initiating a clinical conversation, not a rigid prohibition list. Some drugs on the list are appropriate for specific patients when the benefits clearly outweigh the risks.

Renal and Hepatic Dose Adjustments in Older Adults

Because renal function declines with age, renal dosing adjustments are among the most common medication changes needed in older adults. Drug references provide dosing recommendations based on estimated GFR (eGFR) or creatinine clearanceClearance

The volume of plasma from which a drug is completely removed per unit time, reflecting the body's efficiency at eliminating the drug. Clearance is primarily determined by liver metabolism and kidney e

(CrCl). Common drugs requiring renal adjustment in older adults include:

• Metformin (antidiabetic) — contraindicated with severely reduced GFR
• Gabapentin (nerve pain, seizures) — dose reduction required
• Dabigatran (anticoagulant) — significant accumulation with reduced kidney function
• Many antibiotics (amoxicillin, trimethoprim-sulfamethoxazole, ciprofloxacin)
• Digoxin (heart failure/arrhythmia)

Hepatic dose adjustments are needed less predictably, because liver function decline with age is more variable than renal function decline. For drugs with high first-pass metabolism, reduced doses may be needed.

Practical Strategies for Safer Medication Use

Conduct regular medication reviews: At least once a year, every medication an older adult takes should be reviewed: Is the indication still valid? Is the dose appropriate? Are there interactions? Can anything be safely discontinued?

Use the lowest effective dose: The principle "start low, go slow" applies in geriatrics. Start with lower doses and increase gradually while monitoring for both efficacyEfficacy

The maximum therapeutic effect a drug can produce, regardless of the dose given. A drug with higher efficacy can achieve a greater maximum response than one with lower efficacy, even if the latter is

and side effects.

Simplify regimens: When possible, choose drugs with once-daily dosing. Reduce the number of medications by addressing prescribing cascades.

Maintain an up-to-date medication list: Include prescription drugs, OTC drugs, vitamins, and supplements. Bring this list to every medical appointment and the pharmacy.

Monitor renal function: Periodic monitoring of kidney function is important for adjusting doses of renally cleared drugs. Do not rely on serum creatinine alone.

Watch for fall risks: Medications that cause sedation, orthostatic hypotension, or impaired balance are major fall risks in older adults. These include benzodiazepines, sleep aids, opioids, alpha-blockers, and some antihypertensives.

Key Takeaways

• Aging reduces liver blood flow, kidney function, and lean body mass, altering how drugs are processed and eliminated.
• Fat-soluble drugs have longer half-lives in older adults; water-soluble drugs reach higher concentrations at standard doses.
• Renal function declines with age even when serum creatinine appears normal — use eGFR or CrCl equations for dose adjustment decisions.
• Older adults are more pharmacodynamically sensitive to CNS drugs, anticholinergics, and blood pressure medications.
• Polypharmacy dramatically increases interaction risk; medication review and simplification are regular priorities.
• The Beers Criteria identifies medications potentially inappropriate for older adults.
• "Start low, go slow" is the standard approach when initiating medications in older adults.