4.3 Pharmacokinetic Changes with Aging

Pharmacokinetics vs. Pharmacodynamics in Aging

Pharmacokinetics (PK) describes what the body does to the drug: absorption, distribution, metabolism, and excretion (ADME). Pharmacodynamics (PD) describes what the drug does to the body (receptor sensitivity, homeostatic reserve). Both change with aging; this section focuses on PK changes that reshape assessment findings—unexpected toxicity at “usual” doses, delayed clearance after a drug is stopped, and lab misinterpretation.

GERO-BC assessment uses PK aging knowledge to explain why an older adult becomes sedated on a standard benzodiazepine dose, accumulates digoxin with a “normal” creatinine, or shows higher free phenytoin effect when albumin is low.

Absorption

Age-related GI changes include reduced gastric acid in some older adults, delayed gastric emptying, reduced GI motility, and decreased splanchnic blood flow. For most oral drugs, extent of absorption (bioavailability) changes little. Clinically important absorption issues in assessment are more often:

• Concurrent binders (calcium, iron, antacids, tube-feed interactions)
• Swallowing impairment and crushed/opened formulations altering release characteristics
• First-pass reduction for some high-extraction drugs when hepatic blood flow falls (raising oral bioavailability)

Assessment implication: Do not attribute most toxicity to “poor absorption with age.” Look first at distribution, metabolism, excretion, adherence, and interactions. Ask about timing with supplements and meals when levels are unexpectedly low (e.g., levothyroxine, bisphosphonates, quinolones).

Distribution

Body composition shifts are high-yield:

Albumin and free drug

Malnutrition, frailty, liver disease, and acute illness lower albumin. For highly protein-bound drugs, total serum levels can look “therapeutic” while free drug is high. Assessment pairs drug effect (nystagmus, bleeding, sedation) with nutritional status—not the lab number alone.

Loading doses vs. maintenance

Increased Vd for lipophilic drugs may affect loading concepts in acute care, but chronic outpatient toxicity more often reflects reduced clearance and accumulation. For hydrophilic narrow-index drugs, smaller Vd plus reduced renal clearance is a double hazard.

Metabolism (Hepatic)

Hepatic mass and blood flow decline with age. Two metabolic pathways matter conceptually:

• Phase I (oxidation/reduction/hydrolysis, largely CYP450): often reduced → higher exposure to parent drug for many agents
• Phase II (conjugation: glucuronidation, sulfation, acetylation): relatively preserved → drugs relying mainly on Phase II may be preferable when choices exist (classic teaching example: lorazepam vs. more oxidatively metabolized benzodiazepines)

First-pass metabolism can decrease for some oral drugs, increasing bioavailability. Concurrent CYP inhibitors (macrolides, azoles, amiodarone) magnify age-related metabolic vulnerability.

Assessment implication: New confusion or bradycardia after adding a CYP inhibitor to a previously tolerated regimen suggests accumulation. Chronic liver disease plus advanced age compounds risk.

Excretion (Renal)

Renal excretion is the most clinically important PK change in older adults. Glomerular filtration rate declines with age even when serum creatinine appears “normal,” because lower muscle mass reduces creatinine production.

Estimating kidney function

• Prefer estimated creatinine clearance (CrCl) (commonly Cockcroft–Gault for many drug labels) or validated eGFR tools as appropriate to the drug and setting
• Never assume normal renal clearance from a serum creatinine of 0.8–1.0 mg/dL in a thin older adult
• Acute illness, dehydration, and NSAIDs can abruptly worsen clearance

Drugs that commonly need renal-aware assessment include digoxin, lithium, many antibiotics (aminoglycosides, vancomycin, some fluoroquinolones), DOACs (agent-specific), gabapentin/pregabalin, H2 blockers, and atenolol. Accumulation presents as CNS depression, bradycardia, bleeding, or myoclonus depending on the agent.

Linking PK Changes to Assessment Findings

Use PK reasoning at the bedside:

1. Prolonged sedation days after last benzodiazepine dose → lipophilic distribution + reduced clearance
2. Digoxin toxicity with “normal” creatinine → low muscle mass hiding reduced GFR + ↓ body water
3. Bleeding on stable warfarin dose during acute illness with low albumin → higher free fraction + interacting drugs/diet changes
4. Gabapentin-related myoclonus or sedation after dehydration → renal accumulation
5. Level-effect mismatch for phenytoin → interpret free levels / albumin context

Frailty and reserve

PK changes interact with PD sensitivity (greater CNS depression from sedatives, blunted baroreflexes with antihypertensives). Assessment documents both the drug exposure story and the functional consequence—falls, delirium, syncope—so the team can adjust therapy.

Exam tip: Memorize the directional map—↑ fat, ↓ water, ↓ albumin, ↓ Phase I, ↓ renal clearance—and practice applying it to lipophilic sedatives, hydrophilic narrow-index drugs, and creatinine misinterpretation. Absorption is rarely the main aging villain on GERO-BC items.