Geriatric Pharmacokinetics
How aging affects drug processing, why elderly patients are more susceptible to adverse drug reactions, and principles of geriatric dosing.
## Pharmacokinetics of Aging
Aging produces gradual, predictable changes in body composition and organ function that collectively alter how drugs are processed. These changes increase the risk of adverse drug reactions, which are 2-3 times more common in patients over 65 than in younger adults.
## Absorption Changes
Oral absorption is the least affected PK parameter in aging:
- Gastric acid secretion decreases (~25% reduction by age 70), but clinically significant absorption changes are uncommon
- Gastric emptying slows modestly, delaying Tmax but not usually reducing total absorption
- Intestinal blood flow decreases by ~40%, potentially slowing absorption of some drugs
- First-pass metabolism decreases due to reduced hepatic blood flow, **increasing** oral bioavailability of high-extraction drugs (propranolol, labetalol, morphine)
## Distribution Changes
Body composition shifts significantly with age:
| Parameter | Change | Clinical Effect |
|-----------|--------|----------------|
| Body fat | Increases 20-40% | Increased Vd for lipophilic drugs (diazepam, amiodarone); prolonged effect duration |
| Lean body mass | Decreases 10-15% | Reduced Vd for hydrophilic drugs |
| Total body water | Decreases 10-15% | Higher initial concentrations of water-soluble drugs |
| Serum albumin | Decreases 15-25% | Increased free fraction of acidic drugs (warfarin, phenytoin) |
The increase in fat mass means diazepam's half-life extends from ~20 hours in young adults to ~90 hours in the elderly, greatly prolonging sedation.
## Metabolism Changes
- **Hepatic mass** decreases by 20-30% between ages 25 and 65
- **Hepatic blood flow** declines by 30-40%, reducing clearance of flow-dependent drugs
- **Phase I reactions** (CYP-mediated oxidation) decline significantly with age. Drugs metabolized by CYP3A4 and CYP2D6 show reduced clearance.
- **Phase II reactions** (glucuronidation, sulfation, acetylation) are relatively preserved in aging. Lorazepam and oxazepam (Phase II only) are preferred over diazepam (Phase I + II) in elderly patients for this reason.
## Excretion Changes
Renal function decline is the most clinically important age-related PK change:
- GFR decreases approximately 1 mL/min per year after age 40
- By age 80, GFR may be 50% of young adult values
- Serum creatinine may remain "normal" despite reduced GFR because muscle mass (creatinine source) also decreases
- **Always estimate renal function** using Cockcroft-Gault or CKD-EPI equations before prescribing renally cleared drugs
## Polypharmacy Risk
Elderly patients take a median of 5-9 medications. The probability of a drug-drug interaction increases from ~6% with 2 drugs to ~82% with 7 or more. Combined with age-related PK changes, polypharmacy exponentially increases adverse event risk.
## Geriatric Dosing Principles
1. **Start low, go slow**: begin at 50% of usual adult doses for drugs with narrow therapeutic indices
2. **Prefer Phase II-metabolized drugs** when alternatives exist
3. **Monitor renal function** regularly and adjust doses accordingly
4. **Review medication lists** at every visit to deprescribe unnecessary drugs
5. **Use therapeutic drug monitoring** liberally for drugs with narrow windows
## Key Takeaways
- Reduced hepatic and renal function are the most impactful age-related PK changes
- Phase I metabolism declines; Phase II is relatively preserved
- Increased body fat prolongs the effect of lipophilic drugs
- Always calculate estimated renal function — serum creatinine alone is misleading
- "Start low, go slow" prevents most geriatric adverse drug reactions