PharmacologyTier 1Medical Sciences concept

Age-related pharmacokinetic changes (renal clearance, Vd, protein binding)

Core concept

Domain	Change	Consequence
Absorption	dec acid, dec motility, dec splanchnic flow	Rate slows; extent largely unchanged - least important domain
Distribution	dec total body water, dec lean mass, inc fat (~30% by 80)	dec Vd of water-soluble drugs (digoxin, gentamicin, lithium, ethanol); inc Vd and inc t-half of lipophilic drugs (diazepam, amiodarone)
Metabolism	dec liver mass ~25-35%, dec hepatic blood flow ~40%	inc bioavailability of high-extraction drugs (propranolol, morphine, nitrates); phase I (CYP) declines, phase II conjugation preserved
Excretion	dec GFR ~1 mL/min/year after 40	The dominant change - accumulation of renally cleared drugs

Serum creatinine is a poor guide in the elderly - reduced muscle mass means a "normal" creatinine can conceal a markedly reduced GFR
- Use Cockcroft-Gault (weight-adjusted) for drug dosing, especially DOACs, digoxin and aminoglycosides

Digoxin in the elderly is the model - lower maintenance dose required because
- dec renal clearance (digoxin is excreted largely unchanged) - the main reason
- dec lean body mass -> dec Vd -> lower loading requirement
- Interactions with amiodarone, verapamil (P-gp) compound it
Protein binding
- dec albumin (illness, malnutrition) -> inc free fraction of acidic drugs (phenytoin, warfarin, naproxen)
  - Total phenytoin appears low while free phenytoin is therapeutic - measure free level or correct
- inc alpha-1 acid glycoprotein with inflammation -> dec free fraction of basic drugs (lidocaine, propranolol)
Pharmacodynamic sensitivity changes too, often more than the PK
- inc CNS sensitivity to benzodiazepines, opioids, anticholinergics - falls, delirium
- dec baroreceptor reflex -> orthostatic hypotension on antihypertensives, alpha-blockers, TCAs
- dec beta-receptor responsiveness -> blunted response to beta-agonists and beta-blockers
Prescribing consequences
- Benzodiazepines: use LOT agents (Lorazepam, Oxazepam, Temazepam - phase II conjugation only, no active metabolites)
- Avoid: long-acting sulfonylureas, NSAIDs, tertiary TCAs, first-generation antihistamines, oxybutynin
- "Start low, go slow" - but reach a therapeutic dose; under-treatment of pain, heart failure and depression is equally harmful

Every new symptom in an older patient is an adverse drug effect until proven otherwise - falls, confusion, constipation, incontinence, weight loss
Prescribing cascades - a drug adverse effect treated with another drug (CCB -> oedema -> frusemide; metoclopramide -> parkinsonism -> levodopa)
Screening tools: Beers criteria and STOPP/START - STOPP identifies potentially inappropriate drugs, START identifies omitted beneficial ones
Anticholinergic and sedative load (Drug Burden Index) predicts function and falls better than the number of drugs
Deprescribing is an active intervention with its own plan and monitoring - taper, one drug at a time
Renal drug dosing in acute illness must be recalculated - AKI on a background of low creatinine is easily missed

Determinants of steady-state concentration; dose adjustment from clearance changes
Drug metabolism adjustments in liver failure - LOT benzodiazepines
Comparative anticholinergic potency; falls and polypharmacy
Physiological changes of ageing
Digoxin mechanism of action

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