3 Clinical psychopharmacology3.2 Pharmacokinetics
3.2.2 Kinetic changes in health, disease and across the lifespan
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Written by Resident Doctor Committee · Published
Ageing
Ageing shifts body composition towards more fat and less lean mass and water.
Drug type | Volume of distribution | Consequence |
|---|---|---|
Lipid-soluble (diazepam) | Larger | Longer half-life, with accumulation, sedation and falls |
Water-soluble (lithium) | Smaller | Higher plasma level per dose |
Oral absorption from the gut stays broadly the same in old age, while distribution, hepatic handling and renal clearance change.
Plasma albumin falls with age, so the free fraction of bound drugs rises.
Loss of liver mass and hepatic blood flow reduces first-pass extraction, so more of an oral dose of a high-extraction drug reaches the systemic circulation.
Glomerular filtration rate (GFR) falls with age, so renally cleared drugs accumulate.
Low muscle mass can hide poor renal function behind a normal creatinine.
Pregnancy
Rises | Falls |
|---|---|
Gastric pH | Gastric emptying |
Renal blood flow, GFR and renal clearance | Plasma albumin and protein binding |
Volume of distribution |
GFR rises by about half, through higher cardiac output and renal blood flow, with lower plasma oncotic pressure contributing.
Renally eliminated drugs such as lithium are cleared faster, so levels fall on a fixed dose, and clearance falls again postpartum.
Haemodilution lowers albumin, so highly albumin-bound drugs show a lower total level but a higher unbound fraction.
Lamotrigine clearance can more than double in pregnancy and returns rapidly postpartum.
Liver disease
In cirrhosis, phase I oxidation is lost early while glucuronidation is relatively preserved.
Benzodiazepines cleared by direct glucuronidation, such as lorazepam and oxazepam, do not accumulate, whereas oxidised ones do, which guides the choice in alcohol withdrawal.
Ascites enlarges the volume of distribution of water-soluble drugs.
Infancy and childhood
Neonates are about 75% water against 60% in adults, so water-soluble drugs have a larger volume of distribution per kilogram.
Renal function and liver enzymes are immature at birth, so children's doses follow drug-specific evidence rather than scaled adult doses.
Other states
Renal disease lets renally cleared drugs, especially lithium, accumulate.
Dehydration and sodium depletion reduce lithium clearance, and diuretics, angiotensin-converting enzyme inhibitors and non-steroidal anti-inflammatory drugs also raise lithium levels.
Infection can suppress cytochrome P450 1A2 and raise clozapine levels, especially after someone stops smoking.