Physiological changes associated with ageing can impact the appropriate dosing for many drugs. General principles to keep in mind include:

Absorption:

• Absorption usually does not change with normal ageing.

Distribution:

• Concentrations of water-soluble drugs are usually higher as there is less water and so a lower volume of distribution.
• Concentrations of free or active (unbound) drug are usually higher due to lower serum proteins.

Metabolism:

• The half-life of lipophilic drugs is usually higher due to more fat resulting in an increased volume of distribution and prolonged duration of action.
• There is slower Phase I metabolism (e.g., oxidation, reduction and dealkylation) due to cytochrome P450 pathways resulting in higher levels of drugs dependent on these pathways for metabolism (e.g., warfarin).
• However, Phase II reactions (e.g., conjugation, acetylation, and methylation) are usually unchanged in normal ageing.
• There is a greater risk of drug-drug interactions in metabolism due to increased numbers of drugs for multiple medical problems.

Excretion:

• Hepatic excretion may be impaired.
• Renal clearance may be impaired, and serum creatinine may not be an accurate reflection of renal clearance in elderly patients due to decreased lean body mass (muscle mass).
• Active drug metabolites can accumulate, resulting in prolonged therapeutic actions and a greater risk of adverse effects.

There is also increased susceptibility to adverse effects. Older adults are also more likely to have multiple chronic medical problems, and disease states can result in physiological changes:

• Cardiac disease can result in impaired cardiac output resulting in impaired ADME and greater susceptibility to cardiac adverse effects.
• Liver or kidney disease can decrease metabolism and excretion, reducing drug clearance.
• Neurological diseases result in greater sensitivity to neurological adverse effects due to diminished neurotransmitter levels and/or impaired cerebral blood flow.