One of the most important age-related pharmacokinetic changes is the predictable decline in renal function. Normal ageing results in reduced renal size, perfusion and concentrating ability. Indeed, a gradual decline in glomerular filtration rates begins at the age of 30 years. This is potentiated by conditions such as hypertension and diabetes and by nephrotoxic medications such as NSAIDs, gentamicin and vancomycin. It is recommended that glomerular filtration rate (GFR) is estimated for all older patients at regular intervals using readily available formulae such as the Cockcroft and Gault [13] equation or the modified diet in renal diseases (MDRD) [14]. It must be remembered that serum creatinine concentration is not a reliable measure of renal function in older people because of age-related reductions in muscle mass. Approximately 50% of older patients have a normal serum creatinine level but a reduced creatinine clearance estimate.

Acute kidney injury (AKI) is common in older patients with acute illness and can occur for multiple reasons including hypotension, dehydration, sepsis, cardiorenal syndrome/cardiac failure or NSAID use. In this context, a regularly prescribed renally eliminated medication (e.g. digoxin, dabigatran or metformin) may need to be temporarily withheld or dose reduced in order to avoid high serum levels and toxicity. Once renal impairment has been identified (be it AKI or chronic kidney disease) and creatinine clearance (Cr Cl) estimated, the need for dose alteration of renally eliminated drugs must be determined. In general, dose adjustment is needed when the creatinine clearance is below 60 ml/min (see Table 21.2).

Drugs exert their effects by binding as agonists, partial agonists or antagonists to target molecules and receptors within the body; pharmacodynamics is the study of these effects. Receptor expression, density, activity and affinity change with age, thus leading to altered (usually increased) pharmacodynamic effects of commonly prescribed drugs including anticoagulants, opioids and antipsychotics. In practice, this means that older patients frequently have exaggerated responses to medications at doses that are normally used in younger patients, e.g. the anticoagulant response to warfarin is often increased in older patients compared to a similar dose in a younger patient, thus increasing their bleeding risk. Older patients are particularly susceptible to the central nervous system (CNS) effects of anticholinergics, benzodiazepines, opioids and other centrally acting or psychoactive drugs because of increased blood-brain barrier permeability, reduced cholinergic neurotransmission and alterations in receptor density, affinity and intracellular responses. Clinical examples of the effect of altered pharmacodynamics sensitivity are presented in Table 21.3. It is usually recommended to start such drugs at the lowest possible dose and to slowly up-titrate according to response.

Prescribers should also be aware of age-related changes in homeostatic and thermoregulatory mechanisms. With increasing age, there is a reduction in aortic and large-vessel elasticity and compliance often resulting in systolic hypertension, lower diastolic blood pressure and a tendency towards left ventricular hypertrophy. In addition, baroreceptor sensitivity and resting heart rate are reduced, thus increasing the risk of postural hypotension and falls. Many drugs can exacerbate postural hypotension including antihypertensives, vasodilators (doxazosin and tamsulosin) and drugs with anticholinergic properties, e.g. tricyclic antidepressants and first-generation antihistamines. Falls are commonly caused by orthostatic hypotension. Drugs that contribute to reducing blood pressure in any way should be carefully reviewed and dose reduced or discontinued as appropriate.