Toxicity in Elderly
In elderly people, some drugs can easily achieve toxic levels. Especially when the drug's therapeutic window between efficacy and toxicity are small. Due to altered pharmacokinetic characteristics and intrinsic physiological problems, the concentration of a drug in the circulation can become too high due to a smaller volume of distribution, or the clearance can be slowed because of decreased metabolism or reduced renal excretion, which leads to a prolonged half-life.
The red line represents an example of a drug that achieves a concentration higher than desired and thus becomes toxic. This might be due to smaller volume of distribution, or a reduced clearance as a result of less active biotransformating enzymes or reduced kidney function, but indicates that in elderly the dose needs to be carefully adjusted compared to a ‘generally recommended dose’ (green line).
- Body Weight is an aspect that changes with age. In the first stage after birth, body weight increases until (approximately) adolescence and then declines slowly in elderly. Because body-water spaces, musclemass, organ blood flow, and organ function are related to body weight, so too should volume of distribution, clearance, and hence, dosage regimens of drugs
- Renal Clearance. Examples of drugs that are predominantly excreted by the kidney are ACE-inhibitors, aminoglycosides, chinolones, and diuretics.
- Hepatic Clearance. Also changes in the hepatic clearance may be taken into account for a proper dose adjustment. The volume of the liver decreases with age. This decrease is accompanied by a decrease in phase I reactions (oxidation and hydroxylation), which are mostly mediated by CYP enzymes, leading to reuced CYP-mediated metabolism. This is particularly important for substances with a high hepatic clearance: for example, the hepatic clearance of propranolol may decrease by 45% and that of morphine by 35%. Medicines with a large first-pass effect (including metoclopramide and nifedipine) are therefore often lower dosed.
- Plasma protein binding. Regarding the plasma albumin level, this is generally not or slightly reduced in the elderly population, and decreased albumin levels are usually caused by disease.
Toxicity in the elderly is most likely to occur after
