In the medically ill patient, both pharmacokinetic and pharmacodynamic changes may require dosage adjustments. Pharmacokinetics changes are produced by age, hepatic or renal disease, and drug interactions, as well as by smoking and the use of alcohol and illicit drugs. Many medically ill patients receive polypharmacy (five or more drugs per day), increasing the risk of decreased compliance and undesirable reactions to one of the drugs and of interactions between them.
Age-related changes in body organs may alter the disposition and elimination of drugs and the sensitivity to both, with large variations between individuals. The most important risk is drug accumulation and extended duration of action. For example, age-related increase in body fat results in slower elimination of lipid-soluble drugs (e.g. diazepam). Hepatic function may be impaired, with decreased activity of metabolizing enzymes. Reduced enzymatic activity may affect inactivation differentially; for example, the metabolism of diazepam is often impaired, while the metabolism of oxazepam remains unaltered. Kidney function is usually reduced because of decreased renal blood flow and glomerular filtration rate, potentially leading to increased levels of some drugs (e.g. opioid analgesics, antidepressants, and certain benzodiazepines). Age-related changes in pharmacodynamics generally result in increased sensitivity to drugs, but sometimes there is decreased responsiveness (e.g. to b-receptor blocking agents and b-agonists). Typically, the baroreceptor reflex is impaired, leading to increased hypotensive side-effects (e.g. with neuroleptics, antidepressants, or antiparkinsonian drugs). Degeneration of cholinergic pathways in the brain with ageing, especially in dementia, leads to increased sensitivity to anticholinergic drugs, resulting in cognitive impairment and delirium. Adverse drug reactions due to polypharmacy become more frequent with age. Long-acting benzodiazepines are the most common cause of drug-related falls and cognitive impairment.
The liver is the major organ for biotransformation and elimination of psychotropic drugs. Any dysfunction may result in drug accumulation and alteration of pharmacological effects. Drug elimination by the liver depends on its intrinsic activity, on hepatic blood flow, and on the extent of drug binding to plasma proteins. Acute inflammatory disease impairs metabolizing activity, whereas blood flow is reduced in cirrhosis. Decreased metabolizing activity affects poorly extracted drugs (e.g. benzodiazepines and barbiturates), whereas reduced blood flow decreases hepatic clearance of highly extracted drugs (e.g. tricyclic antidepressants). Decreased protein synthesis and drug binding to plasma proteins may increase the free fraction of psychoactive drugs. The drug classes most affected by liver disease are barbiturates, 2-keto-benzodiazepines (chlordiazepoxide, diazepam, and flurazepam), and tricyclic antidepressants.
Renal elimination of drugs depends on their concentration in blood, the extent of protein binding, the glomerular filtration rate, and tubular secretion and reabsorption. The elimination of water-soluble metabolites can be altered, and toxic or prolonged therapeutic effects may occur if they are pharmacologically active. Hepatic conjugation is reduced in uraemic states. There may be altered drug metabolism in chronic renal failure and haemodialysis. Drugs most affected by renal failure are barbiturates and some benzodiazepines.
One-third of pregnant women take psychotropic drugs at least once during pregnancy, but no preparations are entirely appropriate for expectant mothers. The first trimester is a time of particular risk. Intra-uterine exposure to lithium probably increases the risk of congenital malformation, but such a risk has not been found for most antidepressants and neuroleptics. Intra-uterine exposure during the second and third trimesters can lead to postnatal complications, such as the floppy-infant syndrome after taking benzodiazepines, and extrapyramidal-motor effects on the newborn after neuroleptic therapy during pregnancy. The increased risk of psychiatric disorders during the postpartum period often necessitates psychopharmacological intervention. Lithium prophylaxis in manic-depressive women is indicated after childbirth, and weaning rather than omission of drug treatment is preferable during the puerperium.
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