Altered physiological state
The role of altered physiological status on drug pharmacokinetics and drug actions is of particular importance in the area of adverse reactions to drugs. Neonates and elderly people generally have a lower metabolic capacity compared to subjects between these extremes of age. The enhanced sensitivity of the very young to drugs occurs because the microsomal enzymes responsible for metabolism are not fully active until several months after birth.
Furthermore, very young children do not have the necessary plasma-binding proteins that help to compartmentalise drugs. Infants (over 1 year old) usually metabolise drugs at similar rates and by similar routes as adults, but they require lower doses to produce comparable effects because the drugs are distributed into a smaller volume. It is important that the known pharmacokinetics of a drug in question be examined when neonates, and even children generally, are a focus of an investigation relating to drug effects, since some drugs may behave differently than in adults.
In elderly subjects (over 65 years old) there appears to be a decreasing capacity for drug metabolism as a consequence of a gradual decline in overall physiology. This includes effects on volume of distribution, protein binding and both hepatic and renal clearance. The change in the pharmacokinetics is an explanation of the increased sensitivity to drug effects in the elderly. For example, doses of benzodiazepines are reduced in the elderly to avoid excessive sedation and adverse effects on cognition. Diseases can affect all the processes by which a drug is absorbed, distributed and eliminated from the body. A drug may be absorbed poorly during gastrointestinal disturbance. The rate of uptake of drugs that rapidly cross tissue membranes may be altered in cardiovascular diseases that alter blood flow to critical organs such as the liver, kidney, lungs and heart. Diseases that fundamentally affect metabolic and excretory pathways of drugs also alter their pharmacokinetics. Diseases that affect the liver or kidneys prob ably have the greatest effect on drug concentrations because normal functioning of these organs is essential for efficient metabolism and excretion. The liver has a large metabolic reserve. However, severe disease, such as cirrhosis or drug-induced necrosis, causes the pharmacokinetic terminal elimination half-life to increase dramatically, leading to increased concentrations of drugs in plasma or tissues. Renal disease leads to a decreased ability to excrete drugs and/or their metabolites. A drug accumulates in the plasma or tissues if the interval between doses is such that not all of the previously administered drug is removed before the next dose. Even those drugs for which excretion into the urine does not normally appear to be an important route of elimination can carry a risk of increased toxicity during disease if significant drug accumulation takes place. This is especially true when potentially serious interactions may occur with the accumulated drug or metabolite. For example, metabolites can displace their parent drugs from binding sites on plasma and tissue proteins if their concentrations build up sufficiently.
Another example is the toxicity of benzodiazepines, which is increased in persons with significant respiratory diseases and in the elderly who have some form of age-related reduction in organ function.
