Drugs and Aging

These are two areas that are well understood, and can be taken into account by clinicians in every day practice.

Pharmacokinetics. Pharmacokinetics is a biological science concerned with the characterization and mathematical description of the absorption, distribution, metabolism, and excretion of drugs, their by-products, and other substances of biologic interest.

These processes determine the amount and rate of appearance of drugs in the body, distribution throughout the tissues, and elimination of the drug from the body. In other words, pharmacokinetics is the study of how the drugs move into and out of the body.

It is simplest to begin with the first event that occurs when a patient takes a medication: absorption. Most drugs that are commonly used are given by mouth (although some medications can be applied to the skin, eyes, or by other means). Absorption of the medication takes place at the lining of the stomach or small intestine, depending on the drug. Although there are various agerelated changes in the physiology of the gut, as a whole they do not result in any clinically significant age-related changes in drug absorption.

Distribution. After a drug is absorbed, it is distributed into the bloodstream and various tissues and/or fluids (e.g., skin, lungs, brain, urine, etc.) where the drug will exert its therapeutic action (see below, pharmacodynamics). The degree to which a drug distributes into different tissues varies, and depends on physicochemical properties of the drug: the drug's relative solubility in fat as opposed to water, its affinity for various tissues, and the drug's binding to plasma proteins. Directly relevant to distribution are the following age-related changes in body composition: there is an increase in body fat (about 15–30 percent) accompanied by a decrease in total body water (about 10–15 percent). These alterations can result in an altered drug distribution profile, which may affect the response to the drug. For example, if a patient is given a drug that is mainly water-soluble, its concentration, and thus its effect, may be greater. This is explained by the fact that the older person has less body water in which the drug would distribute into, leading to a higher drug concentration. In most cases however, this will not be clinically significant, and can be accounted for by proper drug dosing (see below, general principles of drug therapy).

Metabolism. Cytochrome P450 refers to a group of enzymes located on the membrane of the endoplasmic reticulum. The ancestral genes for the P-450 proteins have been estimated to have existed as far back as 3.5 million years ago, suggesting that drug metabolism is a secondary role. The original role for these enzymes likely is to: (1) metabolize endogenous compounds (e.g., cortisol); and (2) detoxify exogenous compounds (e.g., especially after oral ingestion). Consequently, the highest concentrations of these enzymes are in the liver and small intestine, with very small quantities found elsewhere, and the liver is the major site where drugs are metabolized.

Metabolism of a drug produces substances that are called metabolites. This process is called biotransformation. Biotransformation may occur via two major groups of reactions (or through a combination of the two) called phase I and phase II reactions. Phase I reactions typically convert a drug to a more polar compound. Phase II reactions generally involve coupling of the parent compound with a substance found in the body to produce a drug conjugate. Most conjugates are inactive and very water soluble, allowing for rapid excretion by the kidneys (Matzke and Milikin). Metabolites may be biologically inactive, just as active as the parent drug, or more or less active than the parent drug. A drug may be metabolized to a number of metabolites, each with potentially different properties. Although some drugs are metabolized by phase I, followed by phase II reactions, many are metabolized by only one these types of reactions.

Various age-related liver changes impair drug metabolism. Liver mass decreases, as does liver blood flow. The metabolic capacity of phase I reactions also decrease. This is illustrated by a decreased clearance (i.e., the drug remains in the body for a longer period of time) of various drugs such as triazolam, diazepam, alprazolam, warfarin, and others (Sotaniemi et al., 1997). Unfortunately, there are no markers that help determine how well the liver is metabolizing drugs. Nonetheless, this reduced clearance has important clinical implications (Gordon et al.).

In contrast, phase II reactions are largely unaffected by aging. Thus, one factor considered by clinicians in drug selection is whether a drug's metabolism is affected by aging. If so, an alternative drug is selected. If this is not possible, alternative strategies are used to avoid problems.

Elimination. The kidneys play a major role in eliminating drugs and other substances from the body. The last step in the movement of drugs is elimination, which is accomplished by the kidneys. Elimination occurs via two (or a combination of the two) mechanisms: drugs can be filtered or actively secreted through the glomerulus (functional unit of the kidney). The rate the glomerulus filters drugs is called the glomerular filtration rate. As people age, this rate, and thus the ability to eliminate certain drugs, decreases (meaning that the drug will persist in the body for a longer period of time) starting at about age forty (Mayersohn). The glomerular filtration rate, unlike liver enzyme activity, can be estimated by using mathematical equations. This estimate is used to help select appropriate drug doses for seniors, since many commonly used drugs are largely eliminated by the kidney. By doing so, drug build-up in the body is prevented that may otherwise lead to side effects.

Pharmacodynamics. Pharmacodynamics is defined as the study of the biological effects resulting from the interaction between drugs and biological systems. More simply stated, it is what the drug does to the body. Aging often results in different responses to the same amount of drug.