SESSION-4-PHARMACOGENETICS.pdf

INDIVIDUAL VARIATION, PHARMACOGENOMICS AND PERSONALISED MEDICINE PHARMACOGENETICS Synonym for pharmacogenomics Study of genetic factors that affect drug responses Personalized medicine is based on using an individual's genetic profile to make the best ther...

INDIVIDUAL VARIATION, PHARMACOGENOMICS AND PERSONALISED MEDICINE PHARMACOGENETICS Synonym for pharmacogenomics Study of genetic factors that affect drug responses Personalized medicine is based on using an individual's genetic profile to make the best therapeutic choice by facilitating predictions about whether that person will benefit from a particular medicine or suffer serious side effects. Drugs are generally tested on a large population of people and the average response is reported. This sort of evidence- based medicine (that is, medical decision making based on empirical data) relies on the law of averages; personalized medicine, on the other hand, recognizes that no two patients are alike. Variability is a serious problem; if not taken into account, it can result in: Lack of efficacy Unexpected harmful effects Types of variability may be classified as: Pharmacokinetic variation o Caused by different concentrations at sites of drug action o Can occur because of differences in absorption, distribution, metabolism or excretion Pharmacodynamic variation o Caused by different responses to the same drug concentration. The main causes of variability are: Age Genetic factors Immunological factors Disease (especially when this influences drug elimination or metabolism, e.g. kidney or liver disease) Drug interactions EPIDEMIOLOGICAL FACTORS AND INTER-INDIVIDUAL VARIATION OF DRUG RESPONSE Ethnicity It is probable that many such ethnic differences are genetic in origin but environmental factors, for example relating to distinctive dietary habits, may also contribute. Age Several important enzymes, including hepatic microsomal oxidase, glucuronyltransferase, acetyltransferase and plasma esterases, have low activity in neonates, especially if premature. The activity of hepatic microsomal enzymes declines slowly (and very variably) with age 1 The distribution volume of lipid-soluble drugs increases, because the proportion of the body that is fat increases with advancing age. Drug elimination is less efficient in newborn babies and in old people, so that drugs commonly produce greater and more prolonged effects at the extremes of life. Glomerular filtration rate (GFR) in the newborn, normalisedto body surface area, is only about 20% of the adult value. Glomerular filtration rate declines slowly from about 20 years of age, falling by about 25% at 50 years and by 50% at 75 years. Other age-related factors, such as variations in pharmacodynamic sensitivity, are also important with some drugs. Body composition changes with age, fat contributing a greater proportion to body mass in the elderly, with consequent changes in distribution volume of drugs. Elderly people consume more drugs than do younger adults, so the potential for drug interactions is also increased. Pregnancy Maternal plasma albumin concentration is reduced, influencing drug protein binding. Cardiac output is increased, leading to increased renal blood flow and GFR, and increased renal elimination of drugs. Lipophilic molecules rapidly traverse the placental barrier. Disease Common disorders such as impaired renal or hepatic function predispose to toxicity by causing unexpectedly intense or prolonged drug effects as a result of increased drug concentration following a ‘standard’ dose. Other disorders affect drug sensitivity by altering receptor or signal-transduction mechanisms. Drug Interactions Many patients, especially elderly ones, are treated continuously with one or more drugs for chronic diseases The administration of one chemical entity (A) can alter the action of another (B) by one of two general mechanisms: Modifying the pharmacological effect of B without altering its concentration in the tissue fluid (pharmacodynamic interaction) Altering the concentration of B at its site of action (pharmacokinetic interaction) 2 GENETIC VARIATION IN DRUG RESPONSIVENESS Several inherited disorders influence responses to drugs, including: Glucose-6-phosphatase deficiency, a sex-linked disorder in which affected men (or rare homozygous women) experience hemolysis if exposed to various chemicals including the antimalarial drug primaquine Plasma cholinesterase deficiency, an autosomal recessive disorder that confers sensitivity to the neuromuscular blocker suxamethonium Acute intermittent porphyria, an autosomal dominant disease more severe in women and in which severe attacks are precipitated by drugs or endogenous sex hormones that induce CYP enzymes Drug acetylator deficiency, a balanced polymorphism Increased susceptibility to ototoxicity from aminoglycosides, which is conferred by a mutation in mitochondrial DNA At present, much data is available regarding the variants (polymorphisms) of the genes for some phase I and phase II enzymes and some drug transporters. These pleomorphisms modify the rate of transport and metabolism of certain drugs. 3