【正文】 , obese極為肥胖 patients undergoing surgery手術 require a larger than normal volume of anaesthetic麻醉劑 since the gases used are particularly fat soluble. Unfortunately, once surgery is over and the patient has regained consciousness知覺 , the anaesthetics stored in the fat tissues will be released and may render the patient unconscious again. 48 ?If fat solubility is a problem, why not design drugs to be as hydrophilic as possible? After all, most drugs will need polar or ionic groups in order to bind to their receptor or enzyme. ?Yet, how would such a molecule cross the fatty barriers of cell membranes? 49 ?Consequently, the best drugs are usually a promise折中 . They are neither too lipophilic nor too hydrophilic. In general, it is found that the most effective drugs have a pKa value in the range 68. In other words, they are drugs which are partially ionized at blood pH and can easily equilibrate between their ionized and nonionized forms. This allows them to cross cell membranes in the nonionized form and to bind to their receptor in the ionized form 50 ?On the other hand, it is sometimes useful to have a fully ionized drug which is incapable of crossing cell membranes. For example, highly ionized sulfonamides are used against gastrointestinal infections(胃腸道感染 ). They are incapable of crossing the gut wall(腸壁 ) and are therefore directed efficiently against the infection. H 2 NN H 2N N S O 2 N H 2 H 2 N S O 2 N H 2 A c H N S O 2 N H 251 Drug dose levels ?Ideally, the blood levels of any drug should be constant and controlled, but this would require a continuous, intravenous(靜脈注入 ) drip(點滴 ) which is clearly impractical(不切實際 ). Therefore, most drugs are taken at regular time intervals(間隔 ) and the doses taken are designed to keep the blood levels of drug within a maximum and minimum level such that they are not too high to be toxic, yet not too low to be ineffective. This works well in most cases, but there are certain situations where it does not. ?. Insulin(胰島素 ) is normally secreted(分泌 ) continuously by the pancreas(胰腺 ) and so the injection of insulin at timed intervals is unnatural and can lead to a whole range of physiological plications(生理并發(fā)癥 ). 52 ?Other plications include differences of age, sex, and race種族 . Diet, environment, and altitude海拔 also have an influence. Body weight is an important factor to be taken into account. Obese(極度肥胖 ) people present a particular problem since it can prove very difficult to estimate how much of a drug will be stored in fat tissue and how much will be free drug. The precise time when drugs are taken may be important since metabolic reaction rates can vary throughout the day. 53 ?Drugs can interact with other drugs. For example, some drugs used for diabetes(糖尿病 ) are bound by plasma(血漿 ) protein in the blood supply and are therefore not ‘free’ to react with receptors. However, they can be displaced from the plasma protein by aspirin and this can lead to a drug overdose(過量用藥 ). A similar phenomenon is observed between anticoagulents(抗凝血劑 ) and aspirin. 54 ?Problems can also occur if a drug taken to inhibit a metabolic reaction is taken with a drug normally metabolized by that reaction. The latter would then be more slowly metabolized, increasing the risk of an overdose. ?. the antidepressant(抗抑郁藥 ) drug phenelzine(苯乙肼 ) inhibits the metabolism of amines(胺 ) and should not be taken with drugs such as amphetamines(安非他明 ) or pethidine(哌替啶 ). Even aminerich foods can lead to adverse effects. 55 ? Pharmacodynamics is concerned with the result of the interaction of drug and body at its site of action, that is, what the drug does to the body. It is now known that a drug is most effective when its shape and electron distribution, that is, its stereoelectronic structure, is plementary互補的 to the steroelectronic structure of the active site or receptor. ? The stereochemistry of the drug is particularly important, as stereoisomers(立體異構體 ) often have different biological effects, which range from inactive to highly toxic. 56 Causes of Variability in Drug Response ? Those related to the conditions of administration 1. Dose, formulation, route of administration. 2. Resulting from repeated administration of drug: drug resistance(耐藥性 )。 drug allergy(過敏 ) 3. Drug interactions: chemical or physical。 GI absorption。 protein binding/distribution。 metabolism (stimulation/inhibition)。 excretion (ph/transport processes)。 receptor (potentiation增強 /antagonism對抗 )。 changes in pH or electrolytes電解液 . LOGO