significant pharmacologic effects.For example,xenon,an "inert"gas,has anesthetic effects at elevated pressures D.DRUG SHAPE The shape of a drug molecule must be such as to permit binding to its receptor site via the bonds just described.Optimally,the drug's shape is complementary to that of the receptor site in the same way that a key is complementary to a lock.Furthermore,the phenomenon of chirality (stereoisomerism)is so common in biology that more than half of all useful drugs are chiral molecules;that is,they exist as enantiomeric pairs.Drugs with two asymmetric centers have four diastereomers,eg,ephedrine,a sympathomimetic drug.In most cases,one of these enantiomers is much more potent than its mirror image enantiomer,reflecting a better fit to the receptor molecule. For example,the (S)(+)enantiomer of methacholine,a parasympathomimetic drug,is over 250 times more potent than the(R)(-)enantiomer.If one imagines the receptor site to be like a glove into which the drug molecule must fit to bring about its effect,it is clear why a"left-oriented"drug is more effective in binding to a left-hand receptor than its"right-oriented"enantiomer. The more active enantiomer at one type of receptor site may not be more active at another type,eg, a receptor type that may be responsible for some other effect.For example,carvedilol,a drug that interacts with adrenoceptors,has a single chiral center and thus two enantiomers(Table 1-1).One of these enantiomers,the (S)(-)isomer,is a potent B-receptor blocker.The (R)(+)isomer is 100-fold weaker at the B receptor.However,the isomers are approximately equipotent as a-receptor blockers.Ketamine is an intravenous anesthetic.The (+enantiomer is a more potent anesthetic and is less toxic than the (-)enantiomer.Unfortunately,the drug is still used as the racemic mixture Finally,because enzymes are usually stereoselective,one drug enantiomer is often more susceptible than the other to drug-metabolizing enzymes.As a result,the duration of action of one enantiomer may be quite different from that of the other. Unfortunately,most studies of clinical efficacy and drug elimination in humans have been carried out with racemic mixtures of drugs rather than with the separate enantiomers.At present,only about 45%of the chiral drugs used clinically are marketed as the active isomer-the rest are available only as racemic mixtures.As a result,many patients are receiving drug doses of which 50%or more is less active,inactive,or actively toxic.However,there is increasing interest at both the scientific and the regulatory levels in making more chiral drugs available as their active enantiomers. E.RATIONAL DRUG DESIGN Rational design of drugs implies the ability to predict the appropriate molecular structure of a drug on the basis of information about its biologic receptor.Until recently,no receptor was known in sufficient detail to permit such drug design.Instead,drugs were developed through random testing of chemicals or modification of drugs already known to have some effect (see Chapter 5). However,during the past three decades,many receptors have been isolated and characterized.A few drugs now in use were developed through molecular design based on a knowledge of thesignificant pharmacologic effects. For example, xenon, an "inert" gas, has anesthetic effects at elevated pressures. D. DRUG SHAPE The shape of a drug molecule must be such as to permit binding to its receptor site via the bonds just described. Optimally, the drug's shape is complementary to that of the receptor site in the same way that a key is complementary to a lock. Furthermore, the phenomenon of chirality (stereoisomerism) is so common in biology that more than half of all useful drugs are chiral molecules; that is, they exist as enantiomeric pairs. Drugs with two asymmetric centers have four diastereomers, eg, ephedrine, a sympathomimetic drug. In most cases, one of these enantiomers is much more potent than its mirror image enantiomer, reflecting a better fit to the receptor molecule. For example, the (S)(+) enantiomer of methacholine, a parasympathomimetic drug, is over 250 times more potent than the (R)(-) enantiomer. If one imagines the receptor site to be like a glove into which the drug molecule must fit to bring about its effect, it is clear why a "left-oriented" drug is more effective in binding to a left-hand receptor than its "right-oriented" enantiomer. The more active enantiomer at one type of receptor site may not be more active at another type, eg, a receptor type that may be responsible for some other effect. For example, carvedilol, a drug that interacts with adrenoceptors, has a single chiral center and thus two enantiomers (Table 1-1). One of these enantiomers, the (S)(-) isomer, is a potent -receptor blocker. The (R)(+) isomer is 100-fold weaker at the  receptor. However, the isomers are approximately equipotent as -receptor blockers. Ketamine is an intravenous anesthetic. The (+) enantiomer is a more potent anesthetic and is less toxic than the (-) enantiomer. Unfortunately, the drug is still used as the racemic mixture. Finally, because enzymes are usually stereoselective, one drug enantiomer is often more susceptible than the other to drug-metabolizing enzymes. As a result, the duration of action of one enantiomer may be quite different from that of the other. Unfortunately, most studies of clinical efficacy and drug elimination in humans have been carried out with racemic mixtures of drugs rather than with the separate enantiomers. At present, only about 45% of the chiral drugs used clinically are marketed as the active isomerthe rest are available only as racemic mixtures. As a result, many patients are receiving drug doses of which 50% or more is less active, inactive, or actively toxic. However, there is increasing interest at both the scientific and the regulatory levels in making more chiral drugs available as their active enantiomers. E. RATIONAL DRUG DESIGN Rational design of drugs implies the ability to predict the appropriate molecular structure of a drug on the basis of information about its biologic receptor. Until recently, no receptor was known in sufficient detail to permit such drug design. Instead, drugs were developed through random testing of chemicals or modification of drugs already known to have some effect (see Chapter 5). However, during the past three decades, many receptors have been isolated and characterized. A few drugs now in use were developed through molecular design based on a knowledge of the