bonding, binding and isomerism

Pharmacology

Bonding, binding and isomerismJohn Sear

AbstractBonding, binding and isomerism influence the activity and elimination

of many drugs. The bonding of drugs by tissues is dependent on their

attraction and combination with cellular groups. Four main types of

chemical bonds are involved (ionic bonds, dipole–dipole interactions,

hydrogen bonds and covalent bonds). Ionic or electrostatic bonds are

reversible bonds between ionized compounds and proteins. hydrogen

bonds are a rapidly reversible type of dipole–dipole interaction, and are

particularly important in biological reactions. covalent bonds are stable

chemical bonds produced by electron sharing between atoms. The action

of most drugs depends on their initial binding by effector proteins (e.g.

enzymes, receptors or ion channels). This results in secondary effects

(e.g. enzyme activation or inhibition, or the accumulation of intermedi-

ate metabolites). In contrast, plasma-protein binding plays an essential

role in drug distribution, and varies widely (even among closely related

drugs). It may be modified in pathological conditions and surgery, and

sometimes restricts the hepatic elimination of drugs. Some extensively

bound drugs may be displaced from plasma proteins by other agents.

Isomers are drugs with the same chemical composition and molecular

formula. Structural isomers have different chemical structures because of

the different arrangement of their atoms (e.g. enflurane and isoflurane).

In contrast, stereoisomers have identical structures but different config-

urations. Enantiomers are pairs of stereoisomers that are mirror images

because of the presence of a chiral centre. a racemic mixture is an equal

mixture of two enantiomers, which may have different pharmacodynamic

activities and pharmacokinetic properties.

Keywords covalent binding; dipole interactions; geometric isomerism;

ionic binding; plasma-protein binding; stereoisomerism

These three physicochemical properties of ligands (bonding, binding and isomerism) are chemical features that can influence the efficacy, potency, and disposition of many drugs.

Drug bondingMost drugs can combine chemically with extra- or intracellular molecules in body tissues. Several different types of chemical bonding may occur, depending on the sites involved. Polar drugs

John Sear, FFARCS, is Professor of Anaesthetics at the University of

Oxford and an Honorary Consultant Anaesthetist. He qualified in

science and medicine from the London Hospital Medical College

and Bristol University. His research interests include the clinical

pharmacology of anaesthetic agents and their mechanisms of action.

aNaESThESIa aND INTENSIVE carE mEDIcINE 8:10 43

tend to bind to hydrophilic sites by ionic bonding, while lipo-philic drugs bind to hydrophobic sites on protein surfaces by van der Waals forces and hydrogen bonding.

Inter-atomic bondsIonic (electrostatic) bonds are readily reversible bonds

between ionized compounds and anionic or cationic sites on pro-teins. They are formed by the transfer of an electron from one atom to another, such that both attain stable outer shell config-urations (with each outer shell usually having eight electrons). A number of examples of electrostatic bonding exist in anaesthesia and intensive care; some positively charged tertiary and quater-nary amines (e.g. acetylcholine, physostigmine, neostigmine) are attracted by an anionic glutamate group in acetylcholinesterase, facilitating their reaction with the enzyme. Similarly, the anti-coagulant heparin contains an anionic pentasaccharide group that is attracted to basic arginine residues in antithrombin III, forming a stable complex.

Covalent bonds are stable chemical bonds produced by the sharing of one or more pairs of electrons from the outer shells of two atoms. They dissociate much less readily than other chemi-cal bonds, and typically occur between molecules that contain carbon atoms. Drugs that are bound to receptors and enzymes by covalent bonds (e.g. phenoxybenzamine) usually have a long duration of action.

Polar covalent bonds are formed when shared electrons are unevenly apportioned between adjacent atoms because the nucleus of one atom has a greater attraction for electrons than the other. One example is the covalent bonding between oxygen and hydrogen in the water molecule. The oxygen nucleus has greater attraction for electrons than that of hydrogen. This attrac-tion is not sufficiently strong to ‘pull’ the electron out of its orbit around the hydrogen nucleus to form an ion, but it does make the bond behave like a dipole (i.e. there is a difference in charge from one end to the other such that the bond will orientate itself in an electrical field). The polarity of the molecule as a whole is determined by the net effect of all the constituent bonds. In the case of water molecules, the vector sum of the two polar bonds result in a dipole-like molecule, making the compound ‘polar’.

Non-polar covalent bonds occur when covalently bonded atoms have equal (or nearly equal) attraction for shared elec-trons. Thus symmetrical molecules such as hydrogen and nitro-gen have non-polar bonds, as do carbon–hydrogen bonds. Thus methane (CH4) has four non-polar bonds. Non-polar compounds are formed when all constituent bonds are non-polar, or when the vector sum of the polar bonds cancels out to zero. For ex-ample, the double carbon–oxygen bond (CaO) is polar, but in the symmetrical molecule carbon dioxide (CO2), the dipoles cancel out to leave a non-polar compound.

Attraction between moleculesAdjacent molecules are also subject to attractive forces; these may be due to opposite charges on ionized molecules or to ion-dipole attraction. These forces are often responsible for drug binding; for example, to receptors and other proteins.

Dipole–dipole interactions occur between molecules with par-tially positive and partially negative charges, which can attract or repel each other in solution; opposite charges are attracted while similar charges are repelled. Both attractive and repulsive

1 © 2007 Elsevier ltd. all rights reserved.

Pharmacology

dipole–dipole interactions depend on intermolecular distance, and are collectively known as van der Waals forces; the criti-cal distance at which this intermolecular attraction is greatest is known as the van der Waals radius. These forces diminish rap-idly with increasing distance between molecules, such that they are strong forces in solids and liquids but very weak in gases.

Hydrogen bonding is an important type of dipole–dipole inter-action, which is particularly significant in biological reactions. There are many hydrogen bonds in biology, each with differ-ent intrinsic energies. Typically this can occur between partially positive hydrogen atoms in hydroxyl (–OH) or secondary amine (–NH) groups and adjacent electro-negative atoms with unshared electrons (e.g. oxygen, nitrogen or fluorine atoms). Hydrogen bonds are rapidly reversible chemical bonds (although they dis-sociate less readily than other dipole–dipole interactions). Thus it is likely that the halogenated volatile anaesthetic agents produce their effects through hydrogen bonding. Indeed there is a cor-relation between the ability to break these bonds and anaesthetic potency (the reversibility of the anaesthetics must depend on low-energy bonding).

When present, these hydrogen bonds also increase the boil-ing point and water solubility of a compound, and may have an important role in determining the shape of very large molecules such as proteins.

Drug bindingThe potency of many drugs depends on their selective binding to target cells or tissues. This principle was recognized more than 100 years ago by the work of Ehrlich and Langley. Although there are some exceptions to this rule, it is still applicable to many drugs used in humans (e.g. β-adrenoceptor-blocking drugs; his-tamine H2-receptor antagonists). Drugs can bind to proteins in the blood, in the extravascular fluids, or inside cells.

The action of most drugs depends on their binding to regula-tory proteins in cells, which subsequently mediate their effects. Regulatory or effector proteins are usually classified as enzymes, receptors, ion channels or other proteins (e.g. carrier proteins). A few drugs are bound by structural proteins (e.g. tubulin, im-munophilin) or by nuclear proteins such as DNA (e.g. cytotoxic agents). The combination of drugs with regulatory proteins usu-ally results in the formation of a transient drug–protein complex, which then produces secondary effects (e.g. enzyme activation, enzyme inhibition, accumulation of intermediate metabolites (second messengers), changes in ionic permeability, or DNA transcription). In many instances, the molecular binding sites of drugs and their regulatory proteins have been investigated by chemical and physical techniques (e.g. X-ray crystallography, nuclear magnetic spectroscopy). Knowledge of the three-dimen-sional relationships of protein-binding sites can help in the design and synthesis of chemical analogues of drugs that bind to their effector proteins with enhanced selectivity or affinity.

Binding to plasma proteins: plasma proteins play an essential role in the transport and distribution of drugs. As these mo-lecules are large, each may have different binding sites with different characteristics. Thus the number of protein molecules is not a good guide to the number of available binding sites. In addition, proteins are amphoteric, carrying ionizable sites of both acidic and basic types, which are affected by the pH of the


environment. For example, each molecule of human albumin has 18 negatively charged sites at pH 7.4.

Most drugs are relatively lipid-soluble, but are poorly soluble in plasma water. Consequently, they are often reversibly bound to plasma proteins, according to the equilibrium reaction:

Unbound drug + protein drug protein complexkk

12

21← → −

The extent of the binding will be influenced by the free-drug concentration, the affinity of the drug for the binding sites, and the binding protein concentration. The bound:unbound equilib-rium is controlled by two rate constants; where k12 is the asso-ciation constant for binding, and k21 the dissociation constant. Thus if a drug has a high affinity for binding, it will have a slow rate of dissociation. In those cases where there is more than one binding site, each site will have its own association and dissocia-tion constants.

There can be saturation of protein-binding sites. Low-potency drugs (e.g. salicylate, sulphonamides) may occupy a significant number of total binding sites, and show non-linear binding. Because they occupy lots of binding sites, these drugs may also alter the binding characteristics of other drugs that have affin-ity at the same site (such as the displacement of warfarin from albumin-binding sites by sulphonamides and non-steroidal anti-inflammatory drugs (NSAIDs)).

The dissociation constants (k12 and k21) for most drug–protein interactions are greatly in excess of the therapeutic concentration range; this means that a constant fraction of drug in the plasma is protein bound at all times regardless of time or dose.

For extremely lipid-soluble drugs, protein binding should be viewed as a means for rapid distribution of drug around the body. As a drug passes into the tissues, the free drug concentra-tion in the plasma will fall and there will be further dissociation of free drug from its protein-binding sites.

In the liver the rate of biotransformation depends on free rather than total drug concentration within the sinusoids. As free drug is cleared, there is a shift of the protein–drug binding equilibrium with release of further unbound drug. Under these circumstances, there is, in essence, clearance of both free and bound drug (unrestrictive clearance). The degree to which blood is cleared of drug depends on the individual Km (drug concentra-tion at which metabolism occurs at half maximal rate), and the number of enzyme sites. The most highly extracted drugs (such as lidocaine and propranolol) are metabolized by high-capacity enzyme systems, resulting in the drug being cleared from blood even at low concentrations. When the concentration of free drug is of the same order as the Km, the rate of clearance may be inadequate to further reduce the free-drug concentration. Thus, here the rate of metabolism is proportional to the free concentra-tion (Cf). If Cf is unchanged, so is the protein–drug equilibrium. If the drug is highly protein bound, the unbound fraction will be reduced, and with it the rate of metabolism. This is termed restrictive clearance.

Plasma-protein binding may restrict the hepatic clearance of highly bound drugs (> 70% bound) with low intrinsic hepatic clearance ratios (e.g. diazepam, phenytoin, warfarin). Under these circumstances, plasma-protein binding will limit the access of drugs to hepatic enzyme systems, thereby decreasing their clearance and increasing their elimination half-lives.


Pharmacology

The extent of plasma protein binding of drugs ranges from 0% to almost 100%, even among closely related drugs (Table 1). Thus, the binding of local anaesthetics to α1-acid glycoprotein ranges from 6% (procaine) to 55% (prilocaine), 65% (lidocaine) and 94–95% (ropivacaine and bupivacaine). In some instances (e.g. diazepam, phenytoin, warfarin) unbound concentrations are only 1–5% of total plasma levels. Unbound drug concentra-tions can be measured by various in vitro techniques (e.g. equi-librium dialysis, ultracentrifugation, ultrafiltration), or indirectly by their concentrations in saliva or cerebrospinal fluid.

Drugs bind in the blood to both albumin and globulins. The plasma concentrations of these proteins are around 40 g/litre (0.6 mM) for albumin (constituting about 50% of all plasma pro-teins), and 400–1000 mg/litre for α1-acid glycoprotein. Albumin is the main binding protein.

Binding to albumin – albumin binds mainly acidic or neu-tral compounds (e.g. salicylates, NSAIDs, oral anticoagulants), although these drugs also bind to β-globulin. Some basic drugs and physiological substrates, such as bilirubin and the amino acid tryptophan, are also bound by albumin.

Most acidic drugs show high affinity binding to albumin, and hence these drugs will have small apparent volumes of distribution. In contrast, many basic drugs (such as amphetamine, pethidine, propranolol), although binding to plasma proteins, also bind exten-sively to extravascular sites. This will result in their having large apparent volumes of distribution (of 4−8 × total body water).

The extent of plasma protein binding of some drugsa used by the anaesthetist

Drugs binding (%) to α1-acid glycoprotein

Procaine (6)

Prilocaine (55)

lidocaine (65)

Tetracaine (75)

ropivacaine (94)

Bupivacaine (95)

morphine (30)

Pethidine (64)

Fentanyl (80)

alfentanil (90)

atracurium (< 20)

Vecuronium (< 20)

Pancuronium (30)

atenolol (0)

Drugs binding (%) to albumin

Pindolol (50)

Propranolol (80)

Thiopental (80)

Phenytoin (95)

Diazepam (97)

Warfarin (99)

awhen measured at clinically relevant drug concentrations

Table 1


Albumin has two drug-molecule binding sites per molecule of protein. There may be competition between drugs for these sites; however, significant effects between two drugs on each other’s binding are not seen unless binding is greater than 50%, and greater than 50% of all the binding sites are occupied. Thus, interactions with lidocaine (which has only 50% free concentra-tion and only 1% of binding sites occupied) are unlikely.

It should not be assumed that two drugs with affinity for the same protein type will exhibit competitive binding, because the large protein molecules may carry two or more quite distinct binding sites which behave independently. In the case of albumin, the type 1 binding sites are occupied by warfarin, chlorothiazide, furosemide, phenytoin, and tolbutamide; while the type 2 binding sites are favoured by benzodiazepines, salicylates, probenecid and ethacrynic acid.

Binding to globulins – plasma globulins mainly bind basic drugs. Drugs are usually bound to β-globulins, or to the acute-phase protein α1-acid glycoprotein. Many vitamins and endo-genous hormones are also bound by plasma globulins.

Examples of drug binding to α1-acid glycoprotein include:• β-adrenoceptor antagonists – propranolol, oxprenolol• anti-arrhythmics – lidocaine, disopyramide• calcium-channel entry blockers – verapamil, nicardipine• opioids – pethidine, methadone• antidepressants and antipsychotics – amitriptyline, nor-

triptyline, imipramine, chlorpromazine• others – metoclopramide, prazosin, hydroxocobalamin.Other ligands that show protein binding to globulins include hydrocortisone (cortisol) to transcortin (a corticosteroid-binding globulin), as well as thyroxine, oestrogens and progestogens, which bind to specific plasma globulins.

Most drugs are active at drug concentrations that do not satu-rate any of their plasma-protein binding sites. However, some are administered at doses near to saturating concentrations (e.g. tol-butamide and some sulphonamides). Competition between these and other drugs or ligands (e.g. bilirubin) can produce saturation kinetics (discussed below).

Drug interactions and plasma-protein binding can be divided into three main types:• competitive inhibition of the binding of one drug to a single

binding site (e.g. warfarin and phenylbutazone)• non-competitive inhibition, where binding of a drug or mo-

lecule at a separate specific site affects the tertiary structure of albumin, and hence leads to a decrease in drug binding (e.g. interactions arising from the presence of high plasma concen-trations of bilirubin or fatty acids)

• where pathophysiology affects binding. In clinical conditions associated with hypoalbuminaemia (e.g. hepatic cirrhosis, nephrosis, trauma or burns), the binding of drugs to plasma proteins is modified. The plasma concentration of unbound drug may be increased, and can cause toxic effects (e.g. with prednisolone or phenytoin). The binding of drugs by albumin may also become saturated, and therefore the unbound drug concentrations increase. Consequently, well-perfused tissues and organs (e.g. liver, kidneys, brain) may receive a higher proportion of the dose, leading to toxic effects. A similar phe-nomenon may occur in renal impairment and in elderly people because of altered affinities of drugs for albumin (Table 2).


Pharmacology

Plasma concentrations of α1-acid glycoprotein increase after operative surgery and in certain other conditions. This may lead to increased binding of basic drugs (e.g. propranolol, local anaes-thetics, opioid analgesics). As a result, there will be a decrease in the concentration of unbound drug, and hence a reduced pharmacological effect. However significant changes in plasma- protein binding will affect a drug’s apparent volume of distribu-tion only if plasma-protein binding is greater than 90%.

Theoretical considerations suggest that drugs that are exten-sively bound to plasma proteins may be displaced by other agents. In practice, protein displacement reactions alone are not an important cause of drug interactions.

Binding to other tissue proteinsBinding to erythrocytes occurs with propranolol, phenytoin,

quinidine, haloperidol, fentanyl and lidocaine. In the case of fen-tanyl, the ratio of binding of drug to erythrocytes is similar to that of plasma proteins; hence kinetic studies based on plasma rather than whole blood concentrations will be incorrect. Red cell drug uptake from plasma may be concentration-dependent (an initial linear process and then a non-linear saturable phase; e.g. as seen with both acetazolamide and chlorthalidone).

Tissue binding will often result in sequestration of drug in different organs without any associated metabolism (e.g. tricyclic antidepressants and catecholamines are taken up into the lungs; chlorpromazine into the brain; tetracyclines into bone; chlo-rinated hydrocarbons such as DDT into fat; iodine into thyroid tissue; mepacrine into mucopolysaccharides; and griseofulvin into keratin). There is also uptake of fentanyl from blood into gastric cells. In general, the kinetics of tissue binding are poorly understood.

Tissue binding has no effect on drug clearance or average steady-state concentration; rather its principal effect is on the time course of a drug in the body. Any increase in clearance or decrease in tissue binding may decrease the half-life of a drug. The importance of tissue binding has received little attention to date; but any drug that binds to plasma proteins will also bind to other proteins with similar physicochemical characteristics.

Disease processes and other factors that affect the blood concentrations of albumin and α1-acid glycoprotein

Decreased albumin Increased α1-acid

glycoprotein

Decreased α1-acid

glycoprotein

Pregnancy

Burns

renal disease

hepatic disease

cardiac failure

Postoperative period

malnutrition

Elderly people

Burns

renal transplant

Infection

Post-myocardial

infarction

Postoperative period/

trauma

malignancy

rheumatoid arthritis

contraceptive pill

Pregnancy

oestrogens

Table 2


IsomerismIsomers are drugs with the same chemical composition and molecular formula. Their physical and chemical properties may be almost identical or quite different (depending on the type of isomerism involved).

Structural (geometrical) isomers have the same molecular for-mula but different chemical structures. Their individual atoms are not arranged in the same manner. Enflurane and isoflurane are well-known examples of structural isomerism (Figure 1). Tautomerism (or dynamic isomerism) is a special type of struc-tural isomerism in which two unstable structural isomers in equi-librium are interconvertible (usually by pH changes). This form of isomerism is partly responsible for the increased lipid solubil-ity of thiopental after its intravenous administration.

Stereoisomers have the same molecular formula and chemi-cal structure, but a different configuration (i.e. their substituent groups differ in their spatial arrangements). These isomers can be further classified as enantiomers and diastereomers.

Enantiomers are pairs of stereoisomers that are not superim-posable mirror images of each other. This type of stereoisomer-ism depends on the presence of a chiral centre in their molecular structure, which is usually a single carbon atom with four differ-ent substituents. An example is the intravenous drug ketamine (Figure 2). Chiral drugs with this type of structure have a mirror image that cannot be superimposed on their original configura-tion, and therefore exist in two enantiomeric forms (r and s iso-mers). Both enantiomers are optically active. One of the isomers rotates polarized light to the right (the (s), (+) or (d) form), while the other rotates polarized light to the left (the (r), (−) or (l) form).

Diastereomers are pairs of stereoisomers that are not mirror images, with two or more chiral centres. They usually show different physical and chemical properties. Examples include the stereoisomers of tramadol, atracurium and mivacurium.

Racemic mixtures are made up of equal amounts of two enan-tiomers, and are therefore optically inactive. Most chiral drugs are administered as racemic mixtures of r and s enantiomers. This is the case with most inhalational anaesthetics, some intravenous agents and local anaesthetics, and many autonomic drugs (Table 3). Although both stereoisomers have the same structure, they have a different molecular configuration with their substituent groups occupying different positions in space. Consequently, they may form different three-dimensional relationships with receptors and enzymes, which mainly consist of l-amino acids with stereoselec-tive properties. There are often differences between the pharma-codynamic activity and pharmacokinetic properties of individual enantiomers because their relationship with specific receptor sites and hepatic enzyme systems may not be identical. Some naturally derived drugs also occur as single stereoisomers (e.g. l-hyoscine) because naturally occurring enzymes are stereoselective and synthesize drugs in a specific configuration.

Differences in pharmacodynamic activity: there may be differ-ences in the potency of individual enantiomers. For example, in most experimental conditions s(+)isoflurane is approximately 20% more potent than r(−)isoflurane. Greater differences in potency are not uncommon: s(+)ketamine is 3–4 times more


Pharmacology

potent than r(−)ketamine; r-etomidate is more potent than the s isomer (18:1); and s-thiopental more than r-thiopental (4:1). Other anaesthetically related drugs with differrences in chiral potency include l-atropine, l-norepinephrine and l-epinephrine, which are 50–100 times more potent than their d-enantiomers. These differences in potency can be expressed by the eudismic ratio (stereospecific index), which represents the activity of the more active isomer (the eutomer) in relation to its antipode (the distomer). Other examples of isomerism affecting potency can be

Structural isomerism of enflurane and isoflurane

Enflurane

Isoflurane

Enflurane and isoflurane have the same molecular formula (F5C3H2OCl)

but different chemical structures. Both drugs possess a chiral centre (*)

and therefore exist in two enantiomeric forms

H C

F

F

F

F

H

Cl

O C C* F

H C

F

F

F

F

H

Cl

O CC* F

Figure 1

Stereoisomerism of ketamine

R(–)ketamine

S(+)ketamine

Cl

*CH3

O

HN

Cl

*CH3

O

HNLike isoflurane and

enflurane, ketamine has a

chiral centre (*). The

hypnotic can be given as the

racemic mixture or as the S(+)

isomer alone (in some parts

of Europe).

Figure 2


seen with some neurosteroids (where, in animals, pregnanolone (5β) was more potent than allo-pregnanolone (5α)). Occasionally the enantiomers have complementary actions, and both contrib-ute to the overall activity of drugs (e.g. tramadol, dobutamine).

Another recent example is the α2-agonist dexmedetomidine. Medetomidine (the racemic mixture) has effects at both pre- and postganglionic α2-receptors, and is widely used as an intravenous anaesthetic in veterinary practice. The racemate has mixed α2/α1 selectivity of about 1620:1; with the α2 activity almost entirely due to the d-enantiomer.

Differences in pharmacokinetic properties: as there are differ-ences in the pharmacodynamic activity of drug isomers, there may similarly be differences in the pharmacokinetics. These may affect protein binding, distribution, metabolism and excretion. Thus, there is much variability in the extent to which drugs (and even related compounds) bind to plasma proteins. One exam-ple is the binding of ampicillin, which is about 25% compared with 90% for its congener cloxacillin. Drug binding is also

Examples of chiral drugs used in anaesthetic practice

Drugs administered as single isomers

Etomidate (r)

levobupivacaine (l)

ropivacaine (l)

Cis-atracurium (1r-cis; 1′ r-cis)

Vecuroniuma

Pancuroniuma

rocuroniuma

hyoscine (l)

morphine (l)

Drugs administered as a racemate of two isomers

halothane

Enflurane

Isoflurane

Desflurane

Thiopental

Ketamine (although also used as the s(+)-ketamine isomer)

Prilocaine

Bupivacaine

Epinephrine

Norepinephrine

Dobutamine

atropine

glycopyrronium

Drugs administered as a mixture of more than two isomers

atracurium (n = 10)

mivacurium (n = 3)

athe active compounds are the 2β, 3α, 5α, 16β, 17β isomers, where α and β refer to the position of molecular groups at the above positions in the steroid ring; α lying below and β above the plane of the steroid ring

Table 3

© 2007 Elsevier ltd. all rights reserved.

Pharmacology

stereospecific, such that albumin binds l-propranolol to a greater extent than d-propranolol, and s-warfarin to a greater extent than r-warfarin; while α1-acid glycoprotein binds s-disopyramide to a greater extent than r-disopyramide.

Of more importance are the different rates of metabolism of enantiomers. r(+)propranolol, r(−)prilocaine and s(+)ketamine are all metabolized more rapidly than their enantiomers, and have a higher hepatic clearance. There may also be inhibition by one enantiomer of the metabolism of its antipode, as has been shown for the effect of r(−)ketamine on the metabolism of s(+)ketamine). Thus, individual stereoisomers may have dif-ferent elimination half-lives, systemic clearances, and apparent volumes of distribution. Some inactive enantiomers can also undergo unidirectional metabolic conversion (inversion) to their active antipodes. Both r(−)ibuprofen and r(−)fenoprofen are converted to the more active s(+)enantiomers after oral absorp-tion, thereby increasing the potency of the racemic mixture.

In current anaesthetic practice, there are a number of single enantiomers of some chiral drugs that have been synthesized (Table 3). They usually have advantages over the racemic mix-tures; for example, levobupivacaine is less cardiotoxic and has a longer duration of action than racemic bupivacaine. Ropivacaine has similar properties.

Complex stereoisomeric mixtures are also widely used in anaesthetic practice (Table 3). Two well-known examples are the muscle relaxants atracurium and mivacurium. Atracurium has four chiral centres, and therefore can exist as 16 stereoisomers. The proprietary preparation contains ten different stereoisomers, each of which can be classified by the conformation at the two carbon atoms (r and s) and by the relative configuration of the


two carbon–nitrogen bonds (either cis or trans). Cis-atracurium is the 1r-cis; 1′ r-cis isomer, and is the most active and potent isomer. It also causes less histamine release than atracurium.

Mivacurium is a mixture of three geometrical isomers (cis-trans; trans-trans; and cis-cis). The first two are the more potent, and make up 94% of activity; while the third isomer has a lower potency, lower clearance and longer elimination half-life. ◆

FurThEr rEADIng

Burke D, henderson DJ. chirality: a blueprint for the future.

Br J Anaesth 2002; 88: 563–76.

calvey TN, Williams NE. Principles and practice of pharmacology for

anaesthetists. 4th edn. oxford: Blackwell Science, 2001, pp 61–3.

Eckenhoff rg, Johansson JS. Interaction between inhaled anesthetics

and proteins. Pharmacol Rev 1997; 49: 343–67.

Kremer Jmh, Wilting J, Janssen lmh. Drug binding to human α1-

glycoprotein in health and disease. Pharmacol Rev 1988; 40: 1–47.

mather lE. Stereochemistry in anaesthetic and analgetic drugs.

Minerva Anestesiol 2005; 71: 507–16.

Acknowledgements

The author is grateful to Dr Norman calvey for his agreement

to the use of parts of his previous review on this subject

(Anaesthesia and intensive care medicine 2004; 5:10: 345–7).


bonding, binding and isomerism

Documents