PHARMACOLOGY

Local anaesthetic agents

Malachy O Columb Richard Ramsaran

Learning objectives
After reading this article, you should: C understand the structure, pharmacokinetics and pharmacodynamics of local anaesthetic agents C be able to appraise enantiomeric local anaesthetics in terms of therapeutic usefulness C have insight to possible further advances in related therapies for chronic pain.

Abstract
Local anaesthetics are weak bases and consist of a lipophilic aromatic ring, a link and a hydrophilic amine. The chemistry of the link classies them as amides or esters. They act by blocking the sodium ionophore, especially in the activated state of the channel, and frequency dependence can be shown. The speed of onset is related to dose and proportion of drug in the unionized lipid-soluble form, which in turn is determined by the pKa and the ambient pH. Local anaesthetic agents, being weak bases, are bound in the plasma to a1-acid glycoproteins, inuencing duration of action. Esters undergo hydrolysis by esterases in the plasma. Amides are subject to phase I and II hepatic cytochrome P450 metabolism. The development of the S-enantiomers, levobupivacaine and ropivacaine, has not been without some controversy with regards to therapeutic benets when assessed by clinical potency models such as the minimum local analgesic concentration (MLAC). Drugs derived from biological toxins that target and bind to the sodium ionophore are gaining acceptance for use as analgesics in chronic pain.

There have also been improvements in our understanding of dosing, particularly in combination with other analgesics such as opioids and a2-adrenergic agonists.

Chemistry
Local anaesthetics have a common chemical structure, consisting of a lipophilic aromatic ring, a link and a hydrophilic amine group (Figure 1); most are tertiary amines. They can be classied into two groups based on the nature of the link: amides [eNHeCOe] and esters [eOeCOe]. The amide group is the most commonly used clinically and includes lidocaine, prilocaine, bupivacaine and ropivacaine. The ester group includes cocaine, procaine, chloroprocaine and amethocaine. Being weak bases they are made soluble for injection by formulating them as strong conjugate acidic hydrochloride salts (pH 3e6). Lidocaine HCl Lidocaine H Cl

Keywords Articaine; bupivacaine; chloroprocaine; levobupivacaine; lidocaine; local anaesthetics; pharmacology; ropivacaine; saxitoxin; tetrodotoxin

Mechanism of action
Drugs that have membrane-stabilizing activity have become widespread in clinical practice since Koller, an ophthalmologist, discovered the local anaesthetic properties of cocaine in 1884. They are now well established in many areas of clinical practice, including nerve blockade, neuropathic pain syndromes, obtunding the pressor response to laryngoscopy, treatment of cardiac arrhythmias, mucosal vasoconstrictors, epilepsy, as a diagnostic tool for suxamethonium apnoea and even for treatment of asthma. Signicant milestones in the development of this class of drugs were procaine (1898), lidocaine (1943) and bupivacaine (1957). More recent advances have come through research into the cardiotoxicity of bupivacaine, and developments in stereochemistry, resulting in the introduction of the S-enantiomers: ropivacaine (1996) and levobupivacaine (1999). Local anaesthetics work by blocking the inward Na current at the sodium ionophore during depolarization, which prevents

Basic local anaesthetic structure

R Link N R Aromatic ring Amine

Malachy O Columb FRCA is a Consultant in Anaesthesia and Intensive Medicine at the University Hospital of South Manchester, Wythenshawe, UK. His research interests include the clinical pharmacodynamics of local anaesthetic agents. Conicts of interest: none declared. Richard Ramsaran MBChB MPhil is a Core Trainee in Anaesthesia at the University Hospital of South Manchester, Wythenshawe, UK. He continues his interest in research now in the eld of anaesthesia, intensive care medicine and medical education. Conicts of interest: none declared.

C Ester link

Amide link

Figure 1 Reproduced from Anaesthesia and Intensive Care Medicine 8: 159e62.

ANAESTHESIA AND INTENSIVE CARE MEDICINE 11:3

113

2010 Elsevier Ltd. All rights reserved.

PHARMACOLOGY

propagation of the axonal action potential. However, research indicates that their mechanism of action is more complicated than this, with calcium, potassium and G-protein-regulated channels also being blocked by local anaesthetics. When delivered by injection, the local anaesthetic is predominantly in the acidic ionized form (pH 3e6). This dissociates in the relatively alkaline perineural tissues (pH 7.4) to the lipid-soluble free base. This crosses the axolemma and re-ionizes in the acidic axoplasm to the active moiety, which blocks the sodium ionophore from within the cell or from the membrane lipid bilayer. Therefore the non-ionized form promotes delivery into the axon and the ammonium or ionized state provides activity. When the nerve is stimulated, the sodium ionophore alters structurally. This initiates its cycle through four functional states: resting, activated, inactivated and deactivated (Figure 2). The complex ionophore can be considered to have two functioning gates, an outer m gate and an inner h gate. In its resting state, the outer m gate is closed and the inner h gate is open. On nerve stimulation, the ionophore enters its active state whereby opening of the outer m gate results in the rapid inux of sodium ions. As the membrane potential increases (to around 20 mV) this triggers the closure of the inner h gate and the ionophore enters an inactive state. The deactivated state is formed as a result of closure of the outer m gate once the membrane potential reaches 60 mV. Whilst in an inactivated or deactivated state, the nerve is resistant to further stimulation. Local anaesthetic block is more readily achieved when the ionophore is in the activated than in the inactivated state and least when in the deactivated or resting state (state-dependent block). When the sodium channel is closed, as is the case in the deactivated or resting states, the local anaesthetic can only gain access via the membrane as free base. However, when the sodium channel is open e as is the case in the activated, and to a lesser extent in the inactivated state e the ionized local anaesthetic can also gain access to the nerve via the channel. In addition, the ionized form

may enter from outside if the ionophore is repeatedly activated or opened. This gives rise to frequency-dependent (or phasic) block. The onset of block with agents that have more ionized molecules outside the membrane can therefore be accelerated by stimulation. Thus, frequency-dependent block is better demonstrated for bupivacaine than for lidocaine. Different local anaesthetics also have varying channel afnity. Lidocaine binds and dissociates rapidly from the channel, whereas bupivacaine binds rapidly but dissociates more slowly. This has little effect on neuronal block, but assumes greater importance when referring to effects on cardiac toxicity. The S-enantiomer of bupivacaine dissociates more quickly, thus reducing cardiotoxicity. The speed of onset of block is related to the concentration of molecules of local anaesthetic that are in the free-base or nonionized state. This depends on the initial dose, the dissociation constant (pKa) and the pH of the tissues. By convention, dissociation constants are applied to the acidic forms and this sometimes causes confusion as inversions of the HendersoneHasselbach equation (Eq. 1) are often used depending on whether an acid or base is involved. pH pKa logbase=acid For an acid : For a base : pH pKa logionized=non-ionized pH pKa lognon-ionized=ionized 1 2 3

It is simpler to use Eq. 1 or a modication for all substances and consider only the acidic version: pH pKa logdissociated=associated 4

It is then helpful when looking at the pKa for bases to consider them in the acidic ionized form. Eqs. 1 and 4 can be further modied to: pKa pH logacid=base 5

Schematic representation of the four states of the sodium channel with axonal action potentials

Outside

m gate

h gate Inside

Resting (90 mV)

Activated (60 mV)

Inactivated (+20 mV)

Deactivated (60 mV)

Figure 2 The sequence of activation of the sodium ionophore is shown. Reproduced from Anaesthesia and Intensive Care Medicine 8: 159e62.

ANAESTHESIA AND INTENSIVE CARE MEDICINE 11:3

114

2010 Elsevier Ltd. All rights reserved.

PHARMACOLOGY

pKa pH logassociated=dissociated

Using either Eq. 5 or 6, and given that pH is 7.4, it can be seen that more molecules of bupivacaine (86%) remain in the associated (ionized) form compared with lidocaine (72%) and therefore onset is slower (Table 1):   0:8 log BH B versus 0:4 log LH L The speed of onset of local anaesthesia can be accelerated by alkalinization or carbonation of the preparation. The addition of bicarbonate causes the strong conjugate acidic ammonium ions to dissociate and increase free-base concentrations. The diffusion of carbon dioxide into the axoplasm renders the interior even more acidic, encouraging reionization e a process referred to as diffusion trapping. Similarly, the acidic environment of an abscess decreases the proportion in the free-base state, which may explain the resistance to conduction block in such situations. However, it is useful to put the role of pKa and pH in perspective. From Table 1 it can be seen that chloroprocaine (used in the USA) has a high pKa consistent with a slow onset of block. However, this agent is used when a fast onset is required for epidural anaesthesia such as for emergency caesarean section. As a 3% w/v solution, larger doses can be given owing to its low potential for systemic toxicity because of ester hydrolysis. Therefore, dosing is more important then pKa. Potencies of local anaesthetic agents are related to lipid solubility and are quantied as octanol partition coefcients (Table 1). In addition, for agents that are enantiomers (enantiomorphs, optical isomers), it has been suggested that S- are more potent than R-enantiomers. However, these apparent differences in potencies are inconsistent and may be related to differences in vasoconstrictive and pharmacokinetic properties.

and therefore have a lower potential for systemic toxicity, but a higher incidence of allergic reactions than the amides, owing to the formation of para-amino benzoic acid (PABA) as a metabolite of hydrolysis. Amides undergo phases I and II hepatic cytochrome P450 metabolism. Phase I includes hydroxylation, N-dealkylation and methylation. Phase II includes conjugation with amino acids such as glycine. Local anaesthetics are extracted as they pass through the acidic lung tissue. This effect of ion trapping is also seen during pregnancy, as the lower foetal pH results in ionization and therefore trapping of the local anaesthetic.

Specic local anaesthetic agents

Cocaine is a benzoic acid ester, found naturally in the leaves of Erythroxylon coca, used for topical anaesthesia of the mucosa of the upper airway because of its vasoconstrictor activity. Other local anaesthetics exhibit a biphasic effect on vasomotor tone, with vasoconstriction at lower, and vasodilatation at higher, concentrations. The use of epinephrine as a vasoconstrictor is unnecessary, particularly as cardiotoxicity may occur because cocaine has indirect sympathomimetic activity. Cocaine blocks the presynaptic reuptake (uptake-1) of norepinephrine. Toxicity is enhanced because it is also resistant to metabolism by plasma pseudocholinesterases. Ester hydrolysis results in the release of ecgonine, a cerebral stimulant. Lidocaine contains a dimethylbenzene moiety termed xylene. The amide link confers the term xylidine or xylidide. The major metabolite of N-dealkylation of one of the eC2H5 groups is monoethylglycine xylidide (MEGX). Hepatic amidases result in various xylidine metabolites. Drugs that decrease hepatic blood ow (for example propranolol) decrease metabolism and clearance. Lidocaine is also used as a class 1b antiarrhythmic agent. When administered spinally at high concentrations, reports of transient radicular irritation suggested that it was neurotoxic. Repeated injection may reveal tachyphylaxis. Prilocaine is a secondary amine. The monomethylbenzene moiety is termed toluene. The amide link confers the term toluidine. The o-toluidine metabolite of prilocaine can oxidize haemoglobin to methaemoglobin, resulting in methaemoglobinaemia.

Pharmacokinetics
Local anaesthetic agents are weak bases and thus become bound in the plasma to a1-acid glycoproteins. Esters undergo rapid ester hydrolysis by plasma pseudocholinesterases (and other esters)

Physicochemical characteristics and suggested dosing maxima

Local anaesthetic Link pKa Octanol partition coefcient 43 25 346 346 115 257 1.7 9 Protein binding (%) 64 55 95 97 94 76 6 Ionized at pH 7.4 (%) 72 76 86 86 83 71 97 95 Half-life (h) Typical maximum dose (mg/kg) 3 4 2 2.5 3 7 8 10 1.5

Lidocaine-H Prilocaine-H Bupivacaine-H Levobupivacaine-H Ropivacaine-H Articaine-H Procaine-H Chloroprocaine-H Cocaine Table 1

Amide Amide Amide Amide Amide Amide Ester Ester Ester

7.8 7.9 8.2 8.2 8.2 7.8 8.9 9.1 8.7

1.6 1.6 3.5 2.6 1.9 0.3 0.14 0.11

ANAESTHESIA AND INTENSIVE CARE MEDICINE 11:3

115

2010 Elsevier Ltd. All rights reserved.

PHARMACOLOGY

Neonates, who have a relative deciency in erythrocytes of methaemoglobin reductase, are a group that are particularly at risk. Methylene blue can be used to reduce this ferric (Fe3) form back to the usual ferrous (Fe2) state. Prilocaine undergoes extensive pulmonary uptake, which results in lower systemic plasma levels and lower likelihood of toxicity. Because of this, it remains the drug of choice for intravenous regional anaesthesia (Biers block). Bupivacaine is the butyl (C4H9) derivative of N-alkyl pipecoloxylidine and is therefore part of the same homologous series as mepivacaine (methyl: CH3) and ropivacaine (propyl: C3H7). All pipecoloxylidine derivatives have an asymmetric carbon atom that confers the property of chirality or enantiomerism. The usual preparation of bupivacaine is as a racemate. Following N-dealkylation, the pipecoloxylidine metabolite still has some activity. Ropivacaine (or propivacaine) is the S-enantiomer of the propyl (C3H7) derivative of N-alkyl pipecoloxylidine. Metabolites include 3-hydroxyropivacaine (40%) and pipecoloxylidine (5%). The octanol partition coefcient for ropivacaine (115) suggests lower potency when compared with bupivacaine (346). However, ropivacaine may exert more vasoconstrictor activity to offset this. At lower concentrations, it may be motor sparing. Its reduced lipid solubility resulting in less penetration of the Ab bres may, in part, explain this. Levobupivacaine is the S-enantiomer of racemic bupivacaine. The plasma-bound fraction for levobupivacaine is greater at 95% compared with the racemate at 93%. Chirocaine is bound by Directive 91/507 of the European Community (EC), which states that the %w/v should be expressed in terms of the agent (free base) alone and not the hydrochloride salt. Therefore, levobupivacaine, by virtue of being expressed as free base, has 13% more molecules than the equivalent %w/v of the racemate bupivacaine (Marcain, AstraZeneca Pharmaceuticals), which predates the directive. This difference in expressed formulation should be considered when comparing it with other local anaesthetics. Chloroprocaine is an ester local anaesthetic used in the USA, which is now again increasing in use in Europe. It has limited cardiotoxicity due to rapid ester hydrolysis and this is born out by a maximum dose of 10 mg/kg. Used throughout the 1970s and 1980s, its use declined after the discovery of neurotoxicity when used in subarachnoid blocks, presumably due to additives. It is generally no longer used for subarachnoid administration. It is particularly useful in rescuing the inadequate obstetric epidural block, where large amounts of amide local anaesthetics have already been used. This is because it has a fast onset of action, despite having a high pKa, which is made possible by using larger doses owing to the lower potential for systemic toxicity. Articaine is an amide local anaesthetic that was rst synthesized in 1969 and is widely used in dental anaesthesia. Its molecular structure includes an additional ester linkage, which provides a good safety prole owing to its rapid metabolism by esterases (elimination half-life <20 min), therefore allowing readministration during the procedure. It has the same pKa and toxicity as lidocaine. The benzene ring is replaced with a thiophene ring, allowing faster and better penetration of the cell membrane and bone. Concerns have been raised regarding persistent paraesthesia due to neurotoxicity in a few cases.

Topical preparations
Topical anaesthetics must cross tissue barriers in order to have their effect. To achieve this, the drug must either have a low pKa, so that more of the drug is in the unionized form, or be used in higher concentrations to that used by injection. The development of a eutectic mixture of local anaesthetics (EMLA) for topical use has been welcomed, particularly in paediatric practice. This 50:50 mixture of crystalline lidocaine and prilocaine as lipid-soluble free bases has the lowest melting point of any combination. Therefore, this mixture becomes a paste at room temperature. This denes the eutectic point and hence eutectic mixture. Methaemoglobinaemia has been reported following extensive application and systemic absorption of prilocaine in infants. Amethocaine is also available for topical application as 4% tetracaine, aqueous cream preparation. It penetrates the skin quickly, but can cause marked skin irritation. A combination of lidocaine and epinephrine (Iontocaine) has recently been introduced, which provides dermal analgesia by iontophoresis, whereby an electric current delivers charged drug ions to the skin.

Stereochemistry
The pipecoloxylidines contain a chiral carbon and can exist as two enantiomers, R () and S (e). The prexes R (rectus) and S (sinister) refer, respectively, to the clockwise or anticlockwise arrangement of atoms or molecules around the asymmetric carbon atom based on an arbitrary hierarchical series of sequence rules. Evidence from animal and human models has indicated that, among certain chiral local anaesthetics, the S- is less toxic than the R-enantiomer or the racemate. This led to the development of the S-enantiomer of the propyl derivative: S-propivacaine (ropivacaine: Naropin). Two human toxicology studies showed that 12e25% more ropivacaine could be tolerated before the onset of central nervous system (CNS) toxicity. This perceived advantage for ropivacaine was based on the assumption of equipotency with bupivacaine. Two recently published studies1,2 using the minimum local analgesic concentration (MLAC) model found that ropivacaine was 40% less potent than bupivacaine. The human toxicology and MLAC efcacy studies have been formally compared to derive therapeutic indexes and the relative therapeutic ratio in humans for both local anaesthetics. The relative therapeutic ratio (ropivacaine: bupivacaine) for clinical CNS toxicity of 0.75 was found to be signicantly in favour of bupivacaine. Therefore, the perceived benets for ropivacaine in relation to toxicity, motor block sparing and differential sensory blockade need to be re-evaluated and may be explained by potency issues.3 The most recent development has been that of S-bupivacaine (levobupivacaine: Chirocaine).4 A human toxicology study found that the median tolerated dose of levobupivacaine for the onset of CNS symptoms was 5% greater than the racemate. Levobupivacaine also caused signicantly fewer reductions in cardiovascular performance as assessed by stroke index, acceleration index and ejection fraction. Some of these effects may represent less vasodilatation or reductions in preload because of the signicant augmentation of diastolic pressure with the racemate. An efcacy MLAC study showed that the potency of levobupivacaine was 98% that of the racemate on a %w/v basis (87% in molar terms). Comparing therapeutic indexes, the relative therapeutic ratio

ANAESTHESIA AND INTENSIVE CARE MEDICINE 11:3

116

2010 Elsevier Ltd. All rights reserved.

PHARMACOLOGY

(levobupivacaine: racemic bupivacaine) for CNS toxicity is 1.03 and therefore marginally in favour of levobupivacaine. There is a spectrum of potencies (low, intermediate, high) for ropivacaine, levobupivacaine and racemic bupivacaine with regard to analgesia, motor block and toxicity. Therefore, although ropivacaine and levobupivacaine may appear to widen sensorymotor separation, the relative ratios of effects suggest that differences are more apparent than real and pharmacologically they may not exist! However, the proles of apparent differences in separation should still be clinically useful for the lower potency pipecoloxylidines and may be explained by differences in potency.

toxins. Their strong and selective afnities for the sodium channel have generated interest for possible roles in pain therapy. There is continuing interest in polymer- and liposomaldelivery systems to enhance duration of analgesia. The therapeutic role of local anaesthetics is likely to expand as researchers elucidate their anti-inammatory, neuroprotective and antithrombotic properties. It has become clear from errors in the development of enantiomers for clinical application that determining the relative potencies of drugs is of prime importance in evaluating claims for perceived advantages in toxicity and blocking characteristics. A

The future
Further understanding of the role of chirality in local anaesthetic pharmacology is required to justify clinical use. Local anaesthetic-sparing combinations with other analgesics such as opioids, epinephrine, clonidine, midazolam and ketamine continue to be studied to develop synergistic regimens.5 Research is continuing for novel local anaesthetics; tonicaine is a longer duration derivative of lidocaine, sameridine has local anaesthetic and opioid receptor agonist properties. Butyl amino-benzoate has a low pKa, is poorly soluble and seems to be selective for Ad and C bres, thus producing minimal motor block with a prolonged duration of action. Naturally occurring toxins such as capsaicin, tetrodotoxin and saxitoxin continue to be of interest. Tetrodotoxin and saxitoxin are naturally occurring neurotoxins, found in marine life, which block the sodium ionophore extracellularly. Tetrodotoxin, which has a pyrimidine and saxitoxin, a purine structure, are some of the most potent non-protein biological
REFERENCES 1 Capogna G, Celleno D, Fusco P, Lyons G, Columb M. Relative potencies of bupivacaine and ropivacaine for labour analgesia. Brit J Anaesth 1999; 82: 371e3. 2 Polley LS, Columb MO, Naughton NN, Wagner DS, Van de Ven CJM. Relative analgesic potencies of ropivacaine and bupivacaine for epidural analgesia in labor: implications for therapeutic indexes. Anesthesiology 1999; 90: 944e50. 3 Columb MO, DAngelo R. MLAC: responding to dosing! Int J Obstet Anesth 2006; 15: 129e36. 4 Hollmann W, Durieux ME, Graf BH. Novel local anaesthetics and novel indications for local anaesthetics. Curr Opin Anaesthesiol 2001; 14: 741e51. 5 McLeod GA, Munishankar B, Columb MO. An isobolographic analysis of diamorphine and levobupivacaine for epidural analgesia in early labour. Brit J Anaesth 2007; 98: 497e502.

ANAESTHESIA AND INTENSIVE CARE MEDICINE 11:3

117

2010 Elsevier Ltd. All rights reserved.