The Pharmacology of Local Anaesthetic Agents (page 1)

Issue 4 (1994) Article 7: Page 1 of 3

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The Pharmacology of Local Anaesthetic Agents

Dr J.M. Tuckley,
Department of Anaesthetics, Royal Devon and Exeter NHS Trust

Classification		Extradural Anaesthesia
Mode of Action		Spinal Anaesthesia
Preparations		Intravenous Local Anaesthesia
Clinical Uses		Toxicity of Local Anaesthetics
Topical Anaesthesia		Management of Acute Toxicity
Infiltration Anaesthesia		Practical Use
Conduction Anaesthesia

Classification

Local anaesthetic agents can be defined as drugs which are used clinically to produce reversible loss of sensation in a circumscribed area of the body. At high concentrations, many drugs that are used for other purposes possess local anaesthetic or membrane stabilising properties. These include Beta-adrenoceptor antagonists, opioid analgesics, anticonvulsants and antihistamines. Most of the clinically useful local anaesthetic agents consist of an aromatic ring linked by a carbonyl containing moiety through a carbon chain to a substituted amino group.

There are 2 classes of local anaesthetic drugs defined by the nature of the carbonyl-containing linkage group. The ester agents include cocaine, procaine, amethocaine and chloroprocaine, whilst the amides include lignocaine, prilocaine, mepivacaine and bupivacaine. There are important practical differences between these two groups of local anaesthetic agents. Esters are relatively unstable in solution and are rapidly hydrolysed in the body by plasma cholinesterase (and other esterases). One of the main breakdown products is para-amino benzoate (PABA) which is associated with allergic phenomena and hypersensitivity reactions. In contrast, amides are relatively stable in solution, are slowly metabolised by hepatic amidases and hypersensitivity reactions to amide local anaesthetics are extremely rare. In current clinical practice esters have largely been superseded by the amides.

Mode of Action

Local anaesthetics cause reversible interruption of the conduction of impulses in peripheral nerves. The primary electrophysiological effect of these compounds is to cause a local decrease in the rate and degree of depolarisation of the nerve membrane such that the threshold potential for transmission is not reached and the electrical impulse is not propagated down the nerve. There is no effect on the resting or threshold potential, although the refractory period and repolarisation may be prolonged. These effects are due to blockade of sodium channels, thereby impairing sodium ion flux, across the membrane.

Most local anaesthetic agents are tertiary amine bases (B) that are administered as water soluble hydrochlorides (B.HCl). After injection, the tertiary amine base is liberated by the relatively alkaline pH of tissue fluids:

B.HCl + HCO₃ <--> B + H₂CO₃ + Cl^-

In tissue fluid the local anaesthetic will be present in both an ionised (BH⁺) and non-ionised form (B); their relative proportions will depend on the pH of the solution and the pKa of the individual drug. The non-ionised base (B) then diffuses through the nerve sheath, perineuronal tissues and the neuronal membrane, to reach the axoplasm where it partially ionises again:

B + H⁺ <--> BH⁺

In the ionised form BH⁺, the local anaesthetic enters the sodium channel (from the interior of the nerve fibre) and either occludes the channel or combines with a specific receptor within the channel that results in channel blockade.

In clinical practice, local anaesthesia may be influenced by the local availability of free base (B), as only the unionised portion can diffuse through the neuronal membrane. Thus, local anaesthetics are relatively inactive when injected into tissues with an acid pH (e.g. pyogenic abscess) which is presumably due to reduced release of free base.

Preparations of Local Anaesthetics

Most local anaesthetics are bases that are almost insoluble in water. Solubility is greatly increased by preparation of their hydrochloride salts which are usually dissolved in modified isotonic Ringer solutions. Dilute preparations of local anaesthetics are usually acid (pH range 4.0-5.5), and contain a reducing agent (e.g. sodium metabisulphite) to enhance the stability of added vasoconstrictors. They also contain a preservative and a fungicide.

The dilute preparations are presented as percentage solutions of local anaesthetic. For example lignocaine is available in 0.5, 1.0, 1.5 and 2% solutions for injection ( with or without adrenaline). A solution expressed as 1% contains 1g of substance in each 100mls. The number of mg/ml can easily be calculated by multiplying the percentage strength by 10. Therefore a 1% solution of lignocaine contains 10mg/ml of solution . A 0.25% solution of bupivacaine has 2.5mg/ml.

Most local anaesthetics produce some degree of vasodilation, and they may be rapidly absorbed after local injection. Consequently, vasoconstrictors are frequently added, to enhance their potency and prolong their duration of action by localising them in tissues. In addition, vasoconstrictors decrease the systemic toxicity and increase the safety margin of local anaesthetics by reducing their rate of absorption (which is mainly dependent on local blood flow). Adrenaline is the most commonly used vasoconstrictor, it is added to local anaesthetic solutions in concentrations ranging from 1 in 80,000 to 1 in 300,000, although most are usually prepared to contain a 1 in 200,000 (5 microgram /ml) concentration of adrenaline.

Practical Point

Adrenaline 1:1000 contains 1 gram of adrenaline per 1000mls solution i.e. 1mg/ml.

To prepare a 1 in 200,000 solution the 1:1000 must be diluted 200 times. This is achieved by taking 0.1ml (= 0.1mg) and adding 19.9 mls of local anaesthetic solution.

The vasoconstrictor felypressin is added to some local anaesthetics (i.e. prilocaine) in a concentration of 0.003 i.u./ml. Felypressin is a non catecholamine vasoconstrictor that is chemically related to vasopressin, the posterior pituitary hormone.

The effect of vasoconstrictors on prolonging the duration of anaesthesia varies according to the local anaesthetic employed and the site of the injection. For example the duration of action of all agents is prolonged by the addition of adrenaline when used for infiltration anaesthesia and peripheral nerve blocks. Adrenaline also increases the duration of extradural anaesthesia when added to procaine, mepivacaine and lignocaine but does not alter markedly the duration of action of extradural prilocaine, bupivacaine or etidocaine.

Adrenaline containing solutions should never be used for infiltration around end-arteries i.e. penis, ring block of fingers or other areas with a terminal vascular supply as the intense vasoconstriction may lead to severe ischaemia and necrosis. Maximum safe dosages are often quoted for local anaesthetics with and without vasoconstrictors ( table 1), but such recommendations should be treated with caution as they ignore variations caused by factors such as the site of injection, the patient's general condition and the concomitant use of a general anaesthetic. For example if one assumes that a plasma concentration of lignocaine of 5 microgram/ml is required for the development of toxic symptoms, this would be achieved by the administration of approximately 300mg in the intercostal area, 500mg extradurally, 600mg in the region of the brachial plexus and 1000mg subcutaneously. Thus recommendation of a single maximum dose without regard to the site of injection is meaningless.

The addition of adrenaline reduces the peak concentration in blood, but the degree of this reduction again depends on the site of injection and the specific local anaesthetic agent.

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