Sodium channels, local anaesthetics

Once inside the neuron dissociation is necessary, because it is the ionized form binds to the sodium ion channel. Local anaesthetic activity is dependent on pH, because pH determines the degree of dissociation into ions. This becomes of clinical importance in inflamed and infected tissue, which often has a more acid pH. Acid conditions result in increased degree of ionization and reduced diffusion of local anaesthetic into neurons. This makes them less effective anaesthetics. 

The putative binding site for local anaesthetic molecules at the sodium channel has been identified as two amino acids in the sixth membrane-spanning segment of domain IV [2]. This binding site is located directly underneath the channel pore and can only be reached from the internal side of the membrane. Because local anaesthetics are applied exterior to the nerve fibre, they have to penetrate the axonal membrane before they can bind to the channel. 

Besides sodium channels, other ion channels such calcium- and potassium channels as well as certain ligand-gated channels are affected by local anaesthetics. However, this plays only a minor role for nerve block but may have more impact on adverse effects induced by systemical concentrations of these drags. 

The amide local anaesthetic lidocaine may also be used as an antianhythmic for ventricular tachycardia and exra-systoles after injection into the blood circulation. Drugs with high lipid solubility such as bupivacaine cannot be used for these purposes because their prolonged binding to the channel may induce dysrhythmias or asystolic heart failure [3]. Systemically applied lidocaine has also been used successfully in some cases of neuropathic pain syndromes [4]. Here, electrical activity in the peripheral nervous system is reduced by used-dependent but incomplete sodium channel blockade. 

This peripheral activity may be a rational basis for the use of systemic local anaesthetics in neuropathic states since ectopic activity in damaged nerves has been shown to be highly sensitive to systemic sodium channel blockers. This too is probably part of the basis for the analgesic effects of established effective anti-convulsants that block sodium channels such as carbamazepine, although central actions are important and may even predominate. The precise actions of excitability blockers therefore remains hazy as does any clear basis for the effectiveness of antidepressants and other adrenergic agents in the treatment of neuropathic pain as both central and peripheral actions, including sympathetic effects are possible. 

Figure 5.6 Sodium channel blockade by local anaesthetic drug, mechanism of action. L, local anaesthetic free base L+, ionised local anaesthetic ECF, extracellular fluid Memb, axonal cell membrane.

Alkalinisation of local anaesthetic solution with sodium bicarbonate (NaHC03) increases the pH of the solution to a value near its pKa. This results in an increased proportion of unionised drug available for neural penetration and thereby reduces the onset time. Carbonation is a term used to describe the acidification of a local anaesthetic solution with carbon dioxide. Following injection, the carbon dioxide diffuses into the axoplasm causing a decrease in the pH. This results in a higher proportion of ionised drug within the cell. In theory this should enhance the Na-i- channel block but in practice the results are disappointing. 

Local anaesthetics directly depress myocardial conduction and contractility in a dose-dependent manner. They bind to and inactivate myocardial sodium channels, reducing the velocity of the cardiac action potential and prolonging the QRS interval. As plasma concentrations approach toxic values sodium channels become progressively inactivated until there is a generalised reduction in automaticity (cardiac slowing) with negative inotropy. Slow increases to near- or above-toxic levels are better tolerated than rapid rises seen following intravascular injection. 

The duration of action of a local anaesthetic is proportional to the time that the drug remains bound to the sodium channels. Measures that prolong contact time will prolong the duration of the local anaesthetic effect. Cocaine has a vasoconstricting effect on blood vessels and prevents its own absorption. Many local anaesthetics are prepared with adrenaline (epinephrine) in order to achieve this effect. Concentrations are usually of the order of 1 200000 or more dilute than this. Care should be exercised when using adrenaline-containing solutions in the presence of halothane as it is known to sensitise the myocardium to the effects of catecholamines. 

Class I drugs have a local anaesthetic-like action, blocking the inward current in sodium channels. This depresses the fast depolarisation (phase 0) which initiates each action potential (Figure 8.5). This membrane-stabilising effect makes them valuable for the treatment of ectopic and tachycardic arrhythmias, such as atrial and ventricular fibrillation, extrasystoles, supraventricular and ventricular tachycardia. Class I drugs also decrease contractility. A sub-classification is made according to the effects on... 

Scholtz A Mechanisms of (local) anaesthetics on voltage-gated sodium and other ion channels. Br J Anaesth 2002 89 52. 

Leuwer M, Haeseler G, Hecker H, et al. An improved model for the binding of lidocaine and structurally related local anaesthetics to fast-inactivated voltage-operated sodium channels, showing evidence of coop-erativity. Br JPharmacol. 2004 141 47-54. 

Local anaesthetics reversibly prevent the transmission of nerve impulses by binding to sodium channels (preventing depolarization) and produce analgesia without loss of consciousness,... 

Lidocaine is structurally similar to cocaine, which was the first clinically useful local anaesthetic (Figure 5.4). The stimulating effect of cocaine, however, is due to its effect on a second, different receptor in the brain that indirectly amplifies the effect of dopamine and norepinephrine (we will deal with this matter in a later lecture). This effect is actually observed at concentrations lower than those required for the blocking of sodium channels. Yet, local application of cocaine will result in very high concentrations that will... 

Page 49, figure 5.5 Toxicology Letters 100-101 247-254 (1998), French R.J. et al Molecular and kinetic determinants of local anaesthetic action on sodium channels. Reprinted with permission from Elsevier. 

Zn, Cd. Pb. A wide variety of other agents may block, modulate or open sodium channels (see SODIUM-CHANNEL activators), local anaesthetics block most of the channels, this being their major mechanism of action. 

Barbato F, LaRotonda IM, Quaglia F. Chromatographic indexes on immobilized artificial membranes for local anaesthetics relationships with activity data on closed sodium channels. Pharm Res 1997 14 1699-705. 

The important thing to remember in this situation is that although 99 out of every 100 local anaesthetic molecules are ionised, there exists an equilibrium between the cation and the unionised free base. This unionised free base (B) can diffuse easily through the cell membrane, where it will become instantly ionised due to the H+ ions present within the cell. Once ionised to the cation (BH+), the local anaesthetic cannot easily diffuse back outside the cell, but it can approach the receptor situated at the internal opening of the sodium channel. Once the 1% of free base has diffused into... 

Strichartz GR, Zhou Z, Sinnott C, Khodorova A 2002 Therapeutic concentrations of local anaesthetics unveil the potential role of Na channels in neuropathic pain. In Sodium channels and neuronal hyperexcitabUity. Wiley, Chichester (Novartis Fund Symp 241) p189-205... 

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