The Resting Membrane Potential

The neuronal membrane contains the enzyme Na⁺/K⁺ ATPase that actively maintains a thirty-fold K⁺ concentration gradient (greater concentration inside) and a ten-fold Na⁺ concentration gradient (greater concentration outside). K⁺ tends to flow down its concentration gradient out of the cell due to the selective permeability of the membrane. However, intracellular anionic proteins tend to oppose this ionic flux, and the balance of these processes results in the resting membrane potential of −80 mV (negative inside). It can, therefore, be seen that the ratio of intracellular to extracellular K⁺ alters the resting membrane potential. Hypokalaemia increases (makes more negative) the resting membrane potential while the Na⁺ concentration has little effect, as the membrane is essentially impermeable to Na⁺ when in the resting state.

The Action Potential

The action potential is generated by altered Na⁺ permeability across the phospholipid membrane and lasts only 1–2 milliseconds. Electrical or chemical triggers initially cause a slow rise in membrane potential until the threshold potential (about −50 mV) is reached. Voltage-sensitive Na⁺ channels then open, increasing Na⁺ permeability dramatically and the membrane potential briefly reaches +30 mV (approaching the Na⁺ equilibrium potential of +67 mV), at which point the Na⁺ channels close. The membrane potential returns to its resting value with an increased efflux of K⁺. The Na⁺/K⁺ ATPase restores the concentration gradients although the total number of ions moving across the membrane is small. Conduction along unmyelinated fibres is relatively slow compared with myelinated fibres where current jumps from one node of Ranvier to another (saltatory conduction) and reaches 120 m.s⁻¹. Retrograde conduction is not possible under normal circumstances due to inactive Na⁺ channels following the action potential (see Figure 11.1).

Figure 11.1 Changes in Na⁺ and K⁺ conductance during the action potential.

Preparations

Local anaesthetics are formulated as the hydrochloride salt to render them water-soluble. They often contain the preservative sodium metabisulfite and a fungicide. Multi-dose bottles contain 1 mg.ml⁻¹ of the preservative methyl parahydroxybenzoate. Only the single-dose ampoules without additives (apart from glucose at 80 mg.ml⁻¹ used in ‘heavy’ bupivacaine) are suitable for subarachnoid administration as the preservatives carry the risk of producing arachnoiditis. Adrenaline or felypressin (a synthetic derivative of vasopressin with no antidiuretic effect) are added to some local anaesthetic solutions in an attempt to slow down absorption from the site of injection and to prolong the duration of action. Lidocaine is available in a large range of concentrations varying from 0.5% to 10%. The high concentrations are used as a spray to anaesthetise mucous membranes (note 1% = 10 mg.ml⁻¹).

Mechanism of Action

Local anaesthetic action is dependent on blockade of the Na⁺ channel. Unionised lipid-soluble drug passes through the phospholipid membrane where in the axoplasm it is protonated. In this ionised form it binds to the internal surface of a Na⁺ channel, preventing it from leaving the inactive state. The degree of blockade in vitro is proportional to the rate of stimulation due to the attraction of local anaesthetic to ‘open’ Na⁺ channels (see Figure 11.2).

Figure 11.2 Mechanism of action of local anaesthetics.

Alternatively, ‘membrane expansion’ may offer an additional mechanism of action. Unionised drug dissolves into the phospholipid membrane and may cause swelling of the Na⁺ channel/lipoprotein matrix resulting in its inactivation.

Physiochemical Characteristics

Local anaesthetics are weak bases and exist predominantly in the ionised form at neutral pH as their pK_a exceeds 7.4. They fall into one of two chemical groupings, ester or amide, which describes the linkage between the aromatic lipophilic group and the hydrophilic group that each group possesses. Esters are comparatively unstable in solution, unlike amides that have a shelf-life of up to 2 years (see Table 11.1; Figure 11.3).

Figure 11.3 Structure of some local anaesthetics. Asterisk marks chiral centre.

The individual structures confer different physiochemical and clinical characteristics.

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  Potency is closely correlated to lipid solubility in vitro, but less so in vivo. Other factors such as vasodilator properties and tissue distribution determine the amount of local anaesthetic that is available at the nerve.

  
  
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  The duration of action is closely associated with the extent of protein binding. Local anaesthetics with limited protein binding have a short duration of action, and conversely those with more extensive protein binding have a longer duration of action.

  
  
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  The onset of action is closely related to pK_a. Local anaesthetics are weak bases and exist mainly in the ionised form at normal pH. Those with a high pK_a have a greater fraction present in the ionised form, which is unable to penetrate the phospholipid membrane, resulting in a slow onset of action. Conversely, a low pK_a reflects a higher fraction present in the unionised form and, therefore, a faster onset of action as more is available to cross the phospholipid membrane.

  
  
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  The intrinsic vasodilator activity varies between drugs and influences potency and duration of action. In general, local anaesthetics cause vasodilatation in low concentrations (prilocaine > lidocaine > bupivacaine > ropivacaine) and vasoconstriction at higher concentrations. However, cocaine has solely vasoconstrictor actions by inhibiting neuronal uptake of catecholamines (uptake 1) and inhibiting monoamine oxidase MAOs.

However, total dose and concentration of administered local anaesthetic will also have a significant effect on a given clinical situation.

Local anaesthetics are generally ineffective when used to anaesthetise infected tissue. The acidic environment further reduces the unionised fraction of drug available to diffuse into and block the nerve. There may also be increased local vascularity, which increases removal of drug from the site.

Lidocaine: pK_a = 7.9

At p. 7.4

pH=pKa+log{[B][BH+]}7.4=7.9+log{[B][BH+]}−0.5=log{[B][BH+]}0.3={[B][BH+]}

Related posts:

Chapter 2 – Absorption, Distribution, Metabolism and Excretion Chapter 3 – Drug Action Chapter 14 – Adrenoceptor Antagonists Chapter 9 – General Anaesthetic Agents Chapter 19 – Antiemetics and Related Drugs Chapter 21 – Intravenous Fluids, Minerals and Nutrition