LOCAL ANAESTHETICS by : Tutik Juniastuti Local ansesthetics are drugs used primarily to inhibit pain by preventing impulse conduction along sensory nerves. They achieve this by blocking voltage-sensitive Na+ channels in the cell membrane. Local anesthetics are also used as antidysrhythmics and in epilepsy The bask eledrophysiology of neurons Sodium channels can exist in three states: resting (i.e. closed), activated (i.e. open) and inactivated (i.e. blocked; explained below). The resting cell. The action of the Na+ pump in cell membranes normally maintains a high level of K+ and a low level of Na+ within the cell. In the resting cell, the membrane is more permeable to K+ than to Na+. The efflux of K+ makes the cell interior negative with respect to the outside, giving a membrane potential between -60 and -90 mV. In the resting cell, the Na+ channels are closed. Activation The action potential , When a nerve cell is stimulated locally (e.g. by noxious stimuli acting on a pain fibre or by neurotransmitter action on a receptor linked to a cation channel) the Na+ channel opens, leading to a local increase in the membrane permeability to Na+ . The resultant increased influx of positive Na+ causes membrane depolarisation and an action potential is generated. This is a regenerative process, as the action potential itself causes more Na+ channels to open, allowing its propagation along the nerve. Inactivation Within 5 ms the Na+ channels are inactivated (i.e. they close and are transiently refractory to being opened) allowing the cell to repolarise. (The delayed opening of K+ channels in response to the membrane depolarisation also contributes to repolarisation.) The rapidity of the sequence of events means that repetitive firing can proceed at high frequency. Local anaesthetics Important examples are procaine, lidocaine (lignocaine), tetracalne (amethocaine), bupivacaine and prilocaine. Cocaine was the first local anaesthetic to be used but has few clinical applications now. LOCAL ANESTHETICS Esters Amides Long Short Surface Long Medium Action Action Action Action Action (Tetra (Procaine) (Benzocaine) (Bupivacaine, (Lidocaine) caine) Ropivacaine) Mechanism of action Local anaesthetics are nearly all weak bases (pK. 8-9) and have similar chemical structures (Fig. 43.3). They act by blocking Na+ channels and stopping the propagation of action potentials in nerve. (Figs 43.1 and 43.4). Local anaesthetics gain access to their binding site either from the cell interior or by lateral diffusion in the cell membrane. In both cases, it is essential for the drug to adopt its lipid-soluble, uncharged form to gain access (Fig. 43.4). This, of course depends on pH and can explain the reduced activity of local anaesthetics in inflamed tissue, where the lower pH increases ionisation. Many local anaesthetics show use-dependence, that is they am more effective in blocking channels once these have been activated. This may be because the drug's binding site is within the channel and accessible only when the channel opens or it may result from greater affinity for the inactivated state of the channel. Local anaesthetics usually block small diameter fibres at lower concentrations than large fibres. Accordingly, pain sensation is blocked before other sensory inputs but it is not usually possible to achieve local anaesthesia without loss of other sensory modalities or local paralysis. Pharmacokinetics The plasma half-life of most local anaesthetics is 1-2 h, but their action persists for longer due to retention at the site of administration. The duration of action can be increased by the use of a vasoconstrictor (epinephrine (adrenaline) or felypressin). The esters (tetracaine, benzocaine, procaine, cocaine) are hydrolysed rapidly by plasma esterases once they reach the bloodstream; whereas most amides (prilocaine, bupivacaine) are relatively resistant to plasma esterases and are subject to N-dealkylation and hydrolysis in the liver at a slower rate. The variable lipid solubility of local anaesthetics determines the rate at which they penetrate tissues to cause nerve block and also their suitability for action on mucous membranes. Table 43.1 summarises the properties of three local anaesthetics. Cocaine and lidocaine penetrate membranes readily: procaine poorly. Benzocaine differs from other local anaesthefics in lacking the amino group; this results in increased lipophilicity and allows rapid entry into tissues, a fast onset and long duration of action. Unwanted effects The unwanted effects of local anaesthetics are due to their entry into the systemic circulation. CNS effects, prominent with procaine, less with lidocaine and prilocaine, are paradoxically stimulatory and include restlessness and tremor; though larger doses are depressant. Respiratory depression may be a cause of death. Local anaesthetics also cause myocardial depression and vasodilatation, which may result in a serious lowering of blood pressure. Cocaine has additional effects related to its ability to inhibit monoamine uptake into nerve-endings (not shared by other local anaesthetics). Sympathomimetic effects arising in this way include a rise in blood pressure. Hypersensitivity reactions, manifest as allergic dermatitis, may occur. Clinical use and administration of local anaesthetics Surface anaesthesia. Lidocalne and tetracaine are used for local anaesthesia of skin. coffee, etc. Infiltration anaesthesia. Most LAs are suitable. Given by Injection for minor surgery. Epinephrine (adrenaline) or felypressin may be coadministered to cause local vasoconstriction and reduct loss to circulation, thus prolonging action. Intravenous regional anaesthesia. A pressure cuff maintains local concentration and prevents entry into the general i circulation. Lidocaine and prilocaine are suitable. Nerve-block anaesthesia. Most LAs are suitable. Injection close to the nerve trunk produces regional anaesthesia for surgery or dentistry. Vasooonstrictors may be used to enhance duration. Spinal anaesthesia. Lidocalne or tetracalne can be injected into the subarachnoid space to act on spinal roots and spinal cord. This Is used for lower body surgery when general anaesthesia Is undesirable. EpIdural anaesthesla. Lidocalne or buplvacalne are injected into the-epIdural space. This Is used for spinal anaesthesia and also, childbirth.