The action of local anaesthetics

The physicochemical properties of drugs that underlie their absorption within the body can be complex, and the pH partition hypothesis is not sufficiently comprehensive to explain all the processes that occur in vivo-, it is, however, a good place to start. Perhaps surprisingly for such a simple theory, the pH partition hypothesis can explain quite complicated pharmacological observations. The processes that occur when a patient swallows a tablet are so complicated that the most powerful computers known to science cannot adequately model the process. It is astonishing, therefore, that a few physicochemical constants (pKa and partition coefficient, for example) can provide useful information and, when used properly, predict 

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 

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Local anaesthetics prevent nerve transmission by blocking sodium ion channels from the inside of the neuron. Sensory nerves that carry the stimulus of pain are the most sensitive to the actions of local anaesthetics. Accidental overdose can cause systemic effects including cardiorespiratory depression and loss of consciousness. Lidocaine is probably the most commonly used local anaesthetic. Qualified, registered podiatrists are allowed to access and administer lidocaine, bupivacaine, prilocaine, mepivacaine, levobupivacaine and ropivacaine. 

Another major category of a-helix rich proteins which is important in dmg action is the ion channel proteins. These proteins are much larger than the receptor-coupled G-proteins and have many transmembrane-spanning helices. For example, the sodium ion channel protein associated with the action of local anaesthetics in nerve blockade has 1988 amino add residues which form 24 transmembrane helices connected by intracellular and extracellular loops. 

Ester and amide local anaesthetics differ in the manner, site and rate of metabolism. There is little relation between the elimination of local anaesthetics and their duration of action. Amethocaine has a prolonged action due to its high affinity for nerve tissue despite being rapidly removed from plasma. Bupivacaine can be detected in the plasma many hours after its effects have worn off due to continuing absorption from the site of injection. The renal excretion of unchanged local anaesthetics is minimal. 

Bicarbonate. This maintains the local anaesthetic in an unionized form, which promotes the movement of local anaesthetic into the neurone/axon, thereby increasing the speed of onset of action,... 

Where is the site of action of local anaesthetics and what process within the neuronal membrane is inhibited by local anaesthetics ... 

Me2NCH2) C2H5)(Me)C-OOC Ph-HCI. Colourless crystalline powder with a bitter taste, m.p. 177-179"C. Prepared by the action of ethyl magnesium bromide on dimethyl-aminoaceione. It is a local anaesthetic, mainly used to produce spinal anaesthesia. 

Adrenaline along with local anaesthetics may be used for infiltration, nerve block and spinal anaesthesia for prolonging the action and to reduce the systemic toxicity of local anaesthetics. 

The coexistence of lipid and water solubility in the same molecule is essential for the action of a local anaesthetic drug. Lipophilicity permits the migration of drug across the phospholipid membrane of the nerve cell hydrophilicity is essential for the ionisation of the drug within the nerve. It follows that lipid and water solubility are the external and internal facilitators of local anaesthetic action in the nerve cell. Both within and without the nerve cell the unionised and ionised forms coexist in dynamic equilibrium. Outside the nerve, the active species is the unionised tertiary amine form. Conversely, inside the cell the ionised form predominates. The lower intracellular pH induces a shift in the equilibrium in favour of ionisation (Figure 5.5). 

Some local anaesthetics, such as benzocaine, are totally insoluble in water and cannot ionise. Consequently, there is no cation and therefore no Na+ channel block from within the cell. It is suggested that agents, such as benzocaine, which are very lipid-soluble, exert their effect in the phospholipid bilayer of the axon. This is the basis of the membrane expansion theory of local anaesthetic action. It is also possible that they diffuse laterally form the bilayer into the Na+ channel without ever accessing the axoplasm and in effect produce another variety of Na+ channel block. Repetitive depolarisation of a nerve recruits more Na+ channels and maintains them in the open state for a longer period than normal. 

Figure 5.7 Effect of local anaesthetics on the propagation of an action potential. A full action potential occurs when a spike potential reaches the level of the tfireshold potential. Local anaesthetics decrease the rate of rise and the frequency of spike potentials. When the value of the spike potential falls below the threshold potential neural transmission ceases.

Epinephrine. This causes local vasoconstriction, which reduces blood loss from the area and decreases rate of removal of local anaesthetic, which in turn increases the duration of action and, in the case of lidocaine, the safe dose that can be administered,... 

In addition to their action as local anaesthetics, the following actions on other parts of the body are possible. These effects are not clinically significant except in intolerant individuals, those with idiosyncratic reactions, in cases where absorption into the blood stream is unexpectedly rapid or in those with impaired metabolism and/or excretion. 

Some local anaesthetics, lidocaine and bupivacaine, can be used in combination with adrenaline. Adrenaline is a vasoconstrictor and its use increases the speed of onset and prolongs the duration of action of the local anaesthetic. Vasoconstrictors should never be used with local anaesthetics in digits or appendages, because of the risk of vasoconstriction leading to ischaemic necrosis. See page 277 for a list of local anaesthetics and other injectable drugs that can be administered by podiatrists. 

No account of sodium channels in excitable membranes would be complete without some mention of local anaesthetic drugs. Some new aspects of local anaesthetic action are included, particularly since they infringe on the mechanisms of sodium channels in excitable membranes. 

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