Читать книгу Medical Pharmacology at a Glance - Michael J. Neal - Страница 16

5 Local anaesthetics

Local anaesthetics (top left) are drugs used to prevent pain by causing a reversible block of conduction along nerve fibres. Most are weak bases that exist mainly in a protonated form at body pH (bottom left). The drugs penetrate the nerve in a non‐ionized (lipophilic) form () but, once inside the axon, some ionized molecules () are formed and these block the Na⁺channels () preventing the generation of action potentials (lower half of the figure).

All nerve fibres are sensitive to local anaesthetics but, in general, small‐diameter fibres are more sensitive than large fibres. Thus, a differential block can be achieved where the smaller pain and autonomic fibres are blocked, whereas coarse touch and movement fibres are spared. Local anaesthetics vary widely in their potency, duration of action, toxicity and ability to penetrate mucous membranes.

Local anaesthetics depress other excitable tissues (e.g. myocardium) if the concentration in the blood is sufficiently high, but their main unwanted systemic effects involve the central nervous system. Lidocaine is the most widely used agent. It acts more rapidly and is more stable than most other local anaesthetics. When given with epinephrine, its action lasts about 90 min. Prilocaine is similar to lidocaine, but is more extensively metabolized and is less toxic in equipotent doses. Bupivacaine has a slow onset (up to 30 min) but a very long duration of action, up to 8 h when used for nerve blocks. It is often used in pregnancy to produce continuous epidural blockade during labour. It is also the main drug used for spinal anaesthesia in the UK. The more toxic agents, tetracaine and cocaine, have restricted use. Cocaine is primarily used for surface anaesthesia where its intrinsic vasoconstrictor action is desirable (e.g. in the nose). Tetracaine drops are used in ophthalmology to anaesthetize the cornea, but less toxic drugs such as oxybuprocaine and proxymetacaine, which cause much less initial stinging, are better.

Hypersensitivity reactions may occur with local anaesthetics, especially in atopic patients, and more often with procaine and other esters of p‐aminobenzoic acid.

Na⁺ channels

Excitable tissues possess special voltage‐gated Na⁺ channels that consist of one large glycoprotein α‐subunit and sometimes two smaller β‐subunits of unknown function. The α‐subunit has four identical domains, each containing six membrane‐spanning α‐helices (S1–S6). The 24 cylindrical helices are stacked together radially in the membrane to form a central channel. Exactly how voltage‐gated channels work is not known, but their conductance (gNa⁺) is given by gNa⁺ = Na⁺m³h, where Na⁺ is the maximum conductance possible, and m and h are gating constants that depend on the membrane potential. In the figure, these constants are shown schematically as physical gates within the channel. At the resting potential, most h‐gates (blue) are open and the m‐gates (yellow) are closed (closed channel). Depolarization causes the m‐gates to open (open channel), but the intense depolarization of the action potential then causes the h‐gates to close the channel (inactivation). This sequence is shown in the upper half of the figure (left to right). The m‐gate may correspond to the four positively charged S4 helices, which are thought to open the channel by moving outwards and rotating in response to membrane depolarization. The h‐gate responsible for inactivation may be the intracellular loop connecting the S3 and S5 helices; this swings into the internal mouth of the channel and closes it.

Action potential

If enough Na⁺ channels are opened, then the rate of Na⁺ entry into the axon exceeds the rate of K⁺ exit, and at this point, the threshold potential, entry of Na⁺ ions further depolarizes the membrane. This opens more Na⁺ channels, resulting in further depolarization, which opens more Na⁺ channels, and so on. The fast inward Na⁺ current quickly depolarizes the membrane towards the Na⁺ equilibrium potential (around +67 mV). Then, inactivation of the Na⁺ channels and the continuing efflux of K⁺ ions cause repolarization of the membrane. Finally, the Na⁺ channels regain their normal ‘excitable’ state and the Na⁺ pump restores the lost K⁺ and removes the gained Na⁺ ions.

Mechanism of local anaesthetics

Local anaesthetics penetrate into the interior of the axon in the form of the lipid‐soluble free base. There, protonated molecules are formed, which then enter and plug the Na⁺ channels after binding to a ‘receptor’ (residues of the S6 transmembrane helix). Thus, quaternary (fully protonated) local anaesthetics work only if they are injected inside the nerve axon. Uncharged agents (e.g. benzocaine) dissolve in the membrane, but the channels are blocked in an all‐or‐none manner. Thus, ionized and non‐ionized molecules act in essentially the same way (i.e. by binding to a ‘receptor’ on the Na⁺ channel). This ‘blocks’ the channel, largely by preventing the opening of h‐gates (i.e. by increasing inactivation). Eventually, so many channels are inactivated that their number falls below the minimum necessary for depolarization to reach threshold and, because action potentials cannot be generated, nerve block occurs. Local anaesthetics are ‘use dependent’ (i.e. the degree of block is proportional to the rate of nerve stimulation). This indicates that more drug molecules (in their protonated form) enter the Na⁺ channels when they are open and cause more inactivation.

Chemistry

Commonly used local anaesthetics consist of a lipophilic end (often an aromatic ring) and a hydrophilic end (usually a secondary or tertiary amine), connected by an intermediate chain that incorporates an ester or amide linkage.

Unwanted effects

Central nervous system

Synthetic agents produce sedation and light‐headedness, although anxiety and restlessness sometimes occur, presumably because central inhibitory synapses are depressed. Higher toxic doses cause twitching and visual disturbances, whereas severe toxicity causes convulsions and coma, with respiratory and cardiac depression resulting from medullary depression. Even cocaine, which has central stimulant properties unrelated to its local anaesthetic action, may cause death by respiratory depression.

Cardiovascular system

With the exception of cocaine, which causes vasoconstriction – by blocking norepinephrine (noradrenaline) reuptake – local anaesthetics cause vasodilatation, partly by a direct action on the blood vessels and partly by blocking their sympathetic nerve supply. The result of vasodilatation and myocardial depression is a decrease in blood pressure, which may be severe, especially with bupivacaine. The R(−)‐stereoisomer of bupivacaine, levobupivacaine may be less cardiotoxic than racemic bupivacaine because the R(−)‐isomer has less affinity for myocardial Na⁺ channels than does the S(+)‐isomer. Ropivacaine is a single (S)‐isomer and may also have reduced cardiotoxicity.

Duration of action

In general, high potency and long duration are related to high lipid solubility because this results in much of the locally applied drug entering the cells. Vasoconstriction also tends to prolong the anaesthetic effect by reducing systemic distribution of the agent, and this can be achieved by the addition of a vasoconstrictor, such as epinephrine (adrenaline) or, less often, norepinephrine. Vasoconstrictors must not be used to produce ring block of an extremity (e.g. finger or toe) because they may cause prolonged ischaemia and gangrene.

Amides are dealkylated in the liver, and esters (not cocaine) are hydrolysed by plasma pseudocholinesterase; however, drug metabolism has little effect on the duration of action of agents actually in the tissues.

Methods of administration

Surface anaesthesia

Topical application to external or mucosal surfaces.

Infiltration anaesthesia

Subcutaneous injection to act on local nerve endings, usually with a vasoconstrictor.

Nerve block

Techniques range from infiltration of anaesthetic around a single nerve (e.g. dental anaesthesia) to epidural and spinal anaesthesia. In spinal anaesthesia (intrathecal block), a drug is injected into the cerebrospinal fluid in the subarachnoid space. In epidural anaesthesia, the anaesthetic is injected outside the dura. Spinal anaesthesia is technically far easier to produce than epidural anaesthesia, but the latter technique virtually eliminates the postanaesthetic complications, such as headache.

Intravenous regional anaesthesia

Anaesthetic is injected intravenously into an exsanguinated limb. A tourniquet prevents the agent from reaching the systemic circulation.