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Mechanisms of Anesthetic Action in Skeletal, Cardiac, and Smooth Muscle by Thomas J.J. Blanck

Neuromuscular blocking agents work at the neuromuscular junction. There are two types, depolarizing and nondepolarizing. They bind to the ACh receptors and generate an action potential. However, because they are not metabolized by acetylcholinesterase, the binding of this drug to the receptor is prolonged resulting in an extended depolarization of the muscle end-plate. The motor nerve fibres reach the muscle fibres at sites called motor end plates, which are located roughly in the middle of each muscle fibre and store vesicles of the neurotransmitter acetylcholine this meeting of nerve and muscle fibres is known as the neuromuscular junction.

The contractile mechanism of skeletal muscles entails the binding of acetylcholine to nicotinic receptors on the membranes of muscle fibres. Acetylcholine binding causes ion channels to open and allows a local influx of positively charged ions into the muscle fibre, ultimately causing the muscle to contract. Because this mechanism is relatively insensitive to drug action, the most important group of drugs that affect the neuromuscular junction act on 1 acetylcholine release, 2 acetylcholine receptors, or 3 the enzyme acetylcholinesterase which normally inactivates acetylcholine to terminate muscle fibre contraction.

Botulinum toxin causes neuromuscular paralysis by blocking acetylcholine release. There are a few drugs that facilitate acetylcholine release, including tetraethylammonium and 4-aminopyridine. They work by blocking potassium-selective channels in the nerve membrane, thereby prolonging the electrical impulse in the nerve terminal and increasing the amount of acetylcholine released. This can effectively restore transmission under certain conditions, but these drugs are not selective enough for their actions to be of much use therapeutically.

Neuromuscular blocking drugs act on acetylcholine receptors and fall into two distinct groups: nondepolarizing competitive and depolarizing blocking agents. Competitive neuromuscular blocking drugs act as antagonists at acetylcholine receptors, reducing the effectiveness of acetylcholine in generating an end-plate potential. When the amplitude of the end-plate potential falls below a critical level, it fails to initiate an impulse in the muscle fibre, and transmission is blocked.

The most important competitive blocking drug is tubocurarine , which is the active constituent of curare , a drug with a long history and one of the first drugs whose action was analyzed in physiological terms.


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Claude Bernard , a 19th-century French physiologist, showed that curare causes paralysis by blocking transmission between nerve and muscle, without affecting nerve conduction or muscle contraction directly. Curare is a product of plants mainly species of Chondodendron and Strychnos that grow primarily in South America and has been used there for centuries as an arrow poison.

Tubocurarine has been used in anesthesia to produce the necessary level of muscle relaxation. It is given intravenously, and the paralysis lasts for about 20 minutes, although some muscle weakness remains for a few hours. After it has been given, artificial ventilation is necessary because breathing is paralyzed. Tubocurarine tends to lower blood pressure by blocking transmission at sympathetic ganglia, and, because it can release histamine in tissues, it also may cause constriction of the bronchi. Synthetic drugs are available that have fewer unwanted effects—for example, gallamine and pancuronium.

The action of competitive neuromuscular blocking drugs can be reversed by anticholinesterases , which inhibit the rapid destruction of acetylcholine at the neuromuscular junction and thus enhance its action on the muscle fibre. Normally this has little effect, but, in the presence of a competitive neuromuscular blocking agent, transmission can be restored.

This provides a useful way to terminate paralysis produced by tubocurarine or similar drugs at the end of surgical procedures. Neostigmine often is used for this purpose, and an antimuscarinic drug is given simultaneously to prevent the parasympathetic effects that are enhanced when acetylcholine acts on muscarinic receptors. Anticholinesterase drugs also are useful in treating myasthenia gravis , in which progressive neuromuscular paralysis occurs as a result of the formation of antibodies against the acetylcholine receptor protein.

The number of functional receptors at the neuromuscular junction becomes reduced to the point where transmission fails. Anticholinesterase drugs are effective in this condition because they enhance the action of acetylcholine and enable transmission to occur in spite of the loss of receptors; they do not affect the underlying disease process. Neostigmine and pyridostigmine are the drugs most often used, because they appear to have a greater effect on neuromuscular transmission than on other cholinergic synapses, and this produces fewer unwanted side effects.

The immune mechanism responsible for the inappropriate production of antibodies against the acetylcholine receptor is not well understood, but the process can be partly controlled by treatment with steroids or immunosuppressant drugs such as azathioprine. Depolarizing neuromuscular blocking drugs, of which succinylcholine is an important example, act in a more complicated way than nondepolarizing, or competitive, agents.

Succinylcholine has an action on the end plate similar to that of acetylcholine. When given systemically, it causes a sustained end-plate depolarization, which first stimulates muscle fibres throughout the body, causing generalized muscle twitching. Koller and Joseph Gartner began a series of experiments using cocaine to produce topical anesthesia of the conjunctiva. The birth of local and regional anesthesia dates from , when Koller and Gartner reported their success at producing topical cocaine anesthesia of the eye in the frog, rabbit, dog, and human.

The use of local anesthesia quickly spread around the world. The American surgeon William Halsted at Roosevelt Hospital in New York reported using cocaine to produce mandibular nerve block in and to produce brachial plexus block less than a year later. These blocks were accomplished by surgically exposing the nerves, then injecting them under direct vision.


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  • Leonard Corning injected cocaine near the spine of dogs, producing what was likely the first epidural in Cocaine spinal anesthesia was used to treat cancer pain in Caudal epidural anesthesia was introduced in by Sicard and Cathelin. Bier described intravenous regional anesthesia in In , Hirschel reported the first three percutaneous brachial plexus anesthesias.

    Fidel Pages reported using epidural anesthesia for abdominal surgery in Cocaine was soon incorporated into many other products, including the original formulation of Coca-Cola devised by Pemberton in This practice ended when cocaine became regulated by the forerunner of the Food and Drug Administration FDA in the early s. Cocaine and all other LAs contain an aromatic ring and an amine at opposite ends of the molecule, separated by a hydrocarbon chain, and either an ester or an amide bond Figure 2. Cocaine, the archetypical ester, is the only naturally occurring LA.

    Skeletal muscle relaxants

    The introduction of the amide LA lidocaine in was transformative. Lidocaine quickly became used for all forms of regional anesthesia. Other amide LAs based on the lidocaine structure prilocaine, etidocaine subsequently appeared. Ropivacaine and levobupivacaine are the only commercially available single-enantiomer single-optical-isomer LAs. All other LAs either exist as racemates or have no asymmetric carbons. Na channels are integral membrane proteins that initiate and propagate action potentials in axons, dendrites, and muscle tissue; initiate and maintain membrane potential oscillations in specialized heart and brain cells; and shape and filter synaptic inputs.

    TABLE 1. Voltage-gated Na channel—neural isoforms. Trends Neurosci. Defined genes contribute specific Na channel forms to each of the unmyelinated axons, nodes of Ranvier in motor axons, and small dorsal root ganglion nociceptors. For example, inherited mutations in Na v 1. It has been shown that certain Na v isoforms proliferate in animal models of chronic pain.

    Such developments, already underway for some Nav isoforms, could revolutionize the treatment of chronic pain. Thus, as the LA concentration increases, it must be applied along a shorter length of nerve to prevent impulse conduction, as is shown in Figure 5. Both normal conduction and the way in which LAs inhibit conduction differ between myelinated and unmyelinated nerve fibers. Conduction in myelinated fibers proceeds in jumps from one Ranvier node to the next, a process termed saltatory conduction. To block impulses in myelinated nerve fibers, it is generally necessary for LAs to inhibit channels in three successive Ranvier nodes Figure 6.

    Unmyelinated fibers, lacking the saltatory mechanism, conduct much more slowly than myelinated fibers. Unmyelinated fibers are relatively resistant to LAs, despite their smaller diameter, due to dispersal of Na channels throughout their plasma membranes. Nodal clustering of channels, essential for high-speed signal transmission, is initiated by Schwann cells in the peripheral nervous system and by oligodendrocytes in the central nervous system CNS.

    During an action potential, neuronal Na channels open briefly, allowing extracellular Na ions to flow into the cell, depolarizing the plasma membrane.

    Description

    After only a few milliseconds, Na channels inactivate where upon the Na current ceases. Na channels return to the resting conformation with membrane repolarization. The process by which channels go from conducting to nonconducting forms is termed gating. Gating is assumed to result from movements of dipoles in response to changes in potential. Anesthesia results when LAs bind Na channels and inhibit the Na permeability that underlies action potentials.

    Our understanding of LA mechanisms has been refined by several key observations. Taylor confirmed that LAs selectively inhibit Na channels in nerves. Strichartz first observed use-dependent block with LAs, showing the importance of channel opening for LA binding. Thus, membrane potential influences both Na channel conformation and Na channel affinity for LAs.

    Use-dependent block appears important for the functioning of LAs as antiarrhythmics and may also underlie the effectiveness of reduced LA concentrations in managing pain. Some LA optical isomers confer greater apparent safety than their opposite enantiomer. Nerve toxins are currently undergoing animal and human testing as possible replacements for LAs.

    These properties do not sort independently.

    INTRODUCTION

    Nerve-blocking potency of LAs increases with increasing molecular weight and increasing lipid solubility. Larger, more lipophilic LAs permeate nerve membranes more readily and bind Na channels with greater affinity. For example, etidocaine and bupivacaine have greater lipid solubility and potency than lidocaine and mepivacaine, to which they are closely related chemically.

    Thus, increased lipid solubility is associated with increased protein binding in blood, increased potency, and longer duration of action.