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C H A P T E R 2 8 Neuromuscular junction blocking agents

N erves communicate with muscles at a synapse called the neuromuscular junction (NMJ). At this point, a nerve stimulates a muscle to contract. If the nerve is not able to communicate with the muscle cell, the muscle will not be able to contract, and paralysis will result. Certain clinical situations require that a person not be able to move muscles, including surgery, diagnostic procedures and mechanical ventilation. Anaesthetics (discussed in Chapter 27) can prevent muscle movement by suppress- ing function through the central nervous system (CNS), with many systemic complications from this depression. The NMJ-blocking drugs are used to prevent the nerve stimulation at the muscle cell and cause paralysis of the muscle directly without total CNS depression and its many systemic effects. THE NEUROMUSCULAR JUNCTION The neuromuscular junction is the point at which a motor neuron communicates with a skeletal muscle fibre. The end result is muscular contraction. NMJ-blocking agents affect the normal functioning of muscles by interfering with the normal processes that occur at the junction of the nerve and muscle cell. The functional unit of a muscle, called a sarcomere , is made up of light and dark filaments formed by actin and myosin molecules. These molecules are arranged in

orderly stacks that give the sarcomere a striated or striped appearance. Normal muscle function involves the arrival of a nerve impulse at the motor nerve terminal, followed by the release of the neurotransmitter acetylcholine (ACh) into the synaptic cleft. At the acetylcholine- receptor site on the effector side of the synapse, ACh interacts with the nicotinic cholinergic receptors, causing depolarisation of the muscle membrane. ACh is then broken down by acetylcholinesterase (an enzyme), freeing the receptor for further stimulation. With stimu- lation, this depolarisation allows the release of calcium ions, stored in tubules, into the cell. The calcium binds to troponin, a chemical found throughout the sarcomere. This binding of troponin releases the actin and myosin binding sites, allowing them to react with each other. The actin and myosin molecules react with each other again and again, sliding along the filament and making it shorter. This is a contraction of the muscle fibre accord- ing to the sliding filament theory (Figure 28.1). As the calcium is removed from the cell during repolarisation of the muscle membrane, the troponin is freed and once again prevents the actin and myosin from reacting with each other. The muscle filament then relaxes or slides back to the resting position. A dynamic balance of excitatory and inhibitory impulses to the muscle results in muscle tone. However, if ACh cannot react with the cholinergic muscle receptor or if the muscle cells cannot repolarise to allow new

Sarcomere

Myosin filaments

Actin filaments

A Muscle relaxed—no contact between actin and myosin

Myosin heads

Contraction

Contraction

B Cross-bridges form, actin filaments move closer together

Cross-bridges

C Cross-bridges return to normal postion, attach to new sites

FIGURE 28.1  Sliding filament mechanism of skeletal muscle contraction. A. Muscle is relaxed, and there is no contact between the actin and myosin filaments. B. Cross-bridges form, and the actin filaments are moved closer together as the muscle fibre contracts. C. The cross-bridges return to their original position and attach to new sites to prepare for another pull on the actin filaments and further contraction.