Drugs that block nicotinic cholinergic transmission: neuromuscular blocking agents and ganglionic blocking agents

The drugs discussed in this chapter block nicotinic cholinergic receptors. The neuromuscular blocking agents block nicotinic_M receptors at the neuromuscular junction. The ganglionic blocking agents block nicotinic_N receptors in autonomic ganglia. The neuromuscular blockers have important clinical applications. In contrast, the ganglionic blockers, once used widely for hypertension, have been replaced by newer drugs.

Neuromuscular blocking agents

Neuromuscular blocking agents prevent acetylcholine from activating nicotinic_M receptors on skeletal muscles, and thereby cause muscle relaxation. These drugs are given to produce muscle relaxation during surgery, endotracheal intubation, mechanical ventilation, and other procedures. Based on mechanism of action, the neuromuscular blockers fall into two major groups: competitive (nondepolarizing) agents and depolarizing agents.

Control of muscle contraction

Before we discuss the neuromuscular blockers, we need to review physiologic control of muscle contraction. In particular, we need to understand excitation-contraction coupling, the process by which an action potential in a motor neuron leads to contraction of a muscle.

Basic concepts: polarization, depolarization, and repolarization

The concepts of polarization, depolarization, and repolarization are important to understanding both muscle contraction and the neuromuscular blocking drugs. In resting muscle there is uneven distribution of electrical charge across the inner and outer surfaces of the cell membrane. As shown in Figure 16–1, positive charges cover the outer surface of the membrane and negative charges cover the inner surface. Because of this uneven charge distribution, the resting membrane is said to be polarized.

Figure 16–1 The depolarization-repolarization cycle of the motor end-plate and muscle membrane.
(ACh = acetylcholine.)

When the membrane depolarizes, positive charges move from outside to inside. So many positive charges move inward that the inside of the membrane becomes more positive than the outside (see Fig. 16–1).

Under physiologic conditions, depolarization of the muscle membrane is followed almost instantaneously by repolarization. Repolarization is accomplished by pumping positively charged ions out of the cell. Repolarization restores the original resting membrane state, with positive charges on the outer surface and negative charges on the inner surface.

The steps leading to muscle contraction are summarized in Figure 16–2. The process begins with the arrival of an action potential at the terminal of a motor neuron, causing release of acetylcholine (ACh) into the subneural space. Acetylcholine then binds reversibly to nicotinic_M receptors on the motor end-plate (a specialized region of the muscle membrane that contains the receptors for ACh) and causes the end-plate to depolarize. This depolarization initiates a muscle action potential (ie, a wave of depolarization that spreads rapidly over the entire muscle membrane), which in turn triggers the release of calcium from the sarcoplasmic reticulum (SR) of the muscle. This calcium permits the interaction of actin and myosin, thereby causing contraction. Very rapidly, ACh dissociates from the motor end-plate, the motor end-plate repolarizes, the muscle membrane repolarizes, and calcium is taken back up into the SR. Because there is no longer any calcium available to support the interaction of actin and myosin, the muscle relaxes.

Figure 16–2 Steps in excitation-contraction coupling.
(ACh = acetylcholine.)

Sustained muscle contraction requires a continuous series of motor neuron action potentials. These action potentials cause repeated release of ACh, which causes repeated activation of nicotinic receptors on the motor end-plate. As a result, the end-plate goes through repeating cycles of depolarization and repolarization, which results in sufficient release of calcium to sustain contraction. If for some reason the motor end-plate fails to repolarize—that is, if the end-plate remains in a depolarized state—the signal for calcium release will stop, calcium will undergo immediate reuptake into the SR, and contraction will cease.

Competitive (nondepolarizing) neuromuscular blockers

In this section, we discuss the competitive neuromuscular blocking agents, drugs that compete with ACh for binding to nicotinic_M receptors. These drugs are also known as nondepolarizing neuromuscular blockers, because, unlike the depolarizing neuromuscular blockers (see below), they do not depolarize the motor end-plate.

The powers of tubocurarine, the oldest competitive neuromuscular blocker, were known to primitive hunters long before coming to the attention of modern scientists. Tubocurarine is one of several active principles found in curare, an arrow poison used for hunting by South American Indians. When shot into a small animal, curare-tipped arrows cause relaxation (paralysis) of skeletal muscles. Death results from paralyzing the muscles of respiration.

The clinical utility of the neuromuscular blockers is based on the same action that is useful in hunting: production of skeletal muscle relaxation. Relaxation of skeletal muscles is helpful in patients undergoing surgery, endotracheal intubation, mechanical ventilation, and other procedures.

Group properties

In all prior editions of this book, we have used tubocurarine as the prototype of the competitive neuromuscular blockers. However, since tubocurarine is no longer used, and since the similarities among the competitive agents are more striking than the differences, we will discuss the properties of these agents as a group, rather than picking one of them to be a prototype.

Chemistry

All of the neuromuscular blocking agents contain at least one quaternary nitrogen atom (Fig. 16–3). As a result, these drugs always carry a positive charge, and therefore cannot readily cross membranes.

Figure 16–3 Structural formulas of representative neuromuscular blocking agents.
Note that both agents contain a quaternary nitrogen atom and therefore cross membranes poorly. Consequently, they must be administered parenterally and have little effect on the central nervous system or the developing fetus.

The inability to cross membranes has three clinical consequences. First, neuromuscular blockers cannot be administered orally. Instead, they must all be administered parenterally (almost always IV). Second, these drugs cannot cross the blood-brain barrier, and hence have no effect on the central nervous system (CNS). Third, neuromuscular blockers cannot readily cross the placenta, and hence have little or no effect on the fetus.

Mechanism of action

As their name implies, the competitive neuromuscular blockers compete with ACh for binding to nicotinic_M receptors on the motor end-plate (Fig. 16–4). However, unlike ACh, these drugs do not cause receptor activation. When they bind to nicotinic_M receptors, they block receptor activation by acetylcholine, causing the muscle to relax. Muscle relaxation persists as long as the amount of competitive neuromuscular blocker at the neuromuscular junction (NMJ) is sufficient to prevent receptor occupation by ACh. Muscle function can be restored by eliminating the drug from the body or by increasing the amount of ACh at the NMJ.

Figure 16–4 Mechanism of competitive neuromuscular blockade.
Pancuronium, a competitive blocker, competes with acetylcholine (ACh) for binding to nicotinic_M receptors on the motor end-plate. Binding of pancuronium does not depolarize the end-plate, and therefore does not cause contraction. At the same time, the presence of pancuronium prevents ACh from binding to the receptor, and hence contraction is prevented.

Pharmacologic effects

TABLE 16–1

Properties of Competitive and Depolarizing Neuromuscular Blockers

		Time Course of Action*
Generic Name	Route	Time to Maximum Paralysis (min)	Duration of Effective Paralysis (min)	Time to Nearly Full Spontaneous Recovery^†	Promotes Histamine Release	Mode of Elimination
Competitive Agents
Atracurium [Tracrium]	IV	2–5	20–35	60–70 min	Yes	Plasma cholinesterase
Cisatracurium [Nimbex]	IV	2–5	20–35	—	Minimal	Spontaneous degradation
Pancuronium	IV	3–4	35–45	60–70 min	No	Renal
Rocuronium [Zemuron]	IV	1–3	20–40	—	No	Hepatic
Vecuronium [Norcuron]	IV	3–5	25–30	45–60 min	No	Hepatic/biliary
Depolarizing Agent
Succinylcholine [Anectine, Quelicin]	IV, IM‡	1	4–6	—	Yes	Plasma cholinesterase