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Chapter 16

Drugs That Block Nicotinic Cholinergic Transmission: Neuromuscular Blocking Agents and Ganglionic Blocking Agents

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Neuromuscular Blockers

Prevent acetylcholine from activating nicotinicM

Cause muscle relaxation (paralysis) No oral forms Cannot cross

Blood-brain barrier • No impact on CNS (paralysis, not sedation)

Placenta• Minimal effects on fetus

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Control of Muscle Contractions

Basic concepts (see Fig. 16-1) Polarization Depolarization Repolarization

Steps in muscle contraction (see Fig. 16-2)

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Classification of Neuromuscular Blocking Agents

Competitive

neuromuscular blockers I:

tubocurarine

(no longer used)

Competitive

neuromuscular blockers II: others

Depolarizing

neuromuscular blockers:

succinylcholine

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

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

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Competitive Neuromuscular Blockers I: Tubocurarine

Oldest competitive neuromuscular blocker (NMB)

No longer used in United States Replaced by newer NMBs One of active principles found in curare, a

poison used by primitive arrow hunters

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Competitive Neuromuscular Blockers

Chemistry Quaternary nitrogen atom

Mechanism of action Competes with ACh for nicotinicM receptors

Pharmacologic effects Muscle relaxation: flaccid paralysis Hypotension Central nervous system

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Competitive Neuromuscular Blockers

Pharmacokinetics Rapid onset of paralysis

Adverse effects Respiratory arrest Cardiovascular effects

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Competitive Neuromuscular Blockers I: Tubocurarine

Precautions and contraindications Myasthenia gravis Electrolyte disturbances

Drug interactions General anesthetics Antibiotics Cholinesterase inhibitors

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Competitive Neuromuscular Blockers I: Tubocurarine

Toxicology Overdose

• Prolonged apnea, massive histamine release, and cardiovascular collapse

Preparations, dosage, and administration No longer used in the United States

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Competitive Neuromuscular Blockers II: Others

Long-acting agents• Doxacurium• Metocurine• Pipecuronium

Intermediate-acting agents• Cisatracurium• Pancuronium• Rocuronium• Vecuronium

Short-acting agents• Mivacurium

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

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Fig. 16-4. Mechanism of competitive neuromuscular blockade.Tubocurarine competes with acetylcholine (ACh) for binding to nicotinicM receptors on the motor end-plate. Binding of tubocurarine does not depolarize the end-plate and therefore does not cause contraction. At the same time, the presence of tubocurarine prevents ACh from binding to the receptor, hence contraction is prevented.

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Depolarizing Neuromuscular Blockers: Succinylcholine

Mechanism of action Pharmacologic effects

Ultrashort-acting • (peak 1 min, fades 4–10 min)

Muscle relaxation Central nervous system

Pharmacokinetics Eliminated by plasma cholinesterases

Therapeutic uses Muscle relaxation during intubation

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Depolarizing Neuromuscular Blockers: Succinylcholine

Adverse effects Prolonged apnea in patients with low

pseudocholinesterase activity Malignant hyperthermia Postoperative muscle pain Hyperkalemia

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Depolarizing Neuromuscular Blockers: Succinylcholine

Drug interactions Cholinesterase inhibitors Antibiotics

Toxicology Preparations, dosage, and administration

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Therapeutic Uses of Neuromuscular Blockers

Muscle relaxation during surgery Facilitation of mechanical ventilation Adjunct to electroconvulsive therapy Endotracheal intubation Diagnosis of myasthenia gravis

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Ganglionic Blocking Agents

Mechanism of action Pharmacologic effects Pharmacokinetics Therapeutic use

Adverse effects• Antimuscarinic effects• Orthostatic hypotension• CNS effects

Preparations, dosage, and administration