Post on 02-Apr-2015
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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