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

2Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Neuromuscular Blockers  Prevent acetylcholine from activating nicotinic M  Cause muscle relaxation (paralysis)  No oral forms  Cannot cross  Blood-brain barrier No impact on CNS (paralysis, not sedation) No impact on CNS (paralysis, not sedation)  Placenta Minimal effects on fetus Minimal effects on fetus

3Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Control of Muscle Contractions  Basic concepts (see Fig. 16-1)  Polarization  Depolarization  Repolarization  Steps in muscle contraction (see Fig. 16-2)

4Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Classification of Neuromuscular Blocking Agents Competitive neuromuscular blockers I: tubocurarine (no longer used) Competitive neuromuscular blockers II: others Depolarizing neuromuscular blockers: succinylcholine

5Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig The depolarization-repolarization cycle of the motor end-plate and muscle membrane. (ACh = acetylcholine.)

6Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig Steps in excitation-contraction coupling. (ACh = acetylcholine.)

7Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

8Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Competitive Neuromuscular Blockers  Chemistry  Quaternary nitrogen atom  Mechanism of action  Competes with ACh for nicotinic M receptors  Pharmacologic effects  Muscle relaxation: flaccid paralysis  Hypotension  Central nervous system

9Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Competitive Neuromuscular Blockers  Pharmacokinetics  Rapid onset of paralysis  Adverse effects  Respiratory arrest  Cardiovascular effects

10Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Competitive Neuromuscular Blockers I: Tubocurarine  Precautions and contraindications  Myasthenia gravis  Electrolyte disturbances  Drug interactions  General anesthetics  Antibiotics  Cholinesterase inhibitors

11Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Competitive Neuromuscular Blockers I: Tubocurarine  Toxicology  Overdose Prolonged apnea, massive histamine release, and cardiovascular collapse Prolonged apnea, massive histamine release, and cardiovascular collapse  Preparations, dosage, and administration  No longer used in the United States

12Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Competitive Neuromuscular Blockers II: Others Long-acting agents Doxacurium Metocurine Pipecuronium Intermediate- acting agents Cisatracurium Pancuronium Rocuronium Vecuronium Short-acting agents Mivacurium

13Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig 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.

14Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig Mechanism of competitive neuromuscular blockade. Tubocurarine competes with acetylcholine (ACh) for binding to nicotinic M 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.

15Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Depolarizing Neuromuscular Blockers: Succinylcholine  Mechanism of action  Pharmacologic effects  Ultrashort-acting (peak 1 min, fades 4–10 min) (peak 1 min, fades 4–10 min)  Muscle relaxation  Central nervous system  Pharmacokinetics  Eliminated by plasma cholinesterases  Therapeutic uses  Muscle relaxation during intubation

16Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Depolarizing Neuromuscular Blockers: Succinylcholine  Adverse effects  Prolonged apnea in patients with low pseudocholinesterase activity  Malignant hyperthermia  Postoperative muscle pain  Hyperkalemia

17Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Depolarizing Neuromuscular Blockers: Succinylcholine  Drug interactions  Cholinesterase inhibitors  Antibiotics  Toxicology  Preparations, dosage, and administration

18Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Therapeutic Uses of Neuromuscular Blockers  Muscle relaxation during surgery  Facilitation of mechanical ventilation  Adjunct to electroconvulsive therapy  Endotracheal intubation  Diagnosis of myasthenia gravis

19Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Ganglionic Blocking Agents  Mechanism of action  Pharmacologic effects  Pharmacokinetics  Therapeutic use  Adverse effects Antimuscarinic effects Antimuscarinic effects Orthostatic hypotension Orthostatic hypotension CNS effects CNS effects  Preparations, dosage, and administration