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Skeletal muscle relaxants Prof. Hanan Hagar
Skeletal muscle relaxants Are drugs used to induce muscle relaxation Classification q Peripherally acting (Neuromuscular blockers). q Centrally acting skeletal muscle relaxants e. g. Baclofen - Diazepam q Direct acting skeletal muscle relaxants e. g. Dantrolene
Neuromuscular blockers Classification: 1) Competitive (non depolarizing blockers) 2) Depolarizing blockers
Binding of Ach to receptors on muscle end-plate
Uses of neuromuscular blockers Facilitate endotracheal intubation Facilitate endoscopy control convulsion electroshock therapy in psychotic patient. Relieve of tetanus and epileptic convulsion. As adjuvant in general anesthesia to induce muscle relaxation orthopedic surgery.
Muscle Relaxants Competitive (Nondepolarizing) muscle relaxants ◦ Short acting ◦ Intermediate acting ◦ Long acting Depolarizing muscle relaxant ◦ Succinylcholine
Competitive NM blockers Long acting ◦ d-tubocurarine ◦ Pancuronium Intermediate acting ◦ Atracurium ◦ Cisatracurium ◦ Vecuronium ◦ Rocuronium Short acting ◦ Mivacurium
Competitive NM blockers Mechanism of Action Are competitive antagonists Compete with Ach for the nicotinic receptors present in postjunctional membrane of motor end plate. No depolarization of postjunctional membrane
Pharmacokinetics They are polar compounds ◦ inactive orally & taken parenterally ◦ Do not cross placenta & CNS Metabolism depend upon kidney or liver Except Mivacurium (degraded by acetylcholinesterase ) Atracurium (spontaneous degradation in blood)
Pharmacological actions: Skeletal muscle relaxation. They produce different effects on CVS Some release histamine and produce hypotension o d. Tubocurarine o Atracurium o Mivacurium Others produce tachycardia ( H. R) o Pancuronium
d – Tubocurarine Long duration of action (1 - 2 hr) Eliminated by kidney 60% - liver 40%. Releases histamine that causes: ◦ Bronchospasm ◦ Hypotension ◦ Tachycardia
Atracurium As potent as curare (1. 5) Has intermediate duration of action (30 min). Eliminated by non enzymatic chemical degradation in plasma (spontaneous hydrolysis at body p. H, Hofmann elimination). used in liver failure & kidney failure (drug of choice). Liberate histamine (Transient hypotension)
Mivacurium Chemically related to atracurium Fast onset of action Metabolized by pseudo cholinesterases. Short duration of action (15 min). Longer duration in patient with liver disease or genetic cholinesterase deficiency. Transient hypotension (due to histamine release).
Pancuronium More potent than curare ( 6 times ). Excreted by the kidney ( 80 % ). Long duration of action. Side effects : hypertension, tachycardia ◦ NE release from adrenergic nerve endings. ◦Antimuscarinic action (block parasympathetic action)
Vecuronium More potent than tubocurarine ( 6 times ). Metabolized mainly by liver. Intermediate duration of action. Has few side effects. ◦No histamine release. ◦No tachycardia.
Depolarizing Neuromuscular Blockers Mechanism of Action combine with nicotinic receptors in postjunctional membrane of neuromuscular junction initial depolarization of motor end plate muscle twitching Persistent depolarization relaxation
Succinylcholine (suxamethonium) Pharmacological Actions 1. 2. 3. 4. SK. muscle : initial contraction followed by relaxation. Hyperkalemia : Cardiac arrest. Eye : intraocular pressure. CVS : arrhythmia
Pharmacokinetics Fast onset of action (1 min. ). Short duration of action (5 -10 min. ). Metabolized by pseudocholinesterase in plasma Half life is prolonged in ◦ Neonates ◦ Elderly ◦ Pseudcholinesterase deficiency (liver disease – malnutrition).
Side Effects Hyperkalemia CVS arrhythmia IOP # glaucoma Can produce malignant hyperthermia May cause succinylcholine apnea due to deficiency of pseudocholinesterase.
Drug Duration Side effects Notes Tubocurarine Long 1 -2 h Hypotension # Renal failure Pancuronium Long 1 -2 h Tachycardia # Renal failure Transient hypotension Histamine release Spontaneous degradation Used in liver and kidney failure Few side effects # Liver failure Atracurium Short 30 min. Vecuronium Short 40 min. Mivacurium Short 15 min. Succinyl choline Short 10 min. Similar to atracurium Hyperkalemia Arrhythmia Increase IOP Metabolized by pseudocholinesterase # Choline esterase deficiency # CVS Diseases # Glaucoma # Liver disease
Alteration of responses Diseases ◦ Myasthenia gravis ◦ Kidney failure ◦ Liver failure Drug interactions ◦ Inhalation & Intravenous anesthetics ◦ Aminoglycosides antibiotics ◦ Anticonvulsants ◦ Magnesium
Malignant hyperthermia Is a rare inherited condition that occurs upon administration of drugs as: ◦ general anesthesia e. g. halothane ◦ neuromuscular blockers e. g. suxamethonium Inability to bind calcium by sarcoplasmic reticulum in some patients due to genetic defect Ca release, intense muscle spasm, hyperthermia
Spasmolytics They reduce muscle spasm in spastic states Baclofen: Centrally acting GABA agonist – acts on spinal cord. Diazepam (Benzodiazepines): Centrally acting facilitate GABA action on CNS. Dantrolene: direct action on skeletal muscles. Used in treatment of malignant hyperthermia
Uses of spasmolytics They reduce muscle spasm in spastic states produced by : Spinal cord injury Cerebral stroke Cerebral palsy
Dantrolene Mechanism of Action It interferes with the release of calcium from its stores in skeletal muscles (sarcoplasmic reticulum). It inhibits excitation-contraction coupling in the muscle fiber. Uses Malignant Hyperthermia. Spastic states. IV, orally t ½ = 8 - 9 hrs.