Skeletal Muscle Relaxants (Neuromuscular Blocking Drugs) PDF

Skeletal Muscle Relaxants (Neuromuscular blocking drugs) Maziana Mahamood 1  Learning Objectives By the end of the lecture, students should be able to: 1. Describe synaptic transmission at the neuromuscular junction & skele...

Skeletal Muscle Relaxants (Neuromuscular blocking drugs) Maziana Mahamood 1  Learning Objectives By the end of the lecture, students should be able to: 1. Describe synaptic transmission at the neuromuscular junction & skeletal muscle contraction 2. List the clinical uses of skeletal muscle relaxants 3. Describe how NMB drugs work – Depolarising neuromuscular blocker – Non depolarising neuromuscular blocker 4. List the adverse effects associated with NMB drugs 5. Compare and contrast depolarising & non-depolarising neuromuscular blockers 2  Learning Objectives By the end of the lecture, students should be able to: 1. Describe synaptic transmission at the neuromuscular junction & skeletal muscle contraction 2. List the clinical uses of skeletal muscle relaxants 3. Describe how NMB drugs work – Depolarising neuromuscular blocker – Non depolarising neuromuscular blocker 4. List the adverse effects associated with NMB drugs 5. Compare and contrast depolarising & non-depolarising neuromuscular blockers 3 4 Somatic motor division: controls skeletal muscle Body movement/ Locomotion Single neuron – CNS origin – Myelinated Skeletal muscle Impulse → muscle contraction 5 Anatomy of a Neuromuscular Junction Each NMJ consists of i. Axon terminal of motor neurons ii. Motor end plate of muscle fibre 6 Transmitter Release at the Neuromuscular Junction 7 Fig 13-7, Kandel, Schwartz, Jessel, 1991 WHAT HAPPENS AT THE NEUROMUSCULAR JUNCTION? 8 9 Nm Nm  Binding of ACh to AChRs opens the channels causing an influx of Na, depolarization of the sarcolemma that travels down the t-tubules and ultimately causes the release of Ca2+ from the sarcoplasmic reticulum - CONTRACTION. 11 12 13  Learning Objectives By the end of the lecture, students should be able to: 1. Describe synaptic transmission at the neuromuscular junction & skeletal muscle contraction 2. List the clinical uses of skeletal muscle relaxants 3. Describe how NMB drugs work – Depolarising neuromuscular blocker – Non depolarising neuromuscular blocker 4. List the adverse effects associated with NMB drugs 5. Compare and contrast depolarising & non-depolarising neuromuscular blockers 15  Skeletal Muscle Relaxants 2 therapeutic groups – To reduce spasticity and spasms – To induce skeletal muscle paralysis; Adjunct to GA Classification : 1. Peripherally acting – Neuromuscular Blockers i.e. suxamethonium, atracurium 2. Centrally acting – Baclofen, diazepam 3. Direct acting – Dantrolene 16  Skeletal muscle relaxants: Peripherally acting What are they used for? – Facilitate intubation of the trachea – Facilitate mechanical ventilation – Provide immobility during surgery (prevent voluntary or reflex-induced muscle contractions during surgical procedures) 17 18  Learning Objectives By the end of the lecture, students should be able to: 1. Describe synaptic transmission at the neuromuscular junction & skeletal muscle contraction 2. List the clinical uses of skeletal muscle relaxants 3. Describe how NMB drugs work – Depolarising neuromuscular blocker – Non depolarising neuromuscular blocker 4. List the adverse effects associated with NMB drugs 5. Compare and contrast depolarising & non-depolarising neuromuscular blockers 19 Skeletal Muscle Relaxant/ Neuromuscular blockers: Mechanism of action?? 20  Two different kinds of functional blockade may occur at the neuromuscular endplate: A. Non-depolarizing blocking agents: act by blocking nAChR B. Depolarizing blocking agents: agonists at the nAChR (i.e., they act by stimulating the nAChR) 21 NON-DEPOLARIZING NEUROMUSCULAR BLOCKING DRUGS 22 Mechanism of Action of Nondepolarizing Neuromuscular Blocking Drugs 23  Non-depolarizing Prototype of Non-depolarizing is tubocurarine Mechanism of Action: – In small clinical doses they act the predominantly at the nicotinic receptor site to block ACh. – At higher dose they can block prejunctional Na channels thereby decreasing ACh release. Because of the competitive nature of the postsynaptic blockade, transient relief of the block can be achieved by increasing ACh levels at the synaptic cleft (i.e. use cholinesterase inhibitors). 24  Nondepolarizing Agents Therapeutic Use: – Adjuvant drugs in surgical anesthesia Pharmacokinetics: – Must be given by injection because they are poorly absorbed orally. Do not cross the BBB. Generally excreted unchanged (i.e. not metabolized). Adverse Effects: – Tubocurarine → release of histamine from mast cells – decrease in blood pressure, bronchospasms, skin wheals. – Newer generation (i.e. muvacurium, atacurium) also cause histamine release, but to a lesser extent unless administered rapidly. 25 Nondepolarizing Muscle Relaxants Long acting – Pancuronium Intermediate acting – Atracurium – Vecuronium – Rocuronium – Cisatracurium Short acting – Mivacurium 26 Nondepolarizing Muscle Relaxants Pancuronium – Aminosteroid compound – Onset 3-5 minutes, long duration 60-90 minutes Elimination mainly by kidney (85%), liver (15%) – Direct vagolytic and symphathomimetic properties – Side effects : hypertension, tachycardia, dysrhythmia 27 Nondepolarizing Muscle Relaxants Atracurium – Onset 3-5 minutes, intermediate duration 25-35 min – Histamine release→ hypotension, bronchospasm – Metabolized by Ester hydrolysis by non-specific esterases in the plasma Hofmann elimination→ Laudonosine Laudanosine – Cross BBB: CNS: Excitement & seizure – CVS→ Hypotension & bradycardia 28 Nondepolarizing Muscle Relaxants Cisatracurium – Isomer of atracurium (4x > potent) – Onset 3-5 minutes, duration 20-35 minutes – Metabolized by Hofmann elimination (75%) – Much less laudanosine produced (lower dose compared to atracurium) – Does not release histamine & with minimal cardiovascular side effects 29 Nondepolarizing Muscle Relaxants Mivacurium – Rapid onset 1-2 minutes, short duration 15 mins – Little direct CV effect, but cause significant histamine release – Significant hypotension 30 Drug Interactions: Cholinesterase Inhibitors – decrease the effectiveness of nondepolarizing agents Aminoglycoside antibiotics (e.g. streptomycin) – decrease ACh release by competing with Ca2+ → increase action of nondepolarizing drugs Calcium channel blockers – increase the actions of nondepolarizing drugs by decreasing the amount of ACh released (i.e. increase action of nondepolarizing drugs) Halogenated carbon anesthetics (e.g. Isoflurane) – enhance neuromuscular blockade by : decreasing excitability of motor neurons, increasing muscle blood flow decreased kinetics of AChRs (increase action of nondepolarizing drugs) 31 DEPOLARIZING NEUROMUSCULAR BLOCKING DRUGS 32 Mechanism of Action of Depolarising Neuromuscular Blockers 33  Mechanism: Phase I Block binding of succinylcholine to nicotinic receptors opening of ion channels & Na+ influx depolarization of muscle cell end-plate membrane generalized disorganized contraction of motor muscles not metabolized by AChE, slow enzyme hydrolysis by pseudocholinesterase membranes remain depolarized & unresponsive flaccid paralysis Mechanism of Action of Depolarising Neuromuscular Blockers 35  Mechanism: Phase II Block repeated dosing &increased concentration of succinylcholine Decreased endplate depolarization repolarization of membrane membrane becomes desensitized.: depolarization by ACh cannot occur Suxamethonium (Succinylcholine) Succinylcholine- used clinically It has a short half-life (5-10 minutes) and must be given by continuous infusion if prolonged paralysis is required. An important aspect of succinylcholine is its hydrolysis by pseudocholinesterase. In patients with pseudocholinesterase deficiency, succinylcholine half-life is greatly prolonged, and such patients may regain control of their skeletal muscles slowly after a surgical procedure. This is the most serious complication of pseudocholinesterase deficiency. 37  Depolarizing Agents Therapeutic Use: – Adjuvant drugs in surgical anesthesia Adverse Effects: – CV effect i.e. bradycardia – Muscle pain – Increased serum K+ – Malignant hyperthermia (When administered with halogenated hydrocarbon anaesthetics, in some genetically susceptible people) Treatment: rapid cooling of the body and dantrolene 38 Malignant Hyperthermia Dantrolene (interferes with EC coupling by decreasing Ca efflux from the SR) Clinical features: Contracture, rigidity and heat production → Severe hyperthermia, Accelerated muscle metabolism, metabolic acidosis & tachycardia 39  Learning Objectives By the end of the lecture, students should be able to: 1. Describe synaptic transmission at the neuromuscular junction & skeletal muscle contraction 2. List the clinical uses of skeletal muscle relaxants 3. Describe how NMB drugs work – Depolarising neuromuscular blocker – Non depolarising neuromuscular blocker 4. List the adverse effects associated with NMB drugs 5. Compare and contrast depolarising & non-depolarising neuromuscular blockers 40  Mechanism of Action Non-Depolarising NMB Depolarising NMB Act the predominantly at the nicotinic receptor site to block ACh 41  Neuromuscular blocking drugs Non- Depolarising Depolarising Tubocurarine , pancuronium, Suxamethonium (only depolarizing drug atracurium, vecuronium in clinical use). NOT reversible by an anticholinesterase Reversible by anticholinesterase drugs drugs Therapeutic Use: Therapeutic Use: – Adjuvant drugs in surgical anesthesia, to – Adjuvant drugs in surgical anesthesia, produce muscle relaxation to produce muscle relaxation Adverse effects: Adverse Effects: – Bradycardia – Tubocurarine: – cardiac dysrythmia – Prolonged paralysis decrease in blood pressure (due to ganglion block), – Anaphylaxis bronchospasms (histamine release – Malignant hyperthermia (genetically by mast cell), skin wheals. Newer susceptible people); treatment with dantrolene, rapid body cooling generation don’t. 42  Reversal of Neuromuscular Blockade Goal : re-establishment of spontaneous respiration and the ability to protect airway from aspiration 43  Antagonism of Neuromuscular Blockade Effectiveness of anticholinesterases depends on the degree of recovery present when they are administered Anticholinesterases – Neostigmine – Pyridostigmine – Edrophonium 44  Antagonism of Neuromuscular Blockade What is the mechanism of action? – Inhibiting activity of acetylcholinesterase – More Ach available at NMJ, compete for sites on nicotinic cholinergic receptors – Action at muscarinic cholinergic receptor Bradycardia Hypersecretion Increased intestinal tone 45  Antagonism of Neuromuscular Blockade Muscarinic side effects are minimized by anticholinergic agents – Atropine – Scopolamine – glycopyrrolate 46 47 The Neuromuscular Junction: a Specialized form of synaptic transmission: communication between neurons and muscle 48