Skeletal Muscle Relaxants.pdf

Clinical Pharmacology and Therapeutics 400Level Lecture Notes SKELETAL MUSCLE RELAXANTS Introduction: Skeletal muscle contraction is evoked by a nicotinic cholinergic transmission process. The blockade of transmis...

Clinical Pharmacology and Therapeutics 400Level Lecture Notes SKELETAL MUSCLE RELAXANTS Introduction: Skeletal muscle contraction is evoked by a nicotinic cholinergic transmission process. The blockade of transmission process at the end plate (the postsynaptic structure bearing the nicotinic receptors) is clinically useful in producing muscle relaxation, a Page | 1 requirement for surgical relaxation, tracheal intubation and control of ventilation. Definition of terms: Depolarizing blockade: Neuromuscular paralysis that results from persistent depolarization of the end plate (eg, by succinylcholine). Desensitization: A phase of blockade by a depolarizing blocker during which the end plate repolarizes but is less than normally responsive to agonists (acetylcholine or succinylcholine). Nondepolarizing blockade: Neuromuscular paralysis that results from pharmacologic antagonism at the acetylcholine receptor of the end plate (eg, by tubocurarine). Stabilizing blockade: Synonym for nonpolarizing blockade. Spasmolytic: A drug that reduces abnormally elevated muscle tone (spasm) without paralysis (eg, baclofen, dantrolene). Malignant hyperthermia: Hyperthermia that results from massive release of calcium from the sarcoplasmic reticulum, leading to uncontrolled contraction and stimulation of metabolism in skeletal muscle. Classification: The skeletal muscle relaxants consist of two dissimilar group of drugs. The groups are: a) Neuromuscular blockers and b) spasmolytics. a) Neuromuscular blockers: These includes i. Drugs that prevent the action of released Acetylcholine: Depolarizers: Suxamethonium (Succinylcholine), Decamethonium Non-Depolarizers: Isoquinoline derivatives: (Tubocurarine, Atracurium, Cisatracurium, Metocurine, Doxacurium, Mivacurium). Steroid derivatives: (Pancuronium, Vecuronium, Pipecuronium, Rocuronium). Others: (Gallamine). ii. Drugs depressing output of acetylcholine: Inhibitors of acetylcholine synthesis: Hemicholinium, Triethylcholine. Inhibitors of acetylcholine release: Mg2+, PO42-, lack of Ca++, Procaine, Botulinum toxin.  Clinical Pharmacology and Therapeutics 400Level Lecture Notes b) Spasmolytics agents: These agents are classed as i) chronic use agents, which can have CNS action eg, baclofen, diazepam and tizanidine) or muscle action eg dantrolene and ii) Acute use agents eg cyclobenzaprine. Page | 2 Nondepolarising Neuromuscular Blockers Mechanism of Action: Nondepolarizing drugs prevent the action of acetylcholine (Ach) at the skeletal muscle end plate. They act as surmountable blockers. This implies that the blockade can be overcome by increasing the amount of agonist (Ach)in the synaptic cleft. They behave as though they compete with ACh at the receptor, and their effect is reversed by cholinesterase inhibitors. Some drugs in this group may also act directly to plug the ion channel operated by the ACh receptor.. Larger muscles (eg, abdominal, diaphragm) are more resistant to neuromuscular blockade, but they recover more rapidly than smaller muscles (eg, facial, hand). Of the available nondepolarizing drugs, rocuronium (60–120 s) has the most rapid onset time. Pharmacokinetics: All agents are given parenterally. They are highly polar drugs and do not cross the blood-brain barrier. Drugs that are metabolized, by plasma cholinesterase, eg, mivacurium or eliminated in the bile such as vecuronium have shorter durations of action (10– 20 min) than those eliminated by the kidney (eg, metocurine, pancuronium, pipecuronium, and tubocurarine), which usually have durations of action of less than 35 min. In addition to hepatic metabolism, atracurium clearance involves rapid spontaneous breakdown (Hofmann elimination) to form laudanosine and other products. At high blood levels, laudanosine may cause seizures. Cisatracurium, a stereoisomer of atracurium, is also inactivated spontaneously but forms less laudanosine and currently is one of the most commonly used muscle relaxants in clinical practice. Depolarizing Neuromuscular Blocking Drugs Mechanism of action: Succinylcholine acts like a nicotinic agonist and depolarizes the neuromuscular end plate. The initial depolarization is often accompanied by twitching and fasciculations (prevented by pretreatment with small doses of a nondepolarizing blocker). Because tension cannot be maintained in skeletal muscle without periodic repolarization and depolarization of the end plate, continuous depolarization results in muscle relaxation and paralysis. Succinylcholine may also plug the end plate channels. When given by continuous infusion, the effect of succinylcholine changes from continuous depolarization (phase I) to gradual repolarization with resistance to depolarization (phase II) (i.e., a curare-like block).  Clinical Pharmacology and Therapeutics 400Level Lecture Notes Pharmacokinetics: Succinylcholine is composed of 2 ACh molecules linked end to end. Succinylcholine is metabolized by cholinesterase (butyrylcholinesterase or pseudocholinesterase) in the liver and plasma. It has a duration of action of only a few minutes if given as a single dose. Blockade may be prolonged in patients with genetic variants of Page | 3 plasma cholinesterase that metabolize succinylcholine very slowly. Such variant cholinesterases are resistant to the inhibitory action of dibucaine. Succinylcholine is not rapidly hydrolyzed by acetylcholinesterase. Pharmacological Effects Skeletal Muscles: Paralysis of skeletal muscles Depolarisers: Initially, transient muscle fasciculations occur especially over the chest and abdomen. This is followed by spreading paralysis. Arm, neck and leg muscles are involved before the facial and pharyngeal muscle. Respiratory muscle involvement occurs lastly. Non-depolarisers: Muscle are paralyzed in following order: (i) Muscles innervated by cranial nerves. (ii) Muscles of limbs & trunk. (iii) Intercostal muscles. (iv) Diaphragm. Recovery from muscle paralysis occurs in the reverse order. Cardiovascular System: Depolarisers: Succinylcholine stimulates nicotinic receptors in both sympathetic & parasympathetic ganglia, & muscarinic receptors in SA-node. This causes; (i) In low doses, negative inotropic & chronotropic effects. (ii) With large doses, positive inotropic and chronotropic effects Nondepolarisers: (i) Vecuronium, doxacurium & pipecuronium have no CVS effect. (ii) Tubocurarine and to a much lesser extent metocurine, atracurium and Mivacurium produce "hypotension." This result from histamine release and in larger doses from ganglionic blockade. (iii) Gallamine & Pancuronium increases heart rate, primarily by vagolytic action and secondarily by sympathetic stimulation. Eye: Succinylcholine causes an inc. in intraocular pressure, which may be due to contraction of tonic myofibrils or transient dilatation of choroidal blood vessels. Gastrointestinal tract: In muscular pts, fasciculations associated with succinylcholine cause an inc. in intragastric pressure. This may result in emesis. Histamine release: Tubocurarine causes moderate while succinylcholine, metocurine, atracurium & mivacurium causes slight increase in histamine release.  Clinical Pharmacology and Therapeutics 400Level Lecture Notes Hyperkalaemia: Succinylcholine causes inc. release of K+ into blood, that may result in cardiac arrest. Clinical Uses Page | 4 As surgical adjuvants to general anesthesia, for promoting skeletal muscle relaxation. For facilitation of endotracheal intubation, laryngoscopy, bronchoscopy, & esophagoscopy. With electro-convulsant shock therapy, to prevent trauma. Treatment of tetanus and other convulsive states. Diagnosis of myasthenia gravis. For control of ventilation, in patients with ventilatory failure to eliminate chest wall resistance & ineffective spontaneous ventilation. Reversal of Blockade The action of nondepolarizing blockers is readily reversed by increasing the concentration of normal transmitter at the receptors. This is best accomplished by administration of cholinesterase inhibitors such as neostigmine or pyridostigmine. In contrast, the paralysis produced by the depolarizing blocker succinylcholine is increased by cholinesterase inhibitors Toxicity Respiratory paralysis: The action of full doses of neuromuscular blockers leads directly to respiratory paralysis. If mechanical ventilation is not provided, the patient will asphyxiate. Specific effects of succinylcholine: Muscle pain is a common postoperative complaint, and muscle damage may occur. Succinylcholine may cause hyperkalemia, especially in patients with burn or spinal cord injury, peripheral nerve dysfunction, or muscular dystrophy. Increases in intragastric pressure caused by fasciculations may promote regurgitation with possible aspiration of gastric contents. Drug interactions: Inhaled anesthetics, especially isoflurane, strongly potentiate and prolong neuromuscular blockade. A rare interaction of succinylcholine (and possibly tubocurarine) with inhaled anesthetics can result in malignant hyperthermia. A very early sign of this potentially life- threatening condition is contraction of the jaw muscles (trismus). Aminoglycoside antibiotics and antiarrhythmic drugs may potentiate and prolong the relaxant action of neuromuscular blockers to a lesser degree.  Clinical Pharmacology and Therapeutics 400Level Lecture Notes Effects of aging and diseases: Older patients (>75 years) and those with myasthenia gravis are more sensitive to the actions of the nondepolarizing blockers, and doses should be reduced in these patients. Conversely, patients with severe burns or who suffer from upper motor neuron disease are less responsive to these agents, probably as a result of proliferation Page | 5 of extra-junctional nicotinic receptors. Bibliography Brunton LL, Lazo JS and Parker KL, editors; Goodman and Gilman’s The Pharmacological Basis of therapeutics, 11th ed. McGraw-Hill, 2006. Katzung BG, editor: Basic & Clinical Pharmacology, 10th ed. McGraw-Hill, 2007. Lippicott’s Illustrated review of Pharmacology, 6th Edition Modern Pharmacology with Clinical Applications by: Charles R. Craig and Robert E Stitzel. Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001. Acetylcholine. Available from: https://www.ncbi.nlm.nih.gov/books/NBK11143. Rang HP et al., Pharmacology 5th ed. Churchill Livingstone, 2003. Trevor AJ et al. editors: Pharmacology Examination & Board Review 10th ed. McGraw-Hill, 2013.