Skeletal Muscle Relaxants (Prelab) PDF

 Types of skeletal muscle relaxants: 2 groups Neuromuscular blockers Spasmolytics Relax normal muscles Reduce spasticity (surgery and assistance of Centrally acting (except ventilation) dantrolene which act on the No central nervo...

 Types of skeletal muscle relaxants: 2 groups Neuromuscular blockers Spasmolytics Relax normal muscles Reduce spasticity (surgery and assistance of Centrally acting (except ventilation) dantrolene which act on the No central nervous system skeletal muscle) activity. Used in a variety of Used primarily as a part of neurologic conditions general anesthesia  Skeletal Muscle Relaxants Neuromuscular Spasmolytics blockers Non-depolarizing (Competitive) D tubocurarine Centrally Directly Pancuronium acting acting Vecuronium Diazepam Dantrolene Atracurium Chlorzoxazone Mivacurium Tizanidine Depolarizing Baclofen (Non-Competitive) Succinylcholine Decamethomium  Skeletal Muscle contraction NMreceptor Motor neuron ACHEsterase Skeletal Muscle Neuromuscular blockers Drugs may act: Pre-synaptically (pre-junctional). Or post-synaptically: 1- non-depolarizing (competitive) 2- depolarizing (non-competitive)  Pre-synaptically (pre-junctional) acting drugs are those that interfere with synthesis and or release of Ach. Pre-synaptically acting drugs 1- Inhibitors of A.Ch release: excess Mg++, lack of Ca++, local anesthetics (procaine), botulium toxin (botox). 2- inhibitors of A.Ch storage: vesamicol. 3. Inhibitors of A.Ch synthesis: hemicholinium (-uptake), triethylcholine (--utilization). by : Amaal Nabil sadek Botulinum Toxin Produced by Botulinum bacteria. Inhibits acetylcholine release. Food poisoning caused by this bacteria can result, within 12-36 hours, in diplopia, dysphagia, dysarthria, and dyspnea. Toxin is use for opthalmic purposes, local muscle spasms, and in the cosmetic treatment of facial wrincles around the eyes and mouth, as well as for generalized spastic disorders like cerebral palsy. Mechanism of action of post-synaptically Neuromuscular Blockers  Normal d-Tubocurarine Succinylcholine Ach A Ch Ach Ach SCh Ach SCh Depolarization No Depolarization Persistent Depolarization Contraction Repolarization (Fasciculation) Contraction No contraction Relaxation Relaxation Flaccid Paralysis Competitive Antagonists  (Non-depolarizing blockers)= competitive Long-acting: d tubocurarine, pancuronium Intermediate: Atracurium , vecuronium , rocuronium , Short-acting: Mivacurium Tubocurarine (prototype). Atracurium (the most rapid onset)  Mechanism of action: Non-depolarizing (competitive): * Reversible. *Compete with Ach at nicotinic receptors. * This action can be overcome by increasing ACH concentration ( by cholinesterase inhibitors) *at higher doses they also block Na channels & this further weakens Neuromuscular transmission. *SO this reduces the ability of cholinesterase inhibitors to reverse their action. Effects are antagonized by: Neostigmine (choline esterase inhibitors): at the end of operation but preceded by ATROPINE to block muscarinic receptors and so avoid bradycardia & cardiac arrest ) Anti-cholinestrases Mechanism of Action (neostigmine, Competitive Antagonism edrophonium) which preserve acetylcholine Agonist are used to reverse the effect of Ach Ach d-tubocurarine Antagonist d-Tubocurarine Affinity : Yes Intrinsic action : No NM receptor Motor End Plate Actions: Non depolarizing: Muscle weakness → Flaccid paralysis Not all muscles are equally sensitive to blockage. Small rapidly contracting muscle of face and eye paralyzed first. Then fingers, limbs, neck and trunk. Intercostal muscles. Lastly diaphragm. Recovery occurs in the reverse order (diaphragm first) Consciousness, appreciation of pain not affected Actions Autonomic ganglion blocking property Histamine release (by d-tubocurarine) CVS Significant fall in BP Increase in Heart rate Vagal gangionic blockade (also ‘ve’ and ‘pan’) Newer competitive blockers: Negligible effect on BP and HR Actions of Neuromuscular Blockers Skeletal Muscle Paralysis. Cardivascular Effects: Mediated by autonomic or histamine receptors. Both sympathetic and parasympathetic ganglia and muscarinic receptors in the heart can be blocked. Usually cause hypotension, which can be attenuated by antihistamines. Adverse effects Hypotension Tachycardia Respiratory paralysis Bronchospasm Aspiration of gastric contents  Advantages of synthetic (Newer) competitive blockers Less histamine release Do not block autonomic ganglia Spontaneous recovery with most of drugs Rapacuronium & rocuronium have rapid onset Atracuronium: Hoffmans elimination Mivacurium short acting  Therapeutic uses (non-depolarizing) Adjuvant drugs to anesthesia during (facilitate incision & intubation, decrease the dose of anesthesia, decrease cough & laryngospasm , producing satisfactory skeletal muscle relaxation) To assess mechanical ventilation ( paralyses resp. muscles to not interfere with mechanical ventilation). For facilitating endotracheal intubation – Rocuronium preferred due to rapid onset of action – Succinylcholine is better due to short lasting duration Pharmacokinetics (non-depolarizing) All NM blockers are injected IV. ( as all of them highly polar compounds & so poor lipid soluble (limit entry to CNS),,, inactive orally) MANY OF THEM ARE NOT METABOLIZED, & then excreted unchanged in urine like tubocurarine or bile like vecuronium  Atracurium is degraded spontaneously in plasma by esterase enzyme (Hofmann elimination) , in addition to liver metabolism, so it is relatively safe in hepatic or renal patients.. (but it releases histamine and its liver metabolite can cause seizures in high doses ). Cisatracurium as atracurium but less side effects so it replace it clinically)  Adverse effects (of Tubocurarine mainly) Tubocurarine has no CNS effects, but causes hypotension , flushing, bronchoconstriction, allergy due to histamine release. Ganglionic blockade ( nicotinic receptors)… ( hypotension). Generally theses agents are safe. Contraindicated in renal disease (renal excreted).  Drug interactions Cholinesterase inhibitors like : neostigmine,…(decrease its effect). Calcium channel blockers (increase NM Blocking). Halogenated hydrocarbon anesthesia like halothane enhance NMB action by stabilizing NM junction & increase its sensitivity to NMB. Aminoglycosides. Like gentamicin enhancing NMB activity. By competing with Calcium ions SO inhibit ACH release  Depolarizing Blocker (Non-competitive Antagonist) Succinylcholine: is the member commonly used clinically Decamethonium. Succinylcholine One Drug, Two blocks, Brief and quick, Genetic variability in metabolism, Malignant hyperthermia  Depolarizing (non-competitive): succinylcholine (partial agonist ) Its action involves 2 phases: ‘’ phase 1 (depolarization): Interact with nicotinic receptors on post-synaptic membrane, causing depolarization. This causes disorganized contraction (initial twitching or fasciculation). Unlike Ach (Ach destroyed rapidly ), it persist attaching to receptors for relatively longer time. Continued binding of it renders the receptor incapable of binding to Ach. “ Phase 2 : receptor desensitized to Ach & causes flaccid paralysis. Phase2 = block or desensitization phase. Usually happen with repeated or prolonged administration of succinylcholine Mechanism of action Agonist at Nicotinic (NM) receptor Produces neuromuscular block by overstimulation, end plate is unable to respond to further stimulation. Longer lasting or persistent depolarization Succinylcholine Actions Small rapidly moving muscles (eye, jaw, larynx) relax before those of limbs and trunks Ultimately intercostals and finally diaphragm paralysis occur → respiratory paralysis Recovery in the reverse order Muscle relaxation: Onset: within 1 min; peak: 2 min, duration: 5 min; longer duration relaxation requires continued IV infusion Sequence of paralysis slightly different. But as it as respiratory muscles are paralyzed last.. Therapeutic uses of depolarizing NMBs: Due to rapid onset (1 minute) and short duration of action (5- 10 minutes) ❖Rapid endotracheal intubation. (to avoid aspiration). ❖Electroconvulsive shock treatment (decrease pain to prevent injury ). Suitable for short-term procedures -Rapid endotracheal intubation during induction of anaesthesia Pharmacokinetics depolarizing NMBs: Iv injection. Destroyed by pseudo cholinesterase. Usually given by continuous infusion. Succinylcholine Adverse Effects Transient Intraocular Tension Hyperkalemia : Fasciculations release potassium in blood Succinylcholine apnoea Malignant hyperthermia: when used alng with halothane in general anaesthesia Treatment is by rapid cooling of patient & dantrolene i.v Postoperative muscle pain Increase intraocular, gastric pressure Actions of Neuromuscular Blockers Skeletal Muscle Paralysis. Cardivascular Effects. Hyperkalemia: Increased Intraocular Pressure: Due to tonic contraction of myofibrils or transient dilation of ocular choroidal blood vessels. Increased Intragastric Pressure: In obese, heavily muscled, diabetics, traumatic patients, fasiculations of succinylcholine can cause regurgitation and aspiration of gastric contents. Muscle Pain: Due to unsynchronized contractions of adjacent muscle fibers just before the onset of paralysis. Actions of Neuromuscular Blockers Skeletal Muscle Paralysis. Cardivascular Effects. Hyperkalemia: In patients with burns, nerve damage, or neuromuscular disease, head injury, and other trauma. Can result in cardiac arrest. Malignant Hyperthermia Rare heritable disorder triggered by a variety of stimuli, including general anesthetics and neuromuscular blockers. Patients have a hereditary impairment of the sarcoplasmic reticulum to sequester calcium. The trigger can causes sudden and prolonged release of calcium, with massive contraction, lactic acidosis, and increased body temperature. Treatment is by cooling, correcting acidosis, and dantrolene to reduce calcium release.  Malignant hyperthermia: When taken with halothane. Sk. Muscles fail to sequester Ca in sarcoplasmic reticulum Muscular rigidity & hyperthermia. In genetically susceptible. Treatment: 1- Rapidly cooling. 2-Dantrolene= Spasmolytic ( block Ca release from sarcoplasmic reticulum) decreasing rigidity.  Apnea: In patient genetically deficient or has atypical form of plasma cholinesterase (due to liver disease). prolonged respiratory muscle paralysis or even the diaphragm. Treatment : No antidote is available Fresh frozen plasma should be infused Patient should be ventilated artificially until full recovery blood transfusion ( to supply the enzyme )  Hyperkalemia: Increase K release from stores. More dangerous in patients with burn or massive tissue damage in which k rapidly lost from cells Comparison of Competitive and Depolarizing Blocking Agents Sr.no Competitive Succinyl choline 1 Competitive blockade Persistant depolarization 2 Non depolarizing Depolarizing 3 Single block Dual block 4 Anticholinesterases Do not reverse reverse blockade 5 Initial fasciculations not Present present 6 Slow onset long duration Rapid onset short duration 7 Release histamine Doesn’t release  Drug interactions Non depolarizing blockers Anticholine-esterases (Neostigmine) Reverse the action of only non depolarizing blockers Halothane, Aminoglycoside antibiotic like gentamicin & calcium channel blockers like nifedipine Enhances the neuromuscular blockade Depolarizing blockers Halothane can cause malignant hyperthermia Spasmolytic Drugs Diazepam: Acts at GABAA receptors in the CNS. Sedative. Spasmolytic Drugs Baclofen: Acts at GABAB receptors, resulting in hyperpolarization and presynaptic inhibition through reducing calcium influx. Can also reduce spasticity by inhibiting release of substance P in the spinal cord. Less sedative, but can cause drowsiness. Can be given intrathecally. Can reduce craving in alcoholics and in migraine. Spasmolytic Drugs Tizanidine: Related to clonidine. Gabapentin: An antiepileptic Glycine. Others Directly Acting Drugs Dantrolene: Related to phenytoin, an antiepileptic. Interferes with excitation-contraction coupling in the muscle fibers by interfering with the release of activator calcium by binding with the ryanodine receptor (RyR) channel of the sarcoplasmic reticulum. Can cause weakness, sedation, and hepatitis. Dantrolene Directly acting skeletal Muscle relaxant Inhibits depolarization induced calcium release from sarcoplasmic reticulum by acting on ryanodine receptors Drug of choice in malignant hyperthermia Myathenia gravis by : Amaal Nabil sadek by : Amaal Nabil sadek by : Amaal Nabil sadek by : Amaal Nabil sadek by : Amaal Nabil sadek Diagnosis Edrophonium IV+ Atropine Or Neostigmine SC + Atropine by : Amaal Nabil sadek by : Amaal Nabil sadek  Medical management 1- Anticholinesterase: Neostigmine or pyridostigmine : increase Ach at both N, M site + direct ms stimulation. 2- Atropine: block unwanted muscarinic actions. 3- Adjuvant treatment: a- Ephedrine: potentiates neostigmine (VD of skeletal BV + facilitate NM transmission). b- Caffeine: potentiates neostigmine ( direct stimulation of ms). 4- Others: a- Cortisol: decrease antibody formation b- Plasmapharesis to wash antibodies c- Thymectomy by : Amaal Nabil sadek by : Amaal Nabil sadek by : Amaal Nabil sadek