Muscle Relaxants PDF

Skeletal Muscle Relaxants  Classification  CNS Muscle Relaxants  Diazepam  Balcofen  Carisoprodol  Cyclobenzaprine  Tizanidine  Neuromuscular Blocking Drugs Non-depolarizing blockers Tubocurarine, Benzylisoquinolines ( atracurium, cisatra c), aminos...

Skeletal Muscle Relaxants  Classification  CNS Muscle Relaxants  Diazepam  Balcofen  Carisoprodol  Cyclobenzaprine  Tizanidine  Neuromuscular Blocking Drugs Non-depolarizing blockers Tubocurarine, Benzylisoquinolines ( atracurium, cisatra c), aminosteroids ( pancuronium, vecuronium) Depolarizing blockers Succinyl choline Neurotoxins ( interferes with influx of extracellular Ca++ into the nerve terminal which is required for the Ach release). Botulinum toxin Neuromuscular Junction 1: Cholinergic motor neurone,2: motor end-plate, 3: vesicles, 4: NMR, 5: mitochondrion  Non-Depolarizing Agents Mechanism of action a) At low doses: These drugs combine with nicotinic receptors and prevent acetylcholine binding as they compete with acetylcholine for receptor binding; they are called competitive blockers 70% of the Ach receptors must be blocked to have clinical effect. This prevent depolarization at end-plate. Hence inhibit muscle contraction & resulting in relaxation of skeletal muscle. 4 12/05/24  Their action can be overcome by increasing conc. of acetylcholine in the synaptic gap (by inhibition of acetylcholine estrase enzyme) – e.g.: Neostigmine, physostigmine, edrophonium Anesthetist can apply this strategy to shorten the duration of blockage or over come the over dosage. 5 12/05/24 At high doses These drugs block ion channels of the end plate. Leads to further weakening of the transmission and reduces the ability of Ach-esterase inhibitors to reverse the action. 6 12/05/24 ACTIONS All the muscles are not equally sensitive to blockade. Small and rapidly contracting muscles are paralyzed first. Respiratory muscles are last to be affected and first to recover. 7 12/05/24  Pharmacokinetics: Administered intravenously Cross blood brain barrier poorly (they are poorly lipid soluble) Some are not metabolized in liver, their action is terminated by redistribution, excreted slowly and excreted in urine unchanged (tubocurarine, mivacurium, metocurine). They have limited volume of distribution as they are highly ionized. 8 12/05/24  Atracurium is degraded spontaneously in plasma by ester hydrolysis – it releases histamine and can produce a fall in blood pressure, flushing and bronchoconstriction. – metabolized to laudanosine ( which can provoke seizures) – Cisatracurium with similar pharmacokinetics is safer. non depolarizers that are excreted via kidney have longer half-life and duration of action than those which are excreted by liver. 9 12/05/24  Vecuronium and rocuronium are acetylated in liver. – clearance can be prolonged in hepatic impairment Can also be excreted unchanged in bile. They differ in onset, duration and recovery Uses: as adjuvant to anesthesia during surgery. Control of ventilation (Endotracheal intubation) Treatment of convulsion 10 12/05/24  Non-depolarizing Agents - summary Therapeutic Use: Adjuvant drugs in surgical anesthesia Pharmacology: 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 causes release of histamine from mast cells – decrease in blood pressure, bronchospasms, skin wheals. Newer generation don’t. Drug Interactions: Cholinesterase Inhibitors decrease the effectiveness of non-depolarizing agents (donepezil Aricept, galantamine Razadyne, rivastigmine Exelon ) Aminoglycoside antibiotics (e.g. streptomycin) decrease ACh release by competing with Ca2+ – increase action of non-depolarizing drugs Drug Interactions contd. Calcium channel blockers increase the actions of non-depolarizing drugs by decreasing the amount of ACh released (i.e. increase action of non- depolarizing drugs) Halogenated carbon anesthetics (e.g. Isoflurane) enhance neuromuscular blockade by – decreasing excitability of motor neurons – increasing muscle blood flow – decreased kinetics of AChR (increase action of non-depolarizing drugs)  Depolarizing Agents Prototype depolarizing agent - SUCCINYLCHOLINE (only depolarizing drug in clinical use). Mechanism of Action: Similar action to ACh, but longer acting. Phase 1: Membrane is depolarized by opening AChR channels causing brief period of muscle fasciculation (twitch). Phase II: End-plate eventually repolarizes, but because succinycholine is not metabolized like ACh it continues to occupy the AChRs to “desensitize” the end-plate.  Insensitive to K+, electrical stimulation Because the mechanism of action of depolazing drugs is similar to ACh, their blocking effects are augmented by AChE inhibitors. Paralyzes skeletal more than respiratory muscles  Depolarizing Agents Therapeutic Use : Adjuvant drugs in surgical anesthesia Pharmacology: Duration of action is short (several minutes) because it is rapidly broken down by plasma cholinesterases (must be administered by continuous infusion) Adverse Effects: When administered with halothane some genetically susceptible people (inherited autosomal dominant condition) experience malignant hyperthermia. Treatment: rapid cooling of the body and dantrolene  SUCCINYLCHOLINE It causes paralysis of skeletal muscle. Sequence of paralysis may be different from that of non depolarizing drugs but respiratory muscles are paralyzed last Produces a transient twitching of skeletal muscle before causing block It maintains depolarization at the end plate, which leads to a loss of electrical excitability. It has shorter duration of action. 17 12/05/24  It act like acetylcholine but diffuse slowly to the end plate and remain there for long enough that the depolarization causes loss of electrical excitability In low dose it produces negative ionotropic and chronotropic effect (weakens the effects) In high dose it produces positive ionotropic and chronotropic effect. (strengthens the effect) 18 12/05/24 Unwanted effects: Bradycardia preventable by atropine. Hyperkalemia in patients with trauma or burns. This may cause dysrrhythmia or even cardiac arrest. Increase intraocular pressure due to contracture of extra ocular muscles Increase intragastric pressure which may lead to emesis and aspiration of gastric content. 19 12/05/24  Unwanted effects: contd. Malignant hyperthermia: rare inherited condition probably caused by a mutation of Ca++ release channel of sarcoplasmic reticulum, which results muscle spasm and dramatic rise in body temperature. (This is treated by cooling the body and administration of Dantrolene) Prolonged paralysis: due to factors which reduce the activity of plasma cholinesterase genetic variants as abnormal cholinesterase, its severe deficiency. anti -cholinesterase drugs neonates liver disease 20 12/05/24  DANTROLENE It acts directly It reduces skeletal muscle strength by interfering with excitation-contraction coupling into the muscle fiber, by inhibiting the release of activator calcium from the sarcoplasmic stores. It is very useful in the treatment of malignant hyperthermia caused by depolarizing relaxants. This drug can be administered orally as well as intravenously. Oral absorption is only one third. Half life of the drug is 8-9 hours. 2.5 mg/kg. dose is repeated after 10 minutes 20 mg vials 60 ml sterile water is added per vial to 21 reconstitute the drug. 12/05/24  Characteristics of neuromuscular-blocking drugs 22 12/05/24 23 12/05/24  Indications Used as adjunctive drug with anesthesia to induce muscle relaxation during surgery. Botulinum toxin is used to relieve muscle spasm by intramuscular injection into the masseter muscle. Used for acute muscle spasm of muscles of mastication. Used for acute myofascial pain dysfunction syndrome  Adverse Effects Tubocurarine also releases histamines resulting in BP reduction, flushing, and bronchoconstriction. Succinyl Choline can cause Hyperkalemia. Myoglobinurea. increase in intraocular pressure. increase in intragastric pressure Botulinum toxin can cause dry mouth, blurred vision, dysphagia, leading to progressive respiratory paralysis.  Baclofen Trigeminal neuralgia Dysfunctional voiding Tension type headache Migraine Cluster headache  Baclofen It acts through GABA B receptors It causes hyper polarization by increased K+ conductance reducing calcium influx and reduces excitatory transmitter in brain as well as spinal cord It also reduces pain by inhibiting substance P. in spinal cord It is less sedative 12/05/24 27 Baclofen, inhibits monosynaptic and polysynaptic reflexes at the spinal level by hyperpolarization of afferent terminals. Baclofen, enhances the activities of the inhibitory neurotransmitter GABA and Glycin Baclofen, decreases the release of the excitatory neurotransmitter Aspartate and Glutamate  Baclofen It is rapidly and completely absorbed orally It has a half life of 3- 4 hours It may increase seizures in epileptics It is also useful to prevent migraine.  Dosage Start therapy from the lowest possible dose and gradually increase to achieve optimum result. Following titration schedule is suggested- 5 mg t.i.d. for 3 days 10 mg t.i.d. for 3 days 15 mg t.i.d. for 3 days 20 mg t.i.d. for 3 days The total dose should not exceed the maximum of 80 mg daily ( 20 mg q.i.d.)  Baclofen- side effects Sedation, drowsiness, muscle weakness, ataxia Sudden withdrawal may precipitate anxiety, tachycardia & Hallucinations It has teratogenic risk in pregnancy Blurred or double vision convulsions (seizures) shortness of breath or unusually slow or troubled breathing vomiting  Tizanidine – Alpha2- adrenoceptor stimulant Causes skeletal muscle relaxation MOA - reduces spasticity by causing presynaptic inhibition of motor neurons via agonist actions at Alpha-2 adrenergic receptor sites where there is reduction in the release of excitatory amino acids like glutamate and aspartate, which usually cause neuronal firing that leads to muscle spasm. SE: Sedation, Asthenia, Dry mouth, Constipation, Blurred, vision  Tizanidine contd. initial dose: 4 mg orally every 6 to 8 hours (maximum of 3 doses in 24 hours). Dose may be increased in 2 to 4 mg steps to optimum effect and tolerance. Maintenance dose: 8 mg orally every 6 to 8 hours (maximum of 3 doses in 24 hours) Maximum dose: Three doses in 24 hours; 12 mg per dose; 36 mg per day  Individual Drug Presentations Baclofen: 10, 20mg tablets- Carisoprodol: 350mg tablets. Tid for short term use. Cyclobenzaprine: 10mg tablets. Tid or qid for long term use. Diazepam: 2, 5, and 10mg tablets. 5-10 mg qid for short term use. Tizanidine: 2mg, 4mg