Skeletal muscle relaxants

Skeletal muscle relaxants

1. Skeletal Muscle Relaxants

2. Skeletal Muscle Relaxants Drugs that act peripherally at neuromuscular junction/muscle fibre or centrally in the cerebrospinal axis to reduce muscle tone or cause paralysis. These drugs are used: To reduce painful muscle spasms. To reduce spastic neurological conditions. Together with anaesthetics to provide muscle relaxation for surgery.

3. Classification: Peripherally acting muscle relaxants 1 . Neuromuscular Blockers A. Non-depolarizing blockers: Long acting: d- tubocurarine , pancuronium Intermediate acting: Vecuronium , Atracurium Short acting: Mivacurium B. Depolarizing blockers: Succinylcholine ( Sch , Suxamethonium ), Decamethonium 2 . Directly acting agents: Dantrolene Sodium,Quinine Centrally acting muscle relaxants Mephenesin congeners: Mephenesin , Chlorzoxazone Benzodiazepines: Diazepam GABA mimetics : Baclofen Central α 2 agonist: Tizanidine

4. Peripherally acting muscle relaxants Non-depolarizing neuromuscular blockers MOA: Block N M receptor at neuromuscular junction on skeletal muscle. d- tubocurarine Pancuronium Vecuronium Atracurium M ivacurium N M receptor is ligand gated Na + channel having two binding site for Acetylcholine (Ach). Ach binding → opens Na + channel → AP → Contraction χ paralysis χ

5. Curare: Tubocurarine , Toxiferin ; arrow poison

6. Tubocurarine It is a toxic alkaloid obtained from the bark of the South American plant Chondrodendron tomentosum historically known for its use as an arrow poison. d- tubocurarine MOA : Competitively binds with the nicotinic receptors N M to prevent the binding of Acetylcholine and prevent depolarization of the muscle cell membrane and inhibit muscular contraction. Because these agents compete with ACh at the receptor without stimulating it, they are called competitive blockers. Antagonism is surmountable so neostigmine, pyridostigmine can reverse the effect. Injected 0.1 to 0.3 mg/kg slow IV L ong duration of action but more side effect so NOT used now !

7. Atracurium is competitive antagonists of acetylcholine causing flaccid paralysis. It is altered spontaneously in the body to an inactive form by a passive chemical process ( Hofmann elimination ). The duration of action is not influenced by the state of the circulation, the liver or the kidneys but at doses of greater than 0.5-0.6 mg/kg histamine release may cause hypotension and bronchospasm . Preferred in renal failure ! Cisatracurium is a stereoisomer of atracurium ; it is less prone to cause histamine release. Vecuronium is a synthetic steroid derivative that produces full neuromuscular blockade about 3 min after a dose of 0.1 mg/kg, lasting for 30 min. It has no cardiovascular side-effects and does not cause histamine release .

8. Pancuronium was the first steroid-derived neuromuscular blocker in clinical use. It is longer acting than vecuronium and causes a slight tachycardia . It is about 5 times more potent & provide good cardiovascular stability than d-TC. It is used in patient in ventilator. Mivacurium belongs to the same chemical family as atracurium and is the only non-depolarising neuromuscular blocker that is metabolised by plasma cholinesterase. It is comparatively short acting (10-15 min), depending on the initial dose. Mivacurium can cause some hypotension because of histamine release.

9. Depolarizing neuromuscular blockers: MOA : Depolarize muscle end plate by opening Na + channel for relatively longer period & causes paralysis. After binding with receptor drug don’t dissociate rapidly from N M receptor→ prolonged depolarization (without repolarization)→ Inactivation of Na + channel → Ach unable to generate Musc . AP→ paralysis paralysis Prolonged depolarization → Succinylcholine Decamethonium

10. Succinylcholine ( Suxamethonium ) MOA : Succinylcholine binds to the nicotinic receptor N M and acts like Acetylcholine to depolarize the skeletal muscle. It attaches to the receptor for a relatively longer time and provides constant stimulation of the receptor. It first( Phase I ) causes the opening of the sodium channel in nicotinic receptors, which results in depolarization of the receptor but continuous binding ( Phase II ) makes the receptor incapable of transmitting further impulses and the sodium channel is blocked causing paralysis . Agonist of N M receptor (NOT a blocker); similar to Ach Most commonly used for intubation (tracheal)- because rapid , complete & predictable paralysis with spontaneous recovery in ~ 5 min Infant require higher dose so precaution

11. Succinylcholine is the neuromuscular blocker with most rapid onset and the shortest duration of action

12. Indication Endotracheal intubation, laryngoscopy, bronchocopy Used as a muscle relaxant in general anaesthesia C ontinuous i.v. infusion for producing controlled muscle relaxation of longer duration Contraindication and Precaution Contraindicated in patients with genetic disorders of plasma pseudocholinesterase , severe burns, hypersensitivity, malignant hyperthermia, massive trauma Precaution should be taken by patients with bone fracture, neuromuscular disease, raised intraocular pressure. Adverse Effects Bradycardia , Hyperkalaemia , Malignant hyperthermia, Raised intraocular pressure, Arrhythmia Dose: Adult: 0.3-1.1 mg/kg IV, 3-4 mg/kg IM Child: 1-2 mg/kg IV, when necessary

13. Peripherally acting muscle relaxants Indication: Adjuvant to General anaesthesia Assisted Ventilation in ICU Endotracheal intubation, laryngoscopy, bronchocopy (brief procedure)- Sch preferred Convulsions & trauma are avoided during ECT Severe cases of tetanus & status epilepticus – NOT controlled by diazepam Adverse effects: Respiratory paralysis & prolonged apnoea Fall in BP & cardiovascular collapse→ in hypovolemic patient when d-TC used Cardiac arrhythmias Malignant hyperthermia- Sch

14. Drug Interactions Thiopentone sodium & Sch (chemical rxn ) GAs potentiate action Anticholinesterase (reverse action) Neostigmine 0.5- 2mg iv + Atropine d. Antibiotics: e.g. Aminoglycosides e. Calcium channel blockers,Diuretics & Antibiotics (potentiate action)

15. Directly acting skeletal muscle relaxants Dantrolene Sodium: Dantrolene acts on the RyR1 ( Ryanodine Receptor ) calcium channels in the sarcoplasmic reticulum of skeletal muscles and prevents Ca 2+ induced Ca 2+ release through these channels. Intracellular release of Ca 2+ needed for excitation-contraction coupling is interfered and causes muscle relaxation. Since Ca 2+ channels in the sarcoplasmic reticulum of cardiac and smooth muscles are of a different subtype (RyR2), these muscles are affected little by dantrolene . Used orally dantrolene (25–100 mg QID) Drug of choice for malignant hyperthermia Reduces spasticity in upper motor neurone disorders Quinine : Quinine increases refractory period and decreases excitability of motor end plates. Thus, responses to repetitive nerve stimulation are reduced . It is also used in malaria.

16. Centrally acting muscle relaxants MOA: D rugs reduce skeletal muscle tone by a selective action in the cerebrospinal axis , without altering consciousness. They selectively depress spinal and supraspinal polysynaptic reflexes involved in the regulation of muscle tone without significantly affecting monosynaptically mediated stretch reflex. Mephenesin Carisoprodol Chlorzoxazone Diazepam Baclofen Tizanidine

17. Mephenesin was the first drug found to cause muscle relaxation in animals without producing unconsciousness. It blocks the action of the spinal internuncial neurone which modulates reflexes maintaining muscle tone. It is not used clinically because orally it causes marked gastric irritation, and injected i.v. , it causes thrombophlebitis, haemolysis and fall in BP. Chlorzoxazone is a centrally acting muscle relaxant used to treat muscle spasm and the resulting pain or discomfort. It acts on the spinal cord by depressing reflexes. It has longer duration of action and better tolerability . Dose: 250-750 mg TDS

18. Diazepam is a benzodiazepine (BZD) which act in the brain on specific receptors enhancing GABAergic transmission and muscle tone is reduced through supraspinal action. Baclofen is a selective GABA B receptor agonist structurally related to γ- aminobutyric acid (GABA), an inhibitory central nervous system ( CNS) transmitter. It inhibits reflex activity mainly in the spinal cord. Baclofen reduces spasticity and spasms. Adverse effects: drowsiness , mental confusion, weakness, ataxia , raised serum transaminases. Sudden withdrawal after chronic use may cause hallucinations, tachycardia and seizures. Dose: 10 mg BD to 25 mg TDS .

19. Tizanidine MOA : Centrally acting α 2 agonist which inhibit release of excitatory neurotransmitter in spinal interneurones . It is absorbed orally, undergoes first pass metabolism; t 1/2 2-3 hours. Indications: spasticity due to neurological disorders painful muscle spasms of spinal origin Adverse effects: drymouth , drowsiness, hallucinations Contraindications: Avoid in patient taking antihypertensive drugs(clonidine) Dose: 2 mg TDS; max 24 mg/day .

20. Centrally acting muscle relaxants Indications : Acute muscle spasms Spastic neurological diseases Torticollis, lumbago, backache, neuralgias Tetanus Electroconvulsive therapy Orthopedic manipulations THANK YOU !

21. THANK YOU !