SKELETAL MUSCLE RELAXANTS.ppt, NEUROMUSCULAR JUNCTION BLOCKERS, CENTRALLY ACTING SKELETAL MUSCLE RELAXANTSx

DRUGS ACT ON SKELETAL MUSCLES AND NEUROMSCULAR JUNCTION.

1. SKELETAL MUSCLE RELAXANT OR SOMATIC NERVOUS SYSTEM DRUGS By Dr. Harshika Patel KeMU 3 rd year Medicine Course : Basics of Pharmacology and Toxicology Date : 05/03/2021

2. Cont …

3. Introduction Definition: NMBA are the drugs that act peripherally at NM-Junction and muscle fiber itself to block neuromuscular (nicotinic – Nm receptor) transmission. Why do we need them ? In order, to facilitate muscle relaxation for surgery and mechanical ventilation during surgery & in ICU.

4. Classification Peripherally-acting Agents: Neuromuscular Junction Blockers Non depolarizing (competitive) blockers: Long acting: d-Tubocurarine, Pancuronium, Doxacurium, Pipecuronium. Intermediate acting: Vecuronium, atracurium, cisatracurium , Rocuronium, Rapacuronium Short acting: Mivacurium. Depolarizing blockers: Succinyl choline ( suxamethonium ). Decamethonium. 2. Direct-acting agents : dantrolene Sodium, Quinine Centrally-acting agents: Mephenesin congeners : Mephenesin , Carisoprodol, Chlorzoxazone, Chlormezanone, Methocarbamol. Benzodiazepines : Diazepam, Triazolam and others. Gabba derivative : Baclofen Central α2 agonist : Tizanidine

5. Nerve transmission at NMJ

6. Structure of Ach receptors Each ACh receptor in the neuromuscular junction normally consists of five protein subunits; two α subunits; and single β, δ, and ε subunits. Only the two identical α subunits are capable of binding Ach molecules. If both binding sites are occupied by Ach, a conformational change in the subunits, briefly (1 ms ) opens an ion channel in the core of the receptor. The channel will not open if Ach binds on only one site

7. Perisynaptic Sodium channel

8. “Another isoform of Ach contains a γ subunit instead of the ε subunit known as fetal or immature receptor, because this form initially expressed in fetal muscle  It is also often referred to as extrajunctional receptors”. Cations flow through the open ACh receptor channel (sodium and calcium in; potassium out), generating an end-plate potential. When enough receptors are occupied by ACh, the end- plate potential will be sufficiently strong to depolarize the peri-junctional membrane.

9. Sodium channels are present in muscle membrane. Peri-junctional areas of muscle membrane have a higher density of these sodium channels than other parts of the membrane. These sodium channels have two types of gate voltage dependent time dependent Sodium ions pass only when both gates are open.

10. NEURO MUSCULAR BLOCKING AGENTS CLASSIFICATION Non depolarizing (competitive) blockers: Long acting: d-Tubocurarine, Pancuronium, Doxacurium, Pipecuronium. Intermediate acting: Vecuronium, atracurium, cisatracurium, Rocuronium, Rapacuronium Short acting: Mivacurium. Depolarizing blockers: Succinyl choline (suxamethonium). Decamethonium.

11. Contd’… C) Directly acting agents: Dantrolene sodium. Quinine. Other agents that interfere with neuro muscular transmission : Aminoglycosides, tetracycline, polypeptide antibiotics: these are not used as muscle relaxants.

12. DEPOLARIZING AGENTS

13. SEQUENCE OF MUSCLE BLOCKADE First muscle to be blocked by both depolarizing and non depolarizing muscle relaxants are the central muscles then peripheral muscles blocked. So the sequence of blockade is... FACE  JAW  PHARYNX  LARYNX  RESPIRATORY  TRUNK MUSCLES  LIMB MUSCLES At recovery these recover in the same order.

14. Depolarizing agents The group is also referred to as persistent depolarizing agents and includes succinyl choline and decamethonium. Persistent depolarization means there is no resting phase of the action potential and hence no response to ACH. It is caused by sustained opening of sodium channels by the depolarizing neuro muscular blocker.

15. Pharmacokinetics: Onset of action of succinyl choline is 1-1.5 minutes after IV injection ad duration of action is 3-6 minutes. It is rapidly hydrolyzed by plasma and tissue pseudo- CHE. Duration of action of succinyl choline is prolonged in patients with pseudo- CHE deficiency or with atypical pseudo –CHE which may lead to respiratory paralysis or succinyl apnea. Decamethonium is not easily metabolized having longest duration of action, hence not used clinically.

16. Pharmacological effects It causes transient fasciculation of groups of muscle fibers for 10-15 seconds followed by flaccid paralysis. This is called phase one block . In this depolarized state (phase), the block cannot be reversed by anticholinesterases like neostigmine or edrophonium. Paralysis of neck and limb muscles occurs before those of face and pharynx . With continued exposure to Succinyl choline, the initial depolarization decreases, the membrane is repolarized but now cannot be depolarized again as long as the succinyl choline is present in the receptor sites. This is called phase II or desensitization block , which can be antagonized by anti cholinesterase.

17. CONTD’… Succinyl choline has muscarinic and ganglion stimulating actions but does not release histamine. It may cause bradycardia in therapeutic doses and tachycardia in larger doses. It may also cause cardiac arrhythmia (extra systole). Muscle power recovery occurs within minutes.

18. ADVERSE EFFECTS Muscle fasciculation and post-operative muscle pain are common and are due to depolarizing effect of the drug. Muscarinic effects are manifested as bradycardia, hypotension, salivation and increases gut motility. Raised intra ocular tension due to prolonged contraction of extra- ocular muscles and transient dilation of choroidal blood vessels. It may be dangerous in acute glaucoma. Hyperkalemia may be due to persistent depolarization, especially in patients of deep burns and muscle damage. Cardiac arrhythmias and arrest can also be caused. Succinyl apneas in patients with atypical pseudo –CHE (genetic variant) which does not hydrolyze succinyl choline. Malignant hyperthermia , a rare congenital abnormality characterized by intense muscle spasm and sudden rise in body temperature. Treated with dantrolene.

19. Drug interactions: The action of Succinyl choline is potentiated by: Drugs which inhibit neuro muscular transmission-aminoglycosides, quinidine, calcium channel blockers, local anesthetics and magnesium ions. Drugs which inhibit pseudo cholinesterase-anticholinesterases, MAOI and cytotoxic agents.

20. NON –DEPOLARIZING AGENTS

21. Mechanism of Action These are competitive inhibitors of acetyl choline at the motor end plate. The motor end plate is found at the junction of the motor nerve and the skeletal muscle and it contains nicotinic Nm or N2 receptors of acetylcholine. ACh Combines with these post synaptic receptors leading to influx of sodium ions and the development of end plate potential causing muscle contraction .

22. The competitive neuro muscular blockers are generally bulky in nature and therefore block access of the nicotinic receptors to ACH with no generation of end plate potentials and causing flaccid paralysis . ACH also acts presynaptically on cholinergic neurons and augments its own release( positive feedback ). D-Tubocurarine can reversibly block both presynaptic and post synaptic receptors while α-bungarotoxin blocks only post synaptic receptors but not presynaptic receptors.

23. Gallamine also inhibits neuronal release of ACH by acting on presynaptic cholinergic M2 receptors. 80-90% of nicotinic receptors must be blocked before neurotransmission fails. Anticholinesterase agents like neostigmine can reverse the effects of neuromuscular blockers by building up the concentration of the agonist (ACH).

24. Pharmacokinetics All competitive neuro muscular blockers are quaternary ammonium compounds: They are: Poorly absorbed after oral administration Low volume of distribution because they don’t cross membranes. Do not penetrate placenta or blood brain barrier. (They are safe in obstetrical surgery except gallamine) They are always administered by IV route although the IM route is also possible.

25. The drugs are first distributed to muscles with higher blood flow and these muscles are affected first. Redistribution to non-muscular tissues plays a role in terminating the activity of the NMJ blocker. Duration of muscle relaxation following IV administration : d-tubocurarine 30 min, gallamine 15 mins, pancuronium 60 min, Atracuronium 10 min, alcuronium 30 mins.

26. Pharmacological actions: D-TUBOCURARINE When injected I.V there is immediate onset of action, peak effect within 5-7 mins. and duration of action of between 30- 60 mins. Effects of d-tubocurarine on skeletal muscles  flaccid paralysis of the muscles. Muscles of fine movements are more sensitive than larger and stronger muscles of coarse movements. Small rapidly moving muscles of the face, neck, eyes and pharynx are affected first, leading to difficulty in speaking, accumulation of secretions in throat, and diplopia.

27. Other small muscles of fingers, toes, hands and intercostal muscles are affected next leading to difficulty in performing delicate motor tasks. Muscles of limb, trunk, abdomen, chest and finally diaphragm are paralyzed with cessation of respiration. Recovery of paralysis occurs in reverse order

28. Effects of d- tubocurarine on other systems… Blocks transmission at autonomic ganglia and decreases secretion of adrenaline from the adrenal glands leading to fall in blood pressure. Releases histamine from mast cells leads to fall in blood pressure and bronchospasm. Contraindicated in patients of bronchial asthma and other allergic states

29. Other Agents All are quaternary ammonium compounds with same pharmacokinetic profile as d-tubocurarine, Gallamine. Does not release histamine or block autonomic ganglia. Blocks M2 muscarinic receptors of the heart and releases NA, inducing tachycardia….!

30. Pancuronium Does not release histamine or block autonomic ganglia. Blocks M2 muscarinic receptors of the heart and releases NA leading to tachycardia. Duration of action: 60-120 mins. Inhibits plasma cholinesterase.

31. Atracurium 4 times less potent than pancuronium and shorter acting (20-35mins.) Neostigmine reversal not required because of short duration of action. It is inactivated by plasma cholinesterase and spontaneous non enzymatic degradation in the plasma (Hofmann elimination) therefore duration of action is not altered by liver diseases. Preferred muscle relaxant for patients of hepatic diseases, neonates and the elderly…. WHY ? Releases histamine and may cause hypotension.

32. Pipecuronium Slow onset and long duration of action (onset2-4min Duration-50-100mins) Recommended for prolonged surgeries. Has little cardiovascular action, though there may be transient hypotension and bradycardia.

33. Vecuronium A close congener of pancuronium with a shorter duration (30-60mins) due to rapid distribution and metabolism Recovery is generally spontaneous not requiring neostigmine reversal unless repeated dose has been given Cardiovascular stability is better due to lack of histamine release and ganglion blockage, tachycardia occasionally occurs CURRENTLY THE MOST COMMONLY USED MUSCLE RELAXANT FOR ROUTINE SURGERY

34. Doxacurium Has the least rapid onset (4-8 mins) and the longest duration of action (60-120 mins). Suitable for long surgeries. Minimal cardiovascular effects. Mivacurium: Shortest acting (onset 2-4 and duration 12-20 mins). Does not need neostigmine reversal. Cause slight histamine release leading to fall in BP but minimal effect on heart rate. Hydrolyzed by plasma cholinesterase and prolonged paralysis can occur in pseudo cholinesterase deficiency.

35. Rocuronium New compound with rapid onset (1-2 mins) and intermediate duration of action (25-40 mins). Onset is dose dependent Can be used as an alternative to succinyl choline for tracheal intubation without the disadvantages of depolarizing block and cardiovascular changes. May serve as maintenance muscle relaxant. Seldom needs neostigmine reversal

36. Adverse effects: Hypoxia and prolonged respiratory paralysis . Managed by artificial respiration, maintenance of patient’s airway and injection of neostigmine (1- 3mg i.v.) and atropine sulfate (0.6 mg i.v.). Atropine is used to block the peripheral muscarinic actions of ACH e.g. bronchospasm and hypotension Bronchospasm due to histamine release as with tubocurarine. Hypotension due to autonomic ganglion blockage and histamine release. Less likely with the new compounds. Neuro muscular paralysis especially in children, myasthenia gravis and patients with hepatic and renal failure.

37. DRUG INTERACTIONS Neuro muscular block and paralysis are potentiated by: Inhalation anaesthetic (ether, halothane, cyclopropane, enflurane) Lignocaine, quinidine, beta blockers, calcium channel blockers and lithium which inhibit ACH release or action . Antibiotics (aminoglycosides, clindamycin) which inhibit ACH release. Anticholinesterases reverse the action of competitive blockers. Neostigmine (0.5- 2mg i.v ) is routinely used after pancuronium and other long acting blockers to hasten recovery at end of operation

38. SUMMARY OF NEWER NONDEPOLARIZING DRUGS No or minimal ganglionic, cardiac or vascular effects. No or minimal histamine release. Many are short acting and easy reversal Some are rapid acting: provide alternative to Succinyl choline without the attendant complications.

39. FACTORS TO BE CONSIDERED WHEN CHOOSING AN NMB Neuromuscular blockers are used whenever relaxation of skeletal muscles is desirable. The following factors must be considered when selecting appropriate NMBs The duration of the surgical procedure: Succinyl choline (duration of action 3-6 mins) is employed for brief procedures e.g. endotracheal intubation, laryngoscopy, bronchoscopy, esophagoscopy, reduction of fractures, dislocations and to treat laryngospasms. Onset of action of the NMB. Cardiovascular effects of the drug. Patient’s hepatic, renal and hemodynamic status.

40. THERAPEUTIC USES OF NMBs 1. As an adjunct to general anaesthetic : For skeletal muscle relaxation, both non-depolarizing and depolarizing neuro muscular blockers are used clinically. For operations lasting more than 30 minutes e.g. intra-abdominal operations or orthopedic maneuvers, d –tubocurarine is used for these reasons: It relaxes muscle tone It reduces the dose of anaesthetic agents and the post anaesthetic complications and keeps the blood pressure on the lower side. D- Tubocurarine has been largely replaced by synthetic derivatives which have fewer side effects (atracurium-duration 20-35 mins, pipecuronium 50- 100 mins, vecuronium, 30-60 mins).

41. 2. In obstetric conditions- any of the nondepolarizing drugs (except gallamine) can be used. 3. In selected cases of arterial surgery , pancuronium is used. 4. For producing transient muscle relaxation as required in endotracheal intubation, bronchoscopy, direct laryngoscopy, esophagoscopy and electroconvulsive therapy (ECT) . Succinyl choline is the drug of choice as the onset of action is immediate and recovery is within 5 minutes. The intravenous muscle relaxant doses in mg are: tubocurarine 10-15, gallamine1-2, pancuronium1-2, and altracurium 0.5-1. 5. In the treatment of painful muscle spasms in tetanus , muscle relaxation is the key to therapy and mild sedation is also desirable. Diazepam i.v as a running drip is given in adults (60-240 mg /24 hours, in children (30-40 mg/24 hours) and in neonates (20-40mg/24 hours). Maintenance on intermittent positive pressure respiration is necessary.

42. 6. In very small doses (1/10) atracurium may be used for diagnosis of myasthenia gravis . 7. Severe cases of status epilepticus which are not controlled by diazepam or other drugs may be paralyzed by an NMB (repeated doses of competitive blocker) and maintained on intermittent positive pressure respiration till the disease subsides.

43. DIRECTLY ACTING MUSCLE RELAXANTS. DANTROLENE : It exerts a direct action on the skeletal muscle by interfering with the release of calcium from the sarcoplasmic reticulum. It interferes with the excitation- contraction coupling Cardiac and smooth muscles are not affected by dantrolene as the mechanism of calcium entry is different in these tissues. It has no effect on CNS and neuro muscular junction.

44. PHARMACOKINETICS It is absorbed after oral administration, but the absorption is slow and incomplete. It penetrates the brain and produces some sedation, but has no selective action on polysynaptic reflexes responsible for spasticity. It is metabolized in the liver and excreted by the kidneys with a half- life of 8-12 hours.

45. THERAPEUTIC USES Neurological spastic disorder s e.g. multiple sclerosis, cerebral palsy, spinal injury, hemiplegia and paraplegia. The initial oral dose is 25mg once a day which is gradually increased to 100mg QDS daily. The dose limiting toxicity is generalized muscle weakness. Malignant hyperthermia following use of succinyl choline or halothane in genetically predisposed people. Dantrolene is given initially 1 mg /kg IV and repeated up to 100 mg/kg IV which is followed by 50-100mg QDS for 2-3 days.

46. ADVERSE EFFECTS Muscle weakness is the dose limiting toxicity. Sedation, malaise lightheadedness and other central effects occur, but are less pronounced than centrally acting muscle relaxants. Troublesome diarrhea. Long term use cause dose dependent liver toxicity in 0.1-0.5 % of patients. This has restricted its use in chronic disorders

47. QUININE It increases refractory period and decreases excitability of motor end plates, thus reducing response to repetitive nerve stimulation. It reduces muscle tone in myotonia congenita. When taken at bedtime (200-300mg) it may abolish nocturnal leg cramps in some patients.

48. CENTRALLY ACTING MUSCLE RELAXANTS These are drugs which reduce skeletal muscle tone by a selective action in the cerebrospinal axis, without altering consciousness. They selectively depress spinal and supra spinal poly synaptic reflexes involved in the regulation of muscle tone. Polysynaptic pathways in the ascending reticular formation which are involved in arousal and attension are also depressed, though to a smaller extent

49. All centrally acting muscle relaxants cause sedation. They have no effect on neuro muscular transmission and on muscle fibres but reduce rigidity, upper motor neuron spasticity and hyperreflexia. Note the differences between peripherally and centrally acting muscle relaxants.

50. CLASSIFICATION Mephenesin congeners : Mephenesin, Carisoprodol, Chlorzoxazone, Chlormezanone, Methocarbamol. Benzodiazepines : Diazepam, Triazolam and others. GABA-B derivative : Baclofen Central α2 agonist : Tizanidine

51. MEPHENESIN First drug to be discovered as a muscle relaxant. Modulates reflexes, maintaining muscle tone. It is not used clinically because it causes gastric irritation, and when administered IV, it causes thrombophlebitis, hemolysis, and marked fall in BP. Topical formulations are available

52. CARIS0PRODOL Has favorable muscle relaxant, sedative, analgesic antipyretic, and anticholinergic properties. It is used in musculoskeletal disorders associated with muscle spasms. CHLORZOXAZONE Pharmacologically similar to mephenesin, it has a longer duration of action and is better tolerated orally. CHLORMEZANONE Has anti-anxiety and hypnotic actions and is used for tension states associated with increased muscle tone.

53. METHOCARBAMOL Less sedative and longer acting than mephenesin. Orally used in reflex muscle spasm and chronic neurological diseases. It can be given IV without producing thrombophlebitis and hemolysis-used for orthopedic procedures and tetanus.

54. DIAZEPAM A benzodiazepine (BDZ) which acts in the brain on specific receptors, enhancing transmission by the inhibitory amino acid neurotransmitter GABA. Muscle tone is reduced by supraspinal rather than spinal action. It has more sedative activity than muscle relaxation and sedation limits the dose that can be used for muscle relaxation. Diazepam is particularly valuable in tetanus and spinal injuries. When combined with analgesics, it is useful for rheumatic disorders associated with muscle spasm.

55. BACLOFEN Is a GABA B receptor agonist which depresses both polysynaptic and monosynaptic reflexes in the spinal cord. It does not produce muscle weakness like diazepam because it does not affect chloride conductance. BDZs facilitates the effect of GABA on GABA A receptors increasing chloride conductance while baclofen acts on GABAB receptors, hyperpolarizing neurons by increasing K+ conductance and altering Ca2+ flux. It reduces spasticity in many neurological disorders like multiple sclerosis, spinal injuries and flexor spasms. It is relatively in effective in stroke, cerebral palsy, rheumatic and traumatic muscle spasms and Parkinsonism.

56. TIZANIDINE It is a new skeletal muscle relaxant that is a clonidine congener. It is a central α2- adrenergic agonist that inhibits the release of excitatory amino acids, e.g., aspartate, in the spinal interneurons while facilitating the inhibitory amino acid neurotransmitter glycine. It inhibits polysynaptic reflexes and reduces muscle tone and frequency of muscle spasms without reducing muscle strength. Efficacy similar to baclofen and diazepam has been noted in multiple sclerosis, spinal injury, and stroke with fewer side effects. It is well absorbed and is administered as tablets of 2 and 4 mg

57. ADVERSE EFFECTS OF CENTRALLY ACTING DRUGS Gastric irritation except for diazepam, Baclofen and tizanidine. All CAMs cause drowsiness and sedation. Baclofen can cause tachycardia, hypotension, and rarely visual and auditory hallucinations. It can also cause ataxia and elevation of serum transaminase. Tizanidine may cause dry mouth, drowsiness, nighttime insomnia, and hallucinations. Dose-dependent elevation of liver enzymes has been noted. No consistent effect on BP has been noticed but should still be avoided in patients receiving anti-hypertensives, especially clonidine.

58. References Lippincott's illustrated pharmacology Internet websites

59. Thank you ?