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Skeletal muscle relaxants, Neuromuscular blocking agents, Neuromuscular blockers

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Skeletal muscle relaxants, Neuromuscular blocking agents, Neuromuscular blockers

  1. 1. NEUROMUSCULAR JUNCTION BLOCKING AGENTS Dr Pranav Bansal Associate Professor BPS GMC, Khanpur kalan, Sonipat
  2. 2. Introduction What are neuromuscular blocking drugs ? These are agents that act peripherally at neuromuscular junction/muscle fibre itself to block neuromuscular transmission. Why do we need them ? In order to facilitate muscle relaxation for surgery & for mechanical ventilation during surgery or in ICU
  3. 3. What are SMRs ? Definition: SMRs are the drugs that act peripherally at neuromuscular junction or muscle fibre itself or in cerebrospinal axis to reduce muscle tone and /cause muscle paralysis.
  4. 4. HISTORY
  5. 5. HISTORY  In 1942 Griffith & Johnson suggested that d-tubocuranine is a safe drug to use during surgery.  Succinycholine for the first time introduced by Thesleff & by Foldes & colleagues in1952.  In 1962 Baird & reid first administered pancuronium  Vecoronium, a amino steroid & atracurium, a benzylisoquinolinium introduced in 1980 and  Mivacurium introduced in 1990.  All modern agents are entirely synthetic
  6. 6. Site of action of neuromuscular blocking agents  Two types  Pre junctional recceptor  Post junctional recceptor
  7. 7. Site of action neuromuscular blocking agents  Post junctional receptor Pentameric structure containing five subunits- 2α,β,δ,Є(adult). Fetal post junctional receptor consists of 2α,β,δ,γ.
  8. 8. Skeletal muscle relaxants A. Nicotinic (Muscle) receptor blockers – Skeletal muscle relaxants. B. Nicotinic (Nerve) receptor blockers – Ganglion blockers
  9. 9. Skeletal muscle relaxants  Skeletal muscle relaxants block peripherally at the neuromuscular junction (Nicotinic receptor of Ach – Muscle).  Types of Skeletal muscle relaxants:  Competitive (Non-depolarizing)  Non-competitive (Depolarizing)  Directly acting Muscle relaxants  Miscellaneous : Aminoglycosides
  10. 10. Skeletal muscle relaxants Pharmacokinetics :  Most peripheral NM blockers are quaternary compounds – not absorbed orally.  Administered intravenously.  Do not cross blood brain barrier or placenta  No analgesia /loss of consciousness  Volatile anes potentiate effect by dec tone of skeletal muscle and dec sensitivity of post synaptic memb to depolarisation  SCh is metabolized by Pseudocholinesterase.  Atracurium is inactivated in plasma by spontaneous non-enzymatic degradation (Hoffman elimination).
  11. 11. Skeletal muscle relaxants  Neuromuscular blockers  Depolarizing blockers : (Non-competitive)  Succinylcholine (Suxamethonium)  Non - depolarizing ( competitive )  Long acting : Pancuronium, Pipecuronium,  Intermediate : Vecuronium, Rocuronium, Atracurium  Short acting : Mivacurium
  12. 12. 12 11/01/15 Mechanism of action (non depolarizing agents)  a) At low doses:  These drugs combine with nicotinic receptors and prevent acetylcholine binding.as they compete with acetycholine for receptor binding they are called competitive blockers  Thus prevent depolarization at end-plate.  Hence inhibit muscle contraction, relaxation of skeletal muscle occurs.
  13. 13.  Their action can be overcome by increasing conc. of acetylcholine in the synaptic gap (by ihibition of acetyle choline estrase enzyme) e.g.: Neostigmine ,physostigmine, edrophonium  Anesthetist can apply this strategy to shorten the duration of blockage or over come the overdosage. 13 11/01/15
  14. 14. 14 11/01/15  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.
  15. 15. 15 11/01/15  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.
  16. 16. 16 11/01/15 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.
  17. 17.  Atracurium is degraded spontaneously in plasma by ester hydrolysis ,it releases histamine and can produce a fall in blood pressure ,flushing and bronchoconstriction. is metabolized to laudanosine( which can provoke seizures),Cisatracurium with similar pharmacokinetics is more safer.  non depolarizers are excreted via kidney ,have long half life and duration of action than those which are excreted by liver. 17 11/01/15
  18. 18. 18 11/01/15  Some (vecuronium, rocuronium) are acetylated in liver.( there clearance can be prolonged in hepatic impairment)  Can also be excreted unchanged in bile.  They differ in onset, duration and recovery (see table)  Uses: as adjuvant to anesthesia during surgery.  Control of ventilation (Endotracheal intubation)  Treatment of convulsion
  19. 19. 19 11/01/15 Drug interactions  Choline esterase inhibitors such as neostigmine, pyridostimine and edrophonium reduces or overcome their activity but with high doses they can cause depolarizing block due to elevated acetylcholine concentration at the end plate.  Halogenated hydrocarbons ,aminoglycosides ,calcium channel blockers synergize their effect.
  20. 20. 20 11/01/15 Unwanted effects  Fall in arterial pressure chiefly a result to ganglion block , may also be due to histamine release this may give rise to bronchospasm (especially with tubocurarine ,mivacurium ,and atracurium)  Gallamine and pancuronium block, muscarinic receptors also, particularly in heart which may results in to tachycardia.
  21. 21. 21 11/01/15 DEPOLARIZING AGENTS  DRUGS Suxamethonium ( succinylecholine)  Decamethonium  Mechanism of action:  These drugs act like acetylcholine but persist at the synapse at high concentration and for longer duration and constantly stimulate the receptor.  First, opening of the Na+ channel occurs resulting in depolarization, this leads to transient twitching of the muscle, continued binding of drugs make the receptor incapable to transmit the impulses, paralysis occurs.  The continued depolarization makes the receptor incapable of transmitting further impulses.
  22. 22. 22 11/01/15  Therapeutic uses:  When rapid endotracheal intubations is required.  Electroconvulsive shock therapy. Pharmacokinetics:  Administered intravenously.  Due to rapid inactivation by plasma cholinestrase, given by continued infusion.
  23. 23. 23 11/01/15 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 causes maintained depolarization at the end plate, which leads to a loss of electrical excitability.  It has shorter duration of action.
  24. 24. 24 11/01/15  It stimulate ganglion sympathetic and para sympathetic both.  In low dose it produces negative ionotropic and chronotropic effect  In high dose it produces positive ionotropic and chronotropic effect.
  25. 25. 25 11/01/15  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  If cholinestrase is inhibited ,it is possible for circulating acetylcholine to reach a level sufficient to cause depolarization block.
  26. 26. 26 11/01/15  Unwanted effects:  Bradycardia preventable by atropine.  Hyperkalemia in patients with trauma or burns  this may cause dysrhythmia 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.
  27. 27. 27  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
  28. 28. Depolarizing block ( Non-competitive ) :  Succinylcholine have affinity and sub maximal intrinsic activity at NM receptors.  They open Na channels which cause initial twitching and fasciculation. (fasciculation or "muscle twitch", is a small, local, involuntary muscle contraction and relaxation visible under the skin arising from the spontaneous discharge of a bundle of skeletal muscle fibers (muscle fascicle).)  It does not dissociate rapidly from the receptors resulting in prolonged depolarization and inactivation of the Na + channels
  29. 29. A.A. Non-depolarizing agents (CompetitiveNon-depolarizing agents (Competitive blockers).blockers). Mechanism of action : • These have an affinity for the Nicotinic (NM) receptors at the muscle end plates but have no intrinsic activity. • The antagonism is surmountable by increasing the conc. of Ach. Neuromuscular blocking agents :
  30. 30. Skeletal muscle relaxants Duration (mins.) Pancuronium 40-80 Pipecuronium 50-100 Vecuronium 20-40 Atracurium 20-40 Rocuronium 20-40 Succinyl choline 3-6
  31. 31. Skeletal muscle relaxants Depolarizing block (Non-competitive) : Succinylcholine  It causes muscle pain.  It causes hyperkalemia.  Malignant Hyperthermia.
  32. 32. Competitive Non-depolarizing Non-Competitive Depolarizing Paralysis Flaccid Fasciculations---› Flaccid Neostigmine Antagonizes Exaggerate / no effect. Examples Pancuronium Succinylcholine
  33. 33. Skeletal muscle relaxants USES OF NEUROMUSCULAR BLOCKERS :  Adjuvant in general anesthesia  Intubation and endoscopies  Brief procedure
  34. 34. Skeletal muscle relaxants Directly acting muscle relaxants : Dantrolene : Depolarization triggered release of calcium from the sarcoplasmic contraction is blocked / reduced.  Dantrolene is used orally/ i.v to reduces spasticity in hemiplegia and cerebral palsy.  It is the drug of choice – malignant hyperthermia
  35. 35. 35 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.
  36. 36. Classification  Two groups  Depolarising or non-competitive type  Non-depolarising or competitive type
  37. 37. Depolarising or non-competitive type  Sccinylcholine -consists of two acetylcholine molecule linked back to back by acetate methyl group.  Mechanism of action- like acetylcholine  it stimulates cholinergic receptor at NMJ &  Nicotinic (ganglionic) & muscarinic autonomic sites to open ionic channel leading to depolarisation.
  38. 38. Metabolism of succinylcholine  ED950.51-0.63mg/kg.  Onset of action-30-60sec.  Duration of action-9-13 min.  Shortest acting neuromuscular blocking agent.  Metabolised by- butrycholinesterase or - plasma cholinesterase or - pseudocholinesterase
  39. 39. Metabolism of succinylcholine  Scuccinycholine on breakdown by butrycholinesterase produces 1- succinylmonocholine - succinic acid & choline 2-choline.  At neuromuscular junction effect of succinylcholine terminated by diffusion.
  40. 40. Factors affecting metabolism of succinylcholine  As succinylcholine enter the circulation, its rapidly metabolized by pseudocholinesterase.  This process is so efficient that only a fraction of injected dose ever reaches neuromuscular junction.  The duration of action is prolonged by high dose or by abnormal metabolism.  Abnormal metabolism may result from hypothermia, low enzyme levels or genetically aberrant enzyme.
  41. 41. Factors affecting metabolism of succinylcholine  Hypothermia decreases rate of hydrolysis.  Low levels of pseudocholinesterase accompany pregnancy, liver dz, renal failure ,neostigmine, perinorm, advanced age, bruns, oral contraceptives.  Obese and m. gravis resistant to s.choline  1 in 50 pts has one normal & abnormal gene, resulting in a slightly prolonged block(20-30 min).  1 in 3000 pts have 2 abnormal genes (homozygus atypical) which will have a very long blockade (eg 6-8 h).  Prolonged paralysis caused by atypical cholinesterase should be treated with cont mechanical ventilation until muscle function returns to normal.
  42. 42. Qualitative analysis of Butrycholinesterase  Dibucain number-  it is a amide based local anesthetic that inhibits normal butrycholinesterase by 80%. Abnormal enzyme by 20%.  Flouride number
  43. 43. Side effects 1. Cardiovascular:  can increase or decrease blood pressure and heart rate (due to stimulation at parasympathetic and sympathetic ganglia)  Bradycardia-  dt stimulation at SA node by succinylmonocholine.More common in;  Unatropinised children  Digitalised and beta-blocked patient
  44. 44. Side effects 2. Hyperkalemia  normal short lasting rise in K+ (0.5-1.0 mmol/L).  Life threatening K+ elevation possible in burn injury,massive trauma,neurologic or muscular disorder.
  45. 45. Side effects 3. Fasciculation 4. Muscle pains 5. Intragastric pressure elevation 6. Intraocular pressure elevation 7. Malignant hyperthermia -potent trigerring agent in patient susceptible to MH. 8. Prolonged paralysis
  46. 46. Side effects 9. Intracranial pressure -slight increase in cerebral blood flow and intracranial pressure in some patients. -can be prevented by pretreating with NDMR and IV Lignocaine (1.5-2mg/kg) 2-3 minutes prior intubation. Indication of use of succinylcholine- rapid sequence induction.
  47. 47. Succinylcholine Recommendations for use:  use Peripheral Nerve Stimulator  maximal dose 1-1.5 mg/kg  look for recovery before admin of NDMR’s  Do not treat with anti AChE unless: proper N-M monitoring is available spont. recovery of TOF is documented or ChE is administered first
  48. 48. Non depolarising neuromuscular blocking drugs classification (on basis of chemical strucure) Benzylisoquinolinium D-tubocurare Metocurine Doxacurium Atracurium Cisatracurium mivacurium Aminosteroid Pancuronium Vecuronium Rocuronium Rapacuronium
  49. 49. Classification of Non-Depolarising Muscle Relaxants Ultra short Short Intermediate Long Rapacuronium Mivacurium Vecuronium Pancuronium GW 280430 Atracurium d-Tubocurare Cis-atracurium Gallamine Rocuronium Metocurine Doxacurium Pipecuronium
  50. 50. Pancuronium  Bis-quaternary Aminosteroid NMJ blocking agent.  ED95 B-70µg/kg  Onset of action-3-5min / Duration-60-90 min.  Dosage-intubation-0.08-0.12mg/kg maintenance-0.04mg/kg  Long acting  No or slight increase on blood pressure, HR (Vagolytic)  Hepatic metabolism & Renal clearance ( dose reduction in failure)  Histamine release
  51. 51. Vecuronium  aminosteriod  ED95 B-50µg/kg  Onset of action-3-5min/Duration-20-35min  Dosage-intubation-0.08-0.12mg/kg maintenance-0.04mg/kg infusion-1-2µg/kg/min  Depends primarily on biliary excretion and secondarily on renal excretion (no dose reduction required)  Intermediate acting  Active metabolites- 3 cis vecuronium responsible for prolonged effect  Prolonged effect in old age, obesity, renal failure, AIDS, obesity
  52. 52. Atracurium  Benzoisoquinoline derivative  Non-organ dependent elimination  Non specific estererase: 60% of elimination  Hofmann elimination : spontaneous nonenzymatic chemical breakdown occurs at physiologic pH and T.  Histamine release at higher clinical dose in 30% of patients(Hypotension,tachycardia,Bronchospasm)  Laudanosine toxicity -breakdown product from Hofmann elimination, assoc. with central nervous system excitation resulting in elevation of MAC and precipitation of seizures.  Temperature and pH sensitivity-action markedly prolonged in hypo- thermic or acidotic patients.
  53. 53. Cis-atracurium  Benzoisoquinoline derivative  3x more potent than atracurium.  No ester hydrolysis.  dosage: 0.1-0.15mg/kg (within 2 min) 1.0-2.0 mcg/kg/min (infusion rate)  Minimal histamine release .
  54. 54. Mivacurium  Bisquaternary benzylisoquinoline  potency, 1/3 that of atracurium  slow onset 1.5 min with 0.25 mg/kg  short duration 12-18 min with 0.25 mg/kg  histamine release with doses 3-4X ED95  hydrolyzed by pChE, recovery may be prolonged in some populations (e.g. atypical pChE) 
  55. 55. Rocuronium Mono-quaternary aminosteroid  potency, approx 1/6 that of Vecuronium  fast onset (< I min with 0.8 mg/kg)  intermediate duration (44 min with 0.8 mg/kg)  minimal CV side effects  onset and duration prolonged in elderly  slight decrease in elimination in RF
  56. 56. Rapacuronium monoquaternary aminosteroid, analogue of Vecuronium  low potency, fast onset, short to intermediate duration  1.5-2.0 mg/kg doses give good intubating conditions at 60 sec  duration of action, dependent on dosage and age of patient  20 % decrease in aBP observed with 2-3 mg/kg doses  principle route of elimination may be liver as 22% is renal excretion.  introduced in 2000 in US and removed from market 19 mos. later, after paediatric deaths (bronchospasm), never available in Canada)
  57. 57. Comparative Pharmacology of Muscle Relaxants Agent ED95 Int Dose Onset DurationElim/Met (mg/kg) (mg/kg) (min) (min) Succinylcholine 0.3 1-1.5 < 1 12 pChE Rapacuronium (1.0) 1.3 1.5 9 nonenzym./Hep. Rocuronium 0.3 0.6 1 60 Hep./Renal Mivacurium 0.08 0.2 2 25 PChE Atracurium 0.2 0.6 2-3 60 Hoff/hydrol. Cis-atracurium 0.05 0.15 3-4 60 Hoff/hydrol. Vecuronium 0.05 0.10 2-3 60 Hep./Renal Pancuronium 0.07 0.10 3-5 100 Renal/Hepatic Pipecuronium 0.05 0.15 2-5 190 Renal Doxacurium 0.025 0.08 3-5 200 Renal/ChE
  58. 58. Percent of Dose Dependant on Renal Elimination > 90% 60-90% 40-60% <25% Gallamine (97) Pancuronium (80) d-TC (45) Succinylcholine Pipecuronium (70) Vecuronium (20) Doxacurium (70) Atracurium (NS) Metocurine (60) Mivacurium (NS) Rocuronium
  59. 59. POSTOPERATIVE RESIDUAL CURARIZATION PORC)  common after NDMRs  long acting > intermediate > short acting  Assoc with respir. morbidity  not observed in children  monitoring decreases incidence
  60. 60. CHOLINESTERASE INHIBITORS (ANTICHOLINESTERASE INHIBITORS (ANTI CHOLINESTERASE)CHOLINESTERASE)  Primary clinical use is to reverse nondepolarising muscle blockade  Neuromuscular transmission is blocked when NDMR compete with Ach to bind to nicotinic cholinergic receptors.  The cholinesterase inhibitors indirectly increase amount of Ach available to compete with NDMR, thereby re-establish NM transmission.
  61. 61. Cholinesterase inhibitors  In excessive doses, Achse inhibitors can paradoxically potentiate a nondepolarizing NM blockade.  It also prolong the depolarization blockade of succinylcholine.
  62. 62. ANTICHOLINESTERASE AGENTS 1. Neostigmine 2. Pyridostigmine 3. Edrophonium 4. Physostigmine
  63. 63. Neostigmine  Quaternary ammonium group  Dosage : 0.04-0.08 mg/kg  Effects apparent in 5-10 min and last more than 1 hour.  Muscarinic side effects are minimized by prior or concomitant administration of anticholinergic agent.  Also used to treat myasthaenia gravis, urinary bladder atonyand paralytic ileus.
  64. 64. Pyridostigmine  Dosage : 0.1-0.4 mg/kg  Onset slower (10-15 min) and duration slightly longer (>2 hours)  Equivalent dose of anticholinergic are required to prevent bradycardia.
  65. 65. Edrophonium  Dosage : 0.5-1.0mg/kg  Less potent  Most rapid onset (1-2 min )  Shortest duration of action  Higher dose prolong duration of action to > than 1 hour.  More effective at reversing mivacurium blockade.
  66. 66. Difficulty reversing block  Right dose?  Intensity of block to be reversed?  Choice of relaxant?  Age of patient?  Acid-base and electrolyte status?  Temperature?  Other drugs?
  67. 67. Atropine  Tertiary amine  Dosage : 0.01-0.02 mg/kg up to usual adult dose of 0.4-0.6 mg.  Potent effects on heart and brochial smooth muscle.
  68. 68. ScopolamineScopolamine  Dose is same as atropine and usually given intramuscularly.  More potent antisialagogue than atropine and cause greater central nervous system effects.  Can cause drowsiness and amnesia.  Prevent motion sickness  Avoided in patient with close-angle glaucoma
  69. 69. Glycopyrrolate  Dosage : 0.005-0.01 mg/kg up to 0.2-0.3 mg in adults.  Cannot cross blood-brain barrier and almost always devoid of central nervous system and ophthalmic activity.  Potent inhibition of salivary gland and respiratory tract secretions.  Longer duration than atropine (2-4 hours)

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