Skeletal Muscle Relaxants


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  • voltage-sensitive sodium channels sense membrane depolarization (as a result of activation of the ACh receptors), they first open (Fig. 1A(b)) and thereafter close and become inactivated
  • RyR1 to remain abnormally open and, as the speed at which calcium is released for SR exceed the speed at which it is uptaken and elimated by the calcium pump, the calcium concetration in the myoplasm greatly increases. In the early phase of MH, the muscle cells attempt to restore homeostasis by sequestering calcium through the increase of aerobic and anaerobic metabolism This abnormal myoplasmic calcium rise eventually reaches the threshold levels for myofibrillar contraction, and results in sustained muscle contraction. This produces a rapid depletion of adenosine triphosphate (ATP) with a concomitant increase in glucose metabolism, oxygen consumption, carbon dioxide production, and heat production. ATP stores become depleted, which progressively lead to the failure of membrane integrity with leakage of muscle cell contents (including electrolytes, myoglobin and various other sarcoplasmic proteins, like CK into the circulation)
  • Skeletal Muscle Relaxants

    1. 1. SKELETAL MUSCLE RELAXANTS -1 Speaker : Dr Rachana Menon
    2. 2. Learning Objective  Introduction  History  Physiology of Neuromuscular Junction  Acetylcholine – Synthesis ,Storage , Release  Nicotinic Receptor  Classification of SMR  Depolarizing agents  Directly acting agents
    3. 3. Drugs that act peripherally at neuromuscular junction or muscle fibre itself or in cerebrospinal axis to reduce muscle tone and cause muscle paralysis. INTRODUCTION
    4. 4. HISTORY  The earliest known use of muscle relaxant drugs dates back to the 16th century.  Natives of the Amazon Basin in South America . The prey was shot by arrows dipped in curare  Curare, led to some of the earliest scientific studies in pharmacology.
    5. 5. HISTORY  1935 – d tubocurarine, active ingredient - Harold King of London, working in Sir Henry Dale’s laboratory  1943, neuromuscular blocking drugs became established as muscle relaxants in the practice of anaesthesia and surgery
    6. 6. HISTORY
    7. 7. Contd..  1967- Baird and Reid first reported on clinical administration of the synthetic aminosteroid pancuronium  1980-Introduction of vecuronium, an aminosteroid, and atracurium. • 1990’s Mivacurium, the first short-acting nondepolarizing neuromuscular blocker was introduced
    8. 8. Neuromuscular Junction • 1- Motor neuron • 2 -Sarcolemma • 3 -Synaptic vesicle • 4 -nAchR • 5- Mitochondria
    9. 9. NNEUROMUSCULAR JUNCTION The neuromuscular junction is made up of a  Motor neuron – Originate in the ventral horn of the spinal cord.  As the axon of a motor neurone enters the structure of skeletal muscle it forms many branches “Axon terminals".  Synaptic end bulb – Bulbous swelling at the end of axon terminal.
    10. 10. Contd.. Each synaptic end bulb contains many synaptic vesicles, each of which contains ACETLYCHOLINE.
    11. 11. Contd.. MOTOR END PLATE - part of the Sarcolemma of the muscle cell that is in closest proximity to the synaptic end bulb SYNAPTIC CLEFT - The area between the axon terminal and the sarcolemma , release Ach occurs with consequent binding to the receptors
    12. 12. Contd..  The surface of motor end plate deeply folded with MULTIPLE CREST and secondary clefts  The nAchR are located on the crests. The clefts contain ACH ESTERASE
    14. 14. Acetylcholinesterase ACh Choline Acetate  Produced on the ribosomes of the motor neuron  Attached - thin collagen threads linking it to the basement membrane  Found junctional gap clefts of the post-synaptic folds in high concentrations Acetylcholinesterase
    15. 15. Transported distally by axoplasmic flow to the terminal button The cholinergic synapse is rich in AchE Breaks down Ach within 1 msec of being released.
    18. 18. SYNTHESIS  Acetic acid ester of choline  Synthesised inside the cholinergic nerve fibre  Choline  Acetyl-coenzyme A  Choline acetyltransferase-
    20. 20. Contd…
    21. 21. The events that translate an Action Potential, (a membrane-electrical event) into a mechanical event (contraction)
    24. 24. •Large extracellular N-terminal domain of ~200 amino acids; that contributes to agonist binding site •Four hydrophobic transmembrane domains (TM1 through TM4) •A large cytoplasmic loop between TM3 and TM4 with variable AA sequence. •The M2 transmembrane region is thought to form the ion pore of the nAChR • Short extracellular C terminus
    25. 25.  (Cys-loop) defined by two cysteines (Cys) that in the mammalian subunits are separated by 13 intervening amino acids.  Subunits are classified into α- and non-α subunits based on the presence of a Cys-Cys pair near the entrance to TM1. Cys-Cys pair • Required for agonist binding • Presence designates the subunit as an α-subtype .
    26. 26. STRUCTURE The N termini of two subunits cooperate to form two distinct binding pockets for Ach , agonist and antagonist • These pockets occur at the α -γ and the α- δ subunit interface. • The M2 membrane-spanning domain of each subunit lines the ion channel.
    27. 27. Contd… Five polypeptide subunits  Arranged around a pseudo-axis of symmetry to circumscribe an internally located channel  Adult receptor has two identical α subunits, one β one δ and one ε subunit in 2:1:1:1 ratio. In the foetus a γ (gamma) subunit replaces the ε
    28. 28. • The neuronal subtypes are various homomeric or heteromeric combinations of twelve different nicotinic receptor subunits. • 7 α-like subunits, termed α2, α3, α4, α5, α6, α7, α9, and α10 • 3 non-α subunits -β2, β3, and β4 cloned from neuronal tissues.
    29. 29. BINDING THE CHANNEL The Acetylcholine-binding site  Opening of the nAChR channel pore requires the binding of a chemical messenger  Acetylcholine.  Location - pockets approximately 3.0 nm above the surface membrane at the α and either γ or δ subunits interface.
    30. 30. OPENING THE CHANNEL The nAChR is a non-selective cation channel  Binding of 2 Ach molecules to the α-subunits initiates conformational changes that open the channel  Allows positively charged ions to move across it; in particular, sodium enters the cell and potassium exits. The net flow of positively-charged ions is inward.
    31. 31.  The cell becomes less negative compared with the extracellular surroundings.  When a threshold of –50mV is achieved (from a resting potential of –80mV), voltage- gated Na open, thereby increasing the rate of depolarisation and resulting in an End plate potential (EPP) of 50-100mV.  Triggers the muscle action potential  Muscle contraction
    32. 32.  Neurotoxins
    35. 35. SMR - Why Required ?  1. In conjunction with GA  2. Painful muscle conditions  3. Spastic neurological conditions
    36. 36. SKELETAL MUSCLE RELAXANT PERIPHERALLY ACTING CENTRALLY ACTING NEURO MUSCULAR ACTING DIRECTLY ACTING Non- depolarising Agents • Short Acting • Intermediate Acting • Long acting Depolarising Agents
    37. 37. A) PERIPHERALLY ACTING • Neuromuscular blockers Non depolarizing agents ( Competitive blockers) Prevent the access of Ach to Nm receptors of motor end plate and prevent depolarisation. Insoquinoline Derivatives • Tubocurarine • Doxacurium • Atracurium • Metocurine • Mivacurium Steroid Derivatives • Pancuronuium • Pipecuronium • Rapacuronium • Rocuronium • Vercuronium
    38. 38. Depolarizing agents • Produce excessive depolarisation which persist for longer duration at NMJ • Resistant to hydrolysis by true AchE present in synaptic cleft – Suxamethonium (Succinylcholine) – Decamethonium
    39. 39. B) CENTRALLY ACTING Benzodiazepine group GABA derivative Diazepam Baclofen clonazepam Central alpha agonist Mephensive group Tizanidine Chlorxoxazone Methocarbamol Chlormezazone Carisoprodol
    40. 40. DEPOLARISING AGENTS SUCCINYL CHOLINE  Also known as suxamethonium  Introduced by Thesleff and by Foldes and colleagues in 1952  Is a nicotinic acetylcholine receptor agonist
    41. 41. STRUCTURE ACTIVITY RELATIONSHIP  Quaternary ammonium compounds  Two molecules of acetylcholine linked back to back through the acetate methyl groups  Long, thin, flexible molecule.  Enable free bond rotation.
    42. 42. Positive charges at these sites in the molecules mimic the quaternary nitrogen atom of the transmitter acetylcholine
    43. 43. MECHANISM OF ACTION  Affinity and sub maximal intrinsic activity for NM receptors  Analouge of Ach  Longer durations at the neuromuscular junction - resistance to AChE  Do not dissociate from receptors quickly  SCh reacts with Nm receptor – Open Na+ channels  Prolonged persistant depolarisation
    44. 44.  Brief period of repetitive excitation  Flaccid paralysis of muscle  Elicit transient and repetitive muscle excitation FASICULATIONS  Neural release of Ach will result in binding of Ach to receptors on a already depolarised plate
    45. 45. • FLACCID PARALYSIS • This initial depolarization block of NEUROMUSCULAR TRANSMISSION AND FLACCID PARALYSIS PHASE l BLOCK The Na+ receptors at the end-plate and the perijunctional zone remain inactivated and junctional transmission is blocked.
    46. 46. • Recovery from Phase I block occurs as Sch diffuse away from the NMJ , down a concentration gradient as the plasma concentration decreases.
    47. 47.  Prolonged exposure to succinylcholine, the initial end plate depolarization decreases membrane becomes repolarized. Despite this repolarization, the membrane desensitized. Phase II Block (Desensitizing)
    48. 48. Contd… Unclear mechanism The channels behave as if they are in a prolonged closed state.Neurotransmission remains blocked through out 1.Presynaptic block reducing the synthesis and mobilization of ACh 2.Post junctional receptor desensitization 3.Activation of the Na-K ATPase pump by initial depolarization, which repolarizes it
    49. 49. Contd…  Later in phase II, the blockade identical to those of a nondepolarizing block  Fade of the train-of-four (TOF) twitch response  Tetanic fade  Post-tetanic potentiation  Inhalation anaesthetic drugs accelerate the onset of Phase II block. Possible reversal by acetylcholinesterase inhibitor
    50. 50. Threshold for TOF: Need at least 0.9 to minimize risk of post op complications Assessment of TOF: Must use quantitative monitoring
    51. 51. Contd… Phase I:  Initially classical depolarization block  Repolarization occurs  Neuromuscular transmission not restored  Cannot reversed by AChE.  Neostigmine potentiates Phase II:  Slow in onset  Desensitization of receptors to Ach  Resembles d-TC  Partially reversed by AChE
    52. 52. PHARMACOKINETICS  Rapid onset of effect and ultra short duration of action.  Not absorbed orally  Does not cross BBB, placenta  I.V route - initiation dose 0.5 – 1 mg/kg .tracheal intubation in adults is 1.0 – 1.5 mg/ kg. Cheeks,abdomen,neck,limb,face, respiratory paralysis  Apnoea within 1 min.Brief duration of action 6-11 min  Elimination - rapid hydrolysis by plasma cholinesterase in liver
    53. 53. Succinylcholine Succinylmonocholine Choline ( weaker NM blocking agent)  No butyrylcholinesterase is present at the NMJ  Butyrylcholinesterase has an enormous capacity to hydrolyse succinylcholine Butrylcholinesterase
    54. 54. Only 10% of the administered drug reaches the neuromuscular junction.  Influences the onset and duration of action of Sch by controlling the rate at which the drug is hydrolyzed before it reaches and after it leaves the NMJ.
    55. 55. Factors that have been found to lower butyrylcholinesterase activity  Liver disease  Advanced age, malnutrition, pregnancy  Burns  OCPs, MAO inhibitors  Ecothiophate, cytotoxic drugs  Anticholinesterase drugs  Neoplastic disease  Tetrahydroaminacrine  Hexafluorenium
    56. 56. DIBUCAINE TEST  Patient with abnormal genetic variant of butyrylcholinesterase ,Sch induced neuromuscular blockade can be significantly prolonged  Dibucaine inhibits normal butyrylcholinesterase to a far greater extent than it does the abnormal enzyme.
    57. 57. Contd… • Under standardized test conditions Dibucaine inhibits  The normal enzyme about 80%  The abnormal enzyme about 20%  Many other genetic variants of butyrylcholinesterase have been identified, dibucaine-resistant variants are the most important
    58. 58. DIBUCAINE NUMBER Measure of the ability of the person to metabolise Sch, identify at risk patients. Doesnot measure the concentration of enzyme in plasma Efficiency of enzyme to hydrolyse the substrate.
    59. 59. THERAPUETIC USES  Adjuvant to General anaesthesia-Rapid-sequence induction of anaesthesia- (DOC)1.0 mg/kg succinylcholine facilitate ETintubation at 60 seconds  Assisted ventilation  To prevent trauma during ECT
    60. 60. Before administering the intubating dose of succinylcholine A small dose of nondepolarizing neuromuscular blocker is commonly given 2 mins. This defasciculating dose of  attenuate increases in intragastric and intracranial pressure  minimize the incidence of fasciculations in response to succinylcholine.
    61. 61. DRUG INTERACTION  Antichloniesterase -Neostigmine / Pyridostigmine. Sch should not be administered to re establish neuromuscular blockade - produces relaxation that will last up to 60 minutes with administration of neostigmine (5 mg). Such prolongation can partly be explained by inhibition of butyrylcholinesterase • .
    62. 62.  Combination of Lithium and succinylcholine resulted in an additive inhibition.  Verapamil potentiates the neuromuscular block.  Bambuterol, produces marked causes prolongation of Sch induced blockage.  Esmolol causes only minor prolongation of blockage
    63. 63. ADVERSE REACTIONS  Hyperkalemia  Arrhythmias  Malignant hyperthermia  Master muscle rigidity  Increased IOP, ICP  Increased IGP  Myalgia- lysine acetylsalicylate  Succinylcholine apnoea  FDA BLACK BOX WARNING IN YOUNG MALES [Rosenberg Anesthesiology 77: 1054, 1992]
    64. 64. Succinylcholine apnoea Occasionally succinylcholine produces prolonged apnoea due to lack of normal plasma (pseudo) cholinesterase levels. Treatment:  Artificial respiration until the muscle power returns.  Fresh blood or plasma transfusion to restore cholinesterase enzyme level.  No specific antidote is available
    65. 65. MALIGNANT HYPERTHERMIA  Rare life-threatening condition  Autosomal dominant disorder  Volatile anaesthetic agents and succinylcholine  Major defects in RYR1, DHPR, CACNA1S triadin and FK 506 C/F :sustained muscle contraction and hyperpyrexia
    66. 66. MANAGEMENT  Dantrolene 2mg/kg I.V.  Procainamide - ventricular fibrillation  Rapid cooling  Inhalation of 100% oxygen  Control of acidosis should be considered adjunct therapy in malignant hyperthermia
    67. 67. DECAMETHONIUM 2 quaternary ammoniums with a 10-carbon chain in between, • It's about 2x as potent as succinylcholine • Derived from decamethylenediamine, • Partial agonist of the nicotinic acetylcholine receptor.
    68. 68. contd… • Persistant depolarisation • Character of muscle responseto indirect tetanic stimulation during partial block -Well-sustained contraction Does not produce unconsciousness or anesthesia, and its effects may cause considerable psychological distress while simultaneously making it impossible for a patient to communicate
    70. 70. SPASTICITY • It is a motor neuron disorder characterized by skeletal muscle rigidity, exaggerated tendon jerks and paralysis of affected muscles. Causes • Cerebral palsy • Stroke • Multiple sclerosis • Traumatic brain injury • Anoxia • Neurodegenerative disease
    71. 71. DANTROLENE  A hydantoin derivative  Planar  Phenol ring, which is rotated approximately 30° out of the plane of the furane ring.  Highly lipophilic
    72. 72. Contd.. • Phenytoin analouge • Antispastic action lie outside CNS • The L-type channel with its T-tubular location serves as the voltage sensor receiving the depolarizing activation signal. • Inhibits Ca2+ release from the sarcoplasmic reticulum of skeletal muscle by limiting the capacity of Ca2+ and calmodulin to activate RYR-1
    73. 73. PHARMACOKINETICS  Poorly absorbed orally  Penetrates brain and produces sedation  Metabolized in liver into 5-hydroxydantrolene  Excreted in kidney.  T 1/2 9 -12 hrs.  Dose: 25-100 mg 4 times daily
    74. 74. THERAPEUTIC USES  UMN disorders – paraplegia, hemiplegia, cerebral palsy  DOC: Malignant hyperthermia (2.5 – 4 mg/kg) • Prophylactic dantrolene administration before trigger-free GA for MH-susceptible patients has been recommended  Neuroleptic malignant syndrome: 1 – 2.5 mg/kg  Heat stroke.
    75. 75. ADVERSE EFFECTS • Sedation- facilitated GABA – depression of brain stem • Malaise • Light headedness • Muscular weakness • Diarrhea • Hepatitis • Neonates are at risk of ‘floppy child syndrome’ –C/s
    76. 76. Drug Interactions  Diltiazem/ Verapamil Severe cardiovascular collapse, arrhythmias, myocardial depressions, and hyperkalemia.  Vecuronium : Neuromuscular blockade is prolonged.  CNS depressants: Sedative action is potentiated.  Combined OCPS and HRT may enhance liver toxicity.
    77. 77. NEWER AGENT-Azumolene • Analogue of dantrolene . • 30-fold more watersoluble • The para-nitrophenole group of dantrolene sodium is replaced by a para-bromo-phenyl group.
    78. 78. • Equipotent to dantrolene in the treatment and prevention of the clinical manifestations of an MH crisis Same potency as Dantrolene in • Inducing relaxation in porcine skeletal muscle in vitro. • In vivo, even more potent in inhibiting gastronemius muscle twitches
    79. 79. QUININE Dual action in skeletal muscle:  Acts directly on the muscle fibre increases the tension response  Increases the refractory period  Decreases the excitability of the motor end-plate  Makes the muscle less susceptible to repetitive neural stimuli  Less Responsive To Acetylcholine
    80. 80. • The typical adult dosing for nocturnal leg cramps is 260 mg at bedtime. Adverse events: • Thrombocytopenia • Hypersensitivity reactions • QT prolongation • FDA Warns of Risks with Unapproved Use of Malaria Drug Qualaquin