Skeletal muscle relaxants (2011) - drdhriti

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A power point presentation on "Skeletal Muscle Relaxants" suitable for UG MBBS level students

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  • Sketch of the sodium channel. The bars v and t represent parts of the molecule that act as gates. Gate v is voltage-dependent, and gate t is time-dependent. (a) Resting state: v is closed while t is open. (b) Active state: v opens when the surrounding membrane is depolarized to allow ion flow; t closes soon afterwards to inactivate the channel. (c) Inactive state: v remains open while t is closed. This state is maintained as long as the surrounding membrane is depolarized. The channel reverts to the resting state (a) when the membrane repolarizes. (B) Several states of nicotinic acetylcholine receptors. Upper (left to right): resting; resting with agonist bound to recognition sites but channel not yet opened; and active with open channel allowing ion flow. Lower (left to right): desensitized without agonist; desensitized with agonist bound to recognition site. Both are non-conducting. All conformations are in dynamic equilibrium. (Reproduced, with permission of Elsevier, from Standaert FG. Neuromuscular physiology and pharmacology. In: Miller RD (ed) Anesthesia, 4th edn. New York: Churchill Livingstone, 1994; 731–54).
  • Skeletal muscle relaxants (2011) - drdhriti

    1. 1. SSKKEELLEETTAALL MMUUSSCCLLEE RREELLAAXXAANNTTSS DDrr.. DD.. KK.. BBrraahhmmaa DDeeppaarrttmmeenntt ooff PPhhaarrmmaaccoollooggyy NNEEIIGGRRIIHHMMSS,, SShhiilllloonngg
    2. 2. Skeletal Muscle Functions From Muscle twitch to sustained contraction Muscle twitching refers to small, local, involuntary muscle contractions (twitching) that may appear like a shiver under the skin
    3. 3. Go Back - Cholinergic Transmission – Acetylcholine! Acetylcholine (Ach) is major neurohumoral transmitter at autonomic, somatic and central nervous system: 1. All preganglionic sites (Both Parasympathetic and sympathetic) 2. All Postganglionic Parasympathetic sites and sympathetic to sweat gland and some blood vessels 3. Skeletal muscles 4. CNS: Cortex Basal ganglia, spinal chord and others Parasympathetic Stimulation – Acetylcholine (Ach) release at neuroeffector junction - biological effects Sympathetic stimulation – Noradrenaline (NA) at neuroeffector junction - biological effects Now, SKELETAL MUSCLES – WHERE ?
    4. 4. AT Neuromuscular (NM) Junction NN type Receptors
    5. 5. Ultimately - The Skeletal Muscle Contraction The complex actin-myosin interaction to cause contraction (Sliding filament theory)
    6. 6. The Ach Receptor (Intrinsic Ion Channel) Depolarization 5 subunits Normally ACh binds in alpha subunits(-ve charged) groups in receptors with its cationic head
    7. 7. Skeletal Muscle Relaxation, why clinically ??? In conjunction with GA:  Facilitate intubation of the trachea  Facilitate mechanical ventilation  Optimized surgical working conditions
    8. 8. Why Skeletal Muscle Relaxation – contd. In Muscle spasm:  It is defined as a sudden involuntary contraction of one or more muscle groups and is usually an acute condition associated with muscle strain (partial tear of a muscle) or sprain • Musculoskeletal Injury • Low Back pain or neck pain • Sports Injury • Fibromyalgia, tension headaches  Involve afferent nociceptive input from damaged area  Excitation of alpha motor outflow  Tonic contraction of affected muscle  Build up of pain-mediating metabolites
    9. 9. Why Skeletal Muscle Relaxation – contd. In Spasticity:  Spastic neurological conditions (Spasticity): It is a motorneurone disorder characterized by skeletal muscle rigidity, exaggerated tendon jerks and paralysis of affected muscles  Associated with Motor neuron conditions • Cerebral palsy, Stroke, Multiple sclerosis, Traumatic brain injury, Anoxia and Neurodegenerative disease • In many patients with these conditions, spasticity can be disabling and painful with a marked effect on functional ability and quality of life
    10. 10. Spastic disorders Danger: Chronic muscle spasm ccaann rreessuulltt iinn mmuussccllee aattrroopphhyy iinn tthhee ssppeecciiffiicc mmuussccllee oorr mmuussccllee ggrroouupp
    11. 11. What are SMRs ???  Definition: SSkkeelleettaall MMuussccllee RReellaaxxaannttss aarree tthhee ddrruuggss tthhaatt aacctt 11.. ppeerriipphheerraallllyy aatt nneeuurroommuussccuullaarr jjuunnccttiioonn oorr mmuussccllee ffiibbeerr iittsseellff 11.. oorr,, cceennttrraallllyy iinn cceerreebbrroossppiinnaall aaxxiiss ttoo rreedduuccee mmuussccllee ttoonnee aanndd //ccaauussee mmuussccllee ppaarraallyyssiiss
    12. 12. 1. Centrally acting 2. Neuromuscular Junction 3. Directly on muscle
    13. 13. Classification: Peripherally acting SMRs A. Neuromuscular Blockers:  Nondepolarizing (Competitive) blockers:  Long acting: d-Tubocurarine, Pancuronium, Doxacurium, Pipecuronium, Gallamine and Metocurine  Intermediate acting: Vecuronium, Atracurium, Cisatracurium, Rocuronium, Rapacuronium  Short acting: Mivacurium  Depolarizing blockers: Succinylcholine (suxamethonium), Decamethonium B. Directly acting:Dantrolene and quinine
    14. 14. History: From Fun hunting in Jungles to Operation theatre  Curare: The arrow poison  Source: Chondrodendrone tomentosum and Strychnos toxifera  Derived from: "ourare“ meaning arrow poison in South American Indian  Tubocurarine name: Because of packing in “hollow bamboo tubes”
    15. 15. What is Competitive - Nondepolarizing Block in Muscles then?  They have affinity but no IA for NM receptors (Antagonist)  They have N+ atoms and get attracted to the ACh receptor site – but cannot bring conformational change like Ach  No EPP generation in nerve endings  However, can only act on closed channels – no action on already opened channels  But after sometime EPP falls to critical value – no propagation of AP and thus no contraction  Action can be overcome by increased Ach or clinically done by Neostigmine  They also block prejunctional Ach receptors on motor nerve endings – FADE PHENOMENON  Twitches turn to depressed on repetitive stimulation
    16. 16. Mechanism of action of non-depolarizing neuromuscular blockers Na Ca K ACh ACh Normal transmission 1- resting 2- active Non depolarizing neuromuscular Low doses: blockade • competitive antagonist of Ach • Action reversed by Ach esterase inhibitors Large doses: • Ion channel is blocked • More weakness of neuromuscular transmission • Action could not be reversed by Ach esterase inhibitors Other actions: Can block pre-junctional sodium channels and interfere with mobilization of Ach at nerve endings
    17. 17. Nondepolarizing Block in Muscles
    18. 18. Non-depolarizing - clinically  Intravenous administration of tubocurarine, 0.1–0.4 mg/kg, will initially cause motor weakness, followed by the skeletal muscles becoming totally flaccid and unexcitable to electrical stimulation  Larger muscles (eg, abdominal, trunk, paraspinous, diaphragm) are more resistant to blockade and recover more rapidly than smaller muscles (e.g. facial, foot, hand)  Diaphragm is usually the last muscle to be paralyzed  Assuming that ventilation is adequately maintained, no adverse effects occur  When administration of muscle relaxants is discontinued, recovery of muscles usually occurs in reverse order
    19. 19. Depolarizing Block – Succinylcholine  Affinity and sub-maximal intrinsic activity for NM receptors  Depolarize the muscle end plate by opening Na+ channel (like Ach)  Initially, twitching and fasciculation occur – partial IA (transient depolarization) and repetitive excitation (chest and abdomen)  But, unlike Ach do not dissociate rapidly from end plate region (resistant to AChE) – only to liver and plasma ChE  Induce prolonged partial depolarization around MEP  Transmembrane potential drops below -50mV - cause Na+ channel inactivation  No action of Ach to produce MAP – Flaccid paralysis
    20. 20. Succinylcholine – contd.  Classically 2 (two) phases can be describe - Phase I block and Phase II block  Phase I block: Rapid onset, results from persistent depolarization of muscle end plate  Phase II block: Slow onset  In spite of presence of depolarizing agent, muscles repolarize again as physiological phenomenon (priming) – activation of sodium–potassium ATPase pump by initial depolarization  But cannot generate fresh depolarization  probably due to desensitization of Ach receptors or  Reduced synthesis and mobilization of ACh  Resembles antagonist like action on muscles – like tubocurarine (non-depolarizing block)  Can partially reversed by AChE  Phase II in man - with fluorinated anaesthetics and with SCh
    21. 21. What Anesthetists do ?  Assessment of neuromuscular block by stimulation of the ulnar nerve  Important for Induction, recovery (reversal drug amount) from anaethesia and also in ICU patients  Monitored from compound action potentials or muscle tension developed in the adductor pollicis (thumb) muscle  Protocols - “train of four” and the “double burst”  Train of four (TOF) – four supramaximal electrical stimuli are applied at 2Hz and strength of contractions are recorded  TOF ratio is 1 at recovery  Non-depolarizing agents show – fading phenomenon  Depolarizing agents in phase I shows no fading and TOF is 1, but in phase II shows fading phenomenon
    22. 22. Train-of-four Monitoring
    23. 23. Other Actions of NM blockers  Autonomic ganglia:  Partial blockade of ganglia (NN type of receptor)  Results in fall in BP and tachycardia  Histamine release:  Hypotension  Bronchospasm, excess bronchial and salivary secretion  CVS: Fall in BP due to  Ganglion blockade, histamine release and reduced venous return  Heart increased – vagal ganglion blockade (All newer NDP agents have negligible effects on BP and Heart rate)  Succinylcholine may cause cardiac arrhythmias  GIT: Paralytic ileus
    24. 24. PPhhaarrmmaaccookkiinneettiicc ooff NNMM bblloocckkeerrss  Polar quaternary compounds - Not absorbed orally, do not cross cell membranes, low Vd and do not cross BBB or placental barrier – always given IV or rarely IM  Muscles with high blood flow affected earlier  Redistribution to non-muscular tissues occur and action may persist longer than half life  Drugs metabolized in plasma/liver – short half-life (Vecuronium, atracuronium, rocuronium etc.) – 20-40 min.  Drugs excreted in urine – longer half-life (dTC and pancuronium) – 60-120 min.  Succinylcholine succinylmonocholine succinic acid + choline (plasma cholinesterase): 3-5 min.  In some – genetically determined abnormality and deficient pseudocholinesterase paralysis & apnoea
    25. 25. Individual compounds - Succinylcholine Advantages: • Most commonly used SMR for ET intubation • Good intubation conditions – relax jaw, separated vocal chords with immobility, no diaphargmatic movements • Quick onset of action (1 – 2 min) • Used as continuous infusion occasionally Disadvantages:  Cardiovascular: unpredictable BP, HR and arrhythmias  Fasciculation  Muscle pain  Increased intraocular pressure  Increased intragastric pressure  Increased intracranial pressure  Hyperkalemia: K+ efflux from muscles, life threatening in CHF, patient with diuretics etc.  Not indicated below 8 years of age  Malignant hyperthermia
    26. 26. What is Malignant hyperthermia  Rare genetically determined reaction to susceptible persons having abnormal RyR receptor Ca+ channel  Caused by Halothane and manifests as high temperature due to persistent muscle contraction – increased intracellular Ca+  Succinylcholine accentuates this condition  Treatment:  Rapid external cooling – ice pack  Bicarbonate infusion  100% oxygen inhalation  Injection of dantrolene: Direct acting muscle relaxant
    27. 27. What is succinylcholine apnoea?  A condition where muscles paralyzed for an increased length of time and cannot breath adequately at the end of an anaesthetic  Can be – inherited or spontaneous in a person with no family history  In inherited – reduced level of plasma cholinesterase  In acquired – normal level but reduced enzyme activity (Pregnancy, Hypothyroidism, Liver disease, Renal disease , Carcinomatosis)  Management:  Anaesthetize the patient and ventilate  Monitor the NM transmission (TOF)  patient should remain ventilated and anaesthetized until breathing spontaneously  Family members should be tested by blood test and tagged if positive
    28. 28. Individual Compounds – contd. PPaannccuurroonniiuumm::  Steroidal compound 5 times more potent than dTC  No cardiac or respiratory toxicity (little ganglion blockade)  Low histamine release – no bronchospasm or flushing  Long duration of action – reversal required  Preferred only in long surgeries VVeeccuurroonniiuumm::  Congener of Pancuronium  Slow onset but prolonged action  CVS stability – no histamine release  Spontaneous and Quick recovery  Mostly commonly used
    29. 29. Individual Compounds – contd.  Atracurium:  Competitive blocker and less potent than pancuronium  Reversal not required  Non-enzymatic spontaneous degradation in addition to cholinesterase  Preferred in elderly and neonates  Rocuronium: Non-depolarizing agent  Rapid and immediate action  Alternative to SCh for tracheal intubation  Also acts as maintenance relaxant and no reversal required  Rapid intubation condition 60 – 90 seconds  Also used in ICU for mechanical ventilation
    30. 30. m Neuro-muussccuullaarr bblloocckkeerrss -- IInntteerraaccttiioonnss 1. Thiopentone Sodium – same syringe 2. General anaesthetics – potentiate blockers 3. Anticholinesterases – Neostigmine 4. Antibiotics – Aminoglycosides 5. Calcium Channel blockers: potentiate blockers (Verapamil) – both competitive and non-competitive 6. Diuretics – hypokalemia: enhances competitive block
    31. 31. NNeeuurroo mmuussccuullaarr bblloocckkeerrss -- uusseess 1. Adjuvant to General anaesthesia 2. Assisted ventilation 3. Convulsion and trauma from electroconvulsive therapy 4. Status epilepticus Vocal cord
    32. 32. Directly acting relaxants - Dantrolene • Different from neuromuscular bblloocckkeerrss,, nnoo aaccttiioonn oonn NNMM ttrraannssmmiissssiioonn • MMOOAA –– RRyyaannooddiinnee rreecceeppttoorrss ((RRyyRR)) ccaallcciiuumm cchhaannnneellss –– pprreevveennttss ddeeppoollaarriizzaattiioonn –– nnoo iinnttrraacceelllluullaarr rreelleeaassee ooff CCaa++++ • AAbbssoorrbbeedd oorraallllyy,, ppeenneettrraatteess bbrraaiinn aanndd pprroodduucceess sseeddaattiioonn,, mmeettaabboolliizzeedd iinn lliivveerr,, eexxccrreetteedd iinn kkiiddnneeyy.. TT11//2 88-112 hhrrss.. • DDoossee:: 255-110000 mmgg 4 ttiimmeess ddaaiillyy • UUsseess:: UUMMNN ddiissoorrddeerrss –– ppaarraapplleeggiiaa,, hheemmiipplleeggiiaa,, cceerreebbrraall ppaallssyy aanndd mmaalliiggnnaanntt hhyyppeerrtthheerrmmiiaa ((ddrruugg ooff cchhooiiccee 2..55 –– 4 mmgg//kkgg)))) • AAddvveerrssee eeffffeeccttss –– SSeeddaattiioonn,, mmaallaaiissee,, lliigghhtt hheeaaddeeddnneessss,, mmuussccuullaarr wweeaakknneessss,, ddiiaarrrrhhooeeaa aanndd hheeppaattoottooxxiicciittyy
    33. 33. CCeennttrraallllyy aaccttiinngg MMuussccllee rreellaaxxaannttss CCllaassssiiffiiccaattiioonn:: 1. Mephenesin congeners – Mephenesin, Carisoprodol, Chlorzoxazone, Methocarbamol and Chlormezanone 2. Benzodiazepines – Diazepam, lorazepam, Clonazepam and others 3. GABA derivative – Baclofen 4. Central α-2 agonist - Tizanidine
    34. 34. CCeennttrraallllyy aaccttiinngg MMuussccllee rreellaaxxaannttss  Drugs that reduce skeletal muscle tone by selective action on cerebrospinal axis  Depress the spinal and supraspinal reflexes of muscle tone  Also depresses polysynaptic reflexes of ascending reticular formation – wakefulness disturbed (sedation)  No effect on NM junction but reduce UMN spasticity and hyperreflexia
    35. 35. CCeennttrraallllyy aaccttiinngg VVss PPeerriipphheerraallllyy aaccttiinngg  CCeennttrraallllyy aaccttiinngg  Decrease muscle tone but no reduction in power  Polysynaptic reflexes in CNS  CNS depression  Orally and parenterally  Spastic conditions, muscle spasm  PPeerriipphheerraallllyy aaccttiinngg  Cause muscle paralysis  Block NM transmission  No CNS effect  Given IV  Short term surgical procedures
    36. 36. CCeennttrraallllyy aaccttiinngg MMuussccllee rreellaaxxaannttss –– ccoonnttdd..  Mephenesin (Relaxyl/medicreme)  Modulation of reflexes in spinal internuncial neurone  Cannot be used systemically  Irritant rather than relaxant – topical preparations  Carisoprodol, Chlorzoxazone (Mobizox), Methocarbamol (Robinax/Robiflam) and Chlormezanone – similar but can be used orally
    37. 37. Benzodiazepines as muscle relaxant  Very potent centrally acting muscle relaxant – supraspinal  Mechanism of action is via “GABAA receptor Cl- complex” enhancement – inhibitory in nature  Diazepam and Clonazepam are the most potent ones  Diazepam is the prototype of BZDs
    38. 38. GABAA-Benzodiazepine receptor-chloride channel complex
    39. 39. BBaaccllooffeenn ((ββ--ppaarraacchhlloorroopphheennyyll GGAABBAA)) Mechanism of action: GABAB agonist - hyperpolariztion of neurones by increasing K+ conductance and alteration of Ca++ flux - Does not affect to Cl- conductance Site of action: spinal chord – depresses polysynaptic and monosynaptic reflexes Clinical effects: decreased hyperreflexia; reduced painful spasms; reduced anxiety Dose: orally 5 mg three times daily, gradually increase to 20 mg four times daily or higher  intrathecally initially 50 mcg/day increase to 300- 800 mcg/day
    40. 40. IInnddiivviidduuaall CCoommppoouunnddss -- TTiizzaanniiddiinnee  Mechanism of action: alpha-2 receptor agonist – inhibits the release of excitatory amino acids in spinal interneurones  Clinical effects: reduced tone, spasm frequency, and hyperreflexia  Doses: tizanidine initial 4 mg three times daily increase to 36 mg/day; clonidine initial 0.1 mg twice daily increase to 2.4 mg/day
    41. 41. Uses of Centrally acting relaxants 11.. AAccuuttee mmuussccllee ssppaassmmss 22.. BBaacckkaacchhee aanndd nneeuurraallggiiaass 33.. AAnnxxiieettyy aanndd tteennssiioonn 44.. SSppaassttiicc nneeuurroollooggiiccaall ddiissoorrddeerrss 55.. TTeettaannuuss 66.. EElleeccttrrooccoonnvvuullssiivvee tthheerraappyy 77.. OOrrtthhooppaaeeddiicc mmaanniippuullaattiioonnss
    42. 42. What to Remember !!  Skeletal Muscle Relaxants - Classification  Mechanism of non-depolarizing  Mechanism of Depolarizing – Phase 1 and phase 2  Succinylcholine apnoea and malignant hyperthermia  Few Drug Interactions of SMRs  Centrally acting Muscle relaxants – names
    43. 43. Thank you

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