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Nondepolarizing muscle relaxants1
- 1. Nondepolarizing muscle relaxants Dr. S. Parthasarathy MD., DA., DNB, MD (Acu), Dip. Diab. DCA, Dip. Software statistics- PhD ( physiology), IDRA
- 2. History • South american hunt game – arrow poisons • De Orbe Novo,a collection of letters written in 1516 – concept of flying death • In 1594, Sir Walter Raleigh visited Venezuela, and this book – his assistant named – ourari • uria, meaning bird and eor to kill
- 3. 1805 • Charles • Demonstration • Three arrows to three asses • 1- shoulder – died • 2- tourniquet and limb – alive but died after tourniquet release 3. give -- but inflate the lungs with bellows – alive
- 4. Claude bernard 1840 and 1850 • Give – animal dies • But if we apply on the muscle , it does not get paralysed – concept of NMJ • Richard gill was a multiple sclerosis patient • His neurologist told him to get plants from SA to treat • He got them – chondrodendron tomentosum and stryhnus group squib and sons derived curare from chondrodendron
- 5. • Holiday devised his rabbit ‘head-drop’ bioassay and standardized the commercial preparation of curare as Intocostrin • Earlier • it was tree test of monkeys !! • Fell down immediate – block intense • Climbs one tree and fell down • Climbs two tress and fell down
- 6. Bennet – neuro psychiatrist • Convulsions and fracture • Used curare • 1940 • Griffith pioneered intubation
- 7. African malouetia schomburgki plant • Malouetine • Compound behind many steroidal muscle relaxants like pancuronium vecuronium • 1960 – 80s
- 8. Mechanism
- 9. D tubocurarine – carried in bamboo tubes earlier
- 10. The order • Ptosis • Diplopia • Facial muscles • Jaw • Neck • Limbs • Abdomen and then the last diaphragm • Relaxation of the small muscles of the middle ear improves acuity of hearing Reverse is recovery
- 11. D tubocurarine • 0.5 mg/kg • 3 minutes • 40-50 minutes • Histamine release • Ganglion block and Hypotension • Crosses placenta small • Anti fibrillatory action ( concentrated in heart muscle )
- 12. Gallamine • Synthetic – may be the first – of the 1940s • Trisquarternary – • both structures (BI or Steroid) are not there • Vagolysis • Crosses placenta ( lipid soluble ) • Renal problem – cant be used • 1 – mg / kg ? • 20 mg/ ml - 2 ml ampoules
- 13. Gallamine thrown out ?? • The only recent use of gallamine in the UK has been as a small pretreatment dose (10 mg) prior to succinylcholine, when it seems to be more efficacious than any other non-depolarizing muscle relaxant in minimizing muscle pains.
- 14. How to classify ? What are the newer ones ??
- 15. This is one classification • The approximate duration of neuromuscular blockade provided by a single dose of these drugs may be • short (<20 minutes), Mivacurium • intermediate (45-60 minutes), • Atracurium, vecuronium, rocuronium, cisatracurium • long (>1 hour). • doxacurium , pipecuronium, pancuronium Ultra short – gantacurium
- 16. This is another ! • Amino steroids (azasteroids) • vecuronium, rocuronium, pipecuronium, pancuronium , doxacurium • Benzylisoquinolines • Mivacurium , atracurium, cisatracurium
- 17. Isoquinoline , benzyl iso, steroid and aza steroid
- 18. Put 2 Ach in a steroid Acetyl choline Steroid
- 19. A D Demethylation and no tachycardia
- 20. Certain terms
- 21. Mivacurium • Short acting BI NDP. • 0.2 mg/kg- 0.25 mg/kg • 2 minutes – onset • 20 minutes – duration • Infusion - The average dose required to maintain approximately 90-95% block is 6-8ug/kg/min • Plasma cholinesterase( k variant – danger ) • But can be reversed – edrophonium ( less inhibition of plasma cholinesterase) • Histamine release significant with high doses Miva Neo Miva No one knows
- 22. • Atracurium and cisatracurium are bis quaternary benzyl isoquinoline diesters- intermediate duration non depolarizers Atracurium
- 23. • 0.5 mg / kg • 0.6 mg/ kg /hour infusion • 0.3 mg/ kg if we have intubated with scoline • Onset – 3 minutes • Duration 45 minutes • At physiological pH and temperature, atracurium is eliminated by spontaneous degradation through Hoffmann elimination and ester hydrolysis
- 24. Metabolism • Hofmann degradation of atracurium produces the tertiary compound laudanosine, which in animal studies is known to produce epileptiform fits. • Ester hydrolysis of atracurium produces a monoquaternary alcohol, which also undergoes Hofmann degradation to laudanosine. Thus, two molecules of laudanosine are produced from the breakdown of each molecule of atracurium. • Laudanosine is more lipid soluble than atracurium; it is metabolized in the liver, and also excreted unchanged in the urine • In long term infusions – clinical significance in humans
- 25. • Hoffman elimination • NH4 + = NH3 + R=R • Physiological means – alkaline pH and normal temperature • But we can boil – non physiological hoffman • 45 % with atracurium – may be more with cisatracurium
- 26. • Kidney and liver problems – ok • But asthmatics ??
- 27. Cis atracurium
- 28. Cis atracurium • One of the ten isomers of atracurium • More potent – 0.15 mg /kg • Slightly slower onset – 3 minutes • Duration 60 minutes • More and almost complete elimination with hoffmann • Less histamine release • Renal failure – less preferred than atracurium • Less laudonosine
- 29. Pancuronium Bromide • This bisquaternary amine, the first steroid muscle relaxant used clinically, was marketed in 1964. • The intubating dose is 0.1 mg/ kg, which takes 3–4 min to reach its maximum effect • 60 minutes are more • Hypertension , tachycardia • Much renal excretion
- 31. Vecuronium • Modified pavulon • Steroidal intermediate NDP • 0.1 mg/kg • 3 minutes • 30 minutes • No histamine release ,CVS stability • Converted to desacetyl vec. --Long time infusions – cumulative== Liver problems - ?? Use Susceptible for hydrolysis Supplied as powder
- 32. Rocuronium • Rocuronium, a low-potency drug was developed as a relaxant with a fast onset of effect in an attempt to develop a non depolarizing agent that would have an onset of action closer to that of succinylcholine. • Rocuronium is a desacetoxy analog of vecuronium is stable in solution and formulated as an aqueous ready to use solution.
- 33. Pharmacokinetics • 0.6 mg/ kg – intubating conditions in 90 seconds (( 1 mg/ kg – scoline like ) more potent than vecuronium • Molecular weight same . Large amount of molecules may reach to hasten onset • 30 minutes – duration • 0.45 mg / kg spontaneous recovery in one hour • RSI
- 34. Rocuronium • more than half of an administered dose of rocuronium is taken up by the liver and excreted unchanged in the bile, about a third of the dose is eliminated in the urine • Cardiovascular stability • Old age , liver and kidney - ?? • Suggamadex
- 35. Others • Rapacuronium – fast action but bronchospasm – withdrawn • Doxocurium – slow onset of 13 minutes doubling the dose also shortens to a maximum of 3.5 minutes – withdrawn • Pipecuronium – slow onset – not much advantages – slowly loosing interest
- 36. Gantacurium • Ultra short acting – isoquinoline • 0.6 mg/ kg ( 3 ED 95) • 1 minute • 8 minutes • Histamine release –3 - 4 - ED 95 ---not much with ganta • in vivo pharmacological activity likely undergoes rapid "chemo-inactivation" via cysteine adduct formation followed by slow biodegradation via ester hydrolysis. Halogenated fumarate era
- 37. Gantacurium • NO cvs side effects • NO bronchospasm • External cysteine administration can reverse blockade of gantacurium • No laudanosine • Rapid spontaneous recovery in 30 -45 minutes
- 38. Structure activity pearls • Lipophilicity and less potency • Shorter inter onium distance – increased ganglion block • Bisquaternary compounds are more potent than their monoquaternary analogs • Increased number of methoxy groups – more potent and less histamine release • Benzyl isoquinolines – more histamine release • Pachy curares (heavy)and lepto curares • SAR or CAR
- 39. 12/20/2016 Dr.SPS 39 Both depolarizers and NDPs don’t cross placenta But NDPS IN LARGE DOSES.. intubate with scoline !! Prefer atracurium
- 40. Summary • History • DTC • Gallamine • Atracurium and cisatracurium • Vecuronium and rocuronium • Gantacurium
- 41. How to write when asked ?? • Type of structure • Duration • Onset • Advantages • CVS stability and histamine release • Vagolysis • Metabolism is outside - not in NMJ • Mode of elimination
- 42. Message • If the patient moves during surgery , give relaxants • Good for you and the surgeon • But for the patient, it is bad – add either narcotic or agent
- 43. Thank you