nondepolarizing muscle relaxants1
TRANSCRIPT
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Nondepolarizing muscle relaxants
Dr. S. Parthasarathy MD., DA., DNB, MD (Acu), Dip. Diab. DCA, Dip.
Software statistics- PhD ( physiology), IDRA
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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
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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
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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
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• 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
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Bennet – neuro psychiatrist
• Convulsions and fracture
• Used curare
• 1940
• Griffith pioneered intubation
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African malouetia schomburgki plant
• Malouetine
• Compound behind many steroidal muscle relaxants like pancuronium vecuronium
• 1960 – 80s
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Mechanism
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D tubocurarine – carried in bamboo tubes earlier
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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
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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 )
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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
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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.
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How to classify ?
What are the newer ones ??
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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
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This is another !
• Amino steroids (azasteroids)• vecuronium, rocuronium, pipecuronium,
pancuronium , doxacurium • Benzylisoquinolines • Mivacurium , atracurium, cisatracurium
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Isoquinoline , benzyl iso, steroid and aza steroid
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Put 2 Ach in a steroid
Acetyl choline
Steroid
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A
D
Demethylation and no tachycardia
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Certain terms
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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
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• Atracurium and cisatracurium are bis quaternary
benzyl isoquinoline diesters- intermediate duration
non depolarizers
Atracurium
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• 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
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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
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• 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
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• Kidney and liver problems – ok
• But asthmatics ??
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Cis atracurium
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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
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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
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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
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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.
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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
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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
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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
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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
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Gantacurium
• NO cvs side effects • NO bronchospasm • External cysteine administration can reverse
blockade of gantacurium • No laudanosine • Rapid spontaneous recovery in 30 -45 minutes
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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
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05/03/2023 39Dr.SPS
Both depolarizers and NDPs don’t cross placenta
But NDPS IN LARGE DOSES..
intubate with scoline !!
Prefer atracurium
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Summary
• History • DTC • Gallamine • Atracurium and cisatracurium • Vecuronium and rocuronium• Gantacurium
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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
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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
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Thank you