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
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.
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
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 ??
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
30.
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
