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 Reverse is recovery 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. 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
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. Susceptible for hydrolysis
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. Halogenated fumarate era
Gantacurium
Ultra short acting – isoquinoline
0.6 mg/ kg ( 3 ED 95)
1 minute
8 minutes
Histamine release – ED 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 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. Both depolarizers and NDPs don’t cross placenta
Prefer atracurium
Both depolarizers and NDPs don’t cross placenta
But NDPS IN LARGE DOSES..
intubate with scoline !!
4/7/2019
Dr.SPS

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