Nondepolarizing muscle relaxants

Dr. S. Parthasarathy MD., DA., DNB, MD (Acu), Dip. Diab. DCA, Dip.

Software statistics- PhD ( physiology), IDRA

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

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

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

• 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

Bennet – neuro psychiatrist

• Convulsions and fracture

• Used curare

• 1940

• Griffith pioneered intubation

African malouetia schomburgki plant

• Malouetine

• Compound behind many steroidal muscle relaxants like pancuronium vecuronium

• 1960 – 80s

Mechanism

D tubocurarine – carried in bamboo tubes earlier

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

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 )

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

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.

How to classify ?

What are the newer ones ??

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

This is another !

• Amino steroids (azasteroids)• vecuronium, rocuronium, pipecuronium,

pancuronium , doxacurium • Benzylisoquinolines • Mivacurium , atracurium, cisatracurium

Isoquinoline , benzyl iso, steroid and aza steroid

Put 2 Ach in a steroid

Acetyl choline

Steroid

A

D

Demethylation and no tachycardia

Certain terms

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

• Atracurium and cisatracurium are bis quaternary

benzyl isoquinoline diesters- intermediate duration

non depolarizers

Atracurium

• 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

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

• 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

• Kidney and liver problems – ok

• But asthmatics ??

Cis atracurium

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

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

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

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.

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

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

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

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

Gantacurium

• NO cvs side effects • NO bronchospasm • External cysteine administration can reverse

blockade of gantacurium • No laudanosine • Rapid spontaneous recovery in 30 -45 minutes

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

05/03/2023 39Dr.SPS

Both depolarizers and NDPs don’t cross placenta

But NDPS IN LARGE DOSES..

intubate with scoline !!

Prefer atracurium

Summary

• History • DTC • Gallamine • Atracurium and cisatracurium • Vecuronium and rocuronium• Gantacurium

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

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

Thank you