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 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

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

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 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

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

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

Halogenated fumarate era 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

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

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