Nondepolarizing Muscle Relaxants

Presenter- Dr. Suresh PradhanModerator- Prof. UC Sharma

History: From Fun Hunting in Jungle to Operation Theatre

•modern use of NMB’s drugs-1932•1st agent to undergo clinical

investigation- INTOCOSTRIN or dTC purified product obtained from plant

Chondodendrom tomentosum

•CURARE – term coined for extracts from these plants

•"curare" comes from the South American Indian name for the arrow poison, ourare

•Used to control skeletal muscle spasms in patient with tetanus

•1940s dTC administered as an adjuvant to drug-induced electroshock therapy

•1942( Griffith and Johnson) used dTC to produce surgical skeletal muscle relaxation during GA

• 1949, succinylcholine prepared by Dr. Daniel Bovet• 1956, distinction between depolarizing and NDM’s

blocked made by William D.M. Paton• 1964, pancuronium was introduced• 1979, vecuronium was introduced• 1993, mivacurium released for clinical use• 1994, rocuronium introduced to clinical practice

ClassificationMuscle Relaxants are classified as:I)Peripherally acting

A. Neuromuscular blocking agents:Depolarizing muscle relaxantsNon-depolarizing muscle relaxants

B. Directly acting: Dantrolene, Quinine

II)Centrally acting • Benzodiazipines - Diazepam• GABA -B Agonist - Baclofen• Central α2 Agonist - Tizanidine• Mephenesin Group - Methenesin, Methocarbamol,

Chlorzoxazone

Non-depolarizing Muscle relaxants

Short acting (15- 20 min) : Mivacurium

Intermediate acting (20-50min) : Atracurium Cisatracurium Vecuronium Rocuronium

Long acting ( >50min) : Doxacurium Pancuronium Pipecuronium

STRUCTURAL CLASSIFICATION broadly divided into steroidal compounds and benzylisoquinoline

compunds• Steroidal compounds

⌐ Pancuronium ⌐ Vecuronium ⌐ Pipecuronium⌐ Rocuronium⌐ Rapacuronium

• Benzylisoquinoline compounds⌐ D-tubocurare⌐ metocurine⌐ doxacurium ⌐ atracurium⌐ mivacurium ⌐ Cisatracurium

• Others⌐ gallamine⌐ alcuronium

Clinical Uses• NMB’s are co-administrated with anesthetic in the

induction phase to induce muscle paralysis• facilitate the surgery, especially intra-abdominal

and intra-thoracic surgeries• facilitate endotracheal intubation• in ICU settings- in patients requiring prolonged

ventilation especially where it is mandatory to reduce the work of breathing

Use of NDMR in Anesthesia• maintenance of anaesthesia• for intubation where succinylcholine is

contraindicated ( rocuronium is of choice)• for precurarization to prevent postoperative

myalgias by succinylcholine (dTC and rocuronium)

Mechanism of Action

• competitive antagonism at the post- synaptic ACh Receptors

• in small clinical doses they act predominantly at the nicotinic receptor site to block Ach

• at higher does they can block prejunctional Na+ channels thereby decreasing ACh release

Characteristics of NDMR Blockade• Skeletal muscle response in presence of NDMR as

evoked by PNS include:⌐ Decreased twitch response to a single stimulus⌐ Fade during continuous stimulation⌐ Post-tetanic potentiation⌐ TOF ratio <0.7⌐ Antagonism by anticholinesterase

Pharmacokinetics• highly ionised and water soluble at physiological pH• all NDMR are quarternary ammonium compounds &

highly water soluble i.e. hydrophilic• hence, they do not cross blood brain barrier & placenta

(except Gallamine)

• Most of the drugs undergo Renal and Hepatic elimination

ED95

• the effective dose of a drug in 95% of individuals

• for neuromuscular blockers, one often specifies the dose that produces 95% twitch depression in 50% of individuals

• denotes potency of a NDMR

D-Tubocurarine• 1st agent to undergo clinical investigation• purified curare – Chondodendrom tomentosum• ED95= 0.5mg/kg• undergoes minimal metabolism- is excreted

10% in urine 45% in bile

• not extensively protein bound• excretion impaired in Renal Failure

CVS Effects hypotension frequently even at doses < ED95 histamine released (skin flushing frequently) autonomic ganglionic blockade- manifests as

hypotension

Clinical Use long duration of action(60 to 120 mins) and CVS

effects restricted its use used as “precurarization”

Atracurium• Bisquaternary ammonium Benzylisoquinoline• ED95 = 0.2 to 0.25mg/kg• Intubating dose- 0.5mg/kg.• Maintenance- 0.05 to 0.1mg/kg• Drug of choice in patient with renal and hepatic

dysfunction• onset of action= 3-5min (0.5mg/kg)• duration of action= 20-35min• about 82% is bound to albumin• triggers dose-dependent histamine release that

becomes significant at doses above 0.5 mg/kg

• may also cause a transient drop in systemic vascular resistance and an increase in cardiac index

• can cause bronchospasm in susceptible individuals• duration of action can be markedly prolonged by

hypothermia and to a lesser extent by acidosis• will precipitate as a free acid if it is introduced into

an intravenous line containing an alkaline solution such as thiopental

• two separate processes for metabolism Ester Hydrolysis (2/3)-catalyzed by nonspecific esterases Hofmann Elimination (1/3)-spontaneous nonenzymatic

chemical breakdown occurs at physiological pH and temperature

• Laudanosine Toxicity⌐ a tertiary amine⌐ breakdown product of atracurium’s Hofmann

elimination⌐ has been associated with CNS excitation, resulting

in elevation of the minimum alveolar concentration and even precipitation of seizures

⌐ Laudanosine is metabolized by the liver and excreted in urine and bile

Cisatracurium• potent isomer of Atracurium• ED95= 0.05mg/kg• Intubating dose= 0.2mg/kg• Maintainence dose= 0.02mg/kg• Duration of action = 30-45 min (0.1 mg/kg)• Metabolism similar to Atracurium

• Hofmann & Ester hydrolysis• Side Effects

Devoid of histamine- releasing properties even at high doses

CLINICAL USES• Facilitate tracheal intubation at the dose 3 -4 times

ED95 (0.15 to 0.2mg/kg)• Blockade maintained at stable level by continuous

intravenous infusion (1-2 µg/kg/min)• Elimination independent on end- organ function,so

Ideal for ICU @5 µg/kg/min

Mivacurium• Benzylisoquinoline derivative• short duration of action• presented as mixture of three isomers (cis-trans,

trans-trans, and cis-cis)• pharmacology governed by trans-trans and cis-trans• ED95= 0.08 to 0.15mg/kg• Intubating dose= 0.2 or 0.25mg/kg• Onset: 2-3 mins• Duration of action: 12-20 mins

• Side Effects• Histamine release• Hypotension, tachycardia, flushing if dose >0.2mg/kg• Bronchospasm rare

• Clearance• Like succinylcholine–metabolized by

pseudocholinesterases

CLINICAL USES surgical procedure require brief relaxation not recommended for RSI small dose (0.04 to 0.08mg/kg) for LMA maintenance of relaxation by constant infusion(5 to

7µg/kg/min) for intubation and maintenance for short

procedures mainly in children

Pancuronium• Bisquaternary aminosteroid compounds• ED95 = 0.07mg/kg• Intubating dose= 0.12mg/kg• Longer duration of action = 1.5 to 2 hrs• Clearance:

• 80% of single dose eliminated unchanged in urine• 10-40%undergoes hepatic deacetylation to

• 3-desacetylpancuronium (50% as potent as Pancuronium)• 17-desacetylpancuronium• 3,17-desacetylpancuronium

CVS EFFECTS- Increased HR, BP, and CO after large doses(2 X ED95) Cause is uncertain but vagolytic effects on

postganglionic nerve terminal no histamine release

CLINICAL USE• slow onset of action limits its usefulness in

facilitating tracheal intubation• administration in divided doses-small dose given 3

min before induction( priming principle), produce small but measurable acceleration

• popular in Cardiac anesthesia (counters bradycardia effect of high dose of opioids)

• Difficult to reverse than other intermediate agents

Pipecuronium• Bisquaternary Aminosteroid compound• ED95: 50 – 60 µg/kg• Onset: 3 – 5 minutes• Duration: 60 – 90 minutes• Like Pancuronium, excretion is mainly from kidneys• Major advantage is

• hepatic cirrhosis doesn’t affect the pharmacokinetics/ dynamics of Pipecuronium

• 10 times less vagolytic than Pancuronium• no histamine release.

• More expensive than Pancuronium

Rocuronium• Monoquaternary aminosteroid• ED95 : 0.3mg/kg• Onset: 1-2 min• Duration: 20-35 min• Clearance:

Largely excreted unchanged in bile (up to 50% in 2 hours) Renal excretion >30% in 24 hrs

• CVS Effects: No histamine release even at 4XED95 (1.2mg/kg) May produce slight vagolytic effect

Useful in surgery with vagal stimulation (laparascopic,opthalmologic)

• Anaphylactic reaction has been described

Clinical Implications• Replacement for succinylcholine for rapid sequence

intubation (>1mg/kg)• Rocuronium and thiopental do not mix- form a

precipitation• Replacing vecuronium• Infusion rates range 5 -10 µg/kg/min

Vecuronium• Monoquaternary aminosteroid• ED95 = 0.04 to 0.05mg/kg• Intubating Dose= 0.12mg/kg• Onset: 3-5 mins• Duration of blockade: 20-35 mins• Clearance

• Undergo both hepatic metabolism and renal excretion• Undergo deacetylation to

• 3- desacetylvecuronium (50% potent as vecuronium)• 17-desacetylvecuronium• 3,17- desacetylvecuronium

• CVS Effects No CVS effects at clinical doses No histamine release

• Hepatic dysfunction Elimination half time at dose 0.1mg/kg IV not increased

in alcoholic liver disease Dose at 0.2mg/kg IV is associated with prolong

elimination half time and corresponding prolong duration of action in hepatic cirrhosis

• Renal dysfunction Elimination half life of vecuronium and 3- desacetyl

vecuronium prolonged with renal failure

Clinical Uses• CVS neutrality and intermediate duration suitable

agents for patient with IHD• Like rocuronium, care should taken with thiopental• At large dose 0.1-0.2mg/kg facilitate tracheal

intubation• For maintenance intermittent bolus- 0.01mg to

0.02mg/kg , continuous infusion – 1 to 2µ g/kg/min

Gallamine• Introduced in 1948• Low potency NDMR (ED95= 2mg/kg)• Longer duration of action• Produced significant tachycardia• Used to prevent succinylcholine- induced

fasciculation

Summary of Pharmacology of NDMR

Clinical characteristics of nondepolarizing muscle relaxants

Considerations in special population

Factors causing altered responses

Inhalational Agents• Inhalation agents potentiate blockade (dose related)• At similar MAC enflurane> isoflurane> halothane• Anesthetic induced depression of CNS• Decreases the sensitivity of post junctional membrane to

depolarizationLocal Anesthetics

• Enhance neuromuscular blockade• Interfere with pre-junctional release of acetylcholine• Stabilize post junctional membranes• Directly depress skeletal muscle fibers

Gender• women are more sensitive to vecuronium than men (duration

of blockade longer in women than men)• May be related to difference in body composition, volume of

distribution and plasma protein concentration• Greater muscle mass in men than women

Renal Function• Aging associated with decreasing renal function; hence

decreased clearance of the drug from the body

Hepatic Clearance• Pancuronium and vecuroniun metabolized significant

degree by liver• hence prolonged duration of Neuromuscular Blockade

(exception atracurium, cisatracurium, and mivacurium)

Magnesium• Interfere with the Calcium channels in the Pre- Synaptic

membrane and cause decreased release of Acetylcholine

• In pre-eclamptic patient always suspect longer duration of blockade

Antibiotics- Aminoglycosides• Enhance blockade• Neomycin and Streptomycin most potent• Mechanism for potentiation of Blockade is similar to that

of Magnesium

Other Drugs• Patients treated chronically with Anticonvulsants

(phenytoin, carbamazepine) • relatively resistant to Pancuronium, Vecuronium,

Rocuronium, Cisatracurium, Doxacurium• But NOT to Mivacurium, Atracurium

• Acute administration of phenytoin has been associated with augmentation of blockade by Rocuronium

Hypothermia• Slowing of hepatic enzyme activity or metabolism• Decreased clearance of the drug and hence

prolonged duration of the blockade

Burn Injury• May cause resistance to effects of non-depolarizing

blockade• manifest 10 days after injury peaks at about 40 days –

declines after about 60 days• Approximately >30% of body must be burnt to produce

resistance• Altered affinity of nicotinic receptors for non-depolarizing

muscle relaxants may be the basis for resistance

Serum K+

• Acute hypokalemia- increases transmembrane potential, causing hyperpolarization of cell membrane

• Increase sensitivity to non-depolarizing blockers• Resistance to depolarizing neuromuscular blockers

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