Nondepolarizing muscle relaxants
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Transcript of Nondepolarizing muscle relaxants
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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