3. In 1912
• The first successful administration of a
neuromuscular blocker (curare) to produce
surgical relaxation in an anesthetized patient
occurred, when Arthur Läwen, a German surgeon
from Leipzig, used a partially purified preparation
of the substance.
• Curare - The South American Indians’ arrow
poisons
4. Classification
Neuromuscular blockers that are currently
available for clinical use are classified as
– (a) nondepolarizing neuromuscular blockers
– (b) depolarizing neuromuscular blockers
5. Depolarizing neuromuscular blockers
• Act as agonists (i.e., they are similar in structure to
acetylcholine) at postsynaptic nicotinic Ach receptors
and cause prolonged membrane depolarization
resulting in NM blockade.
• Produce prolonged depolarization of the endplate
region that results in desensitization of nicotinic Ach
receptors;
• Inactivation of voltage-gated sodium channels at the
NM junction; and
• Increases in potassium permeability in the surrounding
membrane.
The end result is failure of action potential generation
due to membrane hyperpolarization, and block ensues.
6. Nondepolarizing neuromuscular blockers
• Compete with acetylcholine for the active binding
sites at the postsynaptic nicotinic acetylcholine
receptor
• Also called competitive antagonists
• Two acetylcholine molecules to the a subunit initiates
conformational changes that open the channel.
• A single molecule of a nondepolarizing
neuromuscular blocker (a competitive antagonist) to
one a subunit is sufficient to produce neuromuscular
block.
7. Structure of Neuromuscular
Blocking Drugs
• All neuromuscular blockers, being quaternary
ammonium compounds, are structurally related to
acetylcholine.
• The majority of neuromuscular blocking drugs currently
available for clinical use are synthetic alkaloids.
• An exception is tubocurarine, which is extracted from
plants(Amazonian vine Chondodendron tomentosum).
9. Characteristics of Depolarizing Neuromuscular
Block
• Depolarizing block (also called phase I block) is often
preceded by muscle fasciculation.
• (a) decrease in twitch tension,
• (b) no fade during repetitive stimulation (tetanic or
TOF), and
• (c) no post tetanic potentiation
10. Pharmacology of Succinylcholine
• Succinylcholine is a long, thin, fleible molecule
composed of two molecules of acetylcholine
linked through the acetate methyl groups
11. SCh
• Elimination half-life of 47 seconds (95% confidence
interval of 24 to 70 seconds).
• First-order kinetics
• ED95 (95% suppression of twitch height) is
approximately 0.3 mg/kg.
• Tracheal intubation dose in adults is 1.0 mg/kg
• Complete suppression of response to neuromuscular
stimulation in approximately 60 seconds
• Time to recovery to 90% muscle strength following
administration of 1 mg/kg succinylcholine ranges from 9
to 13 minutes
• No advantages to using succinylcholine doses larger
than 1.5 mg/kg in a rapid sequence induction of
anesthesia
12. Phase I block
• End plate depolarization - Sch molecule attaches to one Ach
receptor, detaches & immediately attaches to another Ach
receptor. This keeps the end plate in depolarized state. The
voltage gated Na channels present in the peri junctional area
gets arrested in inactivation state d/t continuous
depolarization of junctional area.
• Desensitization - prolonged exposure of the receptor to the
agonist. Overstimulation of the receptor by agonist enhance
refractoriness while under stimulation results in increased
sensitivity
Total no. of channels available for impulse transmission is
reduced if more receptors remain desensitized. Pt. becomes
more sensitive to NDMR after Sch use.
13. Phase II Block
• After repeated dosing, infusion or single large bolus (5-7 mg/kg)
• Duration of blockade is prolonged and now it resembles
nondepolarizer blockade on neuromuscular monitoring.
– a. Repeated end plate depolarization causing ionic imbalance of
NMJ and altered membrane function.
– b. Desensitization due to continuous presence of agonist at the
site of action. Patients with atypical plasma cholinesterase may
develop phase II block even with usual doses of succinylcholine.
• Reversal with anticholinesterases is not recommended.
14. Butyryl cholinesterase (pseudo)
• Synthesized in liver & found in plasma(t1/2-8-16hrs)
• Metabolism of - succinylcholine, mivacurium, procaine,
chloroprocaine, tetracaine, cocaine, and heroin.
• Short duration of action of SCh is d/t its rapid hydrolysis by
plasma cholinesterase to succinyl monocholine & choline, so only
10% of the administered drug reaches the NMJ.
• There is little or no butyrylcholinesterase at the NMJ
• Influences the onset and duration of action of SCh by controlling
the rate at which the drug is hydrolyzed in the plasma before it
reaches, & after it leaves, the NMJ.
• Recovery from SCh-induced blockade occurs as SCh diffuses away
from the NMJ
15. Factors Affecting Butyrylcholinesterase Activity
• NM block induced by Sch or mivacurium is prolonged when there is a
significant reduction in the conc. /activity of
butyrylcholinesterase.(<75%)
• Factors lowering butyrylcholinesterase activity are
– Advanced liver disease,
– Malnutrition,
– Burns,
– MAO inhibitors
– Cytotoxic drugs, neoplastic disease,
– Anticholinesterase drugs, bambuterol
– Advanced age, pregnancy , OCP
• Th b-blocker esmolol inhibits butyrylcholinesterase but causes only a
minor prolongation of Sch block.
16.
17. Genetic Variants of
Butyrylcholinesterase
• Phenotype is determined by the use of specific enzyme
inhibitors (such as dibucaine or fluoride) that produce
phenotype-specific patterns of dibucaine or fluoride numbers.
• Dibucaine number reflects quality of cholinesterase enzyme
(ability to hydrolyze succinylcholine) and not the quantity of
the enzyme that is circulating in the plasma.
18. • Dibucaine or fluoride number indicates the
genetic makeup of an individual with respect to
butyrylcholinesterase, it does not measure the
concentration of the enzyme in the plasma nor
does it indicate the efficiency of the enzyme in
hydrolyzing succinylcholine or mivacurium.
• Some rare butyrylcholinesterase variants are
associated with increased enzyme activity (two to
three times normal). Resistance to succinylcholine
and mivacurium.
19. Side Effects of Succinylcholine
• CVS - Sinus bradycardia, junctional rhythm, & even sinus arrest.
The ganglionic stimulation reflects an effect of Sch on
autonomic ganglia that resembles the physiologic effect of
acetylcholine at these sites. Ventricular dysrhythmias.
• Hyperkalemia - approximately 0.5 mEq/dL
• Severe hyperkalemia in patients with burn, severe abdominal
infections, severe metabolic acidosis, closed head injury, d/t
upregulation of extrajunctional acetylcholine receptors.
• Myoglobinuria - paediatric patients, patients with
rhabdomyolysis & myoglobinuria may have malignant
hyperthermia or muscular dystrophy.
20. • Increased Intraocular Pressure - peaks at 2 to 4
minutes after administration and returns to normal
by 6 minutes
• Increased Intragastric Pressure –
– (a) the intensity of fasciculations of the
abdominal skeletal muscles can be prevented by
prior administration of a NMDR
– (b) a direct increase in vagal tone.
• Increased Intracranial Pressure - increase can be
attenuated or prevented by pretreatment with a
NMDR
21. • Myalgias – ACC.to theory:myalgia is secondary to
muscle damage by succinylcholine-induced
fasciculations or d/t role of prostaglandins and
cyclooxygenases in succinylcholine-induced
myalgias
• A meta-analysis showed that myalgia may be best
prevented with lidocaine, or nonsteroidal
antiinflammatory drugs
• Masseter Spasm – SCh known trigger agent for
malignant hyperthermia. Although an increase in
tone of the masseter muscle may be an early
indicator of malignant hyperthermia,
23. Characteristics of Nondepolarizing Neuromuscular
Block
• (a) decrease in twitch tension,
• (b) fade during repetitive stimulation (TOF or
tetanic), and
• (c) post tetanic potentiation
• Believed that twitch depression results from block
of postsynaptic nicotinic acetylcholine receptors,
• Where as tetanic or TOF fade results from block of
presynaptic nicotinic acetylcholine receptors.
24. • There is also strong contrary evidence indicating
that fade could be simply a postjunctional
(postsynaptic) phenomenon
• snake toxin, a-bungarotoxin—which binds
irreversibly to muscle (postjunctional) nicotinic
acetylcholine receptors but does not bind to
neuronal (prejunctional) nicotinic acetylcholine
receptors—does produce fade.
28. Tubocurarine
• Mono quarternary,
• Long-acting neuromuscular blocker
• No active metabolite
• Excreted unchanged in the urine, and the liver is
probably a secondary route of elimination
• The onset of action of tubocurarine is slow, its
duration of action is long, and its recovery is slow
• The usual intubating dose is 0.5 to 0.6 mg/kg;
maintenance doses are 0.1 to 0.2 mg/kg.
29. Atracurium
• A racemic mixture of 10 stereoisomers
• Three geometrical isomer groups that are
designated cis-cis, cis-trans, and trans-trans
based on their configuration about the
tetrahydroisoquinoline ring system.
• Atracurium has been designed to undergo
spontaneous degradation at physiologic
temperature and pH by a mechanism called
Hofmann elimination, yielding laudanosine (a
tertiary amine) and a mono quaternary acrylate
as metabolites.
• Furthermore, atracurium can undergo ester
hydrolysis
30. • Hofmann - chemical process that results in loss of
the positive charges by molecular fragmentation to
laudanosine and a monoquaternary acrylate.
• Laudanosine depends on the liver for clearance,
with approximately 70% excreted in the bile and the
remainder in urine.
• Hepatic cirrhosis in humans does not alter
clearance of laudanosine, whereas excretion of this
metabolite is impaired in patients with biliary
obstruction.
• Laudanosine easily crosses the blood–brain barrier,
and it has central nervous system stimulating
properties. The seizure threshold is not known in
humans.
Atracurium
31. Cisatracurium
• 1R cis–1’R cis isomer of atracurium
• Metabolized by Hofmann elimination - 77% of the
total clearance of 5 to 6 mL/kg per minute
• Metabolites : laudanosine and a monoquaternary
alcohol
• Cisatracurium is about four to five times as potent as
atracurium, about five times less laudanosine is
produced.
• Cisatracurium in the clinical dose range does not
cause histamine release.
32. Mivacurium
• Only currently available short-acting NDMR
• A mixture of three stereoisomer
• Metabolized by butyrylcholinesterase at about 70%
to 88% the rate of succinylcholine to a monoester, a
dicarboxylic acid
• Mivacurium may produce histamine release,
especially ifadministered rapidly
33. Pancuronium
• Long-acting neuromuscular
• Blocking drug with both vagolytic and
butyrylcholinesterase-inhibiting properties
• About 40%-60% cleared by kidney, 11% is excreted in
bile, 15% to 20% by deacetylation in the liver.
• Metabolites : 3-OH, 17-OH, and 3,7-di-OH - less
potent, excreted in urine
• Accumulation of the 3-OH metabolite - prolongation
of the duration of blocks
34. Vecuronium
• Monoquarternary, intermediate duration of action,
• Pancuronium without the quaternizing methyl group in the
2-piperidino substitution
• This molecular change in vecuronium is characterized by
– a) a slight decrease in potency;
– (b) virtual loss of the vagolytic properties of pancuronium;
– (c) molecular instability in solution - lyophilized powder
– (d) increased lipid solubility
• Liver is the principal organ of elimination , & renal excretion
- 30%
• In liver, deacetylation into three possible metabolites: 3-
OH, 17-OH, and 3,17-di-OH vecuronium
• 3-OH metabolite has 80% the neuromuscular blocking
potency
35. Rocuronium
• Intermediately acting, mono quaternary , fast onset of
action
• 6 times less potent than vecuronium
• Primarily eliminated by the liver and excreted in bile.
• 30% of rocuronium is excreted unchanged in the
urine.
36. Gantacurium – GW280430A
• Ultra short duration (less than 10 min upto 0.7
mg/kg)
• ED95 = 0.19 mg/kg
• Reversal with cysteine addcut
• No histamine release in dose <2.5 ED95
• No incidence of bronchospasm
37. Olefinic - CW002
• Investigational, intermediate duration
• Cysteine adduction and possibly chemical hydrolysis
more slowly than gantacurium
• In dogs, administration of 0.08 mg/kg
• (10 x ED95) of CW002 resulted in a duration of action
of 71+/-4 minutes
• No signs of histamine release were observed in cats
in doses up to 0.8 mg/kg (40 x ED95).
38. Potency of NM blockers
• Expressed in terms of the dose-response
relationship.
• Dose required to produce 50% or 95% depression of
twitch height, commonly expressed as ED50 and
ED95.
39. Factors that Increase the Potency
1.Inhalational anesthetics – causes decrease in required dose & prolongation of
duration of action
• Desflurane > sevoflurane > isoflurane > halothane > nitrous oxide/opioid
/propofol
• Mechanisms proposed for this potentiation:
– (a) A central effect on a motoneurons & interneuronal synapses
– (b) inhibition of postsynaptic nicotinic Ach.receptors,
– (c) Augmentation of antagonist’s affinity at the receptor site.
2.Antibiotics ( polymyxins, lincomycin and clindamycin - pre & post junc. ,while
tetracyclines exhibit postjunctional activity only)
3.MgSo4 ( high concentrations inhibit calcium channels at the presynaptic nerve
terminals that trigger the release of Ach)
4.Hypothermia
5.Local anesthetics in large doses
6.Antiarrhythmic drugs, such as quinidine
40. Factors that Decrease the Potency
• Resistance to nondepolarizing muscle blockers
mostly seen in patients receiving chronic
anticonvulsant therapy
– increased clearance,increased binding of the
neuromuscular blockers to a1-acid
glycoproteins, and upregulation of
neuromuscular acetylcholine receptors.
• Hyperparathyroidism, hypercalcemia is associated
with decreased sensitivity to atracurium and thus
a shortened duration of NM blockade
41. Adverse Effects of Neuromuscular Blockers
• Autonomic Effects
– Tubocurarine – marked ganglion blockade resulting in
hypotension; manifestations of histamine release such as
flushing, hypotension, reflex tachycardia, and bronchospasm
– Pancuronium - direct vagolytic
• Histamine Release
– Mivacurium, atracurium, and tubocurarine - skin flushing, decreases in
BP & systemic vascular resistance & increases in pulse rate
– Short duration (1-5min)
– Histamine - positive inotropic and chronotropic effects on the
myocardial H2 receptors
– Give over 60 seconds, or the prophylactic use of the combined
histamine H1- and H2-receptor antagonists.
42. • Respiratory Effects
– histamine release, which may result in increased airway
resistance and bronchospasm in patients with
hyperactive airway disease
• Allergic Reactions
– Life-threatening anaphylactic (immune(IgE)-mediated)
or anaphylactoid reactions - exaggerated pharmacologic
responses
– Cross-reactivity - NM blocking drugs with
food,cosmetics, disinfectants etc.
– Treatment - oxygen (100%) and intravenous epinephrine
(10 to 20 mg/kg), Early tracheal intubation
44. Acetylcholinesterase inhibitors
• Neostigmine, edrophonium, pyridostigmine
• Used clinically to antagonize the residual effects of NM blockers and
to accelerate recovery from nondepolarizing neuromuscular blockade
• Ceiling effect on acetylcholinesterase - Because of this, Neostigmine
cannot effectively antagonize profound or deep levels of NM
blockade.
• Factors affecting
– (a) the depth of the blockade when reversal is attempted,
– (b) the anticholinesterase chosen,
– (c) the dose administered,
– (d) the rate of spontaneous clear of the NMB from plasma
• Maximum effective dose
– Neostigmine - 60 to 80 mcg/kg
– Edrophonium - 1.0 to 1.5 mg/kg
45. Acetylcholinesterase inhibitors - Pharmacology
Renal excretion accounts for
– 50% of the excretion of neostigmine and
– 75% of pyridostigmine and edrophonium.
• Renal failure decreases the plasma clearance
CVS
• Because only the nicotinic effects of acetylcholinesterase inhibitors are
desired, the muscarinic effects(Bronchoconstriction, increased airway
resistance/salivation/bowel motility) must be blocked by
– Atropine(7 to 10 mg/kg) matches the onset of action
pharmacodynamic profile of the rapid-acting edrophonium (0.5 to 1.0
mg/kg),
– Glycopyrrolate (7 to 15 mg/kg) matches the slower acting neostigmine
(40 to 70 mg/kg) and pyridostigmine.
46. Non classic Reversal Drugs
• Purified human plasma cholinesterase - effective
and safe in antagonizing mivacurium-induced
neuromuscular blockade.
• Cysteine -reverse the neuromuscular blocking
effects of gantacurium
• Sugammadex, a novel selective relaxant-binding
agent - reverse both shallow and profound amino
steroid induced neuromuscular blockade.
47. Sugammadex
• modified gamma-cyclodextrin
• First selective relaxant-binding agent
• Cyclodextrins are cyclic dextrose units joined
through one to four glycosyl bonds, having a hydrophobic cavity
and a hydrophilic exterior
• Highly water soluble hydrophobic cavity ,large enough to
encapsulate steroidal NMB drugs, especially rocuronium.
• Biologically inactive and does not bind to plasma proteins.75%
of the dose was eliminated through urine.
• After administration of sugammadex, the plasma concentration
of free rocuronium decreases rapidly, but the total plasma
concentration of rocuronium increases
48. • Sugammadex exerts its effect by forming very tight complexes at a 1:1
ratio with steroidal neuromuscular blocking agents (rocuronium >
vecuronium >> Pancuronium)
• The sugammadex-rocuronium complex has a very high association
rate and a very low dissociation rate. It is estimated that for every 30
million sugammadex-rocuronium complexes, only one complex
dissociates.
• Reversal can be accomplished during profound neuromuscular block
• Eliminated unchanged by the kidneys , sugammadex should be
avoided in patients with a creatinine clearance of <30 mL per minute.
• 2 mg/kg - a TOF ratio of 0.9 or greater
• 4 mg/kg - deeper block at a 1 to 2 post tetanic count.
• 8 to 16 mg/kg. - profound block
