NEUROMUSCULAR BLOCKING DRUGS

Physiology of Neuromuscular Transmission

Skeletal muscles are voluntary muscles innervated by somatic motor nerves, which
originate in the spinal cord, terminates at muscle cells, and release acetylcholine as
their neurotransmitter. Upon arrival of an action potential, ACh is released from
synaptic vesicles by exocytosis, crosses the synapse, and interacts with skeletal
muscle nicotinic cholinergic receptor. This interaction increases the permeability
of the motor end plate primarily to Na+, depolarizing the postsynaptic membrane
(the muscle fiber membrane) to produce end plate potential (epp). When the
membrane reaches threshold, a muscle action potential is generated and propagates
along the fiber to initiate excitation-contraction coupling. The action of ACh is
terminated very rapidly (within 1 millisecond) by hydrolysis by
acetylcholinesterase (AChE) located in the synaptic junction or it diffuses back
into the nerve terminal.

Diagram

An illustrative representation of a neuromuscular junction showing one motor end

plate

Neuromuscular Blocking Drugs (Nmbds)

Neuromuscular blocking drugs are the drugs that block cholinergic transmission between
motor nerve endings and the nicotinic ACh receptors (nAChRs) on the skeletal
neuromuscular junction. Through this block, they prevent muscle contraction and induce
paralysis. The site of action of neuromuscular blocking agents is the end plate of skeletal
muscle fibres. NMBDs are classified into two according to their actions at the
postjunctional nicotinic receptor
i) Agonist/ Depolarizing blocker e.g.Succinyl choline (suxamethonium), Decamethonium
(not used clinically).
ii) Antagonist/ Nondepolarizing/ competitive blocker
a) Long-acting e.g. d-tubocurarine, pancuronium, doxacurium
b) Intermediate acting e.g.Vecuronium, Atracurium, cisatracurium, rocuronium,
rapacuronium.
c) Short-acting e.g. Mivacurium.

Non-depolarizing (antagonist/competitive) blockers

Curare was the first drug that was found to be capable of blocking the skeletal
neuromuscular junction and it was used by the native hunters of the Amazon in South
America for game hunting to paralyze animals. Tubocurarine was the muscle paralyzing
active principle from the curare and it is considered to be the prototype agent in this class.
It has been largely replaced by other (newer) agents due to its numerous side effects.

 Mechanism of action
Non-depolarizing neuromuscular blocking drugs bind to the nicotinic receptors on the
motor end plate and block the binding of acetylcholine. These drugs thus prevent
depolarization of the muscle cell membrane and inhibit muscular contraction. Because
these agents compete with acetylcholine at the receptor without stimulating the receptor,
they are called competitive blockers. Their action can be overcome by increasing the
concentration of acetylcholine in the synaptic gap-for e.g., by administration of
cholinesterase inhibitors, such as neostigmine, pyridostigmine, or edrophonium.

 Pharmacological actions
Skeletal muscles: On parenteral administration, tubocurarine initially causes muscular
weakness followed by flaccid paralysis. Not all muscles are equally sensitive to blockade
by competitive blockers. Small, rapidly contracting muscles of the face and eye are most
susceptible and are paralyzed first, followed by the fingers. Thereafter, the limbs, neck,
and trunk muscles are paralyzed. Then the intercostal muscles are affected, and lastly, the
diaphragm muscles are paralyzed. Recovery occurs in the reverse order, i.e. diaphragm is
the first to recover.
Autonomic ganglia: In high doses tubocurarine can block autonomic ganglia and adrenal
medulla resulting in hypotension.
Histamine release: Tubocurarine can cause histamine release from the mast cells leading
to bronchospasm, increased bronchial and gastric secretions. Histamine release also
contributes to hypotension.
Pharmacokinetics
Tubocurarine and other NMBs are quaternary ammonium compounds. They are injected
intravenously or intramuscularly, because their uptake via oral absorption is minimal.
They penetrate membranes very poorly and do not enter cells or cross the blood-brain
barrier. Many of the drugs are not metabolized; their actions are terminated by
redistribution to non-muscular tissues. The duration of action of non-depolarizing
blockers is directly dependent on their elimination half-life. For example vecuronium,
atracurium, cisatracurium, rocuronium and mivacurium are metabolized in the plasma/
liver and they have relatively shorter half -life and duration of action (20-40 min) while
tubocurarine, pancuronium, pipercuronium, and doxacurium are excreted in the urine
unchanged, and they have longer half- life and duration of action (> 60). [Note:
Atracurium has been replaced by its isomer, cisatracurium. Atracurium releases histamine
and is metabolized to laudanosine, which can provoke seizures. Cisatracurium, which has
the same pharmacokinetic properties as atracurium, is less likely to have these effects] .
These drugs are also excreted unchanged in the bile. The choice of an agent will depend
on how quickly muscle relaxation is needed and on the duration of the muscle relaxation. 

Adverse effects
i) Respiratory paralysis and prolonged apnoea- patient should be given artificial
ventilation. Neostigmine may be used to reverse the skeletal muscle paralysis.
ii) Hypotension is due to ganglion blockade and histamine release.
iii) Flushing and bronchospasm due to histamine release by tubocurarine; this is
not seen with newer drugs.
iv) They cause no significant CNS effects because they cannot penetrate the BBB.

Depolarizing (agonist) blockers

Suxamethonium is the only depolarizing muscle relaxant in use today, consisting of 2
molecules of ACh joined through the acetate methyl group. This compound binds to and
activates muscle nicotinic receptors, and opens ion channels which cause depolarization
and contraction in the manner as ACh. However, succinylcholine is not metabolized by
AChE, so a prolonged activation of nACh receptor resulting in receptor occupation for a
prolonged period. It is hydrolyzed by butyrylcholinesterase (pseudocholinesterase),
which is present in the plasma but in low concentration at the neuromuscular junction,
resulting in continuing muscle depolarization. The neuromuscular block produced by
succinylcholine is characterized by two phases.
Phase 1
It occurs as a result of prolonged depolarization, rendering the membrane
unresponsive to further stimuli. It is characterized by initial muscle fasciculation
followed by a flaccid paralysis that is not reversed, but intenstified , by
administration of AChE inhibitor (Neostigmine).
 Phase II
With continued exposure to succinylcholine, the membrane repolarizes because
the initial end plate potential decreases and the membrane become repolarized.
Inspite of the repolarization, ACh cannot depolarize the membrane because of the
continued presence of succinylcholine. This is known as phase II block and its
characteristics are similar to competitive block by tubocurarine.
The prolonged exposure to the succinylcholine can also result in desensitization
block, which occurs when ACh receptors are insensitive to the channel-opening
effects of agonists including ACh itself. An inexcitable area is formed in the
muscle membrane around the end plate, thus preventing impulse-induced by the
action of ACh from spreading. This phenomenon is called desensitization block.

Pharmacological actions

Skeletal Muscles: On intravenous administration, onset of action is very rapid- within 1

minute. Initial transient muscle fasciculation, particularly over the chest and abdomen,
occur briefly, due to stimulation of the muscle fibres by the discharge of action potentials
in them. This is then followed by skeletal muscle paralysis of the neck, limbs,facial,
jaw, eyes, pharynx, trunk This is followed by weakness of the respiratory muscles.
Recovery is rapid. SCh is a short acting muscle relaxant and the effect lasts for 5-10 min.
Hence, it has to be given continuously as an infusion for longer effect.

CVS: Initially hypotension and bradycardia may result from stimulation of vagal ganglia.
This is followed by hypertension and tachycardia due to stimulation of the sympathetic
ganglia. Higher doses can cause cardiac arrhythmias.

Pharmacokinetics

All quartenary ammonium compounds are very poorly absorbed from the GI tract. Rapid
onset (within one minute) is achieved with intravenous administration. Its short duration
of action (5-10 min) is due to rapid hydrolysis of succinylcholine by the
butyrylcholinesterase synthesized by the liver and found in the plasma. It is sometimes
given by continuous infusion to maintain a longer duration of action. Drug effects rapidly
disappear upon discontinuation.

Adverse effects

a) Malignant hyperthermia: Administration of succinylcholine has occasionally caused

malignant hyperthermia (a life threatening event) especially when used with halogenated
hydrocarbon anaesthetic, (e.g. halothane, isoflurane). The clinical features include
contracture, muscle rigidity, hyperpyrexia, increased muscle metabolism, metabolic
acidosis, and tachycardia. Treatment is by intravenous administration of dantrolene,
which blocks Ca2+ release from sarcoplasmic reticulum of skeletal muscles. Rapid
cooling, inhalation of 100% oxygen and control of acidosis should be considered.

b) Cardiac arrhythmias: SCh can cause cardiac arrhythmias. It stimulates the nicotinic
receptors in the ganglia and cardiac muscarinic receptors.

c) Prolonged paralysis: Reduced plasma cholinesterase activity, a result of inherited or

acquired factors, may alter the duration of action of succinylcholine, leading to prolonged
respiratory paralysis and apnea.

d) Hyperkalemia: Depolarizing agents can cause hyperkalemia due to rapid release of

K+ from intracellular site into the blood. Succinylcholine-induced hyperkalemia is a life
threatening complication, thus, it should be used with caution or it should be avoided in
patients with congestive heart failure who are receiving diuretics or digoxin or in patients
with severe soft-tissue trauma or burns.

e) Muscle pain: It may be due to the damage to muscle fibres that occur during initial
fasciculations.

Therapeutic uses of NMBDs

1) The main clinical use of the neuromuscular blocking agents is as an adjuvant to
anaesthesia during surgery to obtain relaxation of skeletal muscle, particularly of
the abdominal wall, to facilitate operative manipulations. Hence, muscle relaxation
no longer dependent on the depth of general anesthesia, a much lighter level of
anesthesia suffices. The risk of respiratory and cardiovascular depression is
minimized, and post-anaesthetic recovery is shortened.

2) NMBDS are used to produce muscle relaxation in various orthopedic procedures,

such as the correction of dislocations and the alignment of fractures.

3) Neuromuscular blocking agents of short duration (SCh, mivacurium) are used to

facilitate endotracheal intubation and also to facilitate internal examinations such
as laryngoscopy, bronchoscopy, and esophagoscopy in combination with a general
anesthetic agent.
4) They are used to prevent trauma during electroshock therapy; the seizures induced
may cause dislocations or fractures. The neuromuscular blocking agents (SCh or
mivacurium) may be used to control the muscular component of convulsions
Drug interactions
a) General anaesthestics augment the action of NMBs
b) Anticholinesterases like neostigmine reverse the action of competitive
blocker.
c) Aminoglycosides and calcium channel blockers potentiate the action of
NMBDs