B- Neuromuscular blockers
- A neuromuscular junction (NMJ) is the junction of the nerve terminal
of a motor neuron with the motor end plate (skeletal muscle fiber).
- Skeletal muscle relaxants: are groups of drugs which affects skeletal
muscle function and decreases the muscular tone. It includes two
categories of drugs, spasmolytics and neuromuscular blockers.
Spasmolytics are a group of drugs was traditionally known as “centrallyacting skeletal muscle relaxants”. However, at least one of these agents
(dantrolene) has no significant central effects.
Spasmolytic drugs are used in the treatment of muscle spasm and
immobility associated with strains, sprains, and injuries of the
extremities, back and neck. In addition to their usage to alleviate
painful muscular spasms associated with many neuropathological
disorders.
- They have diverse mechanisms of action, but they are not directly
affect transmission within motor end plates.
- Guaifenesin , Chlordiazepoxide ,Baclofen , Chlorphenesin, and
Dantrolene are examples of spasmolytics
Neuromuscular blockers are group of drugs act peripherally postsynaptically on motor end plate to interfere with transmission at muscular
nicotinic receptors (NmAChRs). They lack any CNS effects and may share
some charecterestics with autonomic ganglionic blockers.
- They are used mainly to produce a certain level of muscle paralysis
for patients requiring ventilatory assistance during surgical
procedures and in intensive care units.
- Two different kinds of functional blockade may occur at the
neuromuscular endplate, and hence clinically used drugs fall into two
categories
I-Competitive neuromuscular blockers
- These group of drugs act as competitive antagonists with Ach at the
site of NmAChRs.
- No depolarization of postjunctional membrane.
- Cholinesterase inhibitors (like neostigmine) can reverse
this
blockade.
- Examples: d-tubocurarine, Gallamine, Atracurium, Pancuronium,
Vecuronium, and Mivacurium
Pharmacokinetic aspects :
- Competitive neuromuscular-blocking agents are used mainly in
anaesthesia to produce muscle relaxation. They are given
intravenously (inactive when used orally)
- Most of the non-depolarising blocking agents are metabolised by the
liver or excreted unchanged in the urine. With exceptions being
atracurium, and mivacurium, which are hydrolysed by plasma
pseudocholinesterase.
- Their duration of action varies between about 15 minutes and >2
hours , by which time the patient regains enough strength to cough
and breathe properly, although residual weakness may persist for
much longer.
Pharmacological actions:
- Skeletal muscle relaxation is the main pharmacological effect. This
effect is mainly due to motor paralysis. The first group of muscles to
be affected are the extrinsic eye muscles (causing double vision) and
the small muscles of the face, limbs and pharynx (causing difficulty in
swallowing).
- Respiratory muscles are the last to be affected and the first to
recover.
Unwanted side effects:
1- Hypotension is the main side effect many competitive NMBs (dtubocurarine, atracurium and mivacurium), this happened mainly due
to ganglion block effect (d-tubocurarine).
2- Also, stimulation of histamine release from mast cells which can help in
reduction of arterial BP and also give rise to bronchospasm in sensitive
individuals. Gallamine and pancuronium lack these side effects.
3- Gallamine, and pancuronium, block mAChRs, particularly in the heart,
which results in tachycardia.
Anticholinesterase drugs (e.g. neostigmine) are very effective in
overcoming the blocking action of competitive agents.
d-Tubocurarine (curare):
It is a plant alkaloid that has slow onset of action (> 5 min) and
longer duration(1-2 h). It also affect autonomic aganglia.
- The main side effects is Bronchoconstriction and hypotension. In
addition to other side effects related to its ganglion blocking activity
( blurred vision , urine retention , conistipation and male impotence)
Gallamine (Flaxedil):
It is synthetic compound has less potent NM blocking activity than
curare ( 1/5 potency)
- It has shorter onset (2-3 min) and longer duration ( > 2h) than dtubocurarine.
- It is execreted unchanged mainly by kidney. It is contraindicated in
renal failure
- Main side effect is “tachycardia” due to an atropine-like action and
stimulation of NA release from adrenergic nerve endings.
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Mivacurium:
It is new drug that is chemically-related to atracurium. It has Fast
onset (∼2 min) and short duration (∼15 min).
It is metabolized by plasma pseudocholinesterases (Longer duration
in patient with liver disease or genetic cholinesterase deficiency).
Transient hypotension is the main side effect.
Pancuronium:
It is the first steroid-based compound that is more potent than curare
( 6 times ). It has Intermediate onset (2-3 min) and slight long duration
(>2h)
Excreted mainly unchanged by the kidney ( 80 % ).
Tachycardia is the main side effect (due to an atropine-like action
and stimulation of NA release from adrenergic nerve endings).
Vecuronium:
It is more potent NMBs than curare (6times) with Intermediate onset
(2-3 min) and Intermediate duration (30-40 min)
- It is metabolized mainly by liver. Its metabolites have some activity. It
has few side effects (no histamine release, no ganglion block and no
antimuscarinic action). Occasionally causes prolonged paralysis,
probably owing to active metabolite
- It is widely used.
II-Depolarizing neuromuscular blockers
- This group of NMBs have the ability to combine with NmAChRs
and stimulate motor end plates by initiation of membrane
depolarization This initial depolarization is accompanied by
transient twitching of the skeletal muscle (fasciculation)  Phase I
(phase of initial depolarization).
- Phase I block is augmented not reversed by anticholinestrases.
- Continuous exposure to depolarizing NMBs (not liable to be
hydroilized with cholinesterase) and persistent depolarization, the
skeletal muscle tone cannot be maintained, decreases and the
membrane become gradually repolarized (as the sodium channel
closes), and the membrane cannot be depolarized by Ach as long
as the NMB is present , therefore, this continuous a functional
muscle fatigue occurs and paralysis (flaccid paralysis; muscles are
weak and have little or no tone) leads to depolarization  Phase
II ( Phase of desensitization block of the membrane) .
This phase reversed by anticholinesterase.
Succinylcholine and decamethonium are examples of this class
of drugs.
Succinylcholine (suxamethonium)
It has a short onset of action ( 1 min. ) and short duration of
action (5-10 min.). It must be given by continuous IV infusion if
prolonged paralysis is required. It is destroyed by
pseudocholinesterase.
- Mostly used for brief procedures (e.g. tracheal intubation,
electroconvulsive shock therapy).
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Side effects:
Bradycardia ( due to muscarinic agonist effect) .this could be prevented
by atropine.
Cardiac dysrhythmias or even cardiac arrest (increase K+ permeability of
the motor endplates causes a net loss of K+ from muscle and increased
plasma K+ concentration “hyperkalemia”). It should be avoided in
patients with burns or severe trauma .
Raised intraocular pressure (nicotinic agonist effect on extraocular
muscles).
Prolonged paralysis or succinylcholine apnea in patients with liver
insuffecience or genetic deficiency of plasma cholinesterase
Increase the intragastric pressure and may leads to regurgitation of
gastric content to esophagus.
Malignant hyperthermia: Malignant hyperthermia (MH) is a rare
inherited condition, due to a mutation of the Ca2+ release channel of the
sarcoplasmic reticulum (the ryanodine receptor “RYR1”), which results in
intense muscle spasm and a dramatic rise in body temperature with an
increased heart rate and respiratory rate. This is a disorder that can be
considered a gene-environment interaction. In most persons with
Malignant hyperthermia susceptibility, they have few or no symptoms
unless they are exposed to a triggering agent. The most common
triggering agents are volatile anesthetic gases (such as Halothane,and
Isoflurane) , the depolarizing muscle relaxants (Suxamethonium and
Decamethonium) catecholamines (such as EP,NE and DA),
phenothiazines (such as Chlorpromazine, and Promethazine), and MAO
inhibitors (such as Phenelzine, Moclobemide, and Selegiline). Some
other factors could trigger symptoms of MH in suceptable individuals like
physical exercise and hot environment. The condition carries a very high
mortality (about 65%) and is treated by IV administration of Dantrolene,
a drug that inhibits muscle contraction by preventing Ca2+ release from
the sarcoplasmic reticulumin addition to discontinuation of triggering
agents, and supportive therapy to control hyperthermia, and acodosis.