voltage-sensitive sodium channels sense membrane depolarization (as a result of activation of the ACh receptors), they first open (Fig. 1A(b)) and thereafter close and become inactivated
RyR1 to remain abnormally open and, as the speed at which calcium is released for SR exceed the speed at which it is uptaken and elimated by the calcium pump, the calcium concetration in the myoplasm greatly increases. In the early phase of MH, the muscle cells attempt to restore homeostasis by sequestering calcium through the increase of aerobic and anaerobic metabolism This abnormal myoplasmic calcium rise eventually reaches the threshold levels for myofibrillar contraction, and results in sustained muscle contraction. This produces a rapid depletion of adenosine triphosphate (ATP) with a concomitant increase in glucose metabolism, oxygen consumption, carbon dioxide production, and heat production. ATP stores become depleted, which progressively lead to the failure of membrane integrity with leakage of muscle cell contents (including electrolytes, myoglobin and various other sarcoplasmic proteins, like CK into the circulation)
Skeletal Muscle Relaxants
Speaker : Dr Rachana Menon
Drugs that act peripherally at neuromuscular junction or
muscle fibre itself or in cerebrospinal axis to reduce
muscle tone and cause muscle paralysis.
The earliest known use of muscle relaxant drugs dates
back to the 16th century.
Natives of the Amazon Basin in South America . The
prey was shot by arrows dipped in curare
Curare, led to some of the earliest scientific studies
1935 – d tubocurarine, active
ingredient - Harold King of London,
working in Sir Henry Dale’s laboratory
1943, neuromuscular blocking drugs
became established as muscle
relaxants in the practice of
anaesthesia and surgery
1967- Baird and Reid first reported on clinical
administration of the synthetic aminosteroid
1980-Introduction of vecuronium, an aminosteroid, and
• 1990’s Mivacurium, the first short-acting
nondepolarizing neuromuscular blocker was introduced
The neuromuscular junction is made up of a
Motor neuron – Originate in the ventral horn of the
As the axon of a motor neurone enters the structure of
skeletal muscle it forms many branches “Axon
Synaptic end bulb – Bulbous swelling at the end of
Each synaptic end bulb contains many synaptic
vesicles, each of which contains ACETLYCHOLINE.
MOTOR END PLATE - part of
the Sarcolemma of the muscle cell
that is in closest proximity to the
synaptic end bulb
SYNAPTIC CLEFT - The
area between the axon terminal
and the sarcolemma , release
Ach occurs with consequent
binding to the receptors
The surface of motor end plate
deeply folded with MULTIPLE
CREST and secondary clefts
The nAchR are located on the
crests. The clefts contain ACH
Produced on the ribosomes of the motor neuron
Attached - thin collagen threads linking it to the
Found junctional gap clefts of the post-synaptic folds in
Transported distally by axoplasmic flow to the terminal button
The cholinergic synapse is rich in AchE
Breaks down Ach within 1 msec of being released.
•Large extracellular N-terminal domain of ~200 amino acids; that contributes
to agonist binding site
•Four hydrophobic transmembrane domains (TM1 through TM4)
•A large cytoplasmic loop between TM3 and TM4 with variable AA sequence.
•The M2 transmembrane region is thought to form the ion pore of the nAChR
• Short extracellular C terminus
(Cys-loop) defined by two cysteines (Cys) that in the
mammalian subunits are separated by 13 intervening amino
Subunits are classified into α- and non-α subunits based
on the presence of a Cys-Cys pair near the entrance to TM1.
• Required for agonist binding
• Presence designates the subunit as an α-subtype .
The N termini of two subunits cooperate to form two distinct
binding pockets for Ach , agonist and antagonist
• These pockets occur at the α -γ and the α- δ subunit interface.
• The M2 membrane-spanning domain of each subunit lines the
Five polypeptide subunits
Arranged around a pseudo-axis of symmetry to
circumscribe an internally located channel
Adult receptor has two identical α subunits, one β one δ
and one ε subunit in 2:1:1:1 ratio. In the foetus a γ
(gamma) subunit replaces the ε
• The neuronal subtypes are various homomeric or
heteromeric combinations of twelve different nicotinic
• 7 α-like subunits, termed α2, α3, α4, α5, α6, α7, α9,
• 3 non-α subunits -β2, β3, and β4 cloned from neuronal
BINDING THE CHANNEL
The Acetylcholine-binding site
Opening of the nAChR channel pore
requires the binding of a chemical
Location - pockets approximately 3.0
nm above the surface membrane at the
α and either γ or δ subunits interface.
OPENING THE CHANNEL
The nAChR is a non-selective cation channel
Binding of 2 Ach molecules to the α-subunits initiates
conformational changes that open the channel
Allows positively charged ions to move across it; in
particular, sodium enters the cell and potassium exits.
The net flow of positively-charged ions is inward.
The cell becomes less negative compared with the
When a threshold of –50mV is achieved (from a resting
potential of –80mV), voltage- gated Na open, thereby
increasing the rate of depolarisation and resulting in an
End plate potential (EPP) of 50-100mV.
Triggers the muscle action potential
A) PERIPHERALLY ACTING
• Neuromuscular blockers
Non depolarizing agents ( Competitive blockers)
Prevent the access of Ach to Nm receptors of motor end
plate and prevent depolarisation.
• Produce excessive depolarisation which
persist for longer duration at NMJ
• Resistant to hydrolysis by true AchE present in
– Suxamethonium (Succinylcholine)
B) CENTRALLY ACTING
Benzodiazepine group GABA derivative
Central alpha agonist Mephensive group
Also known as suxamethonium
Introduced by Thesleff and by Foldes and colleagues in
Is a nicotinic acetylcholine receptor agonist
STRUCTURE ACTIVITY RELATIONSHIP
Quaternary ammonium compounds
Two molecules of acetylcholine linked back to back
through the acetate methyl groups
Long, thin, flexible molecule.
Enable free bond rotation.
Positive charges at these sites in the molecules mimic
the quaternary nitrogen atom of the transmitter
MECHANISM OF ACTION
Affinity and sub maximal intrinsic activity for NM receptors
Analouge of Ach
Longer durations at the neuromuscular junction -
resistance to AChE
Do not dissociate from receptors quickly
SCh reacts with Nm receptor – Open Na+ channels
Prolonged persistant depolarisation
Brief period of repetitive excitation
Flaccid paralysis of muscle
Elicit transient and repetitive muscle excitation
Neural release of Ach will result in binding of Ach to
receptors on a already depolarised plate
• FLACCID PARALYSIS
• This initial depolarization block of
NEUROMUSCULAR TRANSMISSION AND FLACCID
PARALYSIS PHASE l BLOCK
The Na+ receptors at the end-plate and
the perijunctional zone remain inactivated
and junctional transmission is blocked.
• Recovery from Phase I block occurs as Sch diffuse away
from the NMJ , down a concentration gradient as the
plasma concentration decreases.
Prolonged exposure to succinylcholine, the initial end
plate depolarization decreases membrane becomes
Despite this repolarization, the membrane desensitized.
Phase II Block
The channels behave as if they are in a prolonged closed
state.Neurotransmission remains blocked through out
1.Presynaptic block reducing the synthesis and
mobilization of ACh
2.Post junctional receptor desensitization
3.Activation of the Na-K ATPase pump by initial
depolarization, which repolarizes it
Later in phase II, the blockade
identical to those of a nondepolarizing
Fade of the train-of-four (TOF) twitch
Inhalation anaesthetic drugs accelerate
the onset of Phase II block. Possible
reversal by acetylcholinesterase
TOF: Need at
least 0.9 to
minimize risk of
TOF: Must use
transmission not restored
Cannot reversed by
Slow in onset
receptors to Ach
Partially reversed by
Rapid onset of effect and ultra short duration of action.
Not absorbed orally
Does not cross BBB, placenta
I.V route - initiation dose 0.5 – 1 mg/kg .tracheal
intubation in adults is 1.0 – 1.5 mg/ kg.
Cheeks,abdomen,neck,limb,face, respiratory paralysis
Apnoea within 1 min.Brief duration of action 6-11 min
Elimination - rapid hydrolysis by plasma cholinesterase
( weaker NM blocking agent)
No butyrylcholinesterase is present at the NMJ
Butyrylcholinesterase has an enormous capacity to
Only 10% of the administered drug reaches the
Influences the onset and duration of action of Sch by
controlling the rate at which the drug is hydrolyzed before it
reaches and after it leaves the NMJ.
Factors that have been found to lower
Advanced age, malnutrition, pregnancy
OCPs, MAO inhibitors
Ecothiophate, cytotoxic drugs
Patient with abnormal genetic variant of
butyrylcholinesterase ,Sch induced neuromuscular
blockade can be significantly prolonged
Dibucaine inhibits normal butyrylcholinesterase to a far
greater extent than it does the abnormal enzyme.
• Under standardized test conditions Dibucaine inhibits
The normal enzyme about 80%
The abnormal enzyme about 20%
Many other genetic variants of butyrylcholinesterase
have been identified, dibucaine-resistant variants are the
Measure of the ability of the person to metabolise Sch,
identify at risk patients.
Doesnot measure the concentration of enzyme in plasma
Efficiency of enzyme to hydrolyse the substrate.
Adjuvant to General anaesthesia-Rapid-sequence
induction of anaesthesia- (DOC)1.0 mg/kg
succinylcholine facilitate ETintubation at 60 seconds
To prevent trauma during ECT
Before administering the intubating dose of
A small dose of nondepolarizing neuromuscular blocker is
commonly given 2 mins. This defasciculating dose of
attenuate increases in intragastric and intracranial
minimize the incidence of fasciculations in response to
Antichloniesterase -Neostigmine / Pyridostigmine.
Sch should not be administered to re establish
neuromuscular blockade - produces relaxation that will
last up to 60 minutes with administration of neostigmine
Such prolongation can partly be explained by inhibition of
Combination of Lithium and succinylcholine resulted in
an additive inhibition.
Verapamil potentiates the neuromuscular block.
Bambuterol, produces marked causes prolongation of
Sch induced blockage.
Esmolol causes only minor prolongation of blockage
Occasionally succinylcholine produces prolonged apnoea
due to lack of normal plasma (pseudo) cholinesterase
Artificial respiration until the muscle power returns.
Fresh blood or plasma transfusion to restore
cholinesterase enzyme level.
No specific antidote is available
Rare life-threatening condition
Autosomal dominant disorder
Volatile anaesthetic agents and succinylcholine
Major defects in RYR1, DHPR, CACNA1S triadin
and FK 506
C/F :sustained muscle contraction and hyperpyrexia
Dantrolene 2mg/kg I.V.
Procainamide - ventricular fibrillation
Inhalation of 100% oxygen
Control of acidosis should be considered adjunct
therapy in malignant hyperthermia
2 quaternary ammoniums with a 10-carbon chain in
• It's about 2x as potent as succinylcholine
• Derived from decamethylenediamine,
• Partial agonist of the nicotinic acetylcholine receptor.
• Persistant depolarisation
• Character of muscle responseto indirect tetanic
stimulation during partial block -Well-sustained
Does not produce unconsciousness or anesthesia, and
its effects may cause considerable psychological
distress while simultaneously making it impossible for a
patient to communicate
• It is a motor neuron disorder characterized by skeletal
muscle rigidity, exaggerated tendon jerks and paralysis
of affected muscles.
• Cerebral palsy
• Multiple sclerosis
• Traumatic brain injury
• Neurodegenerative disease
A hydantoin derivative
Phenol ring, which is rotated approximately 30°
out of the plane of the furane ring.
• Phenytoin analouge
• Antispastic action lie outside CNS
• The L-type channel with its T-tubular location serves as
the voltage sensor receiving the depolarizing activation
• Inhibits Ca2+
release from the sarcoplasmic reticulum of
skeletal muscle by limiting the capacity of Ca2+
calmodulin to activate RYR-1
Poorly absorbed orally
Penetrates brain and produces sedation
Metabolized in liver into 5-hydroxydantrolene
Excreted in kidney.
T 1/2 9 -12 hrs.
Dose: 25-100 mg 4 times daily
UMN disorders – paraplegia, hemiplegia, cerebral palsy
DOC: Malignant hyperthermia (2.5 – 4 mg/kg)
• Prophylactic dantrolene administration before trigger-free
GA for MH-susceptible patients has been recommended
Neuroleptic malignant syndrome: 1 – 2.5 mg/kg
• Sedation- facilitated GABA – depression of brain stem
• Light headedness
• Muscular weakness
• Neonates are at risk of ‘floppy child syndrome’ –C/s
Severe cardiovascular collapse, arrhythmias,
myocardial depressions, and hyperkalemia.
Vecuronium : Neuromuscular blockade is prolonged.
CNS depressants: Sedative action is potentiated.
Combined OCPS and HRT may enhance liver toxicity.
• Analogue of dantrolene .
• 30-fold more watersoluble
• The para-nitrophenole group of dantrolene sodium is
replaced by a para-bromo-phenyl group.
• Equipotent to dantrolene in the treatment and prevention
of the clinical manifestations of an MH crisis
Same potency as Dantrolene in
• Inducing relaxation in porcine skeletal muscle in vitro.
• In vivo, even more potent in inhibiting gastronemius
Dual action in skeletal muscle:
Acts directly on the muscle fibre increases the tension
Increases the refractory period
Decreases the excitability of the motor end-plate
Makes the muscle less susceptible to repetitive neural
Less Responsive To Acetylcholine
• The typical adult dosing for nocturnal leg cramps is 260
mg at bedtime.
• Hypersensitivity reactions
• QT prolongation
• FDA Warns of Risks with Unapproved Use of Malaria