MUSCLE RELAXANTS

Skeletal muscle relaxants are drugs that act peripherally at neuromuscular

junction/muscle fibre itself or centrally in the cerebrospinal axis to reduce
muscle tone and/or cause paralysis.
History:
• South amercian indian arrow poisons, known as curae served as the
basis for the devolpment of relaxants
• First successful administartion of neuromuscular blocker in surgery by
Arthur Lawen in 1912
• Griffth and Johnson used in surgery sucessfully in 1942
• Succinyl choline introduced in 1952
• Bairrd and Reid used pancuronium in 1967
• Vecuronium used in 1988
 Non depolarizing neuromuscular blockers Depolarizing neuromuscular blockers

Compete with acetylcholine for the Acts as agonists at the post synaptic
active binding sites at the postsynaptic nicotinic receptors and cause
nicotinic acetylcholine receptors, also prolonged membrane depolarization
called us competitive antagonists resulting in blockade

Principles of Action of Neuromuscular blockade at the neuromuscular

junction:
• In resting state , the ion channel of the acetylcholine receptor is closed.
• Binding of two ACH molecules to the Alpha subunits intiates changes
that open channels.
• Single molecule of non depolarzing agent binding is sufficient enough to
produce neuromuscular blockade.
• Deploarzing blockers produces prolonged depolarization of the endplate
region.

Acetylcholinesterase's Butyrylcholinesterase

1.Seen in the NMJ and responsible 1.Synthesized in the liver , catalyzes

for rapid hydrolysis of released
acetylcholine to aceteic acid and
choline
2.Also called as True cholinesterases/
red cell cholinesterases
the hydrolysis of succinyl choline
2.Also called us plasma
cholinesterases / Pseudo
Cholinesteras

Structure of neuromuscular blocking agent:

1. All blockers are quaternary ammonium compounds.
2. All are structurally related to acetylcholine .
3. All the muscle relaxants are synthetic alkaloids, except Tubocurarine
derived from plants.
CLASSIFICATION:

Succinyl choline (suxamethorium)

Mechanism of action: Succinylcholine binds to Nm receptors first it prduces
muscle contraction follwed by muscle blockade of neuromuscular transmission
The depolarized membranes remain depolarized and unresponsive to
subsequent impules causing muscle paralysis.
➢ Long , thin flexible molecule composed of two molecule of acetyl
choline linked at acetate methyl group
➢ Like ACH , they stimulate cholingeric receptor at NMJ at nicotinic and
muscarnic receptor
➢ T1/2=47 seconds
➢ Elimnation follows first order kinetics
➢ Dose 1mg /kg
MIDARINE, SCOLINE, MYORELEX, ENTUBATE 50 mg/ml inj, 2 ml amp.
PHARMACOKINETICS

Poorly lipid soluble, inactive orally, IV administraction

➢ Time of action =30-90seconds
➢ Recovery from action=9 to 13 minutes
Donot cross placenta and reach CNS
Short duration of action due to its rapid hydrolysis by butyrlcholinesterase to
succinyl mono choline and choline
-Butyrl cholinesterase control the onset and duration of action ,they are
synthesised by liver and found in plasma.

USES:
a. Most commonly used muscle relaxant for passing/placement of
endotracheal tube at the start of anesthetic procedure.
b. SCh is employed for brief procedures, e.g. endotracheal intubation,
laryngoscopy, bronchoscopy,
c. esophagoscopy, reduction of fractures,
d. dislocations, and to treat laryngospasm.
e. Rare- To control muscle contractions in status epilepticus.
f. Occasionally SCh is used by continuous i.v. infusion for producing
controlled muscle relaxation of longer duration.

Side-effects:
1.Bradycardia(CVS)
junctional rhytm followed by adminstration of succinyl choline
ventricular dysarrthimia -mainly due to reduced threshold of ventricle to
catecholamines
2.Hyperkalemia:
Raised potassium seen in Abdominal infection, severe metabolic acidosis, head
injury (Cariac arrest in risk patients).
3.Myoglobinuria
4.Increased intraocular pressure
5.Increased intragastric pressure.
6.Raised intracranial pressure.
7.myalagia, muscle soreness.
8.Masseter spasm- known trigger agent for malignant hyperthermia
9.Succinylcholine apnoea.
Aypical or less pseudocholinesterase
Patient will have respiratory difficulty and will not be able to intake O2
(inspiration and expiration) after from post anesthetic effect, the patient
regains consciousness but will not be able to breath on his own.
Apnoea needing respiratory support longer than 15 mins is considered
abnormal.
Treatment:
Fresh frozen plasma
Artificial ventilation

Factors affecting butyrl Cholinesterases:

• Liver disease
• Age
• Malnurition
• Preganacy
• Burns
• OCP user
• MAO inhibitors
• Cytotoxic drugs

Genetic variant:
Neuromuscular blocker induced by succinyl choline can be prolonged, if
the patient has abnormal genetic variant of butryl cholinesterases
Analysis of butryl cholinesterase involves both enzyme and biochemical
phenotypes determined by dibucaine number and fluoride number.
Malignant hyperthermia:
Rare inherited condition probably caused by a mutation of Ca++ release
channel of sarcoplasmic reticulum, which results muscle spasm and
dramatic rise in body temperature.
Signs of MH
Specific
a. Muscle rigidity
b. Increased CO2 production
c. Rhabdomyolysis
d. Marked temperature elevation
Non specific:
a. Tachycardia
b. Tachypnea
c. Acidosis
d. Hyperkalemia
Immediate Therapy of MH
• Discontinue triggering agents
• Hyperventilate with oxygen
• Dantrolene 2.5 mg/kg
• Cooling the patient
Tubocuraine
➢ Monoquarternary , long acting neuromuscular blockers
➢ No active metabolism of tubocuraine
➢ Its excreted unchanged in urine and liver(not indicated in renal and
hepatic failure)
➢ Onset of action -slow, duration -long and recovery- slow
➢ Intubating dose-0.5to 0.6 mg/kg
➢ Maintenance dose-0.1to 0.2 mg/kg
Because of its prominent histamine releasing, ganglion blocking and
cardiovascular actions as well as long duration of paralysis needing
pharmacological reversal, d-TC is not used now.

Pancuronium
MOA: BLOCKS Nm RECEPTORS AT NEUROMUSCULAR JUNCTION CAUSING PARALYSIS.
A synthetic Aminosteroid compound
Potent long acting with both vagolytic and butyrylcholinesterase inhibiting
properties
Onset 3-5 minutes, duration 60-90 minutes
Intubating dose 0.08-0.12 mg/kg
PAVULON, PANURON, NEOCURON 2 mg/ml in 2 ml amp.
Elimination mainly by kidney (85%), liver (15%)
USES:
1. Its use is now restricted to prolonged operations, especially
neurosurgery.
2. Adjuvant in surgucal anesthesia.
3. Orthopedic procedures for alignment of fractures.
4. IN ICU:
a. Severe spasms of tetanus.
b. Critically ill patients on ventilator.
c. Refractory status epilepticus.
Side effects: hypertension, tachycrdia, dysrhythmia.
Atracurium
➢ A bisquaternary competitive blocker
➢ Non-organ dependent elimination
➢ Non specific estererase: 60% of elimination
➢ The unique feature of atracurium is inactivation in plasma by
Hofmann elimination : spontaneous nonenzymatic chemical
breakdown occurs at physiologic pH and Temperature
➢ Onset 3-5 minutes, duration 15-25 minutes
➢ Intubating dose 0.5 mg/kg
TRACRIUM 10 mg/ml inj in 2 ml vial.
Uses:
• It is the preferred muscle relaxant for liver/kidney disease
patients as well as for neonates and the elderly.
Side effects :
1. Histamine release causing hypotension, tachycardia, bronchospasm
2. Laudanosine toxicity-breakdown product from Hofmann elimination,
assoc. with central nervous system excitation resulting in seizures.
3. Temperature and pH sensitivity-action markedly prolonged in hypo-
thermic or acidotic patients.

Cisatracurium
➢ Isomer of atracurium
➢ Metabolized by Hofmann elimination
➢ Onset 3-5 minutes, duration 20-35 minutes
➢ Intubating dose 0.1-0.2 mg/kg
➢ Most importantly, it does not provoke histamine release.(Side
effects are fewer)
➢ Minimal cardiovascular side effects
➢ Much less laudanosine produced
Vecuronium
➢ Analogue of pancuronium(without the methyl group) much less
vagolytic effect and shorter duration than pancuronium
➢ Onset 3-5 minutes duration 20-35 minutes
➢ Intubating dose 0.08-0.12 mg/kg
➢ NORCURON 4 mg amp, dissolve in 1 ml solvent supplied.
➢ NEOVEC 4 mg amp, 10 mg vial.
➢ Elimination 40% by kidney, 60% by liver.
USES:
Currently, it is the most commonly used muscle relaxant for routine surgery
and in intensive care units.
Side effects: Tachycardia.

Rocuronium
➢ A newer nondepolarizing blocker with a rapid onset and
intermediate duration of action which can be used as
alternative to SCh for tracheal intubation without the
disadvantages of depolarizing block and cardiovascular
changes.
➢ Analogue of vecuronium and pancuronium withot the methyl
group.
➢ Rapid onset 1-2 minutes, duration 20-35 minutes
➢ Onset of action similar to that of succinylcholine
➢ Intubating dose 0.6 mg/kg
➢ ROCUNIUM, CUROMID 50 mg/5 ml, 100 mg/10 ml vials.
➢ Elimination primarily by liver, slightly by kidney
Uses:
It is also being used to facilitate mechanical ventilation in
intensive care units.
Side effects: Mild vagolytic action increases HR somewhat.
Mivacurium
Bisquaternary benzylisoquinoline compound.
It is the shortest acting competitive blocker; does not need reversal.
Potency, 1/3 that of atracurium
Slow onset 1.5 min with 0.25 mg/kg
Short duration 12-18 min with 0.25 mg/kg
Histamine release with higher doses and if adminstered rapidly
Hydrolyzed by AChE, recovery may be prolonged in some
populations
Uses:
1. To facilitate intubations, endoscopy, laryngoscopy.
2. In electric shock treatments of psychatric disorders.
Side effects:
a. Cutaneous flushing can occur due to histamine release.
b. Fall in bp is possible.

Gantacurium:
➢ Its an aymmetric mixed inium chlotofumarate
➢ Its an non depolarizing compound
➢ Onset occurs in 1.5 to 2 minutes and complete spontaneous
recovery occurs in 14 to 15 minutes
➢ Hypotension and tachycardia occurs following adminstration
➢ It undergoes two pathways, one in slower ester hydrolysis and
second one occurs quickly through adduction of cysteine
➢ Adminstration of L-cysteine(10mg/kg) results in rapid
recovery(complete neyromuscular function) within in 1-2
minutes
CW002:
Benzylisoquinololinium fumarate ester based compound.
Designed to undergo cysteine adduction and chemical hydrolysis.
CHOLINESTERASE INHIBITORS(Anti cholinesterase):
1. Primary clinical use is to reverse non-depolarising muscle blockade
2. Neuromuscular transmission is blocked when NDMR compete with Ach
to bind to nicotinic cholinergic receptors.
3. The cholinesterase inhibitors indirectly increase amount of Ach available
to compete with NDMR, thereby re-establish NM transmission.
Inhibiting activity of acetylcholineesterase
• More Ach available at NMJ, compete for sites on nicotinic cholinergic
receptors
• Action at muscarinic cholinergic receptor Bradycardia ,Hypersecretion
and Increased intestinal tone
Antagonism of non depolarizing NMB:
a. Depth of the blockade when reversal attempted
b. Anticholinesterase
c. Dose adminstered
d. Rate of spontaneous clear of neuromuscularblocker from plasma
e. Choice and depth of anesthetic agent administered
Anticholinesterases:
Neostigmine
Pyridostigmine
Edrophonium

Neostigmine
Quaternary ammonium group
Dosage : 0.04-0.08 mg/kg
Effects apparent in 5-10 min and last more than 1 hour.
Muscarinic side effects are minimized by prior or concomitant
administration of anticholinergic agent.
Side effects:
• Bronchoconstriction
• Increased airway resistance
• Increased salivation
• Increased bowel motility
Glycopyrrolate:
Dosage : 0.005-0.01 mg/kg up to 0.2-0.3 mg in adults.
Cannot cross blood-brain barrier and almost always devoid of central
nervous system and ophthalmic activity.
Potent inhibition of salivary gland and respiratory tract secretions.
Longer duration than atropine
Sugammadex:
✓ Novel selective relaxant is able to reverse both shallow and
profound aminosteriod induced neuro muscular blockade
✓ Modified gamma cyclodextrin
✓ It froms a hollow doughnut, have a hydrophobic cavity and a
hydrophilic exterior
✓ Hydrophobic interactions trap the drug into the cyclodextrin
cavity resulting in formation of a water soluble guest-host
complex
✓ Rocuronium>vecuroinum>>pancuronium
✓ It exerts no effect on acetylcholinesterases
✓ Independent of the depth of neuromuscular block, so reversal
can be accomplished even during profound neuromuscular
block
✓ They are biologically inactive, doesnot bind to plasma protein
✓ Elimination through renal, so its should be avoided in patients
with a creatinine clearance of<30ml per minute
✓ Dose of 2mg/kg would be sufficient to produce adequate
neuromuscular recovery , 4 mg /kg sufficient to produce
recovery from deep block
✓ Still more profounf block dose of 8mg to 16 mg /kg requried
✓ Its ineffective against succinyl choline and benzylisoquinolinium
neuromuscular block
✓ If neuromuscular blockade to be reestablished after using
sugammadex , benzylisoquinolinium is considered.
HISTORY
Curare It is the generic name for certain plant extracts used by south
American tribals as arrow poison for game hunting. The animals got
paralysed even if not killed by the arrow. Natural sources of curare
are Strychnos toxifera, Chondrodendron tomentosum and related
plants. Muscle paralysing active principles of these are tubocurarine,
toxiferins, etc.
Tubocurarine was first clinically used in 1930s; many synthetic
compounds including Succinylcholine were introduced subsequently.
Search has continued for neuromuscular blockers to provide greater
cardiovascular stability during surgery and for drugs with differing
onset and duration of action to suit specific requirements. The latest
additions are doxacurium, pipecuronium, rocuronium, mivacurium,
rapacuronium and cisatracurium.
DIRECTLY ACTING MUSCLE RELAXANTS
Dantrolene
This muscle relaxant is chemically and pharmacologically entirely different
from neuromuscular blockers; effect superficially resembles that of centrally
acting muscle relaxants.
MOA: Binds to the RyR1 (Ryanodine Receptor) and inhibits the release of
calcium from the sarcoplasmic reticulum thus prevents interaction between
actin and myosin.
Uses:
1. Used orally dantrolene (25–100 mg QID) reduces spasticity in upper
motor neurone disorders, hemiplegia, paraplegia, cerebral palsy and
multiple sclerosis.
2. Used i.v. (1 mg/kg repeated as required) it is the drug of choice for
malignant hyperthermia.
3. Reduces Spasticity due to central or spinal cord injury.
4. Hyperreflexia.
Adverse effects:
• Generalized muscle weakness.
• Sedation.
• Hepatitis, fatigue, diarrhea.

Quinine
It increases refractory period and decreases excitability of motor end
plates. Thus, responses to repetitive nerve stimulation are reduced.
It decreases muscle tone in myotonia congenita. Taken at bed time
(200–300 mg) it may abolish nocturnal leg cramps in some patients.
Botulinium toxin
Type A and B
It binds irreversibily to presynaptic cholinergic sites and inhibits the
release of ACH from motor nerve endings.
Uses:
1. spasmodic torticolis, Hemifacial spasm, Blepharospasm,
strabismus, lower esophageal spasm, painful anal fissure.
2. Wrinkles on face and neck.
3. Hyperhidrosis of palms and axilla.
Adverse effects:
a) Ptosis.
b) Diplopia.
c) Reduced blinking- dry eyes, lid swelling, minir bruises.
d) Reversible muscle atropy.
CENTRALLY ACTING MUSCLE RELAXANTS
1.Mephenesin
It was the first drug found to cause muscle relaxation in animals without
producing unconsciousness and was called internuncial neurone blocking
agent because its primary site of action is the spinal internuncial neurone
which modulates reflexes maintaining muscle tone. It is not used clinically
because orally it causes marked gastric irritation, and injected i.v., it causes
thrombophlebitis, haemolysis and fall in BP. It has been included in
counterirritant ointments (MEDICREME, RELAXYL) where its irritant rather than
muscle relaxant property could be affording relief.
2. Carisoprodol
It has a favourable muscle relaxant: sedative activity ratio with weak analgesic,
antipyretic and anticholinergic properties. It is used in musculoskeletal
disorders associated with muscle spasm.
CARISOMA 350 mg tab; one tab. TDS-QID, SOMAFLAM 175 mg + ibuprofen 400
mg tab.
3. Chlorzoxazone
It is pharmacologically similar to mephenesin, but has a longer duration of
action and is better tolerated orally.
FLEXON-MR 250 mg + ibuprofen 400 mg + paracetamol 325 mg tab; ULTRAZOX
250 mg + diclofenac 50 mg + paracetamol 325 mg tab; MOBIZOX 500 mg +
diclofenac 50 mg + paracetamol 500 mg tab; PARAFON: 250 mg + paracetamol
300 mg tab, 1–2 tab TDS.
4. Chlormezanone
It has antianxiety and hypnotic actions as well, and has been used for tension
states associated with increased muscle tone.
DOLOBAK 100 mg + paracetamol 450 mg tab, 1–2 tab TDS.
5. Methocarbamol
It is less sedative and longer acting than mephenesin. Orally it has been used in
reflex muscle spasms and chronic neurological diseases. It can be injected i.v.
without producing thrombophlebitis and haemolysis— used for orthopedic
procedures and tetanus.
ROBINAX 0.5 g tab, 1 TDS: 100 mg/ml inj. for i.v. or i.m. use. ROBIFLAM 750 mg
+ ibuprofen 200 mg tab; NEUROMOLMR 400 mg + paracetamol 500 mg tab.
Clinical efficacy of none of the above drugs as muscle relaxant is well
established. Gastric irritation and sedation are the most important side effects.
6. Diazepam
It is the prototype of benzodiazepines (BZDs) which act in the brain on specific
receptors enhancing GABAergic transmission. Muscle tone is reduced by
supraspinal rather than spinal action; muscle relaxant: sedative activity ratio is
low. No gastric irritation occurs and it is very well tolerated, though sedation
limits the dose which can be used for reducing muscle tone. It is particularly
valuable in spinal injuries and tetanus. Combined with analgesics, it is popular
for rheumatic disorders associated with muscle spasm.
Dose: 5 mg TDS orally, 10–40 mg i.v. (in tetanus).
7. Baclofen
This analogue of the inhibitory transmitter GAB-A acts as a selective GABA-B
receptor agonist. The GABA receptors have been divided into:
GABA-A receptor Intrinsic ion channel receptor which increases Cl¯
conductance; blocked by bicuculline; facilitated by BZDs.
GABA-B receptor G-protein coupled receptor; hyperpolarizes neurones by
increasing K+ conductance and altering Ca2+ flux; bicuculline insensitive, but
blocked by saclofen. Baclofen does not affect Cl¯ conductance and its actions
are not antagonized by bicuculline. The primary site of action of baclofen is
considered to be in the spinal cord where it depresses both polysynaptic and
monosynaptic reflexes. As such, it does produce muscle weakness, but is less
sedative than diazepam.
Spasticity in many neurological disorders like multiple sclerosis, amyotropic
lateral sclerosis(ALS), spinal injuries and flexor spasms is reduced, and baclofen
is the preferred drug for symptomatic relief. However, it is relatively ineffective
in stroke, cerebral palsy, rheumatic and traumatic muscle spasms and
parkinsonism.
Baclofen is well absorbed orally and is primarily excreted unchanged in urine
with a t½ of 3–4 hours.
Side effects are drowsiness, mental confusion, weakness and ataxia; serum
transaminases may rise. Sudden withdrawal after chronic use may cause
hallucinations, tachycardia and seizures.
Dose: 10 mg BD to 25 mg TDS. LIORESAL, LIOFEN 10 mg, 25 mg tab.
8. Thiocolchicoside
Chemically related to colchicine, this muscle relaxant is believed to act as a
GABA mimetic and glycinergic drug. Combined with NSAIDs, it is being used for
painful muscle spasms, such as torticolis, sprains, backache, etc. Side effects
are gastric upset and photosensitivity reactions
Dose: 4 mg TDS-QID; NUCOXIA-MR: Thiocolchicoside 4 mg + etoricoxib 60 mg
tabs.
9. Tizanidine
This clonidine congener is a central α2 adrenergic agonist—inhibits release of
excitatory amino acids in the spinal interneurones. It may facilitate the
inhibitory transmitter glycine as well. Polysynaptic reflexes are inhibited
resulting in decreased muscle tone and frequency of muscle spasms without
reducing muscle strength. Efficacy similar to baclofen or diazepam has been
noted in multiple sclerosis, spinal injury and stroke, with fewer side effects.
Tizanidine is absorbed orally, undergoes first pass metabolism and is excreted
by the kidney; t½ 2–3 hours. It is indicated in spasticity due to neurological
disorders and in painful muscle spasms of spinal origin. Side effects are
drymouth, drowsiness, night-time insomnia and hallucinations. Dose-
dependent elevation of liver enzymes occurs. Though no consistent effect on
BP has been observed, it should be avoided in patients receiving
antihypertensives, especially clonidine.
Dose: 2 mg TDS; max 24 mg/day. SIRDALUD 2, 4, 6 mg tab, TIZAN 2, 4 mg tab;
BRUFENMR, TIZAFEN 2 mg + ibuprofen 400 mg tab; TIZANAC 2 mg + diclofenac
50 mg tab, PROXIVON-MR 2 mg + nimesulide 100 mg cap.
Uses of centrally acting muscle relaxants
1. Acute muscle spasms Overstretching of a muscle, sprain, tearing of
ligaments and tendons, dislocation, fibrositis, bursitis, rheumatic disorders, etc.
cause painful spasm of muscles. The mephenesin-like and BZD muscle
relaxants, combined with analgesics, are commonly used, but efficacy is not
impressive.
2. Torticollis, lumbago, backache, neuralgias These are other conditions in
which painful spasm of certain muscles is a prominent feature; respond in the
same way as acute muscle spasms.
3. Anxiety and tension Increased tone of muscles often attends these states.
Diazepam group of drugs and chlormezanone benefit by their antianxiety as
well as muscle relaxant actions.
4. Spastic neurological diseases Impairment of descending pathways in the
cerebrospinal axis and withdrawal of inhibitory influence over the stretch
reflex causes chronic increase in muscle tone or spasticity. Hemiplegia,
paraplegia, spinal injuries, multiple sclerosis, ALS and cerebral palsy fall in this
category. These conditions are benefited by baclofen, diazepam, tizanidine and
dantrolene but not by mephenesin group of drugs. However, therapy of these
disorders is far from satisfactory.
5. Tetanus Most commonly diazepam is infused i.v. and the dose is titrated by
the response. Methocarbamol is an alternative.
6. Electroconvulsive therapy Diazepam decreases the intensity of convulsions
resulting from ECT, without diminishing its therapeutic effect. Often SCh is
used in addition for total suppression of the muscular component of ECT.
7. Orthopedic manipulations These procedures may be performed under the
influence of diazepam or methocarbamol given i.v.