SKELETAL MUSCLE RELAXANTS &

SPASMOLYTICSBy

Dr. Abdul Azeem

I) PERIPHERALLY ACTING1) NEUROMUSCULAR JUNCTION BLOCKERS

a) NON DEPOLARIZING NEUROMUSCULAR BLOCKERS

ISOQUINOLINE DERIVATIVES

D- TUBOCURARINE

GALLAMINE

ATRACURIUM

CIS ATRACURIUM

ALCURIUM

DOXACURIUM

MIVACURIUM

• STEROID DERIVATIVES

PANCURONIUM

VECURONIUM

RAPACURONIUM

PIPECURONIUM

ROCURONIUM

b) DEPOLARIZING NEUROMUSCULAR BLOCKERS

SUXAMETHONIUM (SUCCINYLCHOLINE)

DECAMETHONIUM

2) DIRECTLY ACTING

DANTROLENE

II) CENTRALLY ACTING MUSCLE RELAXANTS (SPASMOLYTICS)

• BENZODIAZEPINES DIAZEPAM CHLORDIAZEPOXIDECLONAZEPAM NITRAZEPAM

• GABA ANALOGUES BACLOFEN PROGABIDE

oALPHA 2 AGONIST TIZANIDINE

OTHERSGLYCINE

MEPROBAMATE

MEPHENESEN

IDROCILAMIDE

RILUZOLE

BOTULINUM TOXIN

NEUROMUSCULAR JUNCTION BLOCKERS Classification according to duration of action

› Short acting Succinylcholine <8 min Mivacurium 10-20 min

› Intermediate acting Atracurium 25-35 min Cisatracurium 25-40 min Rocuronium 25-35 min Vecuronium 25-35 min

Long acting Doxacurium more than 35 min Tubocurarine more than 35 min Pancuronium more than 35 min Pipecuronium more than 35 min

Nicotinic Transmission At NMJ

NEUROMUSCULAR JUNCTION

NICOTINIC ACETYLCHOLINE RECEPTOR

History

Strychnos toxifera

Chemistry

• Pharmakokinetics

MOANon Depolarizing / Competitive N.M Blockers- Tubocurarine etc.

Mechanism of Action:

Non Depolarizing / Competitive N.M Blockers i.e . Tubocurarine etc.

Competitive antagonist to Ach at Nicotinic (Nm) Receptor at MEP

N.M Transmission is interrupted leading to N.M. Blockade.

At Larger doses, some drugs also enter pore of ion channel of Nm ,

further decrease in N.M. Transmission.

Blockade is:

Antagonised by:

Anticholinesterases (Neostingmine, Edrophonium,

Pyridostigmine )

Potentiated by:-

• GA.(Ether, Enflurane, Halothane)

• Amino glycoside Antibiotics. (Streptomycin, Gentamicyn)

• Acidosis

• L.A (Procaine)

• Hypokalemia

• Myasthenia gravis

• Dehydration

• Advanced age-Prolonged Effect

D-TUBOCURARINE (PROTOTYPE)

Non depolarizing N.M. Blocker.

Source:

Chief alkaloid of curare Obtained from

Chondrodendron & Strychnos

Chemistry:

Mono quaternary Ammonium Compound.

Pharmacokinetics: Not Abs. from GIT. Given I/VIt is redistributed. Not metabolised.Excreted unchanged by kidney 40 % / Bile 60

%Crosses Placenta but not harmful.It does not cross BBB.

Mechanism of action: O.O.A : 4 min.D.OA: more than 35 min

Pharmacological effects No central effects Skeletal muscle relaxation. First weakness & then

paralysis. Sequence of Paralysis of Skeletal Muscles:

Eye, Jaw, Facial muscles .Muscles of Neck, Limbs , Trunk.Interocostal musclesDiaphragmRecovery in reverse order.Ganglionic blockade: Mild in high doses

CVS: Hypotension due to

Release of Histamine.Vasodilatation, decreased PR , decreased BP. Bronchoconstriction due to Histamine release

Ganglionic Blockade (Vasodilatation) in larger doses.

PANCURONIUM

› Steroidal quaternary ammounioum compund › 6 times more potent than Tubocurarine› Quick onset of action› No effect on ganglia› Vagolytic effect› Moderate increase in Blood Pressure › No effect on CNS› No effect on foetus › No Histamine release› ›

• ATRACURIUM • Isoquinoline• Intermediate acting • Metabolism – Hepatic

• Hofmann Elimination • Laudanosine

Seizures

• Cis-Atracurium • Mivacurium: Shortest duration of action. Metabolised

by pseudocholine esterase

Depolarizing Skeletal Muscle Relaxant (Succinylcholine)

• Pharmakokinetics

M.O A of Depolarizing drugs (Succinylcholine)The Blockade occurs in 2 Phases

Phase I (depolarizing)

Phase I block: is augmented by anticholinestrase & not reversed

Phase I (depolarizing)1. Succinylcholine reacts with nicotinic receptors2. Ion channels are opened → depolarization of motor end

plate.3. Depolarization spreads to adjacent membrane 4. Result in disorgansed / generalized contraction of motor

unit.5. Not hydrolyzed in synapse → persistent depolarization

→ flaccid paralysis

Phase II Block (Desensitizing Block)With continued exposure—Initial end plate depolarization decreases and membrane is re polarized but unresponsive/ desensitized to Ach. due to:

Blockade of channel.Development of in excitable area in muscle membrane immediately

surrounding the M.E.P which prevent the spread of impulses or desensitization of membrane occurs .

MOA OF SUCCINYLCHOLINE

SUCCINYLCHOLINE › Hydolysed by plasma & liver Pseudochlone & butyryl

cholinesterases› Duration of action is very short (8 min)

DIBUCAINE NUMBER TEST

Adverse Effects• Non Depolarising Drugs

• Histamine Release• Vagolytic Effect

• Depolarising Drugs (Succinyl choline)• Malignant Hyperthermia• Apnea• Hyperkalamia • Increased intra gastric pressure• Increased IOP• Muscular Aches & Pain

•

Drug Interactions

• Uses of NMJ Blockers • Surgical operations • Endotracheal intubation ,laryngoscopy• Orthopedic manipulation • Convulsive disorders• Electroconvulsive therapy (ECT)• For assisted ventilation

SUGAMMADEX

When given post operatively there is rapid recovery from

even profound degree of Neuro muscular blockade.

It rapidly inactivate the steroidal neuro muscular blocking

drugs by forming an in active complex which is excreted in

urine

DANTROLENE MOA: It reduces the release of activator calcium from the

sarcoplasmic reticulum

DANTROLENE MOA

PHARMACOKINETICS

ADVERSE EFFECTS

THERAPEUTICS USES Spasmolytic Malignant hyperthermia

DOSE

PHARMACOKINETICS1/3 of oral dose is absorbed t ½ is 8 hrs.

ADVERSE EFFECTS •Muscle Weakness•Sedation •Occasionally hepatitis

THERAPEUTICS USES Spasmolytic Malignant hyperthermia

DOSE:As SpasmolyticInitially 25mg / day gradually increase over 7 weeks to a maximum of 100 mg 4 times a dayFor Malignant Hyperthemia

Botulinum ToxinMOA

Uses

Strabismus

Blepharospasm

Hemifacial spasm Spasm associated with lower esophageal sphincter and anal fissure

Dystonias e.g. cervical dystonia,Oromandibular dystonia

Generalized spastic disorders( cerebral palsy)

Hyperhidrosis of palms and axillae

Cosmetic procedure for wrinkles of the face

Central Spasmolytics • Spasticity is increased muscle tone. • increase in tonic stretch reflexes and flexor muscle spasm with muscle

weakness • Often observed in

– Cerebral palsy – Multiple sclerosis – Stroke – ALS (Amyotrophic lateral sclerosis)

• Aim• Reduction of excessive skeletal muscle tone without reduction of muscle

strength.

DIAZEPAM

MOA: It facilitates the action of GABA in CNS.

USES: Muscle Spasm (local truma to tetanus)

DOSE: Oral dose initially 5 mg / day and gradually increase to

maximum of 60 mg / day.

ADVERSE EFFECTS Sedation

BACLOFEN MOA: GABA B Agonist ADVERSE EFFECTS• Drowsiness• Increase in seizure activity in epileptic patients• Excessive somnolence• Respiratory depression• Coma THERAPEUTICS USES

– Relieves muscles spasm. Most useful agent for symptomatic treatment of spasticity

– Prevention of migraine – Reduces craving in recovering alcoholics

TIZANIDINE MOA: Centrally acting Alpha 2 agonist Inhibits release of excitatory amino acids in the

spinal interneuronsIt re-inforces both pre-synaptic & post- synaptic inhibition in the cord

ADVERSE EFFECTS Drowsiness Hypotension Dry mouth Asthenia

GABAPENTIN Antiepileptic drug is a good spasmolytic agent in patient

with multiple sclerosis

PRE GABALIN Newer analogue of gabapentin usefull in muscle spasm

PROGABIDE Gaba A and Gaba B agonist and has active metabolites

including GABA itself

Riluzole • Pharmacokinetics – Absorption orally – Highly protein bound – Half life 12 hours –Metabolism --- in liver by both cyotchrome P450-mediated hydroxylation and

glucurnidation MOA– it inhibits glutamate release – It also blocks postsynaptic NMDA- and kainite-type glutamate receptors and

inhibits voltage-dependent sodium channels

Uses • ALSDose• 50 mg every 12 hours Adverse effect • Nausea • Diarrhea • Hepatic injury

GLYCINE inhibitory neurotransmitter. When Given crosses

BBB IDROCILAMIDE

Newer drugs for treatment of ALS MOA

Inhibit glutamatergic transmission in CNS

Meprobamate • Seditive, Hypnotic and Anti anxiety drug

Carisoprodal • Its active metabolite is meprobamate. Cyclobenzaprine

DIAZEPAMMOA

USES

DOSE

ADVERSE EFFECTS

BACLOFEN MOA

ADVERSE EFFECTS

THERAPEUTICS USES– Relieves muscles spasm. Most useful agent for

symptomatic treatment of spasticity – Prevention of migraine –Reduces craving in alcoholics

TIZANIDINE MOA

It re-inforces both pre-synaptic & post- synaptic inhibition in the cord

ADVERSE EFFECTS Drowsiness Hypotension Dry mouth Asthenia

Meprobamate • Saditive, Hypnotic and Anti anxiety drug

Carisoprodal • Its active metabolite is meprobamate.

Glycine