Skeletal Muscle Relaxants Drugs

Skeletal Muscle Relaxants

• The main clinical use of skeletal muscle relaxant is it acts an adjuvant in surgical anesthesia to obtain relaxation of skeletal muscles à this minimizes the risk of respiratory & cardiovascular depression
• These drugs block the post-synaptic actions of ACh at motor end plate
• On the basis of their site & mechanism of action…these are classified as

1. Peripherally acting muscle relaxants[These act peripherally at neuromuscular junction]
2. a) Non-Depolarizing Blockers (Competitive Blockers)

• Basis:These drugs prevent the access of ACh to NM receptor of motor end plate à prevent its depolarization

1. Long Acting: d-Tubocurarine (d-TC), Metocurine, Doxacurium, pancuronium, pipecuronium, gallamine
2. Intermediate acting: Atracurium, Cisatracurium, Vecuronium, Rcuronium

d-Tubocurarine: – Not clinical used do to its histaminic effects. • Succinylcholine: – SCh is the most commonly used muscle relaxant for passing tracheal tube. It induces rapid, complete and predictable paralysis with spontaneous recovery in ~5 min. – Occasionally SCh is used by continuous i.v. infusion for producing controlled muscle relaxation of longer duration. – It should be avoided in younger children unless absolutely necessary, because risk of hyperkalaemia and cardiac arrhythmia is higher

Pancuronium: – It is a synthetic steroidal compound, ~5 times more potent and longer acting than d-TC. – Because of longer duration of action, needing reversal, its use is now restricted to prolonged operations, especially neurosurgery. • Pipecuronium: – Muscle relaxant with a slow onset and long duration of action; steroidal in nature; recommended for prolonged surgeries. Nondepolarizing blockers – Individual compounds

 Vecuronium: – It is a most commonly used muscle relaxant for routine surgery and in intensive care units.. • Atracurium: – Four times less potent than pancuronium and shorter acting. • Rocuronium: – Muscle relaxant 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. Nondepolarizing blockers – Individual compounds

 iii.      Short Acting: Mivacurine, Rapacuronium

1. b) Depolarizing Blockers (persistent depolarizers)

• Basis:They produce an excessive depolarization which persists for longer duration at NMJ à because they are resistant to hydrolysis by true AChE present in synaptic cleft
• Succinyl Choline

1. Centrally Acting Muscle Relaxants

• Basis:These drugs reduce skeletal muscle tone à by selective action in the cerebrospinal axis without altering consciousness
• Carisoprodol, Chlorzoxazone, Diazepam, Clonazepam, Baclofen, Tizanidine

III. Directly Acting Muscle Relaxants

• Basis:These directly interfere with the contractile mechanisms of voluntary muscle
• Dantrolene

1. Misc Group

• Quinine, Botulinum toxins A & B

Comparison of d-Tubocurarine & Succinylcholine

Parameters	d-Tubocurarine	Succinylcholine
1.Mechanism	Competitive blockade at NM receptors	Persistent depolarization of NM receptors followed by their desensitization
2.Potency	++ (Moderate)	+ (less)
3.Onset	4-5 min	1 min
4.Duration	30 – 50 min with no muscle sore	5 – 6 min followed by muscle sore
5.Type of Relaxation	Progressive flaccid paralysis	Initial fasciculations followed by flaccid paralysis
6.Effect of Neostigmine	Reversal i.e antagonism	Potentiation on effect
7.NM  blocking drugs	Potentiation on effect	No effect
8.Hypothermia	Decreases effect	Increased effect
9.Histamine release	++ (Moderate)	Negligible
10.    BP	Hypotension	No effect
11.    Cardiac Muscarinic receptors	No effect	Stimulates. Bradycardia in low doses, tachycardia in large doses
12.    Respiratory effects	Bronchospasm	Nil
13.    GIT Effects	Constipation	Nausea, Vomitting
14.    Serum K+ levels	No change	Hyperkalaemia
15.    Intraocular pressure	No change	Raised
16.    Pharmacogenetic variation in metabolism	Nil (it is excreted through kidney)	Metabolized by pseudocholinesterase (exhibit prolonged apnoea)
17.    Other	Nil	Malignanat hyperthermia

Mechanism of Action of Skeletal Muscle Relaxants Drugs:

Baclofen

• It is orally active GABA-mimetic drug àwhich acts as a GABA agonist at GABA_B receptors
• The GABA_Breceptors are G-protein coupled receptors à which hyperpolarize neurons by increasing K+ conductance & reduce Ca⁺² conductance
• Its actions àresults from an action at spinal level where it inhibits both monosynaptic & polysynaptic reflexes
• Activation of GABAB recptors in the brain àresults in hyperpolarisation in the cord & brain à which interfere with the release of excitatory neurotransmitters
• It also reduces pain associated with spastic conditions ßas it inhibits the release of substance-P in the spinal cord

Baclofen Therapeutic Uses

• To relieve painful spasticity in multiple sclerosis
• It is also used to relieve spasticity from spinal injuries but it is not very useful in cerebral palsy
• It can also serve as an important substitute to treat trigeminal neuralgia & tardive dyskinesia
• It imrves he quality f life of patients suffering with severe spasticity & pain

Baclofen Side Effects

• Sedation, drowsiness, muscle weakness, ataxia
• Sudden withdrawal may precipitate anxiety, tachycardia & Hallucinations
• It is teratogenic & risk in pregnancy

Dantrolene

• It is a phenytoin analogue àbut its site for antispastic action lies ouside the CNS
• It acts directly at the contractile mechanisms of voluntary muscle by reducing depolarization induced Ca+2 release from the sarcoplasmic reticulum
• The muscle fibers still respond to nerve stimulus àthe contractile responses are reduced but not absolutely abolished by dantrolene à the net result is muscle weakness rather than paralysis
• It also facilitates GABA which results in the depression of brain stem reticular functions & efferent motor neuron activity àit produces sedation but no selective action on polysynaptic reflexes

Dantrolene Therapeutic Uses

• It is used to treat spasticity resulting from upper motor neuron lesions such as spinal cord injury, multiple sclerosis & cerebral palsy
• It is the drug of choice for the treatment of malignant hyperthermia
• It is also used in the treatment of neurolept malignant syndrome
• Orally it is poorly absorbed but absorption is consistent
• Plasma half-life is 9-12 hrs
• A/Es– generalized muscle weakness, sedation, diarrhea, hepatitis after prolonged use

References •

Tripathi KD. Essentials of Medical Pharmacology, 7th Ed, New Delhi: Jaypee Brothers Medical Publisher (P) Ltd, 2013.