L39→↑↓ Skeletal Muscle Relaxants and Anti- spasmodics

Question 1

Mechanism, Contraindication, S/E of Depolarizing Neuromuscular Blocker
(Non-competitive) Succinylcholine

Answer 1

MoA
Agoinst at Nicotinic receptor
Produces neuromusclar block by overstimulation end plate is unable to respond to further stimulation
long lasting or persistent depolarizatoin

Phase I Block
→Preceded by muscle fasciculation
→Due to prejunctional action of succinylcholine on ACh receptors causing repetitive firing and release of neurotransmitter
→ Recovery occurs as succinylcholine diffuses away from the NMJ due to reduction in plasma level

Prolonged exposure of succinylcholine (repeated boluses or infusion) to NMJ can result in
→ Phase I block
→ Phase II block (features of a non -depolarizing block)
Characterized by fade seen with tetanic and train-of-four (TOF) stimulation, as well as post-tetanic potentiation
Phase II Block
Adverse Effects
→Transient increase in intraocular tension
→ Increase in intragastric pressure
→ Hyperkalemia: fasciculations release potassium in blood
→ Succinylcholine apnea
→ Malignant hyperthermia: when used along with halothane in general anesthesia
→Caused by a mutation of Ca++ release channel in sarcoplasmic reticulum of the skeletal muscle , i.e. gene encoding ryanodine receptor type 1 (RyR1)
Results in muscle spasm and dramatic rise in body temperature
→ Treatment is by rapid cooling of patient and dantrolene (IV)
→ Muscle pain

Depolarizing neuromuscular blocker
→ Halothane can cause malignant hyperthermia

Question 2

Mechanism, Contraindication, S/E Drug Interaction Non-depolarizing Neuromuscular Blockers (Competitive Antagonists)

Answer 2

Long-acting: kidney excretion
→ D-tubocurarine
→ Pancuronium

Intermediate-acting: eliminated by liver
→Atracurium
→ Rocuronium
→ Vecuronium

Short-acting: inactivated by plasma cholinesterase
→ Mivacurium

MoA
competes with acetycholine for receptor binding site→block the muscle→ muslce relax
→ have high affintity but no intrinisce action
can give anti-cholinesterases to reverse action

Drug Interaction
Non-depolarizing neuromuscular blockers
→ Anti-cholinesterases (neostigmine, physostigmine)
→ Reverse the action of non-depolarizing blockers

Halothane, aminoglycoside antibiotic gentamicin and
calcium channel blockers like nifedipine
→→Enhances the neuromuscular blockade

Question 3

Alternative Classification of Non-depolarizing Neuromuscular Blockers

Answer 3

Benzylisoquinolinium (benzylquinoline derivatives 
→Atracurium
→D-tubocurarine
→ Cisatracurium
→Mivacurium

Aminosteroidal (sterodial)
→ Pancuronium
→ Rapacuronium
→Vecuronium
→Rocuronium

Mechanism of Action
Anti-cholinestrases neostigmine which preserve acetycholine are used to reverse the effect of d-tubocurarine

Question 4

Mechanism, Contraindication, S/E neuromuscular reversal drug Sugammadex

Answer 4

Inactivates and removes non-depolarizing neuro- muscular blockers such as rocuronium and vecuronium

Less effective for pancuronium (aminosteroidal), benzylisoquinoliniums and succinylcholine

Actions (I)
Muscle weakness flaccid paralysis
Recovery in the reverse order
⎼ Consciousness, appreciation of pain – NOT affected

Autonomic ganglion blocking property
→ Histamine release from mast cells
→ Cardiovascular system (CVS)
→ Significant fall in BP
→ Increase in HR
→ Vagal ganglionic blockade

Newer competitive blockers:
→ Negligible effect on BP and HR

Adverse Effects
→Hypotension
→Tachycardia
→Respiratory paralysis
→Bronchospasm
→Aspiration of gastric contents

As an adjunctive agent to general anesthesia
As an adjunctive agent in mechanical ventilation to improve outcomes

Question 5

Mechanism, Contraindication, S/E

of Centrally Acting Muscle Relaxants Diazepam

Answer 5

Acts on GABAA receptors & increase GABAA receptors affinity for GABA in the brain and in the spinal cord
Stimulation by GABA leads to the influx of Cl- →hyperpolarization of the postsynaptic cell

Question 6

Mechanism, Contraindication, S/E 
 of Spasmolytics (Dantrolene)

Answer 6

Inhibits depolarization by acting on ryanodine receptor 1 (RyR 1) – NO induction of calcium release from sarcoplasmic reticulum

Indications: conditions associated with spasticity
→ Spinal cord injury, multiple sclerosis and cerebral palsy

Adverse effects:
→ Generalized muscle weakness
→ Sedation
→ Diarrhea

Question 7

Mechanism, Contraindication, S/E 
 of Spasmolytics (Botulinum Toxin A) (Botox)

Answer 7

A peripherally acting muscle relaxant
→ Binds presynaptically to high-affinity recognition sites on
the cholinergic nerve terminals
→Decreases the release of acetylcholine

Recovery occurs through proximal axonal sprouting and muscle re-innervation by formation of a new neuromuscular junction

Question 8

Mechanism, Contraindication, S/E of (Spasmolytics) Baclofen

Answer 8

A racemic GABAB receptor agonist
→Inhibit activity of motor neurons in the anterior horn of the spinal cord and other sites in the central nervous system

Mechanism of action
→Hyperpolarization of neurons by increasing K+ conductance and
alteration of Ca++ flux
→ Does not affect to Cl- conductance

Indications:
→ To relieve painful spasticity in multiple sclerosis
→ To relieve spasticity from spinal injuries but NOT very useful in cerebral palsy

S/E
hypotension
nausea constipation
urinary frequency
dizziness

Question 9

Mechanism, Contraindication, S/E of

(Spasmolytics) Tizanidine

Answer 9

Clonidine derivative, a central a2-adrenergic receptor agonist

Mechanism of action
→ Inhibits the release of glutamate on polysynaptic pathways

→Metabolized by CYP1A2
CYP1A2 inhibitor drug ciprofloxacin, greatly increases tizanidine plasma level

S/E
Dry mouth
hypotension
bradyarrhythmia