Neuromuscular Blockers

Neuromuscular blockers or skeletal muscle relaxants are drugs that act peripherally or centrally to reduce muscle tone and cause transitory paralysis.

Peripherally acting neuromuscular blockers

1.  Non depolarizing blockers (competitive blockers)
   • Long acting: d-tubocurarine, Gallamine triethiodide, Pancuronium,Doxacurarium, Pipercuronium
   • Intermediate acting: Vecuronium, Atracurarium,
   • Short acting: Mivacurium
2. Depolarizing blockers (non competitive blockers): Succinylcholine, Decamethonium

Centrally acting Neuromuscular blockers

Centrally acting Neuromuscular blockers are Dantrolene sodium, Quinine.

Mechanism of action of Neuromuscular blockers

Competitive Neuromuscular blockers

Competitive Neuromuscular blockers have affinity for the nicotinic (N_M) cholinergic receptors at the muscle end-plate but have no intrinsic activity. Most of competitive blockers have one or more quartenary N⁺ atoms which provide necessary affinity to the same site.

Competitive blockers have a thick bulky molecules hence termed as pachycurare. Ach released from motor nerve endings is not able to combine with its receptors to generate end-plate potential (EPP). d-tubocurarine thus reduces frequency of channel opening but not its duration or the conductance of a channel once opened. When the magnitude of EPP falls below a critical level it is unable to trigger propogated muscle action potential and muscle fails to contract in response to nerve impulse.

At very high concentrations curare like drugs directly block sodium channels to produce noncompetitive neuro muscular blockade. Decamethonim and succinylcholine have affinity as well as submaximal intrinsic activity at the N_M cholinoceptors.

They depolarize musle end-plate by opening sodium channels and initially produce twitching and fasciculation because focal muscle stimulation is transient.

Long lasting depolarization produce repetitive excitation of fibre.

Depolarizing drugs do not dissociate rapidly from the receptor, induce partial prolonged depolarization, inactivation of sodium channels, action potential drops to 50 mV, Ach released from motor nerve endings is unable to generate propogated MAP, flaccid paralysis occurs.

The depolarizing agents produce dual mechanism neuromuscular blockade which is divided as Phase I which is rapid in onset,results from persistent depolarization of EPP and has classical feature of depolarization blockade.The depolarization decline shortly afterwards and repolarization occurs even in the presence of drug at the receptor and Phase II supervenes. Phase II is slow in onset and results from desentization of the receptors to Ach.

Pharmacokinetics of NM blockers

1. All neuromuscular blockers are quaternary compounds- Not orally absorbed
   • Given as i.m or i.v.
   • Muscle with rich blood supply gets affected first
   • Do not cross placenta or BBB
   • Gallamine is not metabolized. 
2. d-tubocurarine, Pancuronium, Doxacurium and Pipercuronium are partly metabolized
   • Vecuronium, Atracurium, Mepvacurium, Rovacurium are largely metabolised
   • Unchanged drug is excreted in urine and bile.
3. Succinylcholine is rapidly hydrolysed by plasma pseudocholinesterase to succinyl monocholine and then to succinic acid and choline.
   • Some may have deficiency of pseudocholinestease thereby entering phase II blockade leading to muscle paralysis and apnoea lasting for hours.

Pharmacological actions of NM blockers

Skeletal muscles

On IV administration of  non depolarizing blocker rapidly produces muscle weakness followed by flaccid muscle paralysis.

• The order of paralysis is as follows: fingers,extraocular,hands,feet,arm,leg,neck,face,trunk,intercostal muscles,diaphragm and respiration stops.
• Recovery occurs in reverse fashion. The peak effect and duration of action depends on several factors like anaesthetic used, haemodynamic status, renal and hepatic status etc.,
• Depolarizing agents produce fasciculations lasting few seconds before inducing flaccid paralysis.
• Apnoea occurs withing 45-90 seconds but lasts 2-5 minutes recovery is rapid.
• d-tubocurarine has maximum effect.

Autonomic ganglia

Cholinergic receptors in autonomic ganglia is nicotinic, competitive blockers produce some degree of ganglionic blockade. Succinylcholine cause ganglionic stimultion by its agonistic action on nicotinic receptors.

CVS

d-tubocurarine produce significant fall in blood prssure – due to ganglionic blockade, histamine release and reduced venous return. Gallamine has muscarinic vagal blocking action in the heart and cause tachycardia. Pancuronium and Vencuronium cause tachycardia with negilible effect on BP and heart rate. Sucinylcholine has variable effect.

Generally bradycardia due to activation of vagal ganglia followed by tachycardia and rise in BP due to stimulation of sympathetic ganglia.

GIT

Competitive blockers may enhance post operative paralytic ileus after opeation.

CNS

Being a quaternary compound do not cross blood brain barrier.

Difference between competitive and non competitive neuromuscular blocker

	Competitive blocker (d-tubocurarine)	Depolarizing blocker (Succinylcholine)
Paralysis in human	Flaccid	Fasciculation resulting in flaccidity
Paralysis in chick	Flaccid	Spastic
Species sensitivity	Rat>Rabbit>Cat	Cat>Rabbit>Rat
Neostigmine	Antagonism block	No effect
Inhalation anaesthetic (ether)	Synergistic	No effect
Order of paralysis	Fingers-eyes-limbs-neck-face-trunk-intercostal muscles	Neck-limbs-face-jaw-eyes-pharynx-trunk-intercostal muscles

Examples of Competitive Neuromuscular blockers

1. d-tubocurarine: is an alkaloid obtained from Chondrodendron  tomentosum
   • Prominent release of histamine
   • Ganglionic blocking
   • Long duration of action
   • Not used now.
2. Gallamine triethiodide
   • Produce marked tachycardia due to vagal blockade,
   • Needs reversal.
3. Pancuronium
   • Synthetic steroidal compound
   • 5 times more potent than d-tubocurarine
   • Long duration of action
   • Reversal required
   • Cardiovascular staility is good.
   • Inexpensive routinely used.
4. Vencuronium
   • Close congener of pancuronium with shortest duration of action.
   • Cardiovascular stability is still better.
5. Atracurium
   • A bisquaternary compound
   • Shorter acting
   • Unique feature is inactivation in plasma by spontaneous non enzymatic degradation.

Examples of Depolarizing neuromuscular blocker

1. Succinylcholine
   • Most commonly used muscle relaxant for passing endotracheal tube.
   • Induce rapid, predictable and complete paralysis with spontaneous recovery in five minutes.

Uses of Neuromuscular blockers

As an adjunct to general anesthesia. Succinylcholine is employed for brief procedures. Convulsions and trauma from electroconvulsive therapy can be avoided by use of muscle relaxants. Succinylcholine can be used for this purpose. In severe cases of tetanus and status epilepticus not controlled by benzodiazepines.

Toxicity of Neuromuscular blockers

1. Respiratory paralysis and prolonged apnoea
2. Flushing common with d-tubocurarine
3. Fall in blood pressure and cardiovascular collapse can occur in hypovolaemic conditions
4. In digitalized individuals cardiac arrhythmias and even arrest can occur with succinylcholine.
5. Precipitation of asthma with d-tubocurarine
6. Post operative muscle soreness with succinylcholine

Drug Interactions of NM blockers

1. Thiopentone  and Succinylcholine-react chemically. Hence donot mix in same syringe.
2. General anaesthetics potentiates competitive blockers.
   • Isoflurane potentiates more than halothane
   • ketamine intensifies nondepolarizing blockers.
3. Adrenaline and other sympathomimetics reduce competitive blocker by increasing Ach release.
4. Diuretics produce hypokalaemia -enchancing competitive block.
5. Calcium channel blockers verapamil potentiate both type of blockers.
6. Anticholinesterases reverse the action of competitive blockers.
7. Muscarinic action of neostigmine can be prevented by atropinization. Pretreatment with antihistamines is indicated.
8. Aminoglycosides reduces Ach release from prejunctional nerve ending by competing with calcium ions. So the dose of competitive blockers should be reduced in patients receiving high doses of antibiotics.

Central and direct acting muscle relaxants

Chemically and pharmacologically different from neuromuscular blockers. Does not affect neuromuscular transmission or EPP but uncouples contraction from depolariztion of the muscle membrane.

Depolarization triggered release of calcium ions from sarcoplasmic reticulum is reduced. Fast contracting twitch muscles are affected than slow contracting. Reduce skeletal muscle tone by a selective action in the cerebrospinal axis, without altering conciousness.

Do not have sedative action. Have no effect on neuromuscular transmission and on muscle fibres. Reduce rigidity,spasticity and hyperreflexia.

• Dantrolene a centrally acting muscle relaxant is-
  1. Absorbed orally
  2. Penetrates BBB and produces sedation
  3. Metabolized by liver and excreted by kidney
  4. Reduces spasticity  upper motor neurones disorders
  5. Drug of choice for malignant hyperthermia due to persistent release of calcium ions from Sarcoplasmic reticulum. (induced by fluorinated anaesthetics and Ach in genetically susceptible individuals)
• Other centrally acting muscle relaxants are-
  • Mephenesin group: Mephenesin, Carisoprodol, Chlorzoxazone, Chlormerzanone, Methocarbamol
  • Benzodiazepines: Diazepam
  • GABA derivatives: Baclofen

Adverse effects of Centrally acting NM blockers

1. Muscle weakness
2. Sedation
3. Malaise
4. Light headedness and other central effects

Clinical uses of centrally acting muscle relaxants

1. Acute muscle spasms
2. Torticollis
3. Lumbago
4. Backache
5. Neuralgia
6. Muscle pull
7. Anxiety
8. Tension
9. Spastic neurological ailments
10. Tetanus
11. Electroconvulsive therapy
12. Orthopedic manipulation

Difference between central and peripherally acting muscle relaxants

Centrally acting muscle relaxants	Peripherally acting muscle relaxants
Muscle tone decreasedNo reduction in voluntary movements	Muscle paralysisVoluntary movements are lost
Postsynaptic reflexes in CNS are inhibited	Neuromuscular transmission is blocked
CNS depression	CNS effect not significant
Administred orally/parentrally	Administered by i.v.only
Value in the treatment of spastic muscle spasms, tetanus	Commonly used for short procedures