NEUROMUSCULAR BLOCKING AGENT IN ANESTHESIA

MUSCLE RELAXANT

1. MUSCLE RELAXANT Presented by: Alim Supervised by: Dr Lim

2. DEFINITION Neuromascular blocking agent (NMBA): A compound that causes paralysis of skeletal muscle by blocking neural transmission at the neuromuscular junction. Owes its paralytic property to the mimicry of Acetylcholine (Ach)

3. NEUROMASCULAR TRANSMISSION

4. Ach RECEPTOR STRUCTURE 5 protein subunits Only the two identical alpha subunits are capable of binding Ach molecules If both binding sites are occupied by Ach > conformational change in the subunit > open an ion channel in the core of receptor Channel will not open if Ach binds on only one site

5. CLASSIFICATION Depolarizing NMBA Acts as Ach receptor agonists Non depolarizing NMBA Acts as a competitive antagonists Distinct differences in the mechanism of action, response to peripheral nerve stimulation and reversal of block.

6. DEPOLARIZING MUSCLE RELAXANT Suxamethonium

7. SUXAMETHONIUM A.K.A diacetylcholine or suxamethonium or scoline Dosage: IV 1.0- 1.5mg/kg Rapid onset of action (30-60s) Very low lipid solubility, thus has a small volume of distribution Short acting Rapidly metabolized by pseudocholinesterase(in plasma) into succinylmonocholine Only a fraction of injected dose reaches the NMJ Short duration of action (<10 mins) As drug level falls, it rapidly diffuses away from NMJ

8. MECHANISM OF DEPOLARIZING NMBA

9. SEQUENCE OF MUSCLE BLOCKADE Central muscle > peripheral muscle Face> jaw> pharynx> larynx> respiratory> trunk muscle> limb muscles This muscles recover in the same order

10. Side effects of Succinylcholine

11. Conditions that cause reduced levels of pseudocholinesterase Pregnancy Liver diseases Renal failure Drugs

12. Hyperkalemia Following denervation injuries (spinal cord injuries, larger burns), immature isoform of ACh receptor may be expressed inside and outside the neuromuscular junction (up-regulation). These extrajunctional receptors allow succinylcholine to cause widespread depolarization and extensive potassium release. Risk of hyperkalemia usually seems to peak in 7–10 days following the injury, but exact time of onset and duration of the risk period vary.

13. Malignant Hyperthermia Due to an uncontrolled increase in intracellular calcium in skeletal muscle. Sudden release of calcium from sarcoplasmic reticulum removes the inhibition of troponin  sustained muscle contraction. Markedly increased ATP activity  uncontrolled increase in aerobic and anaerobic metabolism. The hypermetabolic state markedly increases O2 consumption and CO2 production  severe lactic acidosis and hyperthermia.

14. NON-DEPOLARIZING MUSCLE RELAXANT Rocuronium Atracurium

15. Mechanism of action Competitively binds to nicotinic receptors preventing Ach from stimulating receptors. Also acts on presynaptic receptors by interfering with calcium entry, thus causing inhibition of Ach release.

16. MECHANISM OF NON-DEPOLARIZING NMBA

17. Pharmacologic properties

18. Classification

19. ROCURONIUM Monoquartenary aminosteroidal compound Also called as Esmeron or Zemuron . Low potency, must be given higher dose to achieve clinical effect Dosage: 0.6- 0.9mg/kg Subsequent doses one quarter of this amount RSI: 0.9- 1.2mg/kg, has onset that approaches Succinylcholine but will have longer duration of action

20. Pharmacokinetics Elimination is predominantly hepatic Hepatic failure and pregnancy will prolong its action Not significantly metabolized by either acetylcholinesterase or pseudocholinesterase Its reversal depends on redistribution , gradual metabolism , excretion from body and administration of reversal agents Duration of action 20- 35 mins

21. Pharmacodynamics CNS: no effect on ICP or IOP CVS: minimal, with large doses, mild vagolytic effect leads to slight increase in heart rate and MAP Respiratory: respiratory muscle paralysis No significant histamine release, bronchospasm is uncommon

22. ATRACURIUM Benzylisoquinolonium ester Dosage: 0.3- 0.6mg/kg

23. Pharmacokinetics Metaboslism by two metabolic pathways: Major pathway Hoffmann eliminations: non-enzymatic spontaneous breakdown that occur at physiological pH and temperature (hypothermia, acidosis will prolong the action) Minor pathway Ester hydrolysis: by non specific esterase Metabolites: acrylate and laundanosine

24. Pharmacodynamics CNS: no effect CVS: minimal CVS effect. <5% change in heart rate, mean arterial pressure,systemic vascular resistance causing transient hypotension Respi : respiratory muscle paralysis, risk of bronchospasm due to histamine release (avoid in asthmatic patients)

25. REVERSAL Anticholinesterase and other pharmacologic antagonist to NMBA

26. Reversal of blockade depends on gradual diffusion, redistribution, metabolism, and excretion from the body of the nondepolarizing relaxant ( spontaneous reversal ). Assisted by the administration of specific reversal agents ( pharmacological reversal ).

27. Cholinesterase Inhibitors/ Anticholinesterase The primary clinical use is to reverse nondepolarizing muscle blockade  inactivate acetylcholinesterase by reversibly binding to the enzyme. It indirectly increase the amount of Ach available to compete with the non-depolarizing agent  re-establishing normal neuromuscular transmission.

28. Unwanted muscarinic side effects are minimized by concomitant administration of anticholinergic medications  atropine sulfate or glycopyrrolate . Duration of action is similar among the cholinesterase inhibitors. Clearance is due to both hepatic metabolism (25% to 50%) and renal excretion (50% to 75%). If nondepolarizing muscle relaxant action is prolonged from renal or hepatic insufficiency  will have corresponding increase in cholinesterase inhibitor duration of action too.

29. NEOSTIGMINE Consists of: a carbamate moiety (provides covalent bonding to acetylcholinesterase) and a quaternary ammonium group (renders it lipid insoluble; cannot pass through the BBB) Its effects (0.04 mg/kg) are usually apparent in 5min, peak at 10 min, and last >1 hr. Dose of neostigmine is 0.04-0.08mg/ kg in combination with either: Atropine (0.4 mg of atropine per 1 mg of neostigmine) or Glycopyrrolate (0.2 mg glycopyrrolate per 1 mg of neostigmine)

30. SUGAMMADEX Modified gamma- cyclodextrin ( su =sugar; gammadex =gamma- cyclodextrin molecule). 3D structure resembles a doughnut with a hydrophobic cavity (trap the drug in the cyclodextrin cavity ‘doughnut hole’)and a hydrophilic exterior. Tight formation of a water-soluble guest–host complex in a 1:1 ratio. Dosage: 4–8 mg/kg Selective antagonists of nondepolarizing neuromuscular blockade specifically aminosteroid group ( eg , rocuronium , verocuronium ). Produces rapid and effective reversal of both shallow and profound blockade in a consistent manner.

31. References

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