NEUROMUSCULAR BLOCKING AGENT IN ANESTHESIA
- 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)
- 5. 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
- 8. CLASSIFICATION 1. Depolarizing NMBA Acts as Ach receptor agonists 2. Non depolarizing NMBA Acts as a competitive antagonists Distinct differences in the mechanism of action, response to peripheral nerve stimulation and reversal of block.
- 11. 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
- 12. MECHANISM OF DEPOLARIZING NMBA
- 14. SEQUENCE OF MUSCLE BLOCKADE • Central muscle > peripheral muscle • Face> jaw> pharynx> larynx> respiratory> trunk muscle> limb muscles • This muscles recover in the same order
- 15. Increased intracranial pressure • Muscle fasciculations stimulate muscle stretch receptors, thus increase cerebral activity. • Can be attenuated by maintaining good airway control and instituting hyperventilation. Increased intragastric pressure • Due to abdominal wall muscle fasciculations • Off set by an increase in lower esophageal sphincter tone. • No evidence of increased risk for gastric reflux/ pulmonary aspiration Increased intraocular pressure • Extraocular muscle has multiple motor end-plate on each cell. • Prolonged membrane depolarization and contraction of extraocular muscles transiently raise IOP Side effects of Succinylcholine
- 16. Cardiovascular effect • Stimulation of nicotinic receptors in parasympathetic and sympathetic ganglia, and muscarinic receptors in the SA node can increase or decrease BP and HR. • Low doses can produce negative chronotropic and inotropic effects • Higher doses increase HR, contractility and elevate circulating catecholamine levels. • Children are susceptible to profound bradycardia Fasciculation • Onset of paralysis by succinylcholine is usually signaled by visible motor unit contractions. • Typically not observed in young children and elderly patients. Postoperative myalgia • Due to initial unsynchronized contraction of muscle groups. • Can leads to myoglobinemia and increases in serum creatine kinase
- 17. Masseter muscle rigidity • Increases tone in the masseter muscles. • May have difficulty in opening the mouth due to incomplete relaxation of the jaw. • A marked increase in tone preventing laryngoscopy is abnormal; can be a premonitory sign of malignant hyperthermia. Anaphylaxis • Slight histamine release in some patients Succinylcholine apnea • Reduced levels of normal pseudocholinesterase may have a longer duration of action. • Patients with atypical pseudocholinesterase will experience markedly prolonged paralysis.
- 18. Conditions that cause reduced levels of pseudocholinesterase • Pregnancy • Liver diseases • Renal failure • Drugs
- 19. Hyperkalemia • Normal muscle releases enough K+ during succinylcholine-induced depolarization to increase serum K+ by 0.5 mEq/L. • Life threatening in patients with preexisting hyperkalemia. • Can lead to hyperkalemic cardiac arrest that is refractory to routine resuscitation. Malignant hyperthermia • A hypermetabolic disorder of skeletal muscle • Succinylcholineis a potent triggering agent in patients susceptible to MH. • Resembles neuroleptic malignant syndrome (NMS), but pathogenesis is completely different. • No need to avoid use of succinylcholine in NMS.
- 20. 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.
- 21. 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.
- 24. 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.
- 26. Pharmacologic properties Larger dose or priming prior induction will quicken its onset Suitability for intubation 10-15% of its intubating dose can be given prior succinylcholine to inhibit myalgias Suitability to prevent fasciculation Can add dose based on nerve stimulator monitoring or clinically (spontaneous breathing effort/ movement) to facilitate a surgery Maintenance relaxation
- 27. Classification • One quartenary ammonium group attached to a steroid nucleus • i.e. Rocuronium Aminosteroidal compound • Two quaternary ammonium group joined by a chain of methyl groups • i.e. Atracurium Benzylisoquinolinium
- 28. 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
- 29. 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
- 30. 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
- 31. ATRACURIUM • Benzylisoquinolonium ester • Dosage: 0.3- 0.6mg/kg
- 32. 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
- 33. 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)
- 34. REVERSAL Anticholinesterase and other pharmacologic antagonist to NMBA
- 35. • 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).
- 36. 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.
- 38. • 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.
- 39. 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)
- 40. 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.
- 41. References
- 42. THANK YOU
Editor's Notes
- #4: When the nerve impulse from the peripheral or central nervous system reaches the presynaptic membrane (nerve terminal) of the neuromuscular junction in the form of the action potential, it triggers voltage-gated Ca2+ channels at the active zones of the nerve terminal to open, and Ca2+ ions enter the nerve terminal from the extracellular space. Increased intracellular calcium interact with SNARE proteins; this stimulates synaptic vesicles to fuse with active zones and release their content – ACh into the synaptic cleft. This process is named exocytosis. Increased intracellular calcium in nerve terminals triggers the simultaneous release of a number of ACh quanta. The total number of quanta of ACh released by a stimulated nerve markedly depends on the concentration of Ca2+ ions in the extracellular fluid. If Ca2+ ions are not present, even electrical stimulation of the nerve will not produce the release of transmitter. A 2-fold increase in the extracellular calcium will cause a 16-fold increase in the quantal content of an endplate potential. Released ACh travels across the synaptic cleft towards the motor endplate and binds with the nicotinic ACh receptors, triggering ACh-gated channels to open. The motor endplate on the muscle membrane becomes more permeable to Na+ ions. This changes the membrane potential at the muscle membrane from -90 mV to -45 mV. This decrease in membrane potential is called endplate potential. In the skeletal NMJ, the endplate potential is strong enough to propagate action potential over the surface of the skeletal muscle membrane. This potential is carried along the muscle fiber through the system of T tubules and triggers to release Ca2+ ions from the sarcoplasmic reticulum into the sarcoplasm of muscle, which results in the contraction of the muscle. The remaining ACh in the synaptic cleft gets hydrolyzed by the enzyme acetylcholinesterase (AChE). Interestingly, the presynaptic part of NMJ, the nerve terminal, also has nicotinic ACh receptors. These receptors sense ACh in the synaptic cleft and, via a feedback system, controls the release of ACh. If the concentration of ACh in the synaptic cleft has increased appropriately, the presynaptic ACH receptors will sense, and the nerve terminal will shut down more release. The difference between pre-and postsynaptic ACh receptors is the response of these receptors to different ACh receptor agonists and antagonists.[5][7]
- #13: Phase 1: Binding of drug to nicotinic receptors causes depolarisation of motor endplate Fasciculations (transient contractions of muscle motor units) occur due to spread of impulse to adjacent membranes Depolarised membranes remain depolarised and unresponsive to subsequent impulses, causing flaccid paralysis Phase 2: With prolonged exposure, initial end plate depolarisation decreases and membranes become repolarised Membrane is desensitised and cannot easily be depolarised again
- #25: Rocuronium acts by competing for cholinergic receptors at the motor end-plate. This action is antagonized by acetylcholinesterase inhibitors, such as neostigmine and edrophonium. Rocuronium acts by competitively binding to nicotinic cholinergic receptors. The binding of vecuronium decreases the opportunity for acetylcholine to bind to the nicotinic receptor at the postjunctional membrane of the myoneural junction. As a result, depolarization is prevented, calcium ions are not released and muscle contraction does not occur. Evidence also suggests that nondepolarizing agents can affect ACh release. It has been hypothesized that nondepolarzing agents bind to postjunctional ("curare") receptors and may therefore interfere with the sodium and potassium flux, which is responsible for depolarization and repolarization of the membranes involved in muscle contraction.
- #39: The onset of action of glycopyrrolate (0.2 mg glycopyrrolate per 1 mg of neostigmine) is similar to that of neostigmine and is associated with less tachycardia than is experienced with atropine (0.4 mg of atropine per 1 mg of neostigmine).