Neuromuscular blocking drugs

Neuromuscular blocking Agents

1. NEUROMUSCULAR BLOCKING AGENTS Dr Shreyas Kate Dept of Anaesthesiology & Critical Care

2. Contents Physiology History Succinylcholine Dibucaine Number Classification of Non Depolarizing Neuromuscular Blocking Drugs Pharmacokinetics Metabolism & Elimination

3. Physiology

4. nACHRs P entameric Organizationally it is αεαδβ The subunits are organized to form a transmembrane pore , or channel has extracellular binding pockets for acetylcholine and other agonists or antagonist Are clustered on the crests of the junctional folds The receptor density in this area is 10,000 to 30,000/μm2 Each of the two α subunits has an acetylcholine-binding site . These sites are located in pockets within the receptor protein, approximately 3.0 nm above the surface membrane at the interfaces of the αH-ε and αL-δ subunits The fetal nAChR contains a γ subunit instead of an adult ε subunit (low-conductance channel)

5. History 1942: Griffith and Johnson described d -tubocurarine ( dTc ) as a safe drug to provide skeletal muscle relaxation during surgery 1952 : Succinylcholine, introduced by Thesleff and Foldes and associates 1 967, Baird and Reid reported on the clinical administration of the first synthetic aminosteroid , “ P ancuronium ” 1980s : Vecurominum ( aminosteroid ) / Atracurium ( benzylisoquinolinium ) : 1990s : Mivacurium (Short acting) / Rocuronium (Intermediate acting) B y Foldes and colleagues,“ … first use of … muscle relaxants … not only revolutionized the practice of anesthesia but also started the modern era of surgery and made possible the explosive development of cardiothoracic, neurologic, and organ transplant surgery ”

6. Succinylcholine

7. STRUCTURE-ACTIVITY RELATIONSHIPS The depolarizing NMBD, succinylcholine, is composed of two molecules of ach linked through the acetate methyl groups This mechanism results in desensitization of the nAChR inactivation of voltage-gated Na+ channels at the neuromuscular junction increases in K+ permeability in the surrounding membrane The end results are failure of action potential generation and neuromuscular blockade

8. PHARMACOKINETICS Rapid onset of effect and an ultrashort duration of action. The ED95 is 0.51 to 0.63 mg/kg Administration of 1 mg/kg of succinylcholine results in complete suppression of response to neuromuscular stimulation in approximately 60 seconds Recovery to 90% muscle strength following administration of 1 mg/ kg succinylcholine requires 9 to 13 min T1/2 : 47 seconds Metabolism: rapid hydrolysis by butyrylcholinesterase to succinylmonocholine and choline. only 10% of the intravenously administered drug reaches the neuromuscular junction The initial metabolite, succinylmonocholine , is a much weaker NMBD than succinylcholine and is metabolized much more slowly to succinic acid and choline.

9. SIDE EFFECTS Cardiovascular Effects: stimulates cholinergic autonomic receptors on both sympathetic and parasympathetic ganglia Low doses: both negative inotropic and chronotropic response (attenuated by prior administration of atropine) large doses: positive ino & chronotropic Arrhythmias: Sinus Brady : Stimulation of cardiac muscarinic receptors (predominantly vagal tone, such as in children who have not received atropine) Nodal (Junctional) Rhythms : relatively greater stimulation of muscarinic receptors in the sinus node, thus suppressing the sinus mechanism and allowing the emergence of the atrioventricular node as the pacemaker Ventricular Dysrhythmias : decreases the threshold of the ventricle to catecholamine-induced dysrhythmias

10. SIDE EFFECTS Hyperkalemia : increases the plasma K+ levels by approx 0.5 mEq /dL Exaggerated hyperkalemia is seen in renal failure Uremic neuropathy Severe metabolic acidosis Hypovolumia intraabdominal infections for longer than 1 week 1 week after the injury Conditions that result in the proliferation of extrajunctional acetylcholine receptors upper or lower motor denervation Immobilization burn injuries neuromuscular disease

11. SIDE EFFECTS Increased Intraocular Pressure Develops within 1 minute of injection Peaks at 2 to 4 minutes subsides by 6 minutes Involve contraction of tonic myofibrils and/or transient dilatation of choroidal blood vessels Use of succinylcholine for eye operations is not contraindicated unless the anterior chamber is open Precurarization Increased Intragastric Pressure more variable fasciculations of the abdominal skeletal muscle IGP > 28 cm H2O is required to overcome the competence of the gastroesophageal junction. However, when the normal oblique angle of entry of the esophagus into the stomach is altered (pregnancy, ascites, bowel obstruction, hiatus hernia)the IGP required to cause incompetence of the gastroesophageal junction is frequently less than 15 cm H2O

12. SIDE EFFECTS Myalgia: The incidence of muscle pain varies widely, from 0.2% to 89% damage produced in muscle by the unsynchronized contractions of adjacent muscle fibers just before the onset of paralysis Masseter Muscle Rigidity: increase in masseter muscle tone of up to 500 g lasting 1 to 2 min is a normal finding in adults Anaphylaxis The incidence of anaphylactic reactions may be close to 0.06% When the muscle relaxant cross-links with IgE , degranulation and release of histamine, neutrophil chemotactic factor, and platelet-activating factor occur The release of these mediators can induce cardiovascular collapse, bronchospasm, and skin reaction

13. CLINICAL USES Rapid-sequence induction 1mg/kg of succinylcholine is recommended to facilitate endotracheal intubation at 60 seconds Prior administration of succinylcholine enhances the depth of blockade caused by a subsequent dose of nondepolarizing NMBD INTERACTIONS WITH ANTICHOLINESTERASES The effect of succinylcholine (1 mg/kg) was prolonged from 11 to 35 minutes when it was given 5 minutes after administration of neostigmine (5 mg).

14. Dibucaine Number Succinylcholine-induced neuromuscular blockade can be significantly prolonged if a patient has an abnormal genetic variant of butyrylcholinesterase Dibucaine inhibits normal butyrylcholinesterase to a far greater extent than the abnormal enzyme. This observation led to the establishment of the dibucaine number Although the dibucaine number indicates the genetic makeup of an individual with respect to butyrylcholinesterase

15. NON DEPOLARIZING MUSCLE RELAXANTS

16. BENZYLISOQUINOLINE d -Tubocurarine Atracurium/ Cisatracurium Mivacurium Doxacurium

17. STERIODAL Pancuronium Vecuronium Rocuronium Rapacuronium Pipecuronium

18. POTENCY OF NONDEPOLARIZING NEUROMUSCULAR BLOCKING DRUGS Drug potency is commonly expressed by the dose-response relationship. The dose of an NMBD required to produce an effect (e.g., 50%, 90%, or 95% depression of baseline twitch height, commonly expressed as ED50, ED90, and ED95) defines its potency Onset: potent NMBDs have slower onset times than less potent drugs Buffered diffusion causes repetitive binding and unbinding to receptors, thus keeping potent drugs in the neighborhood of the effector sites and potentially lengthening the duration of effect onset time will be dependent on blood flow to muscle

19. POTENCY OF NONDEPOLARIZING NEUROMUSCULAR BLOCKING DRUGS DURATION OF ACTION: muscle blood flow Redistribution The terminal half-life of atracurium is around 20 minutes, whereas the elimination half-lives of both vecuronium and rocuronium are between 60 and 120 minutes duration of action and recovery IS SIMILAR

20. METABOLISM AND ELIMINATION Steroidal Compounds Pancurnium : deacetylated (Liver) Renal excretion Vec : deacetylated ( Liver) Renal excretion The principal metabolite of vecuronium, 3-desacetylvecuronium, is a potent NMBD (≈80% of the potency of vecuronium) Roc: eliminated primarily by the liver, with a small fraction (≈10%) eliminated in the urine

21. METABOLISM AND ELIMINATION Benzylisoquinolinium Compounds:

22. ADVERSE EFFECTS OF NEUROMUSCULAR BLOCKING DRUGS Autonomic Effects

23. ADVERSE EFFECTS OF NEUROMUSCULAR BLOCKING DRUGS Histamine Release

24. ADVERSE EFFECTS OF NEUROMUSCULAR BLOCKING DRUGS Hypotension Tachycardia Dysrhythmias Bradycardia (opioid coadministration) Respiratory Effects : M2 receptors are located presynaptically ,Blockade causes bronchoconstriction. M3 receptors, which are located postsynaptically , Blockade causes bronchodilation. The affinity of the compound rapacuronium to block M2 receptors is 15 times higher than its affinity to block M3 receptors. This explains the high incidence (>9%) of severe bronchospasm Allergic Reactions: 1 in 6500 administrations of NMBDs