1. Muscle Relaxant, Reversal, Emergency Drugs Dr. Pramesh Shrestha Lecturer Dept. of Anaesthesiology

2. Introduction Skeletal muscle relaxation can be produced by deep inhalational anesthesia, regional nerve block, or neuromuscular blocking agents. Muscle relaxants - routine part of the anesthesiologist's drug arsenal. Muscle relaxation does not ensure unconsciousness, amnesia, or analgesia.

3. NEUROMUSCULAR TRANSMISSION

4. ACh receptor

5. ACh is rapidly hydrolyzed into acetate and choline by the substrate-specific enzyme acetylcholinesterase. Eventually, the receptors ion channels close, causing the end-plate to repolarize. Calcium is resequestered in the sarcoplasmic reticulum, and the muscle cell relaxes.

6. DISTINCTIONS BETWEEN DEPOLARIZING & NONDEPOLARIZING BLOCKADE

7. MECHANISM OF ACTION Similar to ACh, all neuromuscular blocking agents are quaternary ammonium compounds whose positively charged nitrogen imparts an affinity to nicotinic ACh receptors.

8. Depolarizing muscle relaxants very closely resemble ACh and therefore readily bind to ACh receptors, generating a muscle action potential. Unlike ACh, however, these drugs are not metabolized by acetylcholinesterase, and their concentration in the synaptic cleft does not fall as rapidly, resulting in a prolonged depolarization of the muscle end-plate.

9. The end-plate cannot repolarize as long as the depolarizing muscle relaxant continues to bind to ACh receptors; this is called a phase I block. After a period of time, prolonged end-plate depolarization can cause ionic and conformational changes in the ACh receptor that result in a phase II block, which clinically resembles that of nondepolarizing muscle relaxants.

10. Nondepolarizing muscle relaxants bind ACh receptors but are incapable of inducing the conformational change necessary for ion channel opening. Because ACh is prevented from binding to its receptors, no end-plate potential develops. Neuromuscular blockade occurs even if only one subunit is blocked.

11. REVERSAL OF NEUROMUSCULAR BLOCKADE Because depolarizing muscle relaxants are not metabolized by acetylcholinesterase, they diffuse away from the neuromuscular junction and are hydrolyzed in the plasma and liver by another enzyme, pseudocholinesterase. Reversal of their blockade depends on redistribution, gradual metabolism, and excretion of the relaxant by the body, or administration of specific reversal agents (eg, cholinesterase inhibitors).

12. DEPOLARIZING MUSCLE RELAXANTS

13. SUCCINYLCHOLINE The only depolarizing muscle relaxant in clinical use today is succinylcholine.

14. Metabolism & Excretion Rapid onset of action (30–60 s) and short duration of action (typically less than 10 min). Its rapid onset of action is largely due to its low lipid solubility (all muscle relaxants are highly charged and water soluble) and the relative overdose that is usually administered.

15. One in 50 patients has one normal and one abnormal (atypical) pseudocholinesterase gene, resulting in a slightly prolonged block (20–30 min). Even fewer (1 in 3000) patients have two abnormal genes (homozygous atypical) that produce an enzyme with little or no affinity for succinylcholine. In contrast to the doubling or tripling of blockade duration seen in patients with low enzyme levels or heterozygous atypical enzyme, patients with homozygous atypical enzyme will have a very long blockade (eg, 4–8 h) following administration of succinylcholine.

17. Dosage The usual adult dose of succinylcholine needed for intubation is 1–1.5 mg/kg intravenously. If succinylcholine is administered intramuscularly to children, a dose as high as 4–5 mg/kg does not always produce complete paralysis.

18. Side Effects & Clinical Considerations Cardiovascular Fasciculations Hyperkalemia Muscle Pains Intragastric Pressure Elevation Intraocular Pressure Elevation Masseter Muscle Rigidity

19. Malignant Hyperthermia Generalized Contractions Prolonged Paralysis Intracranial Pressure Histamine Release

21. NONDEPOLARIZING MUSCLE RELAXANTS

24. PANCURONIUM

25. Physical Structure Pancuronium consists of a steroid ring on which two modified ACh molecules are positioned (a bisquaternary relaxant). To an ACh receptor, pancuronium resembles ACh enough to bind—but not enough to open—the lock.

26. Metabolism & Excretion Pancuronium is metabolized (deacetylated) by the liver to a limited degree. Its metabolic products have some neuromuscular blocking activity. Excretion is primarily renal (40%), although some of the drug is cleared by the bile (10%).

27. Dosage A dose of 0.08–0.12 mg/kg of pancuronium provides adequate relaxation for intubation in 2–3 min. Intraoperative relaxation is achieved by administering 0.04 mg/kg initially followed every 20–40 min by 0.01 mg/kg.

28. Side Effects & Clinical Considerations Hypertension and Tachycardia Arrhythmias Allergic Reactions

29. VECURONIUM

30. Physical Structure Vecuronium is pancuronium minus a quaternary methyl group (a monoquaternary relaxant). This minor structural change beneficially alters side effects without affecting potency.

31. Metabolism & Excretion Vecuronium is metabolized to a small extent by the liver. It depends primarily on biliary excretion and secondarily (25%) on renal excretion. Although it is a satisfactory drug for patients with renal failure, its duration of action is somewhat prolonged.

32. Dosage Vecuronium is equipotent with pancuronium, and the intubating dose is 0.08–0.12 mg/kg. A dose of 0.04 mg/kg initially followed by increments of 0.01 mg/kg every 15–20 min provides intraoperative relaxation. Alternatively, an infusion of 1–2 µg/kg/min produces good maintenance of relaxation.

33. Side Effects & Clinical Considerations Even at doses of 0.28 mg/kg, vecuronium is devoid of significant cardiovascular effects. Potentiation of opioid-induced bradycardia may be observed in some patients Although it is dependent on biliary excretion, the duration of action of vecuronium is usually not significantly prolonged in patients with cirrhosis unless doses greater than 0.15 mg/kg are given.

34. ROCURONIUM Rocuronium (at a dose of 0.9–1.2 mg/kg) has an onset of action that approaches succinylcholine (60–90 s), making it a suitable alternative for rapid-sequence inductions, but at the cost of a much longer duration of action.

35. ATRACURIUM Atracurium is so extensively metabolized that its pharmacokinetics are independent of renal and hepatic function, and less than 10% is excreted unchanged by renal and biliary routes. Two separate processes are responsible for metabolism. ESTER HYDROLYSIS –This action is catalyzed by nonspecific esterases, not by acetylcholinesterase or pseudocholinesterase. HOFMANN ELIMINATION –A spontaneous nonenzymatic chemical breakdown occurs at physiological pH and temperature

36. Cholinesterase Inhibitors

37. Introduction The primary clinical use of cholinesterase inhibitors, also called anticholinesterases, is to reverse nondepolarizing muscle blockade.

38. Introduction Acetylcholine is synthesized in the nerve terminal by the enzyme choline acetyltransferase, which catalyzes the reaction between acetylcoenzyme A and choline. After its release, acetylcholine is rapidly hydrolyzed by acetylcholinesterase (true cholinesterase) into acetate and choline.

39. Cholinergic receptors have been subdivided into two major groups based on their reaction to the alkaloids muscarine and nicotine. Nicotine stimulates the autonomic ganglia and skeletal muscle receptors (nicotinic receptors), whereas muscarine activates end-organ effector cells in bronchial smooth muscle, salivary glands, and the sinoatrial node (muscarinic receptors).

40. The central nervous system has both nicotinic and muscarinic receptors. Nicotinic receptors are blocked by muscle relaxants and muscarinic receptors are blocked by anticholinergic drugs such as atropine.

41. MECHANISM OF ACTION Cholinesterase inhibitors indirectly increase the amount of acetylcholine available to compete with the nondepolarizing agent, thereby reestablishing normal neuromuscular transmission. Cholinesterase inhibitors inactivate acetylcholinesterase by reversibly binding to the enzyme. The stability of the bond influences the duration of action

42. Organophosphates, a special class of cholinesterase inhibitors, form very stable, irreversible bonds to the enzyme.

44. Unwanted muscarinic side effects are minimized by prior or concomitant administration of anticholinergic medications such as atropine sulfate or glycopyrrolate. The duration of action is similar among the cholinesterase inhibitors. Clearance is due to both hepatic metabolism (25–50%) and renal excretion (50–75%). Thus, any prolongation of action of a nondepolarizing muscle relaxant from renal or hepatic insufficiency will probably be accompanied by a corresponding increase in the duration of action of a cholinesterase inhibitor.

45. NEOSTIGMINE The effects of neostigmine (0.04 mg/kg) are usually apparent in 5–10 min, peak at 10 min, and last more than 1 h. If reversal in not complete in 10 min after 0.08 mg/kg, the time for full recovery of neuromuscular function will depend on the nondepolarizing agent used and the intensity of blockade.

46. Emergency Drugs

47. EPINEPHRINE Clinical Considerations Direct stimulation of β 1 -receptors by epinephrine raises cardiac output and myocardial oxygen demand by increasing contractility and heart rate α 1 Stimulation decreases splanchnic and renal blood flow but increases coronary and cerebral perfusion pressure. Systolic blood pressure rises, although β 2 -mediated vasodilation in skeletal muscle may lower diastolic pressure. β 2 -Stimulation also relaxes bronchial smooth muscle.

48. In emergency situations (eg, shock and allergic reactions), epinephrine is administered as an intravenous bolus of 0.05–1 mg depending on the severity of cardiovascular compromise. To improve myocardial contractility or heart rate, a continuous infusion is prepared and run at a rate of 2–20 µg/min. Some local anesthetic solutions containing epinephrine at a concentration of 1:200,000 (5 g/mL) or 1:400,000 (2.5 g/mL) are characterized by less systemic absorption and a longer duration of action.

49. ATROPINE Dosage: As a premedication, atropine is administered intravenously or intramuscularly in a range of 0.01–0.02 mg/kg up to the usual adult dose of 0.4–0.6 mg. Larger intravenous doses up to 2 mg may be required to completely block the cardiac vagal nerves in treating severe bradycardia.

50. Clinical Considerations Atropine has particularly potent effects on the heart and bronchial smooth muscle and is the most efficacious anticholinergic for treating bradyarrhythmias. Patients with coronary artery disease may not tolerate the increased myocardial oxygen demand and decreased oxygen supply associated with the tachycardia caused by atropine.

51. Atropine has been associated with mild postoperative memory deficits, and toxic doses are usually associated with excitatory reactions. An intramuscular dose of 0.01–0.02 mg/kg reliably provides an antisialagogue effect. Atropine should be used cautiously in patients with narrow-angle glaucoma, prostatic hypertrophy, or bladder-neck obstruction.

52. Thank You