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Non-Depolarizing Muscle Relaxants, Reads
- 2. Mechanism of Action • NDNMBAs do not mimic acetylcholine at the postsynaptic nicotinic receptor. They compete with the neurotransmitter for the α subunit of the receptor, and have been referred to as competitive neuromuscular blocking drugs. If NDNMBAs cling to one α subunit of the receptor, they impair neuromuscular transmission as opening of the ion channel is prevented. Such drugs will remain on the receptor until their plasma concentration decreases.
- 3. • By passive diffusion, they will then move away from the receptor down a concentration gradient back into the plasma from where they are redistributed, metabolized, and excreted. As they do not mimic acetylcholine, they do not possess the muscarinic side-effects of depolarizing drugs. • They are of two main chemical types: • Benzylisoquinolinium • Aminosteroids.
- 4. Benzylisoquinolinium • Benzylisoquinolinium compounds are a group of non-depolarizing neuromuscular blocking agents (NDNMBAs) used in anesthesia to induce muscle relaxation during surgery. They all share a benzylisoquinoline chemical structure and are commonly derived from tubocurarine. Following the introduction of alcuronium, efforts continued to develop an NDNMBA with fewer cardiovascular side effects than tubocurarine, and with reduced reliance on renal function for elimination. This is important because renal dysfunction can occur during general anesthesia, even in patients without chronic kidney disease. Factors such as hypovolemia or hypoxemia can reduce blood flow to the kidneys, temporarily impairing kidney function.
- 5. Aminosteroids • These non-depolarizing neuromuscular blocking agents possess at least one quaternary ammonium group, attached to a steroid nucleus. They produce fewer adverse cardiovascular effects than do the Benzylisoquinolinium compounds and do not stimulate histamine release from mast cells to the same degree. They are excreted unchanged through the kidneys and also undergo deacetylation in the liver. The deacetylated metabolites may possess weak neuromuscular blocking properties. The parent compound may also be excreted unchanged in the bile. • e.g. Vecuronium, Pancuronium, Rocuronium etc.
- 6. Based on Duration of Action
- 7. Benzylisoquinoline • Atracurium: Atracurium has quaternary ammonium group in its structure which is responsible for its unique metabolism. Quaternary ammonium group breaks down spontaneously at variable temperature and pH; a phenomenon known as Hoffman Elimination.
- 8. • Metabolism & Excretion: 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.
- 9. • Hoffman Elimination: A spontaneous nonenzymatic chemical breakdown occurs at physiological pH and temperature. • Dosage: A dose of 0.5 mg/kg is administered intravenously for intubation. After succinylcholine, intraoperative relaxation is achieved with 0.25 mg/kg initially, then in incremental doses of 0.1 mg/kg every 10 to 20 min. An infusion of 5 to 10 mcg/kg/min can effectively replace intermittent boluses. Although dosage requirements do not significantly vary with age, atracurium may be shorter acting in children and infants than in adults. Atracurium is available as a solution of 10 mg/mL. It must be stored at 2°C to 8°C, as it loses 5% to 10% of its potency for each month it is exposed to room temperature. At room temperature, it should be used within 14 days to preserve potency.
- 10. Side effects • Cardiovascular: Cardiovascular side effects are unusual unless doses in excess of 0.5 mg/kg are administered. Atracurium may also cause a transient drop in systemic vascular resistance and an increase in cardiac index independent of any histamine release. A slow rate of injection minimizes these effects.
- 11. • Bronchospasm: Atracurium should be avoided in asthmatic patients. Severe bronchospasm is occasionally seen in patients without a history of asthma. • Laudanosine Toxicity: Laudanosine, a tertiary amine, is a breakdown product of atracurium’s Hofmann elimination and has been associated with central nervous system excitation, resulting in elevation of the minimum alveolar concentration and even precipitation of seizures. Concerns about laudanosine are probably irrelevant unless a patient has received an extremely large total dose or has hepatic failure. Laudanosine is metabolized by the liver and excreted in urine and bile.
- 12. • Temperature & Acidity: Because of its unique metabolism, atracurium’s duration of action can be markedly prolonged by hypothermia and to a lesser extent by acidosis. • Allergic Reactions: Rare anaphylactoid reactions to atracurium have been described. Proposed mechanisms include direct immunogenicity and acrylate-mediated immune activation. Immunoglobulin E-mediated antibody reactions directed against substituted ammonium compounds, including muscle relaxants, have been described. Reactions to acrylate, a metabolite of atracurium and a structural component of some dialysis membranes, have also been reported in patients undergoing hemodialysis.
- 13. Cisatracurium • Cisatracurium is a stereoisomer of atracurium which is 4-5 times more potent than atracurium. It was developed in an attempt to reduce the atracurium’s propensity to produce histamine release. It is potent cis- cis isomer and has delayed onset of action and prolong duration of action.
- 14. • Because it is more potent than atracurium, less dose is administered hence no histamine release and plasma concentration of Laudanosine is lower. Metabolism and elimination are independent of kidney or liver failure. Minor variations in pharmacokinetic patterns due to age result in no clinically important changes in duration of action. It is therefore particularly useful in the critically ill patient requiring prolonged infusion of a neuromuscular blocking drug.
- 15. • Cisatracurium produces good intubating conditions following a dose of 0.1 to 0.15 mg/kg within 3 min and results in muscle blockade of intermediate duration(about 40 mins). The typical maintenance infusion rate ranges from 1.0 to 2.0 mcg/kg/min. Thus, it is more potent than atracurium. Cisatracurium should be stored under refrigeration (2–8°C) and should be used within 21 days after removal from refrigeration and exposure to room temperature
- 16. Side effects • Unlike atracurium, cisatracurium does not produce a consistent, dose- dependent increase in plasma histamine levels following administration. Cisatracurium does not alter heart rate or blood pressure, nor does it produce autonomic effects.
- 17. Aminosteroids Relaxants • Pancuronium: It consists of steroid structure on which 2 modified ACh molecules are attached (a bisquaternary amine). It is the first steroid muscle relaxant used in history. Its duration of action is long and its duration is more prolonged in presence of inhalational agents.
- 18. 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%). • Not surprisingly, elimination of pancuronium is slowed and neuromuscular blockade is prolonged by kidney failure. Patients with cirrhosis may require a larger initial dose due to an increased volume of distribution but have reduced maintenance requirements because of a decreased rate of plasma clearance.
- 19. Dosage • A dose of 0.08 to 0.12 mg/kg of pancuronium provides adequate relaxation for intubation in 2 to 3 min. Intraoperative relaxation is achieved by administering 0.04 mg/kg initially followed every 20 to 40 min by 0.01 mg/kg. • Children may require moderately larger doses of pancuronium. Pancuronium is available as a solution of 1 or 2 mg/mL and is stored at 2°C to 8°C but may be stable for up to 6 months at normal room temperature.
- 20. Side effects • Hypertension and Tachycardia: These cardiovascular effects are caused by the combination of vagal blockade and sympathetic stimulation. The latter is due to a combination of ganglionic stimulation, catecholamine release from adrenergic nerve endings, and decreased catecholamine reuptake. Large bolus doses of pancuronium should be given with caution to patients in whom an increased heart rate would be particularly detrimental (e.g., coronary artery disease, hypertrophic cardiomyopathy, aortic stenosis).
- 21. • Allergic Reactions: Patients who are hypersensitive to bromides may exhibit allergic reactions to pancuronium (pancuronium bromide). Pancuronium does not stimulate histamine release and is therefore useful in patients with a history of allergy.
- 22. Vecuronium • Vecuronium is pancuronium minus a quaternary methyl group (a monoquaternary relaxant). This minor structural change beneficially alters side effects without affecting potency. It was developed in an attempt to reduce the vagolytic side effects produced by pancuronium.
- 23. • Metabolism and Excretion: Vecuronium undergoes deacetylation in liver and some of metabolites retain neuromuscular blocking properties. It is mainly excreted via bile, with some renal clearance. Though safe for kidney failure, its effect may last longer. It has a shorter half-life than pancuronium, but prolonged ICU use may lead to neuromuscular blockade due to metabolite buildup(3-hydroxy vecuronium), altered clearance, and risk factors like kidney failure, steroids, and sepsis. This can mimic denervation and cause paralysis. Monitoring and cautious dosing are essential; avoid unnecessary paralysis in critical care.
- 24. • Dosage: Vecuronium is equipotent with pancuronium, and the intubating dose is 0.08 to 0.12 mg/kg. A dose of 0.04 mg/kg initially followed by increments of 0.01 mg/kg every 15 to 20 min provides intraoperative relaxation. Alternatively, an infusion of 1 to 2 mcg/kg/min produces good maintenance of relaxation.
- 25. Side effects • Cardiovascular: Vecuronium rarely produces histamine release, nor does it have any direct cardiovascular effects, although it allows the cardiac effects of other anaesthetic agents, such as bradycardia produced by the opioids, to go unchallenged.
- 26. Rocuronium • This monoquaternary amine has a very rapid onset of action for a non-depolarizing muscle relaxant. It is six to eight times less potent than vecuronium.
- 27. • Metabolism: Rocuronium undergoes no metabolism and is eliminated primarily by the liver and slightly by the kidneys. Its duration of action is not significantly affected by renal disease, but it is modestly prolonged by severe liver failure and pregnancy. Because rocuronium does not have active metabolites, it may be a better choice than vecuronium in the rare patient requiring prolonged infusions in the intensive care unit setting. • Elderly patients may experience a prolonged duration of action due to decreased liver mass.
- 28. • Dosage: Rocuronium is less potent than most other steroidal muscle relaxants. It requires 0.45 to 0.9 mg/kg intravenously for intubation and 0.15 mg/kg boluses for maintenance. Intramuscular rocuronium (1 mg/kg for infants; 2 mg/kg for children) provides adequate vocal cord and diaphragmatic paralysis for intubation, but not until after 3 to 6 min (deltoid injection has a faster onset than quadriceps).
- 29. Side Effects • 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. The drug stimulates little histamine release or cardiovascular disturbance, although in high doses it has a mild vagolytic property which sometimes results in an increase in heart rate. The drug is excreted unchanged in the urine and in the bile, and thus the duration of action may be increased by severe renal or hepatic dysfunction.
- 30. • Anaphylactic reaction: Anaphylactic reactions are more common after rocuronium than after any other Aminosteroids neuromuscular blocking drug. They occur at a similar rate to anaphylactic reactions to atracurium and mivacurium.
- 31. Reversal Agents • Anticholinesterases: Acetylcholine is synthesized in the nerve terminal and hydrolyzed by acetylcholinesterase in the synaptic cleft to acetic acid and choline. Inhibition of acetylcholinesterase prevents the degradation of acetylcholine. Clinically, neostigmine, edrophonium, and pyridostigmine are used to transiently inhibit this enzyme at the neuromuscular junction. The increased number of acetylcholine molecules compete with the NDNMBA for the postsynaptic nicotinic receptor, diminishing the action of the relaxant and facilitating recovery from neuromuscular block.
- 32. • Anticholinesterases also increase the amount of acetylcholine within parasympathetic synapses (muscarinic receptors), causing bradycardia, spasm of the bowel, bladder and bronchi, increased bronchial secretions, etc. To prevent the unwanted muscarinic effects, they are always given with a suitable dose of an antimuscarinic. The most commonly used anticholinesterase is neostigmine: • A fixed dose of 2.5mg intravenously is used in adults; • Its maximal effect is seen after approximately 5 minutes and lasts for 20–30 minutes; • It is given concurrently with either atropine 1.2mg or glycopyrrolate 0.5mg.
- 33. • Neostigmine: Neostigmine is most frequently used to reverse the action of NDNMBAs. It forms a covalent bond with the esteratic site on acetylcholinesterase. Its onset of action is about 5–10 min with a duration of effect of 20–30 min.
- 34. Sugammadex • Sugammadex is a novel selective relaxant-binding agent. It is a modified γ-cyclodextrin (su refers to sugar, and gammadex refers to the structural molecule γ-cyclodextrin).
- 35. • Physical Structure: Sugammadex consists of eight oligosaccharides arranged in a cylindrical structure to encapsulate all four steroidal rings of rocuronium completely. This cylindrical structure is known as a toroid.
- 37. • The hydrophilic external tails on the toroid are negatively charged, attracting the quaternary nitrogen group on the muscle relaxant and drawing it into the lipophilic core of sugammadex. This interaction draws the relaxant into the central core of sugammadex, where it is tightly held by interactive forces. This terminates the neuromuscular blocking action and restrains the drug in extracellular fluid where it cannot interact with nicotinic acetylcholine receptors.
- 39. • The complex is freely filtered through the glomerulus and almost entirely excreted in the urine. Its plasma clearance equates with glomerular filtration rate (about 90 ml/min). Dissociation of the complex is very slow indeed. To a slightly lesser extent, sugammadex will encapsulate vecuronium, but its reaction with pancuronium is not irreversible.
- 40. • It will not encapsulate the benzylisoquinoliniums which are of a different chemical structure. Following reversal with sugammadex, subsequent neuromuscular blockade with steroidal neuromuscular blockers may be impaired. Benzylisoquinoline relaxants can be employed as an alternative . • Sugammadex does not require coadministration of an antimuscarinic agent.
- 41. • Dosage: The dose needed and time taken for complete return of neuromuscular function vary depending on the intensity of the neuromuscular block to be reversed and range from 4 to 16mg/kg and 1 to 3 minutes, respectively. • If at least two twitches of the TOF response are detectable (when anticholinesterases can be used), 2mg/kg should be given. • If block is still profound, with no response to the TOF and a post-tetanic count (PTC) of 1–2, 4– 8mg/kg should be used. • If it is necessary to reverse block immediately in the case of, for instance, a ‘cannot intubate, cannot ventilate’ scenario, sugammadex 16mg/kg should be used.
- 42. • Drug Interaction: Sugammadex may impair the contraceptive effect of patients using hormonal contraceptives due to its affinity for compounds with steroidal structure. An alternative, nonhormonal, contraceptive should be used for 7 days following sugammadex administration. • Toremifene, an estrogen antagonist, has a high affinity for sugammadex and might delay its reversal of neuromuscular block. • Because of its renal excretion, sugammadex is not recommended in patients with severe kidney dysfunction. • Sugammadex may artifactually prolong the activated partial thromboplastin time.