Neuromuscular Blocking Agents PDF

Neuromuscular Blocking Agents AWAD MOHAMMED ALQAHTANI BSc of Anesthesia Technology King Khalid University, Muhayil Asir  Objectives  Introduction  Depolarizing muscle relaxant  Non-depolarizing muscle relaxant  Introduction  Skeletal muscle...

Neuromuscular Blocking Agents AWAD MOHAMMED ALQAHTANI BSc of Anesthesia Technology King Khalid University, Muhayil Asir  Objectives  Introduction  Depolarizing muscle relaxant  Non-depolarizing muscle relaxant  Introduction  Skeletal muscle relaxation can be produced by  deep inhalational anesthesia.  regional nerve block.  neuromuscular blocking agents.  Association between a motor neuron and a muscle cell occurs at the neuromuscular junction  motor neuron:is a type of nerve cell responsible for transmitting signals from the central nervous system (the brain and spinal cord) to muscles or glands, causing them to contract or perform specific activities. Components of a Motor Neuron: 1) Cell Body (Soma): Contains the nucleus and is responsible for regulating the cell’s vital functions. 2) Axon: Transmits nerve signals from the cell body to target tissues, such as muscles. 3) Axon Terminals: Release neurotransmitters (like acetylcholine) at the neuromuscular junction. 4) Dendrites: Receive signals from other neurons. Function of Motor Neurons: Voluntary Movement: They transmit signals that control skeletal muscle movement based on commands from the brain. Involuntary Movement: Motor neurons also play a role in reflex actions, such as withdrawing a hand from a hot surface. Importance of Motor Neurons: Motor neurons are crucial in the body’s motor control system. They enable voluntary movements like walking and writing and contribute to reflexive actions that protect the body from harm. The neuromuscular junction (NMJ): is the site where a motor neuron meets a muscle cell (skeletal muscle), facilitating communication between the nervous system and the muscle to trigger muscle contraction. Components of the Neuromuscular Junction: 1) Axon Terminal: This is the terminal part of the motor neuron, which contains synaptic vesicles filled with the neurotransmitter acetylcholine (ACh). 2) Synaptic Cleft: This is the small gap between the axon terminal and the muscle fiber. 3) Motor End Plate: A specialized region of the muscle cell membrane (sarcolemma) directly beneath the axon terminal. It contains acetylcholine receptors.  Neuromuscular Transmission  Normal Function of the Neuromuscular Junction:  In normal conditions, communication between the motor neuron and the muscle cell occurs at the neuromuscular junction (NMJ) to trigger muscle contraction. Here’s how it works:  Normal Function of the Neuromuscular Junction:  1) Nerve Impulse: When an action potential reaches the motor neuron’s axon terminal, it triggers the release of acetylcholine (ACh) into the synaptic cleft.  2) Acetylcholine Binding: Acetylcholine binds to its receptors(Nicotinic receptors) on the muscle cell membrane in the motor end plate, opening sodium (Na⁺) channels.  3) Depolarization: The influx of sodium ions into the muscle fiber leads to depolarization of the muscle cell membrane, generating a muscle action potential that travels along the muscle fiber.  4) Muscle Contraction: The muscle action potential stimulates the release of calcium (Ca²⁺) from the sarcoplasmic reticulum, causing muscle fibers to contract by sliding over each other.  When Muscle Relaxants Are Administered: Muscle relaxants can reduce or prevent muscle tension by affecting neural or muscular signaling. These drugs influence the neuromuscular junction in different ways, depending on the type of muscle relaxant: 1) Acetylcholine Inhibitors (e.g., used in general anesthesia): Some anesthetic drugs block acetylcholine release or inhibit its binding to receptors on the motor end plate. Acetylcholine antagonists prevent the transmission of the nerve signal to the muscle, thus blocking muscle contraction. 2) Central-Acting Muscle Relaxants: Some muscle relaxants work on the central nervous system (brain and spinal cord) to reduce muscle tension without directly affecting the neuromuscular junction. These drugs reduce the nervous system’s ability to send contraction signals to the muscles. 3) Neuromuscular Blocking Agents:(e.g., Botulinum toxin): Some drugs may interfere with acetylcholine release at the nerve terminal. Botulism (caused by botulinum toxin) or similar drugs can block acetylcholine release, preventing muscle contraction and causing muscle paralysis.  Ach i s rapidly hydrolyzed into acetate and choline by the substrate-specific enzyme acetylcholinesterase. Thi s enzyme (also called specific cholinesterase or true cholinesterase) i s embedded into the motor end-plate membrane immediately adjacent to the ACh receptors.  Benefits:  A. Preventing Continuous Muscle Contraction.  B. Preparing for the Next Signal.  C. Maintaining Neuromuscular Balance: AChE ensures a delicate balance between nerve signals and muscle contraction, preventing overstimulation or understimulation of muscles.  Problems Associated with Enzyme Dysfunction:  Increased Enzyme Activity: If AChE breaks down acetylcholine too quickly, it can weaken nerve signals, causing muscle weakness.  Decreased Enzyme Activity: If AChE activity is reduced (due to toxins like nerve agents or certain drugs), acetylcholine remains in the synapse for too long, leading to persistent muscle contraction or spasms (a condition called cholinergic crisis).  Distinctions Between Depolarizing & Nondepolarizing Blockade  Neuromuscular blocking agents are divided into two classes: depolarizing and nondepolarizing  This division reflects distinct differences in  the mechanism of action.  response to peripheral nerve stimulation.  and reversal of block.  Depolarizing muscle relaxants:  These drugs are primarily used during surgical procedures to induce complete muscle relaxation.  The most common example is succinylcholine.  How Do They Work? 1) Mimicking Acetylcholine (ACh): Depolarizing muscle relaxants chemically resemble acetylcholine, the neurotransmitter responsible for transmitting nerve signals to muscles. They bind to ACh receptors on the muscle end-plate and stimulate the muscle, causing an initial contraction. 2) Resistance to Breakdown: Normally, acetylcholine is broken down rapidly by the enzyme acetylcholinesterase. These drugs, however, are not easily broken down by this enzyme, so they remain bound to the receptors for a prolonged period. 3) Continuous Depolarization:  Because these drugs keep the receptors activated, the muscle remains in a depolarized state (ion channels stay open, preventing the muscle from returning to its resting state).  This prevents the muscle from responding to further signals, leading to relaxation.  Nondepolarizing muscle relaxants Mechanism of Action: 1) Binding to ACh Receptors: Nondepolarizing muscle relaxants bind to acetylcholine (ACh) receptors at the neuromuscular junction. However, they do not induce the conformational change necessary to open ion channels. As a result, they block the action of acetylcholine without activating the receptor. 2) Prevention of End-Plate Potential: By occupying ACh receptors, these drugs prevent acetylcholine from binding and activating the receptors. This stops the generation of an end-plate potential, which is essential for muscle contraction. Depolarizing Muscle Relaxants: Act as agonists at ACh receptors, mimicking acetylcholine and causing continuous activation. Nondepolarizing Muscle Relaxants: Function as competitive antagonists, blocking ACh from binding and preventing receptor activation.  REVERSAL OF BLOCKADE  Because succinylcholine i s not metabolized by acetylcholinesterase, it unbinds the receptor and diffuses away from the neuromuscular junction to be hydrolyzed in the plasma and liver by another enzyme, pseudo-cholinesterase (nonspecific cholinesterase, plasma cholinesterase, or butyrylcholinesterase)  Fortunately, this i s afairly rapid process, because no specific agent to reverse a depolarizing blockade i s available.  Nondepolarizing agents are not metabolized by either acetylcholinesterase or pseudocholinesterase.  Reversal of their blockade depends on unbinding the receptor, redistribution,metabolism, and excretion of the relaxant by the body, or administration of specific reversal agents (eg, cholinesterase inhibitors) that inhibit acetylcholinesterase enzyme activity. 1) Neostigmine: This is an acetylcholinesterase inhibitor, which prevents the breakdown of acetylcholine in the neuromuscular junction, thereby increasing the concentration of acetylcholine. This helps enhance neuromuscular transmission and reverses muscle relaxation. 2) Sugammadex: This drug works differently by binding to and encapsulating muscle relaxants like rocuronium or vecuronium effectively removing them from the bloodstream. This rapidly reverses their effects and helps restore normal muscle activity. Both medications help counteract the muscle relaxation effects and allow muscles to return to their normal state after the procedure.  Depolarizing Muscle Relaxants SUCCINYLCHOLINE  It i s the only depolarizing muscle relaxant in clinical use today, consisting of two joined ACh molecules.  The popularity of succinylcholine i s due to its rapid onset of action (30–60 s) and short duration of action (typically less than 10 min).  Succinylcholine, like all neuromuscular blockers, has a small volume of distribution due to its very low lipid solubility.  As succinylcholine enters the circulation, most of it i s rapidly metabolized by pseudocholinesterase into succinylmonocholine.  As drug levels fall in blood, succinylcholine molecules diffuse away from the neuromuscular junction, limiting the duration of action.  However, this duration of action can be prolonged by high doses, infusion of succinylcholine, or abnormal metabolism.  Abnormal metabolism may result from hypothermia, reduced pseudocholinesterase levels, or a genetically aberrant enzyme.  Hypothermia decreases the rate of hydrolysis.  Reduced levels of pseudocholinesterase (measured as units per liter) accompany pregnancy, liver disease, renal failure, and certain drug therapies.  Dose: adult dose for intubation 1-1.5 mg/kg IV.  dose requirement in children more than adult in children can be IM 4-5 mg/kg.  Succinylcholine should be stored under refrigeration (2–8°C), and should generally be used within 14 days after removal from refrigeration and exposure to room temperature.  Nondepolarizing Muscle Relaxants A. Suitability for Intubation  None of the currently available nondepolarizing muscle relaxants equals succinylcholine’s rapid onset of action or short duration.  Onset of nondepolarizing muscle relaxants can be quickened by using either a larger dose or a priming dose.  Priming dose: giving 10-15% of intubating dose 5 min before induction. B. Maintenance Relaxation  Monitoring neuromuscular function with a nerve stimulator helps to prevent over- and underdosing and to reduce the likelihood of serious residual muscle paralysis in the recovery room.  ATRACURIUM  The drug is a mixture of 10 stereoisomers Metabolism & Excretion  Atracurium is so extensively metabolized that its pharmacokinetics are independent of renal and hepatic function. Two separate processes are responsible for metabolism: A.Ester Hydrolysis: This action is catalyzed by nonspecific esterases, not by acetylcholinesterase or pseudocholinesterase. B.Hofmann Elimination: A spontaneous nonenzymatic chemical breakdown occurs at physiological pH and temperature.  Side Effects & Clinical Considerations  Dose-dependent histamine release that becomes significant at doses above 0.5 mg/kg.  Hypotension and Tachycardia at doses above 0.5 mg/kg.  Bronchospasm:Atracurium should be avoided in asthmatic patients.  Chemical Incompatibility: Atracurium will precipitate as a free acid if it i s introduced into an intravenous line containing an alkaline solution such as thiopental.  CISATRACURIUM  Cisatracurium i s a stereoisomer of atracurium that i s four times more potent.  Atracurium contains approximately 1 5 % cisatracurium. Metabolism & Excretion: by Hofmann elimination.  Side Effects & Clinical Considerations  Unlike atracurium, cisatracurium doesn’t 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, even at doses as high as eight times ED 95.  VECURONIUM Metabolism & Excretion  Vecuronium i s metabolized to a small extent by the liver. It depends primarily on biliary excretion and secondarily (25%) on renal excretion.  Its duration of action i s somewhat prolonged in patient with renal failure.  Long-term administration of vecuronium to patients in intensive care units has resulted in prolonged neuromuscular blockade (up to several days).  Side Effects & Clinical Considerations A. Cardiovascular  vecuronium i s devoid of significant cardiovascular effects. Potentiation of opioid- induced bradycardia may be observed in some patients. B. Liver Failure  Although it i s dependent on biliary excretion, the duration of action of vecuronium i s usually not significantly prolonged in patients with cirrhosis unless high doses.  ROCURONIUM Metabolism & Excretion  Rocuronium no undergoes metabolism and i s eliminated primarily by the liver and slightly by the kidneys.  Its duration of action i s not significantly affected by renal disease, but it i s modestly prolonged by severe hepatic failure and pregnancy.  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 thecost of a much longer duration of action.  A lower dose of 0.4mg/kg allow reversal as soon as 25 min after intubation.  This intermediate duration of action i s comparable to vecuronium or atracurium. Questions are welcome Thank You  Reference Clinical Anesthesiology 6th edition 2018 the Author ; G.Morgan. Maged Mikhail and Michael Murray, chapter 11, page : 199 – 222.