Skeletal Muscle Relaxants PDF

SKELETAL MUSCLE RELAXANTS Prof. Dr. Aşkın TAŞ SKELETAL MUSCLE RELAXANTS Drugs affecting skeletal muscle function are divided into two main therapeutic groups: 1.Neuromuscular Blocking Agents: Used to induce paralysis during surgical procedures and in intensive care units. 2.Cen...

SKELETAL MUSCLE RELAXANTS Prof. Dr. Aşkın TAŞ SKELETAL MUSCLE RELAXANTS Drugs affecting skeletal muscle function are divided into two main therapeutic groups: 1.Neuromuscular Blocking Agents: Used to induce paralysis during surgical procedures and in intensive care units. 2.Centrally Acting Skeletal Muscle Relaxants/Spasmolytics: Used to reduce spasticity in various neurological conditions. 3. Direct-Acting Skeletal Muscle Relaxant Agents: Dantrolene and Botulinum Toxin DIFFERENCES BETWEEN NEUROMUSCULAR BLOCKERS AND CENTRALLY ACTING MUSCLE RELAXANTS: Action Site: Neuromuscular blockers act directly at the muscle junction, while centrally acting muscle relaxants work through the central nervous system. Use: Neuromuscular blockers are used in surgeries for complete muscle paralysis, requiring unconsciousness, while centrally acting relaxants are used for muscle spasms and pain in conscious patients. Reversal: Neuromuscular blockers can be reversed with specific drugs (e.g., neostigmine), while centrally acting relaxants wear off naturally. Side Effects: Neuromuscular blockers may impair breathing, needing ventilation support, whereas centrally acting relaxants often cause drowsiness or dizziness. 1.NEUROMUSCULAR BLOCKING AGENTS 1.NEUROMUSCULAR BLOCKING AGENTS Neuromuscular blocking agents induce complete muscle relaxation by blocking synaptic transmission at the neuromuscular junction. MOTOR NEURON Motor neuron body Axon and/or dendrite Neuroglia cell and neurofibrils MOTOR END PLATE / NEUROMUSCULAR JUNCTION MOTOR NEURON AXON MOTOR END PLATE SKELETAL MUSCLE The neuromuscular junction is the site where the bare (unmyelinated) ends of motor nerves meet the membrane of skeletal muscle cells. Here, the motor nerve ending flattens into a plate and is called the "motor end plate." MOTOR END PLATE NEUROMUSCULAR JUNCTION In mammals, a single muscle fiber (cell) contains only one end plate, meaning it forms a junction with one nerve branch. A motor axon branches extensively at its peripheral end, with each branch innervating a muscle cell. The group of dozens or hundreds of skeletal muscle cells innervated by branches of a single motor axon constitutes a motor unit. NERVE MUSCLE JUNCTION NICOTINIC RECEPTORS: There are two types of nicotinic receptors: those at the neuromuscular junctions of skeletal muscles and those in the autonomic ganglia and chromaffin cells of the adrenal medulla. Skeletal Muscle Type NM Receptors: Located at the neuromuscular junctions of skeletal muscles, these receptors mediate muscle contraction. They are selectively blocked by muscle-paralyzing agents, such as d- tubocurarine, pancuronium and alpha-bungarotoxin. Neuron Type NN (also known as NG) Receptors: Found in the autonomic ganglia, adrenal medulla (chromaffin cells), and some regions of the central nervous system. These receptors facilitate autonomic nervous system signaling.  Cholinergic Nerve Adrenergic Nerve Motor Nerve (cholinergic but neither sympathetic nor parasympathetic, has no ganglion, terminates at the neuromuscular junction, contains nicotinic receptors, and is broken down by AChE).  EVENTS RELATED TO IMPULSE TRANSMISSION AT THE NEUROMUSCULAR JUNCTION Physiologically, neuromuscular transmission begins with the activation of the motor nerve. The action potential propagating along the motor nerve depolarizes the nerve terminal, allowing Ca²⁺ to enter. This event leads to the release of acetylcholine from the motor nerve terminal. Acetylcholine crosses the synaptic cleft and stimulates the nicotinic receptors (Nm type) located on the postsynaptic membrane.  EVENTS RELATED TO IMPULSE TRANSMISSION AT THE NEUROMUSCULAR JUNCTION As a result, the permeability of the muscle membrane at the end plate to Na⁺ increases. Na⁺ begins to rapidly enter the muscle membrane, leading to a rapid depolarization of the postsynaptic membrane. This local voltage change is called the end plate potential. This potential leads to the formation of an action potential in the muscle membrane and subsequently activates the contractile mechanism.  EVENTS RELATED TO IMPULSE TRANSMISSION AT THE NEUROMUSCULAR JUNCTION The depolarization of the skeletal muscle cell spreads to the transverse (T) tubules, ultimately triggering the release of bound Ca²⁺ ions from the sarcoplasmic reticulum of the muscle cell. The released calcium ions affect the actin- myosin system, causing the contraction of the skeletal muscle cell. EVENTS RELATED TO IMPULSE TRANSMISSION AT THE NEUROMUSCULAR JUNCTION Acetylcholine is quickly broken down by acetylcholinesterase, resetting the junction for the next activation.  MECHANISMS OF ACTION AND CLASSIFICATION OF NEUROMUSCULAR BLOCKING DRUGS Neuromuscular blocking drugs are divided into two groups based on their mechanisms and patterns of action: Competitive blockers (Non- depolarizing blockers) Depolarizing blockers 1. A. COMPETITIVE BLOCKERS (NON-DEPOLARIZING BLOCKERS)  COMPETITIVE BLOCKERS: (NON-DEPOLARIZING BLOCKERS) Curare, with its active compound d-tubocurarine, is a classic example of competitive blockers, initially used by Amazon natives as a muscle-paralyzing poison. These drugs compete with acetylcholine at muscle end plate receptors, reducing or blocking its effects. Increasing acetylcholine at the neuromuscular junction (e.g., using anticholinesterases like neostigmine) can reverse this paralysis, and such anticholinesterases are used clinically as antagonists to these drugs. paralys s olur  BASIC PHARMACOKINETIC PROPERTIES OF NON- DEPOLARIZING BLOCKING DRUGS Administered intravenously, competitive blockers like d-tubocurarine reach peak plasma concentration within 1-2 minutes. Paralysis occurs in a specific sequence: starting with facial and eye muscles, then progressing to the neck, extremities, torso, and finally the intercostal muscles and diaphragm, causing respiratory arrest. This sequence reverses as the drug wears off. A single dose of d-tubocurarine lasts 30-60 minutes. Rocuronium, the fastest-acting non-depolarizing blocker, provides relaxation for intubation within 1 minute. These drugs are eliminated via the liver, kidneys, or plasma hydrolysis. D-TUBOCURARINE CHLORIDE D-tubocurarine chloride, a prototype of curare-like drugs, induces rapid muscle weakness or paralysis at 10-15 mg IV, eventually affecting respiratory muscles at higher doses, necessitating artificial respiration support. Despite its muscle-paralyzing effect, it doesn't alter consciousness or provide analgesia. At high doses, it blocks sympathetic ganglia, lowering blood pressure, often due to histamine release. It acts quickly on the neuromuscular junction, with paralysis onset in 1-2 minutes, lasting 70-90 minutes. Due to its quaternary nitrogen structure, it cannot cross into the central nervous system. ATRACURIUM BESYLATE Atracurium besylate is a synthetic drug similar to dimethyltubocurarine. It is uniquely inactivated non-enzymatically in the body through *Hofmann elimination, producing an inactive metabolite, laudanosine, without liver dependency. After IV injection, muscle paralysis starts quickly, peaks in 3-6 minutes, and lasts about 30 minutes, with faster recovery than similar drugs. It has mild histamine-release and cardiovascular effects, but can cause severe reflex bradycardia during surgery if not premedicated with atropine. Laudanosine can cross into the CNS, causing stimulation. Cisatracurium, an isomer, relies less on liver inactivation, produces less Laudanosine, and reduces histamine release. *Hofmann elimination is a chemical reaction that allows certain drugs (such as atracurium) to break down in the bloodstream independently of enzymes or liver function, based on pH and temperature. This method provides a reliable drug elimination pathway for patients with impaired liver or kidney function. PANCURONIUM BROMIDE Pancuronium compete with acetylcholine at muscle end plate receptors and does not block ganglia making it more predictable and safer in terms of autonomic side effects during anesthesia and surgery and has minimal histamine release. It is partially metabolized in the liver and primarily excreted by the kidneys. Elimination slows in liver or kidney failure. It crosses minimally into fetal circulation, allowing its use in obstetric anesthesia. VECURONIUM BROMIDE Vecuronium, like pancuronium, is an aminosteroid muscle relaxant. It is primarily metabolized in the liver, with partial excretion into bile. After IV administration, muscle paralysis begins in about 1 minute, reaching a maximum at 5-6 minutes. A single dose lasts 30-60 minutes. Vecuronium typically has no cardiovascular effects and does not cause histamine release. ROCURONIUM Rocuronium is a new aminosteroid neuromuscular blocking agent. It has the fastest onset among non-depolarizing blockers. Its pharmacokinetics are similar to vecuronium but with a quicker onset and slightly shorter duration. After IV administration, sufficient relaxation for intubation occurs within 1 minute. It does not cause cardiovascular side effects or histamine release, making it useful for facilitating tracheal intubation.  acethylcol. n half l fe s short YEInyT.l these drugs are select ve ach affectwhole body MIVACURIUM Mivacurium is a short-acting, non-depolarizing neuromuscular blocker, suitable for short surgical procedures. In patients with atypical cholinesterase or those given anticholinesterase agents, its duration of action is prolonged. *This happens because anticholinesterase drugs inhibit the enzyme cholinesterase, which is responsible for breaking down mivacurium which is unique for mivacurium. With cholinesterase activity reduced, mivacurium is metabolized more slowly, leading to an extended duration of its muscle-relaxing effects. It has minimal cardiovascular side effects. Paralysis occurs within 3-6 minutes of IV administration and lasts about 25 minutes, with a quick recovery from its effects. *Mivacurium is unique among non-depolarizing neuromuscular blockers in that it is broken down primarily by plasma cholinesterase (also known as butyrylcholinesterase or pseudocholinesterase), rather than relying on the liver or kidneys for elimination. DRUGS USED IN REVERSING THE EFFECT OF DRUGS THAT BLOCK WITHOUT DEPOLARIZATION Anticholinesterases: These agents reverse the effects of non- depolarizing muscle relaxants. Anticholinesterases increase acetylcholine levels at the neuromuscular junction, outcompeting non-depolarizing muscle relaxants for receptor binding and thereby reversing muscle relaxation. Examples include neostigmine and (not available in Turkey) edrophonium. Sugammadex: A modified γ-cyclodextrin used to reverse neuromuscular blockade caused by rocuronium and vecuronium. This selective drug specifically antagonizes the effects of these steroid-based non- depolarizing muscle relaxants. DRUGS USED IN REVERSING THE EFFECT OF DRUGS THAT BLOCK WITHOUT DEPOLARIZATION SUGAMMADEX Sugammadex is designed to encapsulate amino-steroid neuromuscular blockers like rocuronium and vecuronium. The side chain of sugammadex binds rocuronium through its central cavity, with carboxyl groups electrostatically bonding to rocuronium's nitrogen atoms. Sugammadex is administered as a single intravenous dose, acting within ten seconds. It is excreted unchanged by the kidneys. If further rocuronium or vecuronium is needed within 24 hours after sugammadex, non-steroid muscle relaxants (e.g., atracurium or cis-atracurium) should be used. 1. B. DEPOLARIZING BLOCKERS  DEPOLARIZING BLOCKERS Depolarizing blockers, such as succinylcholine, act similarly to acetylcholine by binding to cholinergic receptors at the neuromuscular junction. Unlike acetylcholine, which causes brief depolarization lasting a few milliseconds, these drugs induce a prolonged depolarization that lasts for minutes. This sustained depolarization leads to receptor desensitization, preventing acetylcholine from further activating the muscle, effectively causing muscle paralysis. Due to their initial stimulatory effect, these drugs may also cause muscle twitching, known as fasciculations, before paralysis sets in. MECHANISM OF SUCCINYLCHOLINE: SUSTAINED DEPOLARIZATION AND EXTENDED REFRACTORY PERIOD IN MUSCLE PARALYSIS Resting State In a resting state, the cell interior is more negatively charged than the outside, creating a polarized membrane potential. Succinylcholine, a depolarizing muscle relaxant, initially mimics acetylcholine by binding to nicotinic receptors, disrupting this resting state. Depolarization When succinylcholine binds, it opens ion channels, allowing sodium ions (Na⁺) into the cell. This influx shifts the membrane potential to positive, briefly contracting the muscle. Activation This depolarization normally triggers an action potential. With succinylcholine, however, the effect is prolonged as the drug stays bound, maintaining the cell in an "activated" state. Refractory Period Due to succinylcholine’s prolonged action, the cell remains in a continuously depolarized state, entering an extended refractory period where it cannot repolarize or respond to further signals, blocking additional contractions. Repolarization Normally, repolarization occurs as potassium ions (K⁺) exit, restoring the negative charge. With succinylcholine still bound, the cell cannot repolarize, remaining in a paralyzed state until succinylcholine is metabolized, allowing normal muscle function to resume.  Depolarization generally leads to contraction in muscle cells. With succinylcholine, muscle relaxation occurs because muscle cells become unresponsive to further stimulation. Initially, there’s a brief contraction (fasciculation) as succinylcholine binds to nicotinic receptors, acting like acetylcholine. 1.Initial Contraction (Fasciculation): Succinylcholine binds to receptors and briefly causes muscle contraction. 2.Sustained Depolarization and Refractory State: Muscle cells remain depolarized, unable to return to their resting state due to succinylcholine’s prolonged receptor binding, preventing repolarization. 3.Unresponsiveness and Paralysis: Since the cells can’t repolarize, they become unresponsive to further signals, resulting in a state of muscle relaxation. Thus, relaxation with succinylcholine isn’t an active relaxation but rather a paralysis caused by the cells being unable to respond to stimulation.  Desensitization is a process that can be induced by acetylcholine released from motor nerve endings. However, under normal physiological conditions, acetylcholine is broken down quickly, so it only causes depolarization, not desensitization. When acetylcholine breakdown is slowed by acetylcholinesterase inhibitors, acetylcholine can also induce desensitization. However, because acetylcholine lacks selectivity, its widespread action on various cholinergic receptors throughout the body makes this approach potentially unsafe. The elevated levels of acetylcholine can lead to overstimulation of both nicotinic and muscarinic receptors, causing undesirable and systemic effects, which is why using acetylcholinesterase inhibitors for sustained desensitization is not a safe clinical practice. In cases of poisoning with anticholinesterase drugs, excessive acetylcholine accumulates at the neuromuscular junction, leading to continuous depolarization and desensitization, which results in paralysis of the skeletal muscles. DEPOLARIZING BLOCKERS Succinylcholine chloride is the fastest- acting neuromuscular blocker in use and also has the shortest duration of action. A small intravenous dose of 20 mg begins to act within 1 minute, reaches its peak effect in 1.5-2 minutes, and lasts for 5-10 minutes. It is inactivated by pseudocholinesterase in the plasma. Due to its rapid onset and short duration, it is the preferred drug for facilitating tracheal intubation at the start of anesthesia. When administered intravenously, it initially causes brief muscle fasciculations (twitching), followed by complete paralysis. SUCCINYLCHOLINE 1 Succinylcholine and other depolarizing agents initially cause muscle fasciculations, especially in the chest and abdominal muscles. Later, muscles in the neck, arms, and legs become paralyzed. If the dose is moderate, muscles in the face, jaw, tongue, pharynx, and larynx only show weakness, while respiratory muscles undergo partial paralysis. Due to its rapid onset and short duration of action, succinylcholine is ideal for brief procedures like endotracheal intubation, endoscopy, managing laryngospasm, orthopedic manipulation, and electroconvulsive therapy. SUCCINYLCHOLINE 2 Side Effects: Cardiovascular: Bradycardia, followed by tachycardia and hypotension. Increased salivation, muscle rigidity, and pain (pre-curarization rarely used). Hyperkalemia, increased intraocular and intragastric pressures. Severe Adverse Effects: 1.Prolonged Apnea: In patients with atypical pseudocholinesterase, succinylcholine-induced apnea may last 1-2 hours after drug cessation. Testing: Dibucaine number test to assess enzyme type. 2.Malignant Hyperthermia: Rare but fatal; involves rapid, extreme fever, rhabdomyolysis, myoglobinuria, and prolonged muscle rigidity. It results from an autosomal dominant mutation, causing excess calcium release in skeletal muscles. Treatment: IV dantrolene, rapid cooling, 100% oxygen, and correction of acidosis. CLINICAL USES OF NEUROMUSCULAR BLOCKING AGENTS These drugs are used during surgical anesthesia to facilitate skeletal muscle relaxation. This allows for a lower dose of general anesthetic and a shorter recovery period from anesthesia. 1.Endotracheal Intubation: Eases the process of placing an endotracheal tube. 2.Orthopedic Manipulation: Useful in procedures like fracture reduction or dislocation adjustments, where muscle relaxation helps facilitate manipulation. 3.Short-acting Neuromuscular Blockers: Often combined with a general anesthetic for procedures requiring intubation, such as laryngoscopy, bronchoscopy, and esophagoscopy. 4.Electroconvulsive Therapy: In psychiatric treatment, neuromuscular blockers can prevent bone fractures or trauma during electroconvulsive therapy. 2. CENTRALLY ACTING SKELETAL MUSCLE RELAXANTS CENTRALLY ACTING SKELETAL MUSCLE RELAXANTS In certain diseases involving the brain and spinal cord, the tone of skeletal muscles increases, causing muscle pain and restricted movement. Reducing muscle tone in such cases helps alleviate pain and improve mobility. Medications used for this purpose include Diazepam, Baclofen, and Tizanidine. CENTRALLY ACTING SKELETAL MUSCLE RELAXANTS These drugs act on the central nervous system (CNS) to reduce muscle tone and alleviate muscle spasms. Unlike neuromuscular blockers that act directly at the neuromuscular junction, centrally acting muscle relaxants affect the brain or spinal cord pathways to achieve muscle relaxation. They are commonly used for conditions involving muscle spasms, spasticity, or musculoskeletal pain.  Centrally acting skeletal muscle relaxants 1.Benzodiazepines (e.g., Diazepam) 1. Act on GABA receptors in the CNS, enhancing inhibitory neurotransmission. 2. Commonly used for muscle spasms, anxiety, and seizures. 2.GABA Agonists (e.g., Baclofen) 1. Specifically target GABAB receptors in the spinal cord. 2. Useful in treating spasticity associated with multiple sclerosis or spinal cord injuries. 3. α2 Adrenergic Agonists (e.g., Tizanidine) 1. Inhibit excitatory neurotransmitter release in the CNS. 2. Effective for spasticity in conditions like multiple sclerosis. 4.Non-GABAergic Agents 1. Cyclobenzaprine: Acts on central nervous pathways related to skeletal muscle tone. Primarily used for acute musculoskeletal pain. 2. Methocarbamol, Carisoprodol: Reduce muscle spasms through CNS depression but without a direct action on the muscle itself. CENTRALLY ACTING SKELETAL MUSCLE RELAXANTS CENTRALLY ACTING SKELETAL MUSCLE RELAXANTS BACLOFEN Oral GABA derivative, crossing the blood-brain barrier, mimicking some GABA agonistic effects. Also stimulates presynaptic inhibitory GABAB​ receptors, reducing excitatory neurotransmitter release like glutamate. Lowers pain by decreasing substance P release in the spinal cord, effective for spasticity (e.g., in multiple sclerosis and spinal injuries). Baclofen also activates postsynaptic GABA-B receptors. This activation opens intracellular potassium channels, leading to hyperpolarization in the postsynaptic cell. Hyperpolarization reduces the excitability of the nerve cell and helps prevent muscle spasms. Side effects include drowsiness, respiratory depression, coma, and increased seizure frequency in epilepsy. Dose should be gradually reduced when stopping. Potential benefits for chronic back pain, reducing alcohol cravings, and migraine prevention. CENTRALLY ACTING SKELETAL MUSCLE RELAXANTS TINAZIDINE: An α2 agonist with fewer cardiovascular effects than clonidine and dexmedetomidine. Enhances presynaptic and postsynaptic inhibition, particularly inhibiting nociceptive transmission in the spinal cord's dorsal horn. Side effects include sedation, hypotension, dizziness, dry mouth, fatigue, and hepatotoxicity. Recommended for nighttime use to minimize sedative impact. Dosage should be reduced in cases of liver and kidney impairment. Also potentially effective in chronic migraine treatment. 3. DIRECT-ACTING SKELETAL MUSCLE RELAXANT AGENTS DANTROLENE Dantrolene acts by directly reducing skeletal muscle contractility. It works by blocking calcium release from the sarcoplasmic reticulum, specifically binding to ryanodine receptors (RyR1), thereby inhibiting excitation-contraction coupling. It is administered intravenously at an initial dose of 1 mg/kg, up to a maximum of 10 mg/kg, for treating and preventing malignant hyperthermia. It’s also effective in treating spasticity from conditions like multiple sclerosis, cerebral palsy, and post-stroke complications. Common side effects include muscle weakness, fatigue, and diarrhea, while idiosyncratic liver toxicity is its most serious risk. BOTULINUM TOXIN (BOTOX) Purified botulinum A toxin-hemagglutinin complex, derived from a specific strain of Clostridium botulinum, is used in treating localized dystonias. It irreversibly blocks acetylcholine release from cholinergic nerve terminals, causing prolonged muscle paralysis where injected (2-6 months). The effect wears off as new motor nerve terminals regenerate in the area. Uses: Treating localized spasticity in cerebral palsy by injecting directly into spastic muscles Managing spastic torticollis, blepharospasm, strabismus due to dystonia, and local spasticity-related hand and wrist disabilities post-stroke Severe underarm sweating (hyperhidrosis) by injecting into the skin Reducing headache days in chronic migraine Cosmetic use for smoothing facial wrinkles (off-label) Dosage should not exceed 300 units monthly to avoid antibody formation, which may reduce efficacy. Side effects can include ptosis and vertical eye deviation.