Neuromuscular Blocking Agents PDF

The neuromuscular junction is a prime target for blocking nerve transmission in skeletal muscles because unlike other parts of the nervous system, the neuromuscular junction mainly uses one neurotransmitter (acetylcholine). Acetylcholine transmits signals from nerves to muscles so if acetylcho...

The neuromuscular junction is a prime target for blocking nerve transmission in skeletal muscles because unlike other parts of the nervous system, the neuromuscular junction mainly uses one neurotransmitter (acetylcholine). Acetylcholine transmits signals from nerves to muscles so if acetylcholine is blocked at the neuromuscular junction, the signal can't be transmitted effectively. As a result, the muscle doesn't receive the command to move, leading to paralysis. Skeletal muscle relaxation can be produced by deep inhalational - anesthesia, regional nerve block, or neuromuscular blocking agents. - - - - - -1 Muscle relaxation does not ensure unconsciousness, amnesia, or - - odl analgesia. (muscle relaxant à paralysis of skeletal muscles) - In 1942, Harold Griffith published the results of a study using an extract of curare (a South American arrow poison) during anesthesia. Following the introduction of succinylcholine as a “new approach to muscular relaxation,” these agents rapidly became a routine part of the anesthesiologist’s drug arsenal.  Definition: NMBA are the drugs that act peripherally at NM-Junction and muscle fiber itself to block neuromuscular transmission. Why do we need them ? In order to facilitate muscle relaxation for surgery and mechanical ventilation during surgery & in ICU.  Neuromuscular junction Association between a motor neuron and a muscle cell. Synaptic cleft: The cell membranes of the neuron and muscle fiber are separated by a narrow (20-nm) gap. The neurotransmitter responsible for neurotransmission at the neuromuscular junction is acetylcholine. It is synthesized in the cytoplasm by combination of choline and coenzyme A with the help of choline acetyl transferase. These synthesized acetylcholine stored in vesicles. A single vesicle contains about a quantum of Ach (10000 molecules of Ach)  As a nerve’s action potential depolarizes its terminal, an influx of calcium ions through voltage-gated calcium channels into the nerve cytoplasm allows storage vesicles to fuse with the terminal plasma membrane and release their contents. The ACh molecules diffuse across the synaptic cleft to bind with nicotinic cholinergic receptors on a specialized portion of the muscle membrane at the motor end-plate. Each neuromuscular junction contains approximately 5 million of these receptors. - Among these minimum 500000 receptors required to be activated for * normal muscle contraction. Vesicles containing acetylcholine  Another isoform of Ach contains a γ subunit instead of the ε subunit known as fetal or imature receptor , because this form initially expressed in fetal muscle. It is also often referred to as extrajunctional receptors. Cations flow through the open ACh receptor channel (sodium and calcium in; potassium out), generating an end-plate potential. When enough receptors are occupied by ACh, the end- plate potential will be sufficiently strong to depolarize the perijunctional membrane. 6 - - - -  Structure of ACh receptors: Each ACh receptor in the neuromuscular junction normally consists of five protein subunits; two α subunits; and single β, δ, and ε subunits. ---- Only the two identical α subunits are capable of binding Ach molecules. If both binding sites are occupied by ACh, a conformational change in the subunits, briefly (1 ms) opens an ion channel in the core of the receptor. The channel will not open if Ach binds on only one site  Sodium channels are present in muscle membrane. - Perijunctional areas of muscle membrane have a higher density of these sodium channels than other parts of the membrane. These sodium channels have two types of gate - voltage dependent - time dependent Sodium ions pass only when both gates are open.  With the opening of sodium channels and entry of sodium, calcium ions release from sarcoplasmic remem reticulum. This intracellular calcium allows the contractile proteins actin and myosin to interact, bringing about muscle contraction.  NMBA are divided into two major groups 1. Depolarizing muscle relaxants à agonists (produce action potential) 2. Non-Depolarizing muscle relaxants à antagonists (don’t produce action potential) Distinctions Between Depolarizing & Nondepolarizing Blockade: Neuromuscular blocking agents are divided into two classes: depolarizing and nondepolarizing Chemical structure: - All neuromuscular blocking agents are- quaternary ammonium compounds whose Spositively charged( nitrogen imparts an affinity to nicotinic ACh receptors Whereas most agents have two quaternary ammonium mmmmmmmm atoms, a few protonated at physiological pH ④ - & have one quaternary ammonium cation and one tertiary amine that is  Mechanism of action of muscle relaxants Depolarizing muscle relaxants: Ø When a nerve releases acetylcholine at the neuromuscular junction, it stimulates receptors on the muscle, initiating muscle contraction. However, acetylcholine is immediately metabolized by acetylcholinesterase enzyme. This prevents continuous stimulation of the receptor by acetylcholine so it will go back to its pre-stimulation state. Ø However, succinylcholine (a depolarizing drug) behaves differently. After stimulating the receptor at the NMJ, it is Inot immediately metabolized.( Instead, it remains active for 5-10 minutes before being metabolized by an enzyme called pseudocholinesterase in the plasma. Ø During these 5-10 minutes, it continuously stimulates the receptors at the NMJ. This prevents the receptor from returning to its pre-stimulation state à succinylcholine overstimulates the receptor, causing it to become temporarily& unresponsive to both acetylcholine and succinylcholine. Ø As long as succinylcholine is stimulating the receptor, the muscle remains paralyzed because the receptor doesn't respond to any further stimulation. This paralysis persists until succinylcholine is metabolized. Ø Once succinylcholine is metabolized, its concentration decreases, allowing the receptors to gradually regain their sensitivity to acetylcholine. This leads to the resumption of muscle movement after succinylcholine stimulation ceases. Nondepolarizing muscle relaxants: Ø These drugs bind to the receptors at the NMJ but do not stimulate them to produce action potential, so the muscle remains paralyzed from the start (without the initiation of action potentials, muscle movement cannot occur). Ø Due to the law of mass action, acetylcholine cannot bind to the receptors à if the concentration of the muscle relaxant at the NMJ is higher than the concentration of acetylcholine, it will kick acetylcholine off the receptors and occupy them, preventing acetylcholine from binding and initiating muscle contraction, resulting in paralysis.  Depolarizing muscle relaxants act as ACh receptor agonists, whereas nondepolarizing muscle relaxants function as competitive antagonists Depolarizing muscle relaxants very closely resemble ACh and 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. ⑪ Depolarizing MJ blocker (muscle relaxant MOA Onset Duration Adverse effects * Binds to Ach receptors => persistent depolarization => motor end plate that is unresponsive to subsequent nerve impulses (depolarized block) flaccid => paralysis of the skeletal nerve. Does NOT target autonomo-60s sm succinylcholine receptors musce nicotonic * Targets N receptors at NMJ.  Continuous end-plate depolarization causes muscle relaxation because opening of perijunctional sodium channels is time limited After the initial excitation and opening these sodium channels inactivate and cannot reopen until the end-plate repolarizes 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 poorly understood changes in the ACh receptor that result in a phase II block Non-classical Blockade Some drugs interfere without agonist or antagonist properties (without binding to the receptors at the neuromuscular junction) - - - Include inhaled anesthetic, local anesthetic or ketamine of unknown mechanisim of its action in blocking the receptor. Interfere with normal functioning of ach binding site and/or opening and closing of receptor channel Closed channel blockade : during closed channel blockade, drug physically plugs up the channel preventing resting - the channel closed is in state a passage of cations whether or not Ach has activated the receptor. when the blocker binds drug * prevents the channel from opening Open channel blockade: when the stimules arrived. Drug enters and obstructs ach receptor channel after opened Occurs with antibiotics, cocaine and quinidine T Interferes with blockade reversal # - Depolarizing and non-depolarizing Muscle Relaxants Depolarizing Non-depolarizing Short-acting Short-acting Succinylcholine Mivacurium Used in short surgeries Intermediate-acting and emergency intubation Atracurium; Cisatracurium - => Rocuronium; Vecuronium = E Long-Acting Doxacurium Pancuronium; Pipecuronium -  Succinylcholine (Suxamethonium) Only depolarizing in clinical use Only given through IV route Copycat Ach structure Water-soluble drug Used for rapid sequence induction of anesthesia, Rapid onset (30-60s) which is a method used in emergency situations to minimize the risk of aspiration: Low lipid solubility as well as relative 1. Pre-oxygenation: Administer 100% oxygen for 3-5 overdose given minutes to increase the oxygen reserve 2. Administer a hypnotic drug such as propofol to Short duration of action (< 10 min) induce unconsciousness rapidly à absence of eyelash reflex As it enters the system, most is 3. Sellick maneuver: Apply pressure on the cricoid cartilage to occlude the esophagus and help prevent metabolized by pseudocholinesterase regurgitation and aspiration of gastric contents during induction and intubation. Only small fraction of injected dose reach 4. Administer succinylcholine to achieve muscle NMJ relaxation and facilitate intubation.  ⑳ - ji · rapid In push Skip - -  - Duration of Action: Succinylcholine Prolonged by high dose or abnormal metabolism Hypothermia Decreased rate of hydrolysis Low pseudo-cholinesterase levels Dibucaine is a local anesthetic used as Pregnancy, liver disease, renal failure and drugs a diagnostic tool in the (dibucaine number test) & Esmolol, metoclopramide, OCP among others to pseudo cholinestrase Genetically variable enzyme assess activity 1 in 50 = one normal and one abnormal gene Slightly prolonged block (20-30 min) 1 in 3000 2 abnormal genes, up to 4-8 hour blockade & Dibucaine resistant –most common abnormal pseudocholinesterase - -  ¯pseudocholinesterase activity à ­prolongation of action of succinylcholine - - Pe - 0 - = I ⑪ C Drug Interactions: Succinylcholine Cholinesterase inhibitors Prolong phase 1 block Inhibit acetylcholinesterase=higher ach concentration which increase depolarization Reduce hydrolysis of succinylcholine Inhibit pseudocholinestrase Dosage: Succinylcholine Adult Intubation 1-1.5 mg/kg IV *(possibly excessive).5 mg/kg acceptable if defasciculating dose of non-depolarizer is not used Maintenance Repeated small bolus (10mg) or drip (1g in 500-1000ml titrated to effect) Children Intubation Infants/Small kids: 2mg/kg à pediatric patients require higher doses of medications because their receptors are not as well matured as those in adults, leading to reduced responsiveness to standard doses. Older children and Adolescents 1mg/kg Side Effects Cardiovascular Variable Secondary to possible stimulation of nicotinic receptors in parasympathetic and sympathetic ganglia, as well as muscarinic receptors in SA node Low doses Can produce negative chronotropic/inotropic effects Higher doses Tend to increase heart rate and contractility as well as elevate circulating catecholamine Children Particularly susceptible to bradycardia Often treated prophylactically with atropine Side effects cont. Fasciculation Signals onset of paralysis Prevented by non-depolarizing relaxant Muscle Pains Increased post-op myalgia Possibly from unsynchronized contraction of muscle groups Increased CK and myoglobinemia can be found after succinylcholine given Reduced by NSAID preoperatively -  hyperkalemia ad arrhythmia to - cardiac arrest Side Effects - normal levels 3. 5- Hyperkalemia Intubating dose Normal muscle releases potassium to raise serum potassium level by.5 meq/l Excessive hyperkalemia( k level approaching 7meq/l ) in cases of Preexisting hyperkalemia (renal failure) - I Burn Injury - & - Massive Trauma / - I Neurological disorders S Many more Cardiac arrest can prove to be quite refractory to routine cardiopulmonary resuscitation Cardiac arrest due to hyperkalemia is often refractory to routine resuscitation because standard CPR drugs (like epinephrine) do not directly counteract hyperkalemia. Treatment of succinylcholine-induced hyperkalemia includes: Calcium gluconate (stabilizes cardiac membranes). Insulin + glucose (shifts K⁺ into cells). Sodium bicarbonate (if acidosis is present). Beta-agonists (e.g., albuterol shifts K⁺ intracellularly). Hemodialysis (if severe or in renal failure patients).  Hyperkalemia A. Causes 1. Increased total-body potassium a. Renal failure (acute or chronic) b. Hypoaldosterone states: Addison disease, hyporeninemic hypoaldosteronism, ACE inhibitors, potassium-sparing diuretics (spironolactone) c. Iatrogenic–excessive doses of potassium (use caution when administering potassium in patients with renal failure) and certain medications (e.g., trimethoprim-sulfamethoxazole) d. Blood transfusion—usually due to lysed cells FIGURE 8.4 Diagnostic evaluation of hypokalemia. (Adapted from Humes DH, DuPont HL, Gardner LB, et al. Kelley’s Textbook of Internal  Medicine. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2000:1165, Figure 146- 2.) Quick HIT Hyperkalemia inhibits renal ammonia synthesis and reabsorption. Thus, net acid excretion is impaired and results in metabolic acidosis. This further exacerbates hyperkalemia due to K+ movement out of cells. 2. Redistribution—translocation of potassium from intracellular to extracellular space a. Acidosis (notably not seen in lactic or ketoacidosis) b. Tissue/cell breakdown—rhabdomyolysis (muscle breakdown), chemotherapy, hemolysis, burns c. GI bleeding d. Insulin deficiency—insulin stimulates the Na+-K+-ATPase and causes K+ to shift into cells. Therefore, insulin deficiency and hypertonicity (high glucose) promote K+ shifts from ICF to ECF e. Rapid administration of β-blocker 3. Pseudohyperkalemia (spurious) a. This refers to an artificially elevated plasma K+ concentration due to K+ movement out of cells immediately before or after venipuncture. Contributing factors include prolonged use of a tourniquet with or without repeated fist clenching. This can cause acidosis and subsequent K+ loss from cells. Nevertheless, plasma (not serum) K+ should be normal. (Repeat the test to confirm this.) b. Additionally, if the sample is not processed quickly, some red blood cells will hemolyze and cause spillage of K+ leading to a falsely elevated result. The test should be repeated in this case. c. Other contributing factors include leukocytosis and thrombocytosis.  FIGURE 8.5 Diagnostic evaluation of hyperkalemia. (Adapted from Humes DH, DuPont HL, Gardner LB, et al. Kelley’s Textbook of Internal Medicine. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2000:1168, Figure 147-1.) Quick HIT ECG changes in hyperkalemia become prominent when K+ >6 and include: Peaked T waves (by 10 mm) A prolonged PR interval Widening of QRS and merging of QRS with T wave Ventricular fibrillation and cardiac arrest (with increasing levels of K+) B. Clinical Features 1. Arrhythmias—The most important effect of hyperkalemia is on the heart (Figure 8-5). Check an ECG immediately in a hyperkalemic patient. With increasing potassium, ECG changes progress through tall, peaked T waves, QRS widening, PR interval prolongation, loss of P waves, and finally a sine-wave pattern. 2. Muscle weakness and (rarely) flaccid paralysis 3. Decreased deep tendon reflexes 4. Respiratory failure 5. Nausea/vomiting, intestinal colic, diarrhea 6. Acidosis due to decreased ammonium formation in renal tubules Quick HIT Of all electrolyte disturbances, hyperkalemia is the most dangerous and can be the most rapidly fatal. C. Treatment 1. If the hyperkalemia is severe, or if ECG changes are present, first give IV calcium. a. Calcium stabilizes the resting membrane potential of the myocardial membrane —that is, it decreases membrane excitability. b. Use caution in giving calcium to patients on digoxin. (Hypercalcemia predisposes the patient to digoxin toxicity.) 2. Shift potassium into the intracellular compartment. a. Glucose and insulin—Works via stimulation of Na+/K+ pump. Glucose alone will stimulate insulin from β-cells, but exogenous insulin is more rapid (and thus should be one of the first steps in management). Give both to prevent hypoglycemia. b. Beta agonists (e.g., albuterol)—Also works via stimulation of Na+/K+ pump. Transient management in those with symptoms or EKG changes. c. Sodium bicarbonate—Increases pH level, which shifts K+ into cells via H+/K+ pump. Similar to β agonists, an emergency measure in severe hyperkalemia. 3. Remove potassium from the body. a. Kayexalate—GI potassium exchange resin (Na+/K+ exchange in GI tract) absorbs K+ in the colon, preventing reabsorption (passed in stool, thus reliant on patient being able to defecate). b. Diuretics (furosemide)—Effect is variable and thus is rarely used as monotherapy. c. Hemodialysis. Most rapid and effective way of lowering plasma K+. Reserved for intractable hyperkalemia (usually over 7) and for those with renal failure. Side effects Malignant Hyperthermia Potent triggering agent in patients susceptible to MH Intracranial pressure May lead to increase in cerebral blood flow and ICP Attenuated with hyperventilation/good airway control Pre-treat with non-depolarizing muscle relaxant and IV lidocaine 2-3 minutes prior to intubation How to manage it? Hyperventilation: Reduces CO₂ levels, causing cerebral vasoconstriction, which helps lower ICP. Good airway control: Ensures oxygenation without excessive airway stimulation (which can worsen ICP). Pre-treatment options: A small dose of a non-depolarizing muscle relaxant (e.g., rocuronium) before succinylcholine can prevent fasciculations and minimize ICP elevation. IV lidocaine (1-1.5 mg/kg) given 2-3 minutes before intubation can also blunt the ICP rise by stabilizing neuronal membranes. Side effects Intragastric pressure elevation Abdominal wall fasciculations increase pressure Offset by increase LES tone ~ No increase reflux/aspiration 5 ~ Abolished by pretreatment Intraocular pressure elevation Extra-ocular muscle knare- multiple motor-end plates each cell Prolonged depolarization and contraction of muscle transiently raise IOP Worrisome in patient’s with injured eye Non-Depolarizers ED95: We need to block at least 95% of the receptors to completely paralyze the patient If there is still some movement give a top-up dose à (1/16-1/10 of the initial dose) Drug Structure Metabolism Primary Onset Duration Hist. Vagal Excretion Release Blockade Atracurium Benzylisoquinolone +++ x ++ ++ + 0 Cisatracurium Benzylisoquinolone +++ x ++ ++ 0 0 (used nowadays) Mivacurium Benzylisoquinolone Cholinesterase x ++ + + 0 enzymes Doxacurium Benzylisoquinolone Insignificant Renal +++ +++ 0 0 Pancuronium Steroidal + Renal +++ +++ 0 ++ Pipercuronium Steroidal + Renal +++ +++ 0 0 Vecuronium Steroidal + Biliary ++ ++ 0 0 Rocuronium Steroidal insignificant Biliary + ++ 0 + (only steroidal used) Drug Intubation dose Onset of Duration of Maintenance Maintenance (mg/kg) action for action dosing by dosing by infusion Intubating (min) boluses (ug/kg/min) dose (mg/kg) (min) Succinylcholine 1-1.5.5-1 5-10.15 2-15 mg/min Rocuronium.6 1.5-2.5 35-75.15 9-12 Mivacurium.2 2.5-3.0 15-20.05 4-15 Atracurium.5 2.5-3.0 30-45 ,1 5-12 Cisatracurium.2 3-4 40-75.02 1-2 Vecuronium.12 2-3 45-90.01 1-2 Pancuronium.12 2-3 60-120.01 x Pipercuronium.1 2-3 80-120.01 x Doxacurium.07 4-5 90-150.05 x  Non-depolarizers Three types Benzylisoquinolines Release histamine Steroids Vagolytic Related allergic history Other compounds ( like chlorofumarates ) Muscle relaxants are not anesthetic drugs, they work on the NMJ outside the CNS. They are water-soluble drugs; clinically speaking, they don’t penetrate the BBB à all drugs penetrate the BBB, BUT muscle relaxants penetrate the BBB in a very insignificant amount, so they have no clinical effect on the brain. Never use muscle relaxants as sedative drugs. Anesthetic drugs should be administered when using muscle relaxants for amnesia. Chemical structure of muscle relaxants  priming bose Non-depolarizers ↳ a small close give before the full to intubating dose Intubation accelerate paralysis [ None as rapid onset as succinylcholine , M Quickened by larger dose or priming dose S SI cose - Prolongs duration of blockade and exacerbates SEesideelect , # Priming dose 8 10-15 % of intubating dose 5 minutes before - induction will occupy enough receptors so that paralysis quickly follows full dose - recuronium can provide Intubation conditions at 60s (Rocuronium) - good intubation 90s with other intermediate-acting depolarizers conditions in 60s. Does not usually lead to clinically significant paralysis # (75-80% of receptors blocked) Can cause dyspnea, dysphagia and diplopia - Non-depolarizers Maintenance relaxation LARGE VARIABLE IN DOSE RESPONSES Large Variability in Dose Response Train-of-four (TOF) monitoring using a peripheral nerve stimulator is the gold standard for assessing Requires Close monitoring with Neuro-stimulator neuromuscular blockade. This helps adjust dosing to avoid excessive or inadequate paralysis. Bolus or infusion should be guided by stimulator as well as clinical signs Movement Spontaneous ventilation Some return of neuromuscular transmission should be evident prior to bolus dose This means that before giving another bolus dose of a non-depolarizing neuromuscular blocker (NDNMB), you should see signs that the previous dose is wearing off. Infusion should be titrated at or just above rate that allows return of neuromuscular transmission 4. Bolus vs. Infusion Dosing Bolus dose: Given intermittently when muscle relaxation wanes. Continuous infusion: Titrated to maintain adequate blockade without excessive drug accumulation. Both should be guided by: Neurostimulator readings (TOF ratio) Clinical signs (e.g., return of movement or spontaneous ventilation) Non-depolarizers Potentiated by inhalational anesthetics Volatile agents decrease dosage requirements by at least 15 % Depends on agent Des> Sevo > Iso and Enflurane > Halothane > N202 Muscle relaxant Pancuronium > vecuronium and atracurium ↳ Hypothetically due to volatile induced enhanced affinity for non-depolarizing muscle relaxants Muscle Relaxant Differences: Which NDNMBs Are Affected the Most? Pancuronium > Vecuronium & Atracurium Pancuronium is most affected (requires the largest dose reduction). Vecuronium and Atracurium are also potentiated, but to a lesser extent. Autonomic side Effects Older agents (tubocurarine/metocurine) 2. How Do They Affect the Autonomic Nervous System? Blocked autonomic ganglia → This interferes with normal sympathetic and parasympathetic responses, leading to: Blocked autonomic ganglia Decreased contractility (weakened heart muscle contraction). Reduced response to hypotension (the body struggles to compensate when blood pressure Decreased contractility/response to hypotension drops). Pancuronium Blocks vagal muscarinic receptors Tachycardia Newer agents Devoid of significant autonomic effects  Hoffmann Elimination (Hofmann Degradation) in Neuromuscular Blockers Excretion 1. What is Hoffmann Elimination? A unique way some drugs are metabolized that does not require liver or kidney function. Instead, the drug spontaneously breaks down in plasma due to temperature and pH changes. Hepatic 2. Which Neuromuscular Blockers Undergo Pancuronium\Vecuronium metabolized mostly by liver Hoffmann Elimination? Liver failure Atracurium Cisatracurium (a more potent form of atracurium) Prolongs pancuronium as well as rocuronium blockade Less effect on vecuronium 3. Why is This Important? No effect on Cisatracurium or atracurium à Hoffman Safe in patients with liver or kidney failure → Since these drugs don’t rely on organ metabolism, Renal they are ideal for patients with hepatic or renal dysfunction. Doxacurium/Pancuronium/Vecuronium and pipecuronium excreted by kidneys Prolonged action in patients with renal failure  Characteristics Greater Potency=slower onset Temperature Hypothermia prolongs blockade Decreased metabolism and excretion Acid-Base Respiratory acidosis Potentiates blockade Hypokalemia/Hypocalcemia Prolong blockade Hypermagesemia Prolongs blockade by competing with Ca++ at motor-end plate Seen in preeclampsia Age : Neonates have an increased sensitivity to nondepolarizing relaxants because of their immature neuromuscular junctions. This sensitivity does not necessarily decrease dosage requirements, as the neonate’s greater extracellular space provides a larger volume of distribution. Depolarizing: ­Dose with ¯Age Non-depolarizing: ¯Dose with ¯Age Atracurium Benzylisoquinoline Metabolized independent of renal and biliary routes Hoffman elimination Triggers dose –dependent histamine release above.5mg/kg (intubating dose) Hypotension/reflex tachycardia/cutaneous flush Laudanosine toxicity Product of breakdown of atracurium CNS excitation: possibly seizures Only relevant at extremely high doses or hepatic failure Precipitate as free acid if placed in IV line with alkaline solution (thiopental) Cisatracurium Stereoisomer of atracurium 4 times more potent Hoffman elimination *Does not produce a dose-dependent increase in histamine Also lower laudaonsine toxicity PH/Temperature sensitive Secondary to unique metabolism Prolonged action by hypothermia/acidosis Mivacurium Metabolized by pseudocholinesterase Also prolonged by low pseudocholinesterase levels Also causes histamine release Brief duration of action About half of atracurium/vec/rocuronium Markedly prolonged by prior administration of pancuronium Doxacuronium Benzylisoquinoline Renal excretion Similar to other long acting non-depolarizers Slow onset (4-6 minutes).05mg/kg for tracheal intubation within 5 min No cardiac or histamine-release side effects Duration:60-90 minutes Pancuronium Steroid base Primarily renal excretion Slowed by renal failure Some excretion by bile Cirrhotic patients require higher initial dose Side Effects: HTN and tachycardia Combination of vagal blockade and sympathetic stimulation Caution with CAD, aortic stenosis Arrhythmias Increases AV conduction and catecholamine release Worsened in patients using TCA and halothane Allergic reaction possible in patients hypersensitive to bromide Pipecuronium Steroid base (similar to Pancuronium) Renal excretion No cardiovascular side effects Advantage over pancuronium Vecuronium Biliary and renal excretion Satisfactory in renal failure however some prolongation occurs Side effects No significant CV effects Can cause potentiation of opioid-induced bradycardia *Long term administration causes buildup of active 3-hydroxy metabolite: elongates drug clearance and can cause polyneuropathy  Shorter onset of action. Rocuronium If you give rocuronium in a dose of 1-1.2 mg/kg and above, you can intubate your patient in 60 seconds. But the quality of relaxation of succinylcholine is better for intubation. Analogue of vecuronium designed for rapid onset No active metabolite Better choice for long term infusion Can cause prolonged duration of action in elderly Primary hepatic and renal elimination Duration of action prolonged by hepatic disease and pregnancy Not Significantly affected by renal failure Rocuronium Useful for quick onset of action Closest non-depolarizer to succinylcholine.1 mg/kg shown to be rapid and effective agent (decreased fasciculations and post-op myalgias for precurarization administration of succinylcholine Slight vagolytic tendencies  Gantacurium gantacurium demonstrated an ultrashort duration of action, similar to that of succinylcholine. Its pharmacokinetic profile is explained by the fact that it undergoes nonenzymatic degradation by two chemical mechanisms: rapid formation of inactive cysteine adduction product and ester hydrolysis. At a dose of 0.2 mg/kg (ED95), the onset of action has been estimated to be 1-2 min, with a duration of blockade similar to that of succinyl- choline Its clinical duration of action ranged from 5-10 min; recovery can be accelerated by edropho- nium, as well as by the administration of exogenous cysteine. Cardiovascular effects suggestive of histamine release were observed following the use of three times the ED95 dosage.  REVERSAL OF NEUROMUSCULAR blocking agents : Cholinergic receptors have been subdivided into two major groups : 1.(Nicotinic receptors)Nicotine stimulates the autonomic ganglia and skeletal muscle receptors , 2.(Muscarinic receptors) : muscarine activates end-organ effector cells in bronchial smooth muscle, salivary glands, and the sinoatrial node. Both receptors are activated by acetylcholine Nicotinic receptors are blocked by muscle relaxants and muscarinic receptors are blocked by anticholinergic drugs, such as atropine.  REVERSAL OF NEUROMUSCULAR blocking agents : When reversing neuromuscular blockade, the primary goal is to maximize nicotinic transmission with a minimum of muscarinic side effects. Normal neuromuscular transmission critically depends on acetylcholine binding to nicotinic cholinergic receptors on the motor end-plate. Nondepolarizing muscle relaxants act by competing with acetylcholine for these binding sites, thereby blocking neuromuscular transmission. Reversal of blockade depends on gradual diffusion, redistribution, metabolism, and excretion from the body of the nondepolarizing relaxant (spontaneous reversal), often assisted by the administration of specific reversal agents (pharmacological reversal). Cholinesterase inhibitors ) as neostigmine ) indirectly increase the amount of acetylcholine available to compete with the nondepolarizing agent, thereby reestablishing normal neuromuscular transmission.  The increase in acetylcholine caused by cholinesterase inhibitors affects not only the nicotinic receptors of skeletal muscles ,but they can also act at cholinergic muscarinic receptors of several other organ systems, including the cardiovascular and gastrointestinal systems. Muscarinic side effects of Cholinesterase inhibitors: Parasympathetic activation  Unwanted muscarinic side effects are minimized by prior or concomitant administration of anticholinergic medications, such as atropine sulfate or glycopyrolate. Atropine has faster onset and shorter duration of action than glycopyrolate.  Succinylcholine is 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, pseudocholinesterase (nonspecific cholinesterase, plasma cholinesterase, or butyrylcholinesterase) The ONLY time neostigmine reverses neuromuscular block after succinylcholine is when there is a phase II block AND sufficient time has passed for the circulating concentration of succinylcholine to be negligible  Sugammadex, a cyclodextrin, is the first selective relaxant-binding agent; it exerts its reversal effect by forming tight complexes in a 1:1 ratio with steroidal nondepolarizing agents (vecuronium, rocuronium,) it does not act on Ach receptors. This drug has been in use in the European Union for the past few years. And FDA approved in the U.S. In doses of 2 mg/kg , sugamadex will reverse both rocuronium and vecuronuim from a TOF of 2 to TOF of 0.9 in 2-4 min. doses of 4 mg/kg , sugamadex will reverse deeper levels of neuromuscular block to TOF of 0.9 within 2.9 min. Immediate reverse from profound block such as that encountered during failed RSI in which mask ventilation is not possible ( cannot intubate ,cannot ventilate) requires doses of 16mg/kg of sugamadex to reverse the relaxant effect of rocuronuim. Sugamadex has no side effects related to coagulation profile, respiratory or cardiovascular system. Sugamadex is reliable in reversing the action of rocuronuim in morbidely obese patients, in patients with neuromuscular disorders and after intense neuromuscular block, within very short period of time and far shorter than the reverse induced by neostigmine. Sugamadex is not effective in reversing the effect of benzylisoquinoline type of muscle relaxants. The newer neuromuscular blocking agents, such as gantacurium, which are still under investigation, show promise as ultrashort-acting nondepolarizing agents; they undergo chemical degradation by rapid adduction with L-cysteine.