Neuromuscular physiology & pharmacology

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Neuromuscular physiology & pharmacology:

Neuromuscular physiology & pharmacology Presentor – Dr Bikram Gupta


PREJUNCTIONAL RECEPTORS These are nicotinic receptors present at presynaptic membrane. Sch act on these prejunctional receptors & responsible for fasciculation. This fasciculations can be prevented by defasculating dose of NDMRs. Because NDMRs prevent fasciculation, it was concluded that they acted on the same prejunctional receptor.


EXTRAJUNCTIONAL RECEPTOR These tend to be concentrated around the end plate, where they mix with post junctional receptors but may be found anywhere on the muscle membrane. In them, the adult epsilon subunit is replaced by the fetal gamma subunit. They are not found in normal active muscle, but appear very rapidly after injury or whenever muscle activity has ended. They can appear within 18hrs of injury and an altered response to neuromuscular blocking drugs can be detected in 24hrs of the insult.

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When a large number of extrajunctional receptors are present, resistance to non-depolarising muscle relaxants develops, yet there is an increased sensitivity to depolarising muscle relaxants. In most extreme cases, increased sensitivity to succinylcholine results in lethal hyperkalemic receptors with an exaggerated efflux of intracellular potassium. The longer opening time of the ion channel on the extrajunctional receptor also results in larger efflux.

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Different pools of acetylcholine in the nerve terminal have variable availability for release The immediately releasable stores, VP2: Responsible for the maintainance of transmitter release under conditions of low nerve activity. 1% of vesicles The reserve pool, VP1: Released in response to nerve impulses. 80% of vesicles The stationary store: The remainder of the vesicles.

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Contents of a single vesicle constitute a quantum of acetylcholine. Release of acetylcholine may be Spontaneous or In response to a nerve impulse.

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Docking of the vesicle and subsequent discharge of acetylcholine by exocytosis, involves several other proteins. Membrane protein called SNAREs ( Soluble N-ethylmatrimide sensitive attachment proteins) are involved in fusion, docking, and release of acetylcholine at the active zone. SNARE includes – synaptic vesicle protein synaptobrevin, synataxin and SNAP-25.


STRUCTURE OF NA CHANNEL This Na channel is cylindrical Has membrane protein Its two ends act as gates Both should be open to allow passage of ions. Voltage dependent gate is closed in resting state and opens only on application of a depolarising voltage, remains open as long as the voltage persists

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The time dependent gate is normally open at rest closing a few milliseconds after the voltage gate opens and remains closed as long as the voltage gate is open It reopens after the voltage gate closes. The channel is patent, allowing sodium ions only when the gates are open.


POSSIBLE CONFIGURATION OF Na CHANNELS Resting state : Voltage gate closed Time gate open Channel closed Depolarization: Voltage gate open Time gate open Channel open With in a few milliseconds: Voltage gate open Time gate closed Channel closed End of depolarization: Voltage gate closed Time gate open Channel closed


ROLE OF CALCIUM The concentration of calcium and the length of time during which it flows into the nerve ending, determines the number of quanta release. Calcium current is normally stopped by the out flow of potassium. Calcium channels are specialized proteins, which are opened by voltage change accompanying action potentials


ACETYLCHOLINESTERASE This protein enzyme is secreted from the muscle, but remain attached to it by thin stalks of collagen, attached to the basement membrane. Acetylcholine molecules that don’t interact with receptors are released from the binding site & are destroyed almost immediately by acetylcholinesterase, in <1 ms, after its release into the junctional cleft.

Desensitization Block:

Desensitization Block Some receptors that bind to agonists, however, do not undergo the conformational change to open the channel. Receptors in these states are called desensitized (i.e., they are not sensitive to the channel-opening actions of agonists). The mechanisms by which desensitization occurs are not known.

Drugs That Can Cause or Promote Desensitization of Nicotinic Cholinergic Receptors:

Drugs That Can Cause or Promote Desensitization of Nicotinic Cholinergic Receptors Volatile anesthetics –Halothane, Sevoflurane , Isoflurane Antibiotics - Polymyxin B Cocaine Alcohols – Ethanol, Propanol Barbiturates –Thiopental, Agonists - Succinylcholine Acetylcholinesterase inhibitors - Neostigmine Local anesthetics - Lidocaine Phenothiazines Phencyclidine Calcium channel blockers - Verapamil

Phase II block:

Phase II block A phase II block is a complex phenomenon that occurs slowly at junctions continuously exposed to depolarizing agents. The repeated opening of channels allows a continuous efflux of potassium and influx of sodium, and the resulting abnormal electrolyte balance distorts the function of the junctional membrane. Factors influencing the development of a phase II block : - the duration of exposure to the drug, the particular drug used and its concentration the type of muscle (i.e., fast or slow twitch) Interactions with anesthetics and other agents

Clinical characteristics of phase 1 and phase 2 neuromuscular blockade during Sch infusion:

Clinical characteristics of phase 1 and phase 2 neuromuscular blockade during Sch infusion Characteristic Phase 1 Transition Phase 2 Tetanic stimulation No fade Slight fade Fade Post-tetanic facilitation None Slight Yes Train-of-four fade No Moderate fade Marked fade Train-of-four ratio >0.7 0.4-0.7 <0.4 Edrophonium Augments Little effect Antagonizes Recovery Rapid Rapid to slow Increasingly prolonged Dose requirements (mg/kg) * 2-3 4-5 >6 Tachyphylaxis No Yes Yes

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The reversal response of a phase II block produced by a depolarizing muscle relaxant to administration of cholinesterase inhibitors is difficult to predict. It is therefore best that reversal by cholinesterase inhibitors not be attempted, although the response to tetanus or train-of-four stimulation resembles that produced by nondepolarizers .


PHYSICAL CHANNEL BLOCKADE Various drugs can block the neuromuscular junction and prevent depolarisation . Blockade can occur in two modes Blocked when open Blocked when closed


OPEN CHANNEL BLOCK In this, the drug molecule enters a channel which has been opened by acetylcholine. This is use dependent block Physical blockade by a molecule of an open channel relies on the open configuration of the channel and the development of this is proportional to the frequency of channel opening.

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This mechanism may explain the synergy that occurs with certain drugs such as local anaesthetic , antibiotics and muscle relaxants. In addition, the difficulty in antagonizing profound neuromuscular blockade may be due to open channel block by the muscle relaxants


CLOSED CHANNEL BLOCK The drugs occupy the mouth of the channel and prevents ions from passing through the channel to depolarise the end plate. Tricyclic drugs and naloxone may cause physical blockade of a closed by impending interaction of acetylcholine with the receptor. For drugs interfering with the function of the acetylcholine receptor, without acting as an agonist or antagonist, the receptor lipid membrane interface may also be another site of action. Eg : Volatile agents, Local anaesthetic and Ketamine

Muscle relaxant:

Muscle relaxant Muscle relaxants are anesthetic adjuncts administered to improve relaxation of skeletal muscles during surgical or diagnostic procedures. NMBA are the drugs that producing their effects by action at neuromuscular junctions.

Muscle Relaxants: Definition ::

Muscle Relaxants: Definition : Neuromuscular blockers ( NMB’s ) : Drugs that completely paralyze skeletal muscles (from normal tone to zero) by interfering with acetylcholine at neuromuscular junction. Spasmolytics : Drugs that used to relieve skeletal muscle spasm & bring them from hypertonic state to normal muscle tone . >>> Drugs that decrease muscle tone

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Muscle Relaxants are classified as: I)Peripherally acting A.Neuromuscular blocking agents :- Depolarizing muscle relaxants. Non-depolarizing muscle relaxants B.) Directly acting: Dantrolene , Quinine II)Centrally acting Chlorzoxazone,Chlormezanone , Diazepam, Baclofen , Tizanidine , Metaxalone .

Classification of Muscle Relaxants According to Mechanism of Action:

Classification of Muscle Relaxants According to Mechanism of Action Ultra-Short Short Intermediate Long Succinylcholine Mivacurium Vecuronium Pancuronium Atracurium Rocuronium Cis-atracurium 40


Succinylcholine Drug Onset & Duration Metabolism (%) Elimination Metabolites Kidney (%) Liver (%) Sch ( 2 molecules of Ach) Onset ( 1 mg/kg approx. 60 seconds DOA - (9 to 13 minutes) Butyrylcholinesterase (98%-99%) <2% None Monoester ( succinyl monocholine ) and choline ; monoester metabolized much more slowly than succinylcholine

What factors increase DOA of Sch ?:

What factors increase DOA of Sch ? 1- Quantitaive decrease in plasma choline-esterase level : liver disease, cancer, pregnancy & certain drugs like cyclophosphamide, phenylzine, monoamine oxidase inhibitors. 2- Qulitative decrease in plasma choline-esterase level : genetically inherited 42

Dibucaine Number and Atypical Butyrylcholinesterase Activity:

Dibucaine Number and Atypical Butyrylcholinesterase Activity Dibucaine number is a number expressing the percentage by which cholinesterase activity in a serum sample is inhibited by dibucaine . Under standardized test conditions, dibucaine inhibits expression of the normal enzyme by about 80% and the abnormal enzyme by about 20% .

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T he dibucaine number indicates the genetic makeup of an individual with respect to butyrylcholinesterase , it does not measure the concentration of the enzyme in plasma, nor does it indicate the efficiency of the enzyme in hydrolyzing a substrate such as succinylcholine or mivacurium . Both of the latter factors are determined by measuring butyrylcholinesterase activity, which may be influenced by genotype.

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Relationship between dibucaine number and duration of succinylcholine or mivacurium neuromuscular blockade :- Type of Butyrylcholinesterase Genotype Incidence Dibucaine Number * Response to Succinylcholine or Mivacurium Homozygous typical E 1 u E 1 u Normal 70-80 Normal Heterozygous atypical E 1 u E 1 a 1/480 50-60 Lengthened by 50%-100% Homozygous atypical E 1 a E 1 a 1/3200 20-30 Prolonged to 4-8 hr

Depolarizing Agents / Pharmacodynamics:

Depolarizing Agents / Pharmacodynamics Dynamics CNS : - NO effect on consciousness, pain threshold & cerebral fnx - ↑ intra-ocular pressure - ↑ intracranial pressure CVS : Bradycardia Dysarrythmia Sinus arrest Resp : -respiratory muscles paralysis MSS : -skeletal muscles paralysis - myalagia - myoglobinemia , myoglobinurea - messeter muscle spasm GU: Coz metabolites excreted by kidneys, pts with RF may have hyperkalemia 46


Hyperkalemia In patients with metabolic acidosis and hypovolemia , correction of the acidosis by hyperventilation and administration of sodium bicarbonate should be attempted before administration of succinylcholine . If severe hyperkalemia occur, it can be treated with :- immediate hyperventilation , 1.0 to 2.0 mg of calcium chloride intravenously, 1   mEq /kg of sodium bicarbonate, and 10 units of regular insulin in 50  mL of 50% glucose for adults or , for children, 0.15 units of regular insulin per kilogram in 1.0  mL /kg of 50% glucose.


Hyperkalemia Patients with intra-abdominal infections persisting for longer than 1 week, the possibility of a hyperkalemic response to Sch should be considered . A patient is susceptible to the hyperkalemic response for probably at least 60 days after massive trauma or until adequate healing of damaged muscle has occurred.

Intraocular pressure:

Intraocular pressure Succinylcholine usually causes an increase in intraocular pressure (IOP). The increased IOP is manifested within 1 minute after injection, peaks at 2 to 4 minutes, and subsides by 6 minutes . Despite this increase in IOP, the use of Sch for eye operations is not contraindicated unless the anterior chamber is open.

Increased Intragastric Pressure:

Increased Intragastric Pressure The increase in IGP from succinylcholine is presumed to be due to fasciculations of abdominal skeletal muscle . Generally , an IGP of greater than 28 cm H 2 O is required to overcome the competence of the gastroesophageal junction . However, when the normal oblique angle of entry of the esophagus into the stomach is altered, as may occur with pregnancy, an abdomen distended by ascites , bowel obstruction, or a hiatal hernia, the IGP required to cause incompetence of the gastroesophageal junction is frequently less than 15 cm H 2 O .

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In these circumstances, regurgitation of stomach contents after the administration of succinylcholine is a distinct possibility, and precautionary measures should be taken to prevent fasciculation. Endotracheal intubation may be facilitated by administration of either a nondepolarizing neuromuscular blocker or a defasciculating dose of a nondepolarizing relaxant before the succinylcholine .

Defasciculating dose:

Defasciculating dose A small dose of NDMA ( 10- 15 % of a NDMA intubating dose ) is commonly given 2 minutes before the intubating dose of succinylcholine . This defasciculating dose of NDMA will attenuate any increases in IGP & ICP and minimize the incidence of fasciculations in response to succinylcholine .

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Prior administration of a NDMA will render the muscle relatively resistant to Sch , so, the Sch dose should be increased by 50%. The use of a defasciculating dose of a NDMA may also slow the onset of Sch and produce less favorable conditions for tracheal intubation.

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Succinylcholine has no effect on the duration of action of pancuronium , pipecuronium , or mivacurium but increases that of atracurium and rocuronium . Succinylcholine should not be administered to reestablish neuromuscular blockade because it produces relaxation that will last up to 60 minutes when given soon after the administration of neostigmine .

Nondepolarizing Neuromuscular Blockers:

Nondepolarizing Neuromuscular Blockers Classification of nondepolarizing neuromuscular blockers according to duration of action (time to T1 = 25% of control) after twice the ED 95 - Class of Blocker Clinical Duration Long-Acting (>50 min) Intermediate-Acting (20-50 min) Short-Acting (15-20 min) Ultrashort -acting (<10-12 min) Steroidal compounds Pancuronium Pipecuronium Vecuronium Rocuronium     Benzylisoquinolinium compounds d -Tubocurarine Metocurine Doxacurium Atracurium Cisatracurium Mivacurium   Others          Asymmetrical mixed-onium chlorofumarates       Gantacurium  Phenolic ether Gallamine        Diallyl derivative of toxiferine Alcuronium


Atracurium In a Hofmann elimination reaction, a quaternary ammonium group is converted to a tertiary amine by cleavage of a carbon-nitrogen bond . This is a pH- and temperature-dependent reaction in which higher pH and temperature favor elimination .

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Hofmann elimination is a purely chemical process that results in loss of the positive charges by molecular fragmentation to laudanosine (a tertiary amine) and a monoquaternary acrylate , compounds that were thought to have no neuromuscular and little or no cardiovascular activity of clinical relevance. Laudanosine , a metabolite of atracurium , has CNS-stimulating properties. Unlike atracurium , laudanosine is dependent on the liver and kidney for its elimination and has a long elimination half-life.

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Atracurium is a mixture of 10 optical isomers. Cisatracurium is the 1R cis– 1′R cis isomer of atracurium . Like atracurium , cisatracurium is metabolized by Hofmann elimination to laudanosine and a monoquaternary acrylate . In contrast, however, there is no ester hydrolysis of the parent molecule. Because cisatracurium is about four or five times as potent as atracurium , about five times less laudanosine is produced.


Is an intermediate acting drug Is one of the 10 isomers of atracurium and more potent than atracurium The main advantage for this agent over atracurium is that it lacks the possibility of histamine release. It is the ideal choice for a patient with renal or hepatic insufficiency requiring muscle relaxation. eliminated by Hoffman degradation reaction. ED 95 is ( 0.5 mg/kg ) Cisatracurium 59

Steroidal Neuromuscular Blockers:

Steroidal Neuromuscular Blockers Pancuronium is a potent neuromuscular blocking drug with both vagolytic and butyrylcholinesterase -inhibiting properties. The minor molecular modification relative to pancuronium (i.e., vecuronium lacks the N -methyl group at position 2) results in :- ( 1) a slight change in potency ( 2) a marked reduction in vagolytic properties ( 3) molecular instability in solution b/o hydrolysis of the 3-acetate & ( 4) increased lipid solubility, which results in greater biliary elimination of vecuronium than pancuronium .

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Rocuronium lacks the acetyl ester that is found in the steroid nucleus of pancuronium and vecuronium in the A ring. As a result, rocuronium is about 6 and 10 times less potent than vecuronium and pancuronium , respectively . At room temperature, rocuronium is stable for only 60 days, whereas pancuronium is stable for 6 months . The reason for this difference in shelf life is related to the fact that rocuronium is terminally sterilized in manufacturing and pancuronium is not. Terminal sterilization causes some degree of degradation.

Potency of Nondepolarizing Neuromuscular Blockers:

Potency of Nondepolarizing Neuromuscular Blockers The dose of a neuromuscular blocking drug required to produce an effect (e.g., 50%, 90%, or 95% depression of twitch height, commonly expressed as ED 50 , ED 90 , and ED 95 , respectively) is taken as a measure of its potency.

Schematic representation of drug disposition into different Compartments:

Schematic representation of drug disposition into different Compartments Distribution to and from 2 nd comp distribution to and from 3 rd comp. peripheral compartment ( volume = V 3 ) Central compartment ( volume = V 1 ) peripheral compartment ( volume = V 2 ) k 12 k 21 k 13 k 31 E ffect k eo Drug adm . Drug elimination NMJ K 10

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In general, this conceptual model is appropriate for all the neuromuscular blockers, with the exception of atracurium and cisatracurium , which also undergo elimination (by degradation) from tissues . For most nondepolarizing neuromuscular blockers, the process of distribution is more rapid than the process of elimination, and the initial rapid decline in plasma concentration is due primarily to distribution of the drug to tissues. An exception to this rule is mivacurium , which has such rapid clearance, because of metabolism by butyrylcholinesterase , that elimination is the principal determinant of the initial decline in plasma concentration.

Guide to nondepolarizing relaxant dosage (mg/kg) with different anesthetic techniques *:

Guide to nondepolarizing relaxant dosage (mg/kg) with different anesthetic techniques * ED 95 under N 2 O/O 2 Dose for Intubation Supplemental Dose after Intubation Dosage for Relaxation N 2 O Anesthetic Vapors [†] Long-Acting Pancuronium 0.07 0.08-0.12 0.02 0.05 0.03 d -Tubocurarine 0.5 0.5-0.6 0.1 0.3 0.15 Intermediate-Acting Vecuronium 0.05 0.1-0.2 0.02 0.05 0.03 Atracurium 0.23 0.5-0.6 0.1 0.3 0.15 Cisatracurium 0.05 0.15-0.2 0.02 0.05 0.04 Rocuronium 0.3 0.6-1.0 0.1 0.3 0.15 Short-Acting Mivacurium 0.08 0.2-0.25 0.05 0.1 0.08 Continuous Infusion Dosage (µg/kg/min) Required to Maintain 90%-95% Twitch Inhibition under N 2 O/O 2 with Intravenous Agents Mivacurium Atracurium Cisatracurium Vecuronium Rocuronium 3-15 4-12 1-2 0.8-1.0 9-12      

Initial and Maintenance Dosage:

Initial and Maintenance Dosage The initial dose is determined by the purpose of administration. Traditionally, doses used to facilitate tracheal intubation are twice the ED 95 (this also approximates four times the ED 50 ). Management of individual patients should always be guided by monitoring with a peripheral nerve stimulator. Supplemental (maintenance) doses of neuromuscular blockers should be about one-fourth (in the case of intermediate- and short-acting neuromuscular blockers) to one-tenth (in the case of long-acting neuromuscular blockers) the initial dose and should not be given until there is clear evidence of beginning of recovery from the previous dose. The infusion dosage is usually decreased by 30% to 50% in the presence of potent inhaled anesthetics.

Neuromuscular Blockers and Tracheal Intubation:

Neuromuscular Blockers and Tracheal Intubation The speed of onset is inversely proportional to the potency of nondepolarizing neuromuscular blockers. The onset of neuromuscular blockade is much more rapid in the muscles that are relevant to obtaining optimal intubating conditions (laryngeal adductors, diaphragm, and masseter ) than in the muscle that is typically monitored (adductor pollicis ). Thus, neuromuscular blockade develops faster, lasts a shorter time, and recovers more quickly in these muscles.

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Muscle blood flow rather than the drug's intrinsic potency may be more important in determining the onset and offset time of nondepolarizing neuromuscular blockers. More luxuriant blood flow (greater blood flow per gram of muscle) at the diaphragm or larynx would result in delivery of a higher peak plasma concentration of drug to the central muscle in the brief period before rapid redistribution is well under way.

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Onset of blockade occurs 1 to 2 minutes earlier in the larynx than at the adductor pollicis after the administration of nondepolarizing neuromuscular blocking agents. The pattern of blockade (onset, depth, and speed of recovery) in the orbicularis oculi is similar to that in the larynx. By monitoring the onset of neuromuscular blockade at the orbicularis oculi , one can predict the quality of intubating conditions.

Rapid Tracheal Intubation:

Rapid Tracheal Intubation Succinylcholine remains the drug of choice when rapid tracheal intubation is needed because it consistently provides muscle relaxation within 60 to 90 seconds.


THE PRIMING TECHNIQUE Since the introduction of rocuronium , the use of priming has decreased considerably. a small subparalyzing dose of the nondepolarizer (about 20% of the ED 95 or about 10% of the intubating dose) be given 2 to 4 minutes before a large second dose for tracheal intubation. This procedure, termed priming, has been shown to accelerate the onset of blockade for most nondepolarizing neuromuscular blockers by 30 to 60 seconds, which means that intubation can be performed within approximately 90 seconds of the second dose.

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Moreover, priming carries the risks of aspiration and difficulty swallowing, and the visual disturbances associated with subtle degrees of blockade are uncomfortable for the patient.


THE HIGH-DOSE REGIMEN FOR RAPID TRACHEAL INTUBATION Larger doses of neuromuscular blockers are usually recommended when intubation must be accomplished in less than 90 seconds. Increasing the dosage of rocuronium from 0.6 mg/kg (twice the ED 95 ) to 1.2 mg/kg (four times the ED 95 ) shortened the onset time of complete neuromuscular blockade from 89 ± 33 seconds (mean ± SD) to 55 ± 14 seconds but significantly prolonged the clinical duration (i.e., recovery of the first twitch of TOF [T1] to 25% of baseline) from 37 ± 15 minutes to 73 ± 32 minutes.

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Whatever technique of rapid-sequence induction of anesthesia and intubation is elected, the following four principles are important: (1) Preoxygenation must be performed (2) sufficient doses of intravenous drugs must be administered to ensure that the patient is adequately anesthetized (3) intubation within 60 to 90 seconds must be considered acceptable (4) cricoid pressure should be applied subsequent to injection of the induction agent

Low-Dose Relaxants for Tracheal Intubation:

Low-Dose Relaxants for Tracheal Intubation low doses of neuromuscular blocking drugs can be used for routine tracheal intubation. In the vast majority of patients receiving 15 µg/kg of alfentanil followed by 2.0 mg/kg of propofol and 0.45 mg/kg of rocuronium , good to excellent conditions for intubation will be present 75 to 90 seconds after the completion of drug administration.

Metabolism and elimination of neuromuscular blocking drugs:

Metabolism and elimination of neuromuscular blocking drugs Drug Duration Metabolism (%) Elimination Metabolites Kidney (%) Liver (%) Succinylcholine Ultrashort Butyrylcholinesterase (98%-99%) <2% None Monoester ( succinyl monocholine ) and choline ; monoester metabolized much more slowly than succinylcholine Atracurium Intermediate Hofmann elimination and nonspecific ester hydrolysis (60%-90%) 10%-40% None Laudanosine , acrylates , alcohols, and acids. Although laudanosine has CNS-stimulating properties, the clinical relevance of this effect is negligible.

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Drug Duration Metabolism (%) Elimination Metabolites Kidney (%) Liver (%) Cisatracurium Intermediate Hofmann elimination (77%?) Renal clearance is 16% of total   Laudanosine and acrylates . Ester hydrolysis of the quaternary monoacrylate occurs secondarily. Because of the greater potency of cisatracurium , laudanosine quantities produced by Hofmann elimination are 5 to 10 times lower than in the case of atracurium , thus making this not an issue in practice.

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Drug Duration Metabolism (%) Elimination Metabolites Kidney (%) Liver (%) Vecuronium Intermediate Liver (30%-40%) 40%-50% 50%-60% The 3-OH metabolite accumulates, particularly in renal failure. It has about 80% the potency of vecuronium and may be responsible for delayed recovery in ICU patients.       (Metabolites excreted in urine and bile, ≈40%)   Rocuronium Intermediate None 10%-25% >70% None Pancuronium Long Liver (10%-20%) 85% 15% The 3-OH metabolite may accumulate, particularly in renal failure. It is about two thirds as potent as the parent compound.

Approximate autonomic margins of safety of nondepolarizing neuromuscular blockers :

Approximate autonomic margins of safety of nondepolarizing neuromuscular blockers Drug Histamine Release Benzylisoquinolinium Compounds Mivacurium 3.0 Atracurium 2.5 Cisatracurium None d -Tubocurarine 0.6 Steroidal Compounds Vecuronium None Rocuronium None Pancuronium None These autonomic responses are not reduced by slower injection of the relaxant.

Clinical autonomic effects of neuromuscular blocking drugs:

Clinical autonomic effects of neuromuscular blocking drugs Drug Autonomic Ganglia Cardiac Muscarinic Receptors Histamine Release Depolarizing Substance Succinylcholine Stimulates Stimulates Slight Benzylisoquinolinium Compounds Mivacurium None None Slight Atracurium None None Slight Cisatracurium None None None d -Tubocurarine Blocks None Moderate Steroidal Compounds Vecuronium None None None Rocuronium None Blocks weakly None Pancuronium None Blocks moderately None

Clinical Cardiovascular Manifestations of Autonomic Mechanisms:

Clinical Cardiovascular Manifestations of Autonomic Mechanisms HYPOTENSION  TACHYCARDIA DYSRHYTHMIAS  BRADYCARDIA

Respiratory Effects:

Respiratory Effects The administration of benzylisoquinolinium neuromuscular blocking drugs (with the exception of cisatracurium ) is associated with histamine release, which may result in increased airway resistance and bronchospasm in patients with hyperactive airway disease.

Drug Interactions and Other Factors Affecting Response to Neuromuscular Blockers:

Drug Interactions and Other Factors Affecting Response to Neuromuscular Blockers Interactions Among Nondepolarizing Neuromuscular Blockers Mixtures of two nondepolarizing neuromuscular blockers are considered to be either additive or synergistic. Interactions between Succinylcholine and Nondepolarizing Neuromuscular Blockers it is recommended that the dose of succinylcholine be increased after the administration of a defasciculating dose of a nondepolarizing neuromuscular blocker.

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Interactions with Inhaled Anesthetics Inhaled anesthetics will decrease the dose of neuromuscular blockers needed, as well as prolong both the duration of action of the blocker and recovery from neuromuscular blockade, depending on the duration of anesthesia,the specific inhaled anesthetic, and the concentration (dose) given.The rank order of potentiation is desflurane > sevoflurane > isoflurane > halothane > nitrous oxide–barbiturate– opioid or propofol anesthesia

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Interactions with Antibiotics The aminoglycoside antibiotics, the polymyxins , and lincomycin and clindamycin primarily inhibit the prejunctional release of acetylcholine and also depress postjunctional nAChR sensitivity to acetylcholine. Calcium should not be used to hasten the recovery of neuromuscular function for two reasons: the antagonism that it produces is not sustained, and it may prevent the antibacterial effect of the antibiotics Temperature Hypothermia prolongs the duration of action of nondepolarizing neuromuscular blockers. They include diminished renal and hepatic excretion, changing volumes of distribution, altered local diffusion receptor affinity, changes in pH at the neuromuscular junction, and the net effect of cooling on the various components of neuromuscular transmission.

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The Hofmann elimination process of atracurium is slowed by a decrease in pH and especially by a decrease in temperature. [279] In fact, atracurium's duration of action is markedly prolonged by hypothermia. [274] For instance, the duration of action of a 0.5-mg/kg dose of atracurium is 44 minutes at 37°C but 68 minutes at 34.0°C. Interactions with Magnesium and Calcium Magnesium sulfate, given for the treatment of preeclampsia and eclamptic toxemia, potentiates the neuromuscular blockade induced by nondepolarizing neuromuscular blockers. The mechanisms underlying the enhancement of nondepolarizing blockade by magnesium probably involve both prejunctional and postjunctional effects.

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Interactions with Lithium Interactions with Local Anesthetic and Antidysrhythmic Drugs Interactions with Antiepileptic Drugs Interactions with Diuretics Interactions with Other Drugs

Conditions associated with upregulation and downregulation of acetylcholine receptors:

Conditions associated with upregulation and downregulation of acetylcholine receptors nAChR upregulation Spinal cord injury    Stroke    Burns    Prolonged immobility    Prolonged exposure to neuromuscular blockers    Multiple sclerosis    Guillain-Barré syndrome nAChR downregulation Myasthenia gravis    Anticholinesterase poisoning    Organophosphate poisoning

Reported indications for the use of muscle relaxants in the intensive care unit:

Reported indications for the use of muscle relaxants in the intensive care unit Facilitate mechanical ventilation Facilitation of endotracheal intubation    Enable patients to tolerate mechanical ventilation High pulmonary inflation pressures, e.g., acute respiratory distress syndrome Hyperventilation for increased intracranial pressure Facilitate therapeutic or diagnostic procedures Tetanus Status epilepticus Reduce oxygen consumption Abolish shivering Reduce work of breathing

Complications of muscle paralysis in the ICU:

Complications of muscle paralysis in the ICU Short-term use    Specific, known drug side effects    Inadequate ventilation in the event of ventilator failure or circuit disconnection    Inadequate analgesia and/or sedation    Long-term use    Complications of immobility   Deep venous thrombosis and pulmonary embolism Peripheral nerve injuries   Decubitus ulcers   Inability to cough Retention of secretions and atelectasis Pulmonary infection

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Dysregulation of nicotinic acetylcholine receptors Prolonged paralysis after stopping relaxants Persistent neuromuscular blockade Critical illness myopathy Critical illness polyneuropathy Combination of the above Unrecognized effects of drug or metabolites Succinylcholine and metabolic acidosis/ hypovolemia 3-Desacetylvecuronium and neuromuscular blockade Laudanosine and cerebral excitation

Causes of generalized neuromuscular weakness in the intensive care unit:

Causes of generalized neuromuscular weakness in the intensive care unit Central nervous system Septic or toxic-metabolic encephalopathy Brainstem stroke Central pontine myelinolysis Anterior horn cell disorders (e.g., amyotrophic lateral sclerosis) Peripheral neuropathies Critical illness polyneuropathy Guillain-Barré syndrome Porphyria Paraneoplasia Vasculitis Nutritional and toxic Neuromuscular junction disorders Myasthenia gravis Lambert-Eaton myasthenic syndrome Botulism Prolonged neuromuscular junction blockade

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Myopathies Critical illness myopathy Cachectic myopathy Rhabdomyolysis Inflammatory and infectious myopathies Muscular dystrophies Toxic Acid maltase deficiency Mitochondrial   Hypokalemia Hypermetabolic syndromes with rhabdomyolysis (e.g., neuroleptic malignant syndrome)

Recommendations for the use of neuromuscular blockers in the intensive care unit:

Recommendations for the use of neuromuscular blockers in the intensive care unit Avoid the use of neuromuscular blockers by: Maximal use of analgesics and sedatives Manipulation of ventilatory parameters and modes Minimize the dose of neuromuscular blocker: Use a peripheral nerve stimulator with train-of-four monitoring. Do not administer for more than 2 days continuously. Administer by bolus rather than infusion. Administer only when required and to achieve a well-defined goal. Continually allow recovery from paralysis Consider alternative therapies: Avoid vecuronium in female patients with renal failure. Use isoflurane in place of muscle relaxants in patients with severe asthma. Minimize the dose of steroid in patients with asthma

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