Muscle Relaxan

NON-DEPOLARISING AGENTS e.g. atracurium, mivacurium, pancuronium, rocuronium, vecuronium

These agents are competitive anatagonists at ACh receptors - 75% must be blocked before there is no longer muscle contraction

Highly ionised at body pH with two quaternary ammonium groups Poorly lipid soluble and poorly protein bound Rapid redistribution from blood --> ECF Used for prolonged paralysis when rapid intubation is not required Reversible by increasing ACh with anticholinisterases

DEPOLARISING AGENTS e.g. suxamethonium

Stimulation of ACh receptor causes depolarisation. Mimics action of ACh at ACh receptors without rapid hydrolysis by acetylcholinesterase

Peristance of the ligand prevents repolarisation and is therefore refractory to further stimulation

Reversal of the block can occur by diffusion of the drug away from the junction or from competitive agonist ACh (Increased by anticholinesterases)

Rapid onset of muscle fasciculation before blockade May --> muscle pains Suxamethonium used for paralysis of rapid onset and short duration e.g. to allow tracheal

intubation

Dr. Ni Putu Wardani – Residen Anestesiologi Reanimasi – Om Awighnam Astu Namo Siddham

Table. Depolarizing and Nondepolarizing Muscle Relaxants.

Depolarizing Nondepolarizing

Short-acting Short-acting

Succinylcholine Mivacurium

Intermediate-acting

Atracurium

Cisatracurium

Vecuronium

Rocuronium

Long-acting

Doxacurium

Pancuronium

Pipecuronium

Table. A Summary of the Pharmacology of Nondepolarizing Muscle Relaxants

Relaxant Chemical Structure1

Metabolism Primary Excretion

Onset2

Duration3

Histamine Release4

Vagal Blockade5

Atracurium B +++ Insignificant ++ ++ + 0

Cisatracurium B +++ Insignificant ++ ++ 0 0

Mivacurium B +++ Insignificant ++ + + 0

Doxacurium B Insignificant Renal + +++ 0 0

Pancuronium S + Renal ++ +++ 0 ++

Pipecuronium S + Renal ++ +++ 0 0

Vecuronium S + Biliary ++ ++ 0 0

Rocuronium S Insignificant Biliary +++ ++ 0 +

1. 1B, benzylisoquinolone; S, steroidal.2. 2Onset: +, slow; ++, moderately rapid; +++, rapid.3. 3Duration: +, short; ++, intermediate; +++, long.4. 4Histamine release: 0, no effect; +, slight effect; ++, moderate effect; +++, marked effect.5. 5Vagal blockade: 0, no effect; +, slight effect; ++, moderate effect.


Table. Clinical Characteristics of Nondepolarizing Muscle Relaxants.

Drug ED95 for Adductor Pollicis During N2/O2 Anesthesia (mg/kg)

Intubation Dose (mg/kg)

Onset of Action for Intubating Dose (min)

Duration of Intubating Dose (min)

Maintenance Dosing by Boluses (mg/kg)

Maintenance Dosing by Infusion (g/kg/min)

Succinylcholine 0.5 1.0 0.5 5–10 0.15 2–15 mg/min

Rocuronium 0.3 0.8 1.5 35–75 0.15 9–12

Mivacurium 0.08 0.2 2.5–3.0 15–20 0.05 4–15

Atracurium 0.2 0.5 2.5–3.0 30–45 0.1 5–12

Cisatracurium 0.05 0.2 2.0–3.0 40–75 0.02 1–2

Vecuronium 0.05 0.12 2.0–3.0 45–90 0.01 1–2

Pancuronium 0.07 0.12 2.0–3.0 60–120 0.01 —

Pipecuronium 0.05 0.1 2.0–3.0 80–120 0.01 —

Doxacurium 0.025 0.07 4.0–5.0 90–150 0.05 —

Characteristics of Neuromuscular Blockade

Depolarizing (Phase I) Block Muscle fasciculation preceding the onset of neuromuscular blockade Absence of posttetanic potentiation Lack of fade to frequent stimulation (e.g., tetanus, train of four, or double burst) Block antagonized by nondepolarizing drugs Block potentiated by acetylcholinesterase inhibitors

Nondepolarizing and Phase II Block Absence of muscle fasciculation Presence of posttetanic potentiation Fade with frequent stimulation Possible synergism between various groups of nondepolarizing relaxants Phase II block and nondepolarizing block potentiate each other


Block may be reversed by acetylcholinesterase inhibitors

Criteria of Adequate Recovery

Criteria used depend on whether the patient is awake or somnolent.Patient Is Awake Opens eyes widely to command and denies diplopia

Sustains tongue protrusion Swallows effectively Sustains a head lift for 5 seconds Sustains a firm hand grip Has an effective cough Has a vital capacity of at least 15 mL/kg Can generate an inspiratory force of at least 30 cm H2O

Patient Is Somnolent Can generate an inspiratory force of at least 30 cm H2O Responds to nerve stimulator appropriately, including sustained

tetanic response to 50 Hz for 5 seconds TOF or DBS stimulus yields ratio >0.7 or no discernible fade of fully

abducted thumb

* DBS, double-burst stimulation; TOF, train of four.

ANESTHESIA SECRET

1. Describe the anatomy of the neuromuscular junction (NMJ)

A motor nerve branches near its terminus to contact many muscle cells, losing myelin to branch further and come into closer contact with the junctional area of the muscle surface. Within the most distal aspect of the motor neuron, vesicles containing the neurotransmitter acetylcholine (ACh) can be found. The terminal neuron and muscle surface are loosely approximated with protein filaments, and this intervening space is known as the junctional cleft. Also contained within the cleft is extracellular fluid and acetylcholinesterase, the enzyme responsible for metabolizing ACh. The postjunctional motor membrane is highly specialized and invaginated and the shoulders of these folds are rich in ACh receptor

2. What is the structure of the ACh receptor?

The ACh receptor is contained within the motor cell membrane and consists of five glycoprotein subunits: two alpha and one each of beta, delta, and epsilon. These are arranged in a cylindrical fashion; the center of the cylinder is an ion channel. ACh binds to the alpha subunits.

3. In regards to neuromuscular transmission, list all locations for ACh Receptors

ACh receptors are found in several areas:

1. About 5 million ACh receptors per NMJ are located on the postjunctional motor membrane. 2. Prejunctional receptors are present and influence the release of ACh. The prejunctional and

postjunctional receptors have different affinities for ACh.


3. Extrajunctional receptors are located throughout the skeletal muscle in relatively low numbers owing to suppression of their synthesis by normal neural activity. In cases of traumatized skeletal muscle or denervation injuries, these receptors proliferate.

4. Review the steps involved in normal neuromuscular transmission

1. A nerve action potential is transmitted and the nerve terminal is depolarized. 2. ACh is released from storage vesicles at the nerve terminal. Enough ACh is released to bind

500,000 receptors. 3. ACh molecules bind to the alpha subunits of the ACh receptor on the postjunctional membrane,

generating a conformational change and opening receptor channels. Receptors do not open unless both alpha receptors are occupied by ACh (a basis for the competitive antagonism of nondepolarizing relaxants).

4. Sodium and calcium flows through the open receptor channel generating an end-plate potential.

5. When between 5% and 20% of the receptor channels are open and a threshold potential is reached, a muscle action potential (MAP) is generated.

6. Propagation of the MAP along the muscle membrane leads to muscle contraction. 7. The rapid hydrolysis of acetylcholine by acetylcholinesterase (true cholinesterase) within the

synaptic cleft and return of normal ionic gradients return the neuromuscular junction to a nondepolarized, resting state, and the ACh receptors are closed.

5. What are the benefits and risks of using muscle relaxants?

By interfering with normal neuromuscular transmission, these drugs paralyze skeletal muscle and can be used to facilitate endotracheal intubation, assist with mechanical ventilation, and optimize surgical conditions. Occasionally, they may be used to reduce the metabolic demands of breathing and to facilitate the treatment of raised intracranial pressure. Because they paralyze all respiratory muscles, they are dangerous drugs to use in the unintubated patient unless the caregiver is trained in airway management.

6. How are muscle relaxants classified?

Depolarizing relaxants: Succinylcholine (SCH) is two molecules of ACh bound together, is an agonist at the NMJ, and is the only depolarizing relaxant available clinically. As such, SCH binds to the alpha subunits of the ACh receptor. After binding, SCH can open the ion channel and depolarize the end plate. Though SCH, like ACh, binds only briefly to the receptor, it is not hydrolyzed in the synaptic cleft by acetylcholinesterase. In fact, SCH molecules may unbind and rebind receptors repeatedly. SCH must diffuse away and be broken down in the plasma by enzymes called plasma- or pseudocholinesterase, and time for clearance from the body is an accurate measure of its duration of effect.

Nondepolarizing relaxants: These drugs are competitive antagonists to ACh at the postsynaptic membrane. They need only bind to one of the two alpha subunits to prevent opening of the ionic pore.


7. What are the indications for using SCH?

SCH provides the most rapid onset and termination of effect of any NMB currently available. Its onset is 60-90 seconds and duration of effect only 5-10 minutes. When the patient has a full stomach and is at risk for pulmonary aspiration of gastric contents, rapid paralysis and airway control are priorities, and SCH is often the drug indicated. (Rocuronium when given in large doses also has a succinylcholine-like onset of action, though a prolonged duration of effect would contraindicate its use in patients likely to be difficult to ventilate or intubate.) Patients at risk for full stomachs include those with diabetes mellitus, hiatal hernia, obesity, pregnancy, severe pain, bowel obstructions, and trauma.

8. If SCH works so rapidly and predictably, why not use it all the time?

Succinylcholine has numerous side effects:

SCH stimulates both nicotinic and muscarinic cholinergic receptors. Stimulation of muscarinic receptors within the sinus node results in numerous bradyarrhythmias, including sinus bradycardia, junctional rhythms, ventricular escape and asystole.

SCH is a trigger for malignant hyperthermia. Prolonged exposure of the receptors to SCH results in persistent open receptor channel and

ionic fluxes through the ion pore, known as phase II or desensitization blockade. Normal depolarization/repolarization is not possible until SCH is metabolized.

In patients ambulatory soon after surgery, random generalized muscle contractions (fasciculations) have been associated with painful myalgias. Whether pretreating with a subparalyzing dose of a nondepolarizing relaxant prior to SCH is effective in reducing myalgias continues to be a matter of debate.

SCH increases intracranial pressure (ICP). The etiology is not completely understood but it is known that a subparalyzing dose of a nondepolarizing relaxant prior to SCH administration reduces the increase in ICP, so perhaps fasciculations are the cause of the increase in ICP.

In the presence of immature extrajunctional receptors, administration of SCH may result in severe hyperkalemia and malignant ventricular arrhythmias. Extrajunctional receptors are normally suppressed by activity. Any condition that decreases motor-nerve activity results in a proliferation of these receptors. Examples include spinal cord and other denervation injuries, upper and lower motor neuron disease, closed head injuries, burns, neuromuscular diseases, and even prolonged immobility.

SCH increases intraocular pressure (IOP). There is a theoretical risk for the use of SCH in patients with open eye injury, that being extrusion of extraocular contents. However, the increases in IOP are modest and from a clinical perspective, extrusion of ocular contents has not been observed. Certainly if a nondepolarizing agent is administered instead of SCH, and the patient is intubated prior to optimal intubating conditions, coughing on the endotracheal tube (called "bucking") increases IOP significantly and puts the patient at risk for extruding ocular contents.

9. Differentiate between qualitative and quantitative deficiencies in pseudocholinesterase

Pseudocholinesterase is produced in the liver and circulates in the plasma. Quantitative deficiencies of pseudocholinesterase are observed in liver disease, pregnancy, malignancies, malnutrition, collagen vascular disease, and hypothyroidism; they slightly prolong the duration of blockade with SCH. There may also be qualitative deficiencies in pseudocholinesterase; that is, the activity of the


enzyme is impaired. These are genetic diseases and as such can be present in heterozygotic or homozygotic forms. The most common form is called dibucaine-resistant cholinesterase deficiency and refers to the laboratory test that characterizes it. When added to the serum under study, dibucaine inhibits normal plasma cholinesterase by 80%, while the atypical plasma cholinesterase is inhibited by only 20%. Hence, a patient with normal pseudocholinesterase is assigned a dibucaine number of 80. If a patient has a dibucaine number of 40-60, then that patient is heterozygous for this atypical pseudocholinesterase and will have a moderately prolonged and usually clinically insignificant block with SCH. If a patient has a dibucaine number of 20, the patient is homozygous for atypical plasma cholinesterase and will have an extremely prolonged block with SCH.

10. Review the properties of nondepolarizing muscle relaxants

Nondepolarizing relaxants are competitive antagonists at the NMJ and are classified by their duration of action (short-, intermediate-, and long-acting).

Table . PROPERTIES OF NONDEPOLARIZING MUSCLE RELAXANTSRelaxant ED95*

(mg/kg)Intubating Dose (mg/kg)

Onset after Intubating Dose (minutes)

Duration† (minutes)

Short-actingMivacurium 0.08 0.2 1-1.5 15-20Rocuronium 0.3 0.6 2-3 30Intermediate-actingRocuronium‡ 0.3 1.2 1.0 60Vecuronium 0.05 0.15-0.2 1.5 60Atracurium 0.23 0.75 1-1.5 45-60Cisatracurium 0.05 0.2 2 60-90Long-actingPancuronium 0.07 0.08-0.12 4-5 90Pipecuronium 0.05 0.07-0.85 3-5 80-90Doxacurium 0.025 0.05-0.08 3-5 90-120

*ED95 = dose expected to reduce single twitch height by 95%.†Duration measured as return of twitch to 25% of control.‡Rocuronium, when administered in a dose of 1.2 mg/kg, has an onset similar to succinylcholine, though the duration is significantly longer.

11. Review the metabolism of nondepolarizing NMBs

Aminosteroid relaxants (e.g., pancuronium, vecuronium, pipecuronium, and rocuronium) are diacetylated in the liver, and their action may be prolonged in the presence of hepatic dysfunction. Vecuronium and rocuronium also have significant biliary excretion, and their action may be prolonged with extrahepatic biliary obstruction.

Relaxants with significant renal excretion include tubocurarine, metocurine, doxacurium, pancuronium, and pipecuronium.

Atracurium is unique in that it undergoes spontaneous breakdown at physiologic temperatures and pH (Hoffmann elimination) as well as ester hydrolysis, and thus it is ideal for use in patients with compromised hepatic or renal function.

Mivacurium, like SCH, is metabolized by pseudocholinesterase.

12. Describe common side effects of nondepolarizing NMBs


Histamine release is most significant with d-tubocurarine but is also noted with mivacurium, atracurium, and doxacurium. The amount of histamine released is frequently dose related. Cisatracurium does not seem to cause significant histamine release. Tachycardia is usually a side effect of pancuronium due to ganglionic stimulation and vagolysis.

13. Review medications that potentiate the actions of muscle relaxants

Volatile anesthetics potentiate relaxants for a number of reasons, including central nervous system (CNS) depression, increasing blood flow (and relaxant molecules) to muscle, and desensitization of the postjunctional membrane.

Local anesthetics affect the prejunctional, postjunctional, and motor membranes, depressing normal functions at all these sites.

Calcium channel and -adrenergic blockers impair ion transport but the clinical significance at βthe NMJ is probably not important.

Antibiotics, and most notably aminoglycosides, appear to have negative prejunctional and postjunctional effects. Penicillin and cephalosporins do not affect relaxant activity.

Magnesium inhibits the release as well as the depolarizing effect of ACh and decreases muscle fiber excitability. Lithium also potentiates neuromuscular blockade.

Long-term use of steroids results in a myopathy and also has some affect on the NMJ, particularly when muscle relaxants have been used for a prolonged period.

Dantrolene depresses skeletal muscle directly and impairs excitation-contraction.

14. What clinical conditions potentiate the actions of neuromuscular blockers?

Respiratory acidosis, metabolic alkalosis, hypothermia, hypokalemia, hypercalcemia, and hypermagnesemia potentiate blockade. Hepatic or renal dysfunction also increases the duration of action of relaxants.

15. Discuss important characteristics of a nerve stimulator

A nerve stimulator should be capable of delivering single-twitch stimulation at 0.1 Hz (1 stimulus every 10 seconds), train of four (TOF) at 2 Hz (2 per second), and tetanic stimulation at 50 Hz (50 per second). The black electrode of the stimulator is negatively charged and the red electrode is positively charged. The black electrode depolarizes the membrane while the red electrode hyperpolarizes the membrane. Although stimulation is possible however the electrodes are placed, maximal twitch height occurs when the negative electrode is placed in closest proximity to the nerve.

16. List the different patterns of stimulation

Single stimulus TOF stimulation Tetanic stimulation Posttetanic facilitation and posttetanic count


Double-burst stimulation

17. Which is the simplest mode of stimulation?

Single stimulus is the simplest mode of stimulation. It consists of the delivery of single impulses separated by at least 10 seconds but is of limited clinical utility.

18. Which mode is most commonly used to assess degree of blockade? How is it done?

TOF stimulation is the most common modality used to assess degree of blockade. Four stimuli are delivered at a frequency of 2 Hz (2 per second), and the ratio of the amplitude of the fourth to the first response in a train (T4:T1 ratio) estimates the degree of block. The four twitches of the TOF disappear in reverse order as the degree of blockade deepens. The fourth twitch of the TOF disappears when 75-80% of the receptors are occupied, the third twitch disappears at 85% occupancy, the second twitch disappears at 85-90% occupancy, and the first twitch disappears at 90-95% occupancy. However, there is accumulating evidence that visual or tactile evaluation of the TOF response is inadequate for evaluating neuromuscular function because it has been demonstrated repeatedly that even with experienced practitioners, subjective TOF estimations correlate poorly with true TOF fade. There has recently been a call for more objective measures of return of motor function, such as accelomyography, strain-gauge monitoring, and electromyography.

19. What is tetanic stimulation?

Tetanic stimulation consists of repetitive, high-frequency stimulation at frequencies of 50 Hz or greater. Loss of contraction during tetanic stimulation, known as tetanic fade, is a sensitive indicator of residual neuromuscular blockade. Tetanus stimulates the release of ACh from the prejunctional membrane, decreasing the validity of further nerve stimulation for upward of 30 minutes, leading to overestimating the return of neuromuscular function. A tetanic stimulus is painful.

KEY POINTS: MUSCLE RELAXANTS1. Metabolism of relaxants is more important that pharmacological reversal

for termination of relaxant effect. 2. Train-of four assessment is highly subjective and has been repeatedly

demonstrated to underestimate residual neuromuscular blockade. 3. It may be a best practice to administer reversal agents to all patients

receiving nondepolarizing relaxants. 4. Leave clinically weak patients intubated and support respirations until the

patient can demonstrate return of strength.

20. Explain posttetanic facilitation and posttetanic count

This mode of stimulation is useful during periods of intense neuromuscular blockade (when there is no response to TOF stimulation) and extends our range of monitoring. It provides an indication as to when recovery of a single twitch is anticipated and, hence, when reversal of neuromuscular blockade


is possible. An application of a 50-Hz stimulus for 5 seconds is followed in 3 seconds by repetitive single twitches at 1 Hz. The number of twitches observed is inversely related to the degree of blockade.

21. What is double-burst (DB) stimulation?

DB stimulation appears to be more sensitive than TOF stimulation for detecting small degrees of residual neuromuscular blockade. DB involves the application of an initial burst of three 0.2-millisecond impulses at 50 Hz followed by an identical stimulation in 750 milliseconds. The magnitude of the responses to double burst is approximately three times greater than that of TOF stimulation, thus making it easier to assess degree of fade present.

22. Which nerves can be chosen for stimulation?

Any easily accessible nerve may be used, but the most common nerve stimulated is the ulnar nerve. Contraction of the adductor pollicis muscle of the thumb is observed. The ophthalmic branch of the facial nerve may also be stimulated, monitoring the contraction of the orbicularis oculi muscle. Stimulating the peroneal nerve near the fibular head results in dorsiflexion of the ankle. Stimulating the posterior tibial nerve and ankle results in plantar flexion of the big toe.

23. What are the characteristic responses to the various patterns of stimulation produced by nondepolarizing agents?

Repetitive stimulation (TOF or tetanus) is associated with fade in the muscle response. Following a tetanic stimulus, response to subsequent stimulations is increased (posttetanic

facilitation). This may be due to increased ACh release or increased sensitivity at the end plate).

24. Summarize the characteristic responses to the various patterns of stimulation produced by depolarizing relaxants (succinylcholine)

The single-twitch, TOF, and tetanus amplitudes are uniformly decreased at any level of blockade. There is lack of fade in response to TOF and tetanus and lack of posttetanic facilitation. A desensitization or phase II blockade may develop with prolonged exposure to SCH. Phase II blockade has the same twitch characteristics as nondepolarizing blockade

25. For surgical purposes, based on nerve stimulation, what is adequate muscular relaxation?

Adequate relaxation is generally present when one to two twitches of the TOF response are present,


correlating with 80% depression of single-twitch height. However, volatile anesthetics, other medications, and the patient's underlying health also affect strength and, under these conditions, lighter levels of blockade may be satisfactory.

26. Discuss the appropriate time to reverse neuromuscular blockade, based on nerve stimulation

The best method of terminating the relaxant effect is to dose sparingly and allow the relaxant to be metabolized. Recall that only one of the alpha subunits of the postjunctional receptor need be occupied by a relaxant molecule to inhibit function, whereas two molecules of ACh are necessary to stimulate the receptor, so, even though the nondepolarizing relaxants are competitive antagonists, the receptor dynamics favor the relaxants. With these caveats, neuromuscular blockade can be reversed when there is at least one twitch with TOF stimulation. However, this still reflects a very deep level of blockade and the clinician should monitor the patient closely for clinical signs of inadequate return of strength. The greater the TOF when reversed, the better. It is also important to remember that recent tetanic stimuli will result in overestimating the TOF.

27. Review the drugs and doses commonly used to antagonize nondepolarizing blockade

Acetylcholinesterase inhibitors prevent the breakdown of acetylcholinesterase, increasing the amount of ACh available at the NMJ. Neostigmine 25-70 g/kg and edrophonium 0.5-1 mg/kg are commonly μused for this purpose perioperatively. Edrophonium also stimulates the prejunctional membrane, increasing release of ACh. These medications contain positively charged quaternary ammonium groups, are water soluble, and are renally excreted.

28. Review important side effects of acetylcholinesterase administration

Increasing the available acetylcholine at the NMJ (a nicotinic receptor) will also stimulate muscarinic cholinergic receptors. Of particular concern is the effect on cardiac conduction. Unopposed muscarinic effects will impair sinus-node conduction, resulting in sinus bradycardia, junctional rhythms, and in the extreme, asystole. To prevent this, anticholinergics are administered in concert with the acetylcholinesterase. Glycopyrrolate 7-15 g/kg is coadministered with neostigmine and atropine 7-μ10 g/kg with edrophonium so that the onset of anticholinergic activity is appropriately timed with μthe onset of acetylcholinesterase inhibition.

29. Should all patients who receive nondepolarizing relaxants be reversed?

There is mounting evidence that residual neuromuscular blockade and clinical weakness occur with disturbing frequency, even when the patient has received only one dose of an intermediate-duration nondepolarizing relaxant. These residual effects have been noted even 2 hours after a single dose. Part of the problem appears to be subjective misinterpretations of full return of TOF, as discussed earlier. It appears that routine reversal of all patients might be a prudent practice.

30. Review the clinical signs associated with return of adequate strength


Table. TESTS OF RETURN OF NEUROMUSCULAR FUNCTION

Test ResultsPercentage of Receptors Occupied

Tidal volume >5 mL/kg 80Single twitch Return to baseline 75-80Train of four No fade 70-75Sustained tetanus (50 Hz, 5 seconds)

No fade 70

Vital capacity >20 mL/kg 70Double-burst stimulation No fade 60-70Sustained tetanus (100 Hz, 5 seconds)

No fade 50

Inspiratory force >-40 cm H2O 50Head lift Sustained 5 seconds 50Hand grip Return to baseline 50Sustained bite Sustained clinching of a tongue

depressor50

31. A patient appears weak after pharmacologic reversal of neuromuscular blockade. What factors should be considered?

Has enough time elapsed to observe peak reversal effect? Was blockade so intense that reversal is not possible? Is your twitch monitor functioning and are leads well placed? Are body temperature, acid-base status, and electrolyte status normal? Is the patient receiving medications that potentiate neuromuscular blockade? What is the patient's renal and hepatic function? Importantly, if the patient is weak, do not extubate. Time usually cures all that ails.


Muscle Relaxan

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