pharmacology- muscle relaxant saq

Q. Compare and contrast atracurium and cisatracurium

atracurium cisatracurium

Intermediate acting non-depolarizing muscle relaxant

intermediate acting non-depolarising agent from the Bissquaternary benzylisoquinolone

intermediate acting non-depolarizing muscle relaxant

intermediate acting non-depolarising agent from the benzylquinolone group

physicochemical properties Presentation

clear, colourless or faint yellow, PCY

preparation sterile solution containing atracurium

besylate 10 mg, in each mL of Water for Injections.

pH of solution The solution also contains

benzenesulfonic acid to adjust the pH to 3.2 to 3.7.

Storage condition stored at 2 to 8 Do not freeze. Protect from light

presentation pale yellow greenish solution PYG

additive no antimicrobial preservative

pH of solution solubilized in benzenesulfonic acid

therefore, both is available for use but has to be kept in refrigerator

structure activity relationship

bisquartenary benzylquinolone group mixture of ten isomers 15% by weight is cistracurium

Constitute 15% of the mixture of 10 isomers of atracurium

50% of the relaxant axtivity of atracurium is from cis-atracurium

R-cis isomer of atracurium , where R is tetrahydropapavarine rings and cis is the dimethoxy and 2 alkyl ester group at C1 and N2

Dose and administration

intubating dose

0.4-0.5 0.1

ED95

0.25 0.05

cisatracurium is more potent than atracurium because it need less drug to block 95% contraction on single twitch stimulation The ED90 (dose required to produce 90% depression of the twitch response of the thumb to stimulation of the ulnar nerve) during intravenous anaesthesia

Onset of action

slow onset3-5

slow onset3- 5

Atracurium has similar onset of action as atracurium

Duration of action

20-35 20-35? Duration of action - similar ? Mentioned recovery time

atracurium and cisatracurium are intermediate acting muscle relaxant

Volume of distribution 0.2

Both compound are distributed mainly in ECF

Elimination

eliminated in in plasma via two nonoxidative pathways:

1. ester hydrolysis, catalysed by nonspecific esterases; 67%

2. Hofmann elimination, a nonenzymatic chemical process which occurs at physiological pH and body temperature. 33%

Atracurium eliminated mainly by ester hydrolysis 2/3

Hoffman degradation= 1/3

The rate of Hofmann elimination, principal route of elimination for atracurium, is increased at a higher pH or at higher temperatures, and reduced at a lower pH or lower temperatures

In vivo degradation and biological metabolism

Rapidly broken by spontaneous chemical reaction ie hoffman elimination

No effect of pseudocholinesterase Hoffman degradation >broken down

to tertiary amine laudanosine

Biologicall metabolism >monoquartenary alcohol and monoquartenary acid

Mneomonic -bisquartenary amine so 2 mono

Eliminate mainly by hoffman elimination 77% and 16% by renal excretion

Metabolites: laudanosine, monoquartenary alcohol and monoquartenary acid

Metabolites not active at NMJ

Metabolites : alcohol and quartenary monoester are inactive at NMJ

less laudanosine formation compared to atracurium

little hepatic

Largely elimination in bile

35% urine

No deacetylated metabolite

No hydroxy metabolites with neuromuscular action

No metabolites activity

Clearance

5.5 ml/kg/min

Organ independence clearance

Therefore can be administered in renal and hepatic dysfunction

Absence of cumulative effect Thus , good as infusion

5.5 ml/kg/min

organ independence clearance

non-plasma esterases doesnt involve



Elimination

Not dependent on renal function Not dependent on liver function

renal elimination 16%unknown

Elimination half life

21 min Slightly unchanged 18-25 in renal failure Unchanged 20-25 in renal failure

22- 30 min25 min 21

Excretion

10% excreted unchanged in urine NS in bile

5% ( <10%) excreted unchanged in urine , NS in bile

Effect of renal disease

No effect on elimination

Efffct of hepatic disease total bilairy obstruction , cirrhosis


CVS effect

Atracurium does not have significant vagal or ganglion blocking properties in the recommended dosage range.

No histamine induced CVS effect with rapid IV even at 8 x ED953 x ED95% in neurosurgical patient has less cerebral effect

atracurium will not counteract the bradycardia produced by many anaesthetic agents or by vagal stimulation during surgery.

BP & PR: no effect

may produce bradycardia , hypotension, hypertension, vasodilatation (flushing), tachycardia, bradycardia.

Decrease MAP, increase heart rate with3 x ED95

Circulatory effect is transient within 60-90 second

BP & PR: no effect

Respiratory effect

Bronchospasm

Histamine induce CVS effect

Bronchospasm

no Histamine release:

Q. Compare and contrast atracurium and mivacurium

atracurium mivacurium


short acting non-depolarizing muscle relaxant

physicochemical properties

presentation clear, colourless or faint yellow, sterile

solution PCY

preparation containing atracurium besylate 10

mg, in each mL of Water for Injections.

The solution also contains benzenesulfonic acid to adjust the pH to 3.2 to 3.7.

storage condition stored at 2 to 8 Do not freeze. Protect from light

Nature Weak acid/weak acid? But it cannot be mix with alkaline

solution

presentation

clear, pale yellow, sterile aqueous solution in glass ampoules PCY

preparation prepared as solution with addition of

sodium besylate to provide water solubility and adjust the pH to 3-3.5

the ph is adjusted to 3-3.5 to minimize risk of in vitro degradation

acidic (approximately pH 4.5)

storage condition 5%decerase in potency if stored in room

temperature every 30 days Shelf Life-18 months Store below 25 캜. Protect from light. Do not freeze. Premature breakdown by increase in pH

compatibility

Should not mixed with alkaline solution such as barbiturate

preparation

containing 2mg/ml mivacurium, present as mivacurium chloride.



bisquartenary benzylquinolone group mixture of ten isomers

bisquartenary benzylquinolone group Has three isomers 2 are the most active and equipotent are

the trans-trans 92% and the cis-trans 96% cis-cis isomer has been estimated from

studies in cats to have one-tenth of the neuromuscular blocking potency of the other two stereoisomers.


intubating dose

0.4-0.5 0.25

ED95

0.25 0.08

atracurium is less potent than mivacurium because it need more drug to block 95% contraction on single twitch stimulation The ED90 (dose required to produce 90% depression of the twitch response of the thumb to stimulation of the ulnar nerve) during intravenous anaesthesia

Onset of action

slow onset3-5

Moderate onset2-3

mivacurium has faster onset than atracurium

Duration of action

20-35 12-20

mivacurium is short acting muscle relaxant atracurium is intermediate acting muscle relaxant

Volume of distribution 0.2


Elimination

eliminated in in plasma via two nonoxidative pathways: 1. ester hydrolysis, catalysed by nonspecific esterases 67% and 2. Hofmann elimination, a nonenzymatic chemical process which occurs at physiological pH and body temperature 33%

The rate of Hofmann elimination, principal route of elimination for atracurium, is increased at a higher pH or at higher temperatures, and reduced at a lower pH or lower temperatures


1/3 rd of the termination of activity by spontaneous chemical degradation in vivo

2/3 rd metabolised biologically in lung and plasma esterase

In vivo hoffman degradation


No effect of pseudocholinesterase Hoffman degradation >broken down

to tertiary amine laudanosine


elimination mainly by enzymatic hydrolysis by plasma cholinesterase

the metabolism produced quaternary alcohol and a quaternary monoester metabolite.

Pharmacological studies in cats and dogs have shown that the metabolites possess insignificant neuromuscular, autonomic or cardiovascular activity at concentrations higher than seen in man.

Metabolites: laudanosine


Metabolites : alcohol and quartenary monoester are inactive at NMJ

little hepatic


35% urine




Clearance

5.5 ml/kg/min




5.5

clearance dependence on plasma hydrolysis

Elimination


unknown


21 minSlightly unchanged 18-25 in renal failure Unchanged 20-25 in renal failure

1-3 minUnknownUnknown

Excretion

10% excreted unchanged in urine

NS in bile

5% ( <10%) excreted unchanged in urine , NS in bile


No effect on elimination Minor excreted in urine 7% of total dose

Insignificant prolongation of the action of miva in anephritic patient

But not due to renal failure per-se , due to decrase in plasma esterase activity cause by renal failure


No effect on elimination Significant decrease in metabolism by plasma pseudocholinesterase

CVS effect


mivacurium does not have significant vagal or ganglion blocking properties in the recommended dosage range.


mivacurium no clinically significant effects on heart rate and will not counteract the bradycardia produced by many anaesthetic agents or by vagal stimulation during surgery




Minimal CVS effect at 2 x ED95

3 x ED95 over 10-15 seconds > histamine release

Decrease blood pressure by 13-18%

More pronounced effect on hypertensive patient

Uncommon = 1/1,000 and < 1/100 (=0.1% and <1%)

Transient tachycardia

Respiratory effect

Bronchospasm


Q. Compare and contrast atracurium and rocoronium

atracurium Rocoronium



physicochemical properties atracurium presented clear, colourless or faint yellow, sterile solution containing atracurium besylate 10 mg, in each mL of Water for Injections. The solution also contains benzenesulfonic acid to adjust the pH to 3.2 to 3.7. stored at 2 to 8°C. Do not freeze. Protect from light

rocoronium presented as a clear, aqueous solution for intravenous injection

the solution contain sodium acetate, sodium chloride, acetic acid and water for injections.

No preservative has been added. Store in the refrigerator at 2-8°C. can be stored outside the refrigerator at a

temperature of up to 30°C for a maximum of 12 weeks.



bisquartenary benzylquinolone group mixture of ten isomers

rocoronium is monoquartenary amminosteroid

resemble vecuronium with the presence of acetyl group on the A-ring of steroid nucleus


intubating dose

0.4-0.5 0.6- 1.2

ED95

0.25 0.3

atracurium is more potent than rocoronium because it need less drug to block 95% contraction on single twitch stimulation The ED90 (dose required to produce 90% depression of the twitch response of the thumb to stimulation of the ulnar nerve) during intravenous anaesthesia

Onset of action

Moderate onset3-5

Moderate onset1-2

Rocoronium has faster onset than atracurium, because 3 x ED95 means higher molecular load , according to fick principle of diffusion , the faster diffusion to NMJ, faster onset

Duration of action

20-35 20-35

Both vatracurium and rocoronium is moderate acting muscle relaxant

Volume of distribution 0.2 0.3


Elimination

eliminated both by plasma hydrolysis and in vivo degradation




eliminated both by hepatic metabolism and renal excretion

less lipid soluble , therefore less hepatic metabolism

10-20% dependent on liver degradation

No plasma hydrolysis



No effect of pseudocholinesterase Hoffman degradation >broken down to tertiary amine laudanosine





little hepatic


35% urine




Clearance

5.5 ml/kg/min




4.0 ml/min/kg

clearance dependence on renal function and hepatic function

Elimination


Dependent on renal functionDependent on liver function


21Slightly unchanged 18-25 in renal failure Unchanged 20-25 in renal failure

87Moderately prolonged in renal failure97Moderately prolonged in liver failure 97

Excretion


NS in bile

10-25% excreted unchanged in urine 50-70 % excreted unchanged in bile

Animal studies : > 50% excreted unchanged in bile Renal excretion may be more than 30%


No effect on elimination Prolonged DOA

Renal excretion > 30 % in 24 hours


No effect on elimination Increased in Vd> longer DOA especially wirh repeated dose or prolonged IV

CVS effect


No histamine induced CVS effect even with rapid, large dose

May produce slight vagolytic effect that is not occur with other aminosteroid


rocoronium is useful in procedure that associated with vagal stimulation




Respiratory effect

Bronchospasm


Q. Describe the cardiovascular effects of muscle relaxant

Non-depolarising drug Cardiovascular effect Overview

Nondepolarising NMB that causes the release of histamine or vasoactive substance affect muscarinic cardiac receptors or nicotinic ach receptors at autonomic ganglia

Degree of cardiovascular effect The degree of circulatory effect varies from patients to patients Depend on underlying autonomic nervous activity, preoperative medications ,

maintainance drug

Autonomic margin of safery It is the difference between dose of neuromuscular agent that produce

neuromuscular blockade and circulatory effect The narrow autonomic margin of safety result in Example ; the ED95 of pancuronium that produce neuromuscular blockade is likely to

cause circulatory effect Therefore , the autonomic margin is narrow Example ; the ED95 of vecuronium , rocoronium , cisatracurium wide autonomic

margin of safety ED95 for circulatory effect is less than dose that affect circulation

Cardiovascular effect Drug Mivacuriu

m Atracurium Rocoroni

um Cistaracurium

Vecuronium

Pancuronium

Dose Minimal CVS effect at 2 x ED95

3 x ED95 over 10-15 seconds > histamine release

2 x ED95 during nitrous oxide/fentanyl and isoflurane

No histamine induce CVS effect even with rapid administration

3 x ED95 with presence of nitrous/fentanyl increase the heart rate and decrease MAP


No histamine induced CVS effect with rapid IV even at 8 x ED95

3 x ED95% in neurosurgical patient has less cerebral effect

No histamine induce CVS effect No circulatory effect even at dose > 3 x ED95

Modest increase in heart rate, MAP and cardiac output

Mechanism


Plasma histamine concentration has to be double before CVS effect occur

Selective cardiac vagal blockade and activation of symphathetic nervous system

These 2 mechanism release the NA and block the uptake of the NA

It also interefere with the muscranic activity that usually uptake

the NA

Increase in heart rate due to blocking the vagal muscarinic receptor at SA node

Effect Decrease blood pressure by 13-18%

More pronounced effect on hypertensive patient



vagolytic

May produce slight vagolytic effect Useful in procedure that associated with vagal stimulation

vagotonic

May produce vagotonic effect causing bradycardia in the absence of anticholinergic drug

vagotonic

Depolarising drug cardiovascular effect Cardiac arrhythmias

Overview

Suxamethonium can cause sinus bradycardia , junctional rhythm,and sinus arrest

Mechanism

suxamethonium has cholinomimetic actions,

Sux may act at,

parasympathetic & sympathetic autonomic ganglia causing ganglionic stimulation M2 receptors of the heart causing effect of ach

CVS effect the CVS effects are variable, adults who have received premedication with antimuscarinic drugs frequently

develop tachycardia and increased BP children may show bradycardia or sinus arrest, especially if antimuscarinic

premedicant has been omitted

Sinus bradycardia the incidence of sinus bradycardia or a junctional rhythm is greater after a second

dose

It occur approximately 5 minutes after first dose Mechanism ; possibly due to metabolites of sux (succinylmonocholine and choline)

that produce bradycardia steolting : Administration of atropine doesn't prevent the slowing of heart after

second dose

Sinus tachycardia The effect of sux on autonomic ganglia > increases in heart rate and systemic blood

pressure The action of sux on autonomic ganglia is similar as physiological effect of ach in

autonomic ganglia

Q. Outline the possible reasons for prolongation of paralysis induced by an intravenous dose of 1 mg.kg-1 of suxamethonium. Briefly indicate the consequences of such a prolonged block.Overview

sux apnoea is the presence of apnoea despite predicted return of neuromuscular function after suxamethonium

Causes normal intubating dose of sux : 1 mg/kg dose 2-4 mg/kg may cause phase 11 block

Mechanism suxamethonium is rapidly broken down in the plasma by butyrylcholinesterase, or

“pseudocholinesterase”, to the monocholine form this has ~ 0.05 times the potency of the dicholine parent this is then further metabolised to acetate & choline the elimination half life, tb½ ~ 5 min The rate of hydrolysis result in only a small fraction of the administered dose reaches the motor

endplate termination of action is then by dissociation & diffusion, as there is no pseudocholinesterase at the

endplate pseudocholinesterase therefore controls the duration of suxamethonium blockade by determining the

amount which reaches the endplate the effect may therefore be prolonged with both congenital and acquired enzyme abnormalities Reaction ;sux broken down to monocholine, monocholine then broken down to choline and acetate,

occur in plasma ,

Depolarizing neuromuscular blockade altered plasma cholinesterase function prior administration of an anticholinesterase plasma cholinesterase deficiency/ atypical plasma cholinesterase - acquired or congenital phase II block drug interactions

Acquired Enzyme Deficiency plasma cholinesterase levels are reduced in the following conditions,

age the newborn, reaching adult levels by 2-6 months

disease patients with acute or chronic liver diseases collagen diseases chronic anaemia uraemia myxedema other chronic debilitating diseases severe burns

nutrition malnutrition

pregnancy pregnancy

drug chronic pesticide exposure & accidental poisoning drugs MAO inhibitors trimethaphan cytotoxic drugs - azathioprine echothiopate eye drops hexafluorenium bromide, tetrahydroaminocrine quinidine propanidid OCP chlorpromazine

non-depolarizing pancuronium, neostigmine

Inherited Enzyme Defect overview

plasma cholinesterase is coded for by two allelomorphic genes on an autosomal chromosome

gene four variants are described,

normal gene N dibucaine resistant gene D fluoride resistant gene F silent gene S

the most frequent atypical form, the dibucaine resistant gene, has a far lower affinity for succinylcholine at normal serum concentrations

the population prevalence for the D-gene is ~ 1:53 (? reference, doesn’t support below)

Phase 11 block repeated doses of suxamethonioum or a prolonged infusion is given may result in phase 11 block phase 11 block resemble of non-depolarisng or competitive block the characteristics of competitive blockade,

TOF ratio < 1.0 fade of tetanic response post-tetanic potentiation occur

Onset of phase 11 block initially it appear as tachyplaxis and the need to increase infusion of sux or large increment of subsequent

dose it occur with dose : 2-4 mg/kg

Phase II Blockade and reversal

during recovery from this phase 11 block, anti-AChE agents, which normally intensify phase I block are effective in reversal

causes of phase 11 block depolarising drugs act as partial agonists, a part of their action being receptor antagonism after prolonged use they may decrease ACh synthesis / mobilisation, therefore act presynaptically the initial depolarisation may activate a membrane pump, which then repolarises the membrane, despite

the continued presence of the depolarising agent

management continue ventilation and sedation especially in ICU monitor neuromuscular function by nerve stimulator investigate the family for possible inherited gene

Q. Outline the properties of an ideal meuromuscular blocking agent

Physichochemical properties Stability

stable in solution

Sterile sterilizable

Shelf-life long shelf life with easy storage without any need for refrigeration

Preparation easy to prepare , no need to be reconstitute in water easy administration useful for all groups of patients

Incompatible no chemical interaction with other drug

Costs low cost with synthesis not too complex

Pharmacokinetic Onset

rapid onset within one circulation time ; rapid onset and rapid recovery

Onset(minutes)

mivacurium slow onset 2-3

atracurium moderate onset 3-5

rocoronium Fast onset1-2

cisatracuriumModerate3-5

vecuronium Moderate onset3-5

pancuronium Moderate onset3-5

Duration of action Short duration of action Suitable for infusion flexible / controllable duration of action Duration less than 0.5 hour

Duration(Minutes)

mivacuriumshorter duration 12-20

atracurium20-35

rocoronium20-35

cisatracurium20-35

vecuronium20-35

pancuronium60-90

comparison mivacurium has duration of action of 12-20 minutes that are advantageous in short

procedure atracurium , rocoronium, cistaracurium and vecuronium has duration of action of 25-

30 minutes for surgical procedure with 30 minutes atracurium and cistaracurium has rapid recovery after cessation of infusion therefore

suitable as infusion pancuronium

Distribution no significant tissue placental transfer, or BBB ie with only one or two quartenary

compound

Metabolism rapid metabolism to inactive product no pharmacological active metabolites no cumulative effect

Mechanism of action mechanism of action confined to NMJ Do not activate other nicotinic receptors at cardiac or cns

Pharmacodynamic CVS

cardiovascular stability

Respiratory doesnt cause bronchospasm

Side effect no histamine release no local effect

Drug interaction no drug interaction

Q. What are the indication for monitoring of muscle relaxant effect

Overview Periheral nerve system should be availabl;e for every patient but certain condition warranted the used of neuromuscular function

1. where the pharmacokinetic profile will be abnormal, severe renal disease liver disease severe illness extremes of age - neonate

2. where the pharmacodynamic profile will be abnormal, neuromuscular disease – myasthenia gravis

drug interactions

burns

3. where spontaneous offset of blockade is undesirable ophthalmological procedures

neurosurgery

any microsurgical procedure

4. where maximal postoperative muscle power is required, and those patinet susceptible to residual paralysis effect severe pulmonary disease

myopathic & neuromuscular disorders

marked obesity

risk of aspiration

5. where pharmacological reversal of blockade is contraindicated, severe heart disease

severe bronchial asthma

6. prolonged procedures where neuromuscular blockade is produced by continuous infusion prolonged surgery with intermittent boluses of sux

Q. Give examples of drugs that enhance the action of the non-depolarising neuromuscular blocking agents at the neuromuscular junction. Briefly describe the mechanisms of their actions.Q. Give examples of drugs that decrease the action of the non-depolarising neuromuscular blocking agents at the neuromuscular junction. Briefly describe the mechanisms of their actions.Q. Describe the factors that may modify response to muscle relaxant

Overview the response to non-depolarising muscle relaxant can be modify by several factors Factors Affecting Neuromuscular Blockade are :

Drug Interactions

Inhalational Anaesthetic Agents

Aminoglycosides antibiotics local anaesthetics Antidysrhythmics Anticholinesterases Diuretic Calcium channel blockers Magnesium and lithium

Electrolyte Disturbances

hypokalaemia / hyperkalaemia hypocalcaemia hypermagnesaemia Acid-Base Balance

Temperature

Disease States

hypovolaemia myasthenia gravis & myasthenic syndrome the myotonias upper & lower motor neurone diseases morbid obesity Age renal disease hepatic disease

Drug Interactions

Antibiotics

Antibiotics such as aminoglycosides

Aminoglycosides Aminoglycosides enhanced the neuromuscular blockade of nondepolaring

Mechanism Possible mechanism 1 ; the aminoglycosides reduce the quantal release of ACh from

prejunctional membrane Possible mechanism 2; stabilize postjunctional membrane Possiblity; Aminoglycosides compete with Ca++ Therefore , their effects are reversible with Ca++ salts (MCQ) similar effects are seen with tetracyclines, ? due to chelation of Ca++ lincomycin and clindamycin effectively block open channels other antibiotics effect either the pre- or post-junctional membrane

Special note antibiotics devoid of neuromuscular action are the,

penicillins cephalosporins chloramphenicol

Local Anaesthetics & Antidysrhythmic Agents Overview

Small doses of LA > enhance neuromuscular blockade produced by nondepolaring neuromuscular blocking agent

Large doses> block neuromuscular transmission

Mechanism Possible mechanisms -example lignocaine 1. reduce the prejunctional neuronal release of ACh- interfere with release 2.stabilisation of the post-junctional membrane - by reducing the action potential in

neighbouring areas to the motor end plate 3. Direct depression of skeletal muscles fiber Ester LA may compete with other drug for plasma cholinesterase Prolongation of blockade caused by sux

Anticonvulsant Overview

Chronic phenytoin; resistant to pancuronium , vecuronium , rocoronium , cisatracurium , pipecuranium, doxacurium

Chronic phenytoin; not resistant to mivacurium , atracurium

Mechanism More likely due to pharmacodynamic mechanism Due to the dose that needed for blockade in chronic phenytoin is higher than non-

treated phenytoin interfere with neuromuscular transmission by causing exacerbations of

myasthenia gravis

Degree of blockade Phenytoin and carbamazepine; resistant of vecuronium in children Acute administration of phenytoin; augment the neuromuscular blockade by

rocoronium

Cardiovascular drug Quinidine potentiate the action of the neuromuscular blocking drugs, nondepolaring

and depolarising Quinidine ; interfere with prejunctional release Lidocaine ; iv lidocaine augment the preexisting neuromuscular blockade the calcium channel blockers potentiate the action of NMB agents by decreasing

Ca++-dependent ACh release,

Anticholinesterase Agents

neostigmine, pyridostigmine and edrophonium causes increased [ACh] in NMJ It also has direct effects on the post-junction membrane therefore, these agents are used for the reversal of neuromuscular blockade If these agent is given with depolarising agent it will intensify the block Therefore ,these intensify the blockade produced by suxamethonium they also block the action of pseudocholinesterase, therefore its affect mivacurium

action

Frusemide & Diuretics Overview

Frusemide ;1 mg/kg > enhanced neuromuscular blockade produced by nondepolarising neuromuscular blocking drugs

Mechanism frusemide has dose dependent effects,

low doses - inhibits protein kinases higher doses - inhibits phosphodiesterase

Low dose Frusemide inhibit cAMP production > decrease in prejunctional release of ACH

High dose frusemide inhibit phosphodisterase >increases in cAMP production > antagonise the action of nondepolaring nmb

therefore, phosphodiesterase inhibitors such as azathioprine will increase ACh release and antagonise competitive blockade

the thiazides and ethacrynic acid also potentiate the effects of the neuromuscular blockers

Mechanism of action : thiazide and ethacrynic causes diusis that may altered volume of distribution and electrolyte balance

Mannitol ; doesn't influence the neuromuscular blockade even in the presence of diuresis

Chronic diuretic therapy that causes chronic hypokalemic > decrease requirements for pancuronium

Chronic diuretic therapy that causes chronic hypokalemic also> increase dose for neostigmine for reversal

Other Drugs Lithium enhanced the action of both nondepolaring and depolarising drugs chlorpromazine potentiates the non-depolarising agents D-penicillamine that is used in the treatment of Wilson’s disease, causes a

myasthenia like syndrome

azathioprine antagonises the non-depolarising blockade by inhibiting phosphodiesterase

Inhalational Anaesthetic Agents

Overview

Inhalational agent causes dose dependent enhancement of magnitude and duration of neuromuscular blockade of nondepolaring

Mechanism

Possible mechanisms by which the volatile agents affect neuromuscular blockade include,

1. Anesthetic-induced depression of the CNS that reducing the muscle tone 2. increased muscle blood flow to the deliver more drug to NMJ that occur with

isoflurane only 3. decrease the endplate sensitivity to depolarisation 4. action at a site distal to the motor endplate 5. direct effects on the ACh receptor NB: there is no evidence for presynaptic inhibition of ACh release

Degree of blockade

Greatest with isoflurane , enflurane , sevoflurane , desflurane Least effect with nitrous oxide and narcotic anaesthesia Sevoflurane ; marked inhibition on neuromuscular transmission Therefore , it causes rapid onset within 30 minutes of sevoflurane -induction of

enhanced nondepolaring neuromuscular blockade For rocoronium , the 1.25 MAC of isoflurane , desflurane , and sevoflurane produce

similar potency , infusion requirements and recovery from neuromuscular blockade The requirements to decrease the dose of intermediate action is less than that for

long action nondepolaring neuromuscular blockade agent The effect of changes in alveolar concentration of inhalational agent has less impact

on blockade produced by intermediate action nmb compared to that of long acting nmb

Electrolyte Disturbances

Overview

the resting membrane potential is primarily determined by the ratio of intra/extra-cellular potassium

Hyperkalemia Hyperkalaemia decreased resting transmembrane potential and partly depolarise

the membrane Thus it potentiate the effects of the depolarising agents But it oppose the effect of nondepolarising hyperkalemia diminish the effects of the non-depolarising agents

Hypokalemia Hypokalaemia causes increased transmembrane potential & hyperpolarisation of the

membrane

therefore it potentiate the effects of the non-depolarising agents But , diminish the effects of the depolarising agents

CalciumOverview

Effect of hypercalcemia> decrease blockade Hypocalcemia > increase blockade

Mechanism increased Ca++,

increases the quantal release of ACh decreases the sensitivity of the post-junctional membrane to ACh enhances excitation-contraction coupling Decrease the degree of blockade

Magnesium Overview

Effect of hypermagnesemia> enhanced neuromuscular blockade by nondepolaring Lesser extent > enhances sux neuromuscular blockade

Mechanism increased Mg++, decreases the quantal release of ACh decreases the sensitivity of the post-junctional membrane to ACh

Degree of blockade The magnesium interaction with vecuronium ; more blockade than other

nondepolaring NMB

Factors affect blockade Increase blockade Low serum Ca++, or High serum Mg++ this may be relevant during RX for toxaemia of pregnancy

Acid-Base Balance respiratory acidosis enhances dTC & pancuronium induced neuromuscular junction

blockade

It also opposes reversal by neostigmine,

NB: “it is impossible to antagonise a nondepolarising neuromuscular blockade in the presence of significant respiratory acidoses (PaCO2 > 50 mmHg)

the effects seen during other disorders tend to be conflicting possibly, respiratory alkalosis & metabolic acidosis antagonise neostigmine reversal of neuromuscular junction blockade

Temperature Overview

Hypothermia prolonged the blockade of tubucurarine and pancuronium

Mechanism hypothermia produces profound changes in the pharmacokinetic &

pharmacodynamic changes Therefore,the hepatic and renal elimination of both dTC and pancuronium, and thus their duration of action are prolonged

Degree of blockade in the case of atracurium, the rate of Hofmann degradation is also reduced metabolism of both classes of agents is reduced

Disease state in general, severely ill patients are likely to be more sensitive to neuromuscular

junction blocking The exception is in patients with disease that causes the delocalisation of ACh

receptors from the motor end-plate

BurnOverview

Burn injury > resistance to nondepolarising effect after 10 days of burn The resistance is greater at 40 days The resistance decline after 60 days

Degree of blockade The resistance occur mostly if the burn more than 30% Onset for intubating condition ; prolonged in burned patients compared with non-

burned; need 1.2 mg/kg

Mechanism The resistance to nondepolarising blockade not due to changes in density of

receptors

Hypovolaemic States both the rate of onset and decay of effect, of both groups of drugs can be

significantly delayed by decreased muscle circulation

this can occur with any disease state resulting in a decrease in circulating blood volume

those agents associated with a significant degree of histamine release may result in, or markedly exacerbate, hypotension

Myasthenia Gravis & Myasthenic Syndrome

these patients are sensitive to the non-depolarising agents,

their response to suxamethonium may be reduced

neuromuscular blockade is best avoided in these people,

anaesthesia can usually be achieved with volatile agent alone

prior to administration of a neuromuscular agent, the level of pre-existing blockade should be assessed by a TOF response

if the baseline TOF significantly depressed, the addition of further which is essentially irreversible

if additional relaxation is required, deepening the level of anaesthesia is preferable

need to electively ventilate postoperatively

the myasthenic (Eaton-Lambert) syndrome, is an association between carcinomatous conditions, particularly oat-cell carcinoma of the lung, and motor neuropathy

clinically it resembles myasthenia, however, they often show increased sensitivity to both groups and often readily develop phase II block

therefore, neuromuscular function should be monitored intraoperatively

The Myotonias patients with myotonia dystrophica, myotonia congenita and paramyotonia

congenita, exhibit generalised muscular spasm after the administration of depolarising agents

myotonia dystrophica (atrophica) is the most common variety in addition to the usual clinical features, cardiac failure and conduction defects are

frequently present, as is involvement of the respiratory muscles the increased mortality in these patients is partly attributable to respiratory failure in

the postoperative period the generalised muscle spasms which may follow depolarising agents are not

relieved by the administration of a competitive agent these patients may respond normally to the non-depolarising agents, as the disease

is one of the muscle membrane they are also prone to develop apnoea following the administration of sedative or

anaesthetic drugs

Upper & Lower Motor Neurone Diseases

Overview

hemiplegia from cerebral ischaemia is associated with differing responses to nondepolarising relaxants on the 2 sides of the body

muscles on the affected side are relatively resistant to blockade

Clinical significant

Assessment made on paralyzed part may lead to

relative overdose , therefore may have difficulty during reversal false assessment of degree of blockade by monitoring the most resistant muscles Therefore ; monitor degree of blockade on the unaffected limb

Note the use of succinylcholine in such patients is associated with the risk of

hyperkalaemia the time course of such sensitivity is not well defined, with case reports from, 1 week to 6 months following the onset of hemiplegia 3 days following SCI patients with mixed LMN disease processes, such as, amyotrophic lateral sclerosis lower motor neurone disease syringomyelia may exhibit either an exaggerated or reduced response to the non-depolarising

agents, due to delocalisation of the ACh receptors from the motor endplate

Familial periodic paralysis familial periodic paralysis may be associated with hypo/normo/hyperkalaemia it is characterised by intermittent attacks of flaccid paralysis, usually sparing the

bulbar group muscle relaxants should generally be avoided if possible the potassium status should be managed in a standard fashion

GenderOverview

Women are more sensitive to vecuronium than men

Dose requirements 22% decrease in dose of vecuronium for blockade in female Women 33% more sensitive to rocoronium than men

Duration of blockade The duration for vecuronium-induced blockade is longer in women than men

Clinical Reduce dose of rocoronium in women

Mechanism Unclear Differences in body composition , volume of distribution , plasma protein

concentration Greater percentage of skeletal muscles in men

Allergic reaction and anaphylactoid Overview

Allergic reaction and anaphylactoid reaction occur commonly with iv nondepolarising than sux

Mechanism Possible crossreactivity among nondepolarising compound ie the quartenary

ammonium compounds Drug with single quartenary ammonium group ; pancuronium , vecuronium ,

rocoronium less likely cause allergic reaction

Incidence Female have higher incidence of allergic reaction to neuromuscular blocking agent

Age Overview of use in pediatric

neonates appear more sensitive to the effects of the non-depolarising agents, the response of the small infant closely resembles that of the myasthenic adult

Anatomical consideration development of the neuromuscular junction is not complete until ~ 2 months

Degree of blockade Term or preterm

premature infants are more susceptible to post-tetanic exhaustion than term infants

Neonate and infant NB: neonates and infants display increased sensitivity to dTC Therefore ,the dose should be reduced in the presence of hypothermia, acidosis, or

prematurity however, this group has a larger VdSS, therefore doses are similar to those in the

adult

Neonate Neonate has longer elimination half life for NMB agent , therefore the subsequent doses can be give at less frequent intervals

Infants

infants have an increased sensitivity to vecuronium compared with adults however, there is a marked increase in duration of action this is related to its increased volume of distribution in neonate despite a normal

clearance

Vecuronium in neonate thus, vecuronium is a long-action muscle relaxant in the neonate

Atracurium in neonate the duration of action of atracurium is not significantly different in paediatric versus

adult patients,thus volume of distribution increases total clearance increased the half life is unaltered

Requirements for antagonism in terms on antagonism, doses of neostigmine and edrophonium used for adults are

appropriate for children,

Overview of use in elderly

studies are now considering whether elderly patients (> 60 yrs) may respond differently from younger patients to the nondepolarising muscle relaxants

McLeod et al. found the clearance of pancuronium inversely related to age

Therefore , clearance in the 3rd decade ~ 2x that in the 9th decade

Succinycholine followed by nondepolarising Overview

Prior administration of sux , 1 mg/kg enhanced magnitude of twitch response suppression produce by nondepolaring nmb

However after initial dose of sux , the duration of action of nondepolarising atracurium and vecuronium not prolonged

Sux with vecuronium Small initial dose 0.5 mg/kg> doesn't prolonged effect of vecuronium

Q. Explain physiology of neuromuscular transmission. Describe whiat do you understand with margin of safety of neuromuscular transmission. How this may interefere with to produce muscle relaxation

Overview

muscle relaxation is the state of immobilization during general anesthesia that depend on the function of neuromuscular junction The immobilization is produce by the failure of neuromuscular transmission immobility during general anesthesia is dependent on NMJ

Neuromuscular junction

The neuromuscular junction consist of prejunctional motor nerve that is separated from postjunctional membrane of muscles by synaptic cleft

The synaptic cleft

The space that separate the prejunctional motor nerve from postjunctional muscles membrane

The space- ach cross the cleft after release by vesicle

Motor endplate

The neuromuscular endplate is the contact zone between the axons of motor neurons and striated muscle fibres. The area where the action potential generated that give to neuromuscular transmission

Motor neurone The motor neurone comprises of a projection that extend to motor endplate of the muscles membrane

End feet

As the motor neurone approach the motor end plate it looses it myelin sheath Then it form projection to Motor end plate known as end feet

Vesicles-filled ACH The terminal axon of motor neuron terminals have vesicles that contain acetylcholine located at the active zone of presynaptic membrane The release sites are located directly over the acetylcholine receptors The vesicles mostly congregated near thick transverse bands of axonal membrane, or active zones

Synthesis of vesicles the vesicles are synthesised in the cell body The vesicles travel to the terminals via microtubular transport

Numbers of vesicles there are ~ 1000 active zones Each nerve terminal has 300,000 vesicles the average motor endplate of muscles membrane (MEP) contains ~ 50 million ACh receptors each nerve action potential releases ~ 60 vesicles Each vesicle contain 10,000 ACh molecules

Content of vesicles the vesicles contain acetylcholine

Postsynaptic Postsynaptic membrane is thickened portion of the muscle cell membrane Beneath the nerve ending, the endplate membrane is thrown into a number of palisades The active zones are adjacent to the shoulders of the post-synaptic palisades, The shoulder of postsynaptic pallisades is populated with ACh receptors

Basement membrane Basement membrane is a collagen-like material rich in carbohydrate that contain most of the junctional acetylcholinesterase Basement membrane -located on the postsynaptic membrane

Location of acetylcholinesterase acetylcholinesterase molecules are embedded in the post-junctional membrane

Acetylcholine Receptor origin of nicotinic receptor

the nicotinic receptor of cells are derived from the neural crest (autonomic ganglia),

Molecular structure The receptor is pentamer the receptors and are arranged in a “rosette”, with a central ion channel It has five integral protein subunits (2a , 1b , 1g , 1d ), that surround a central ion channel pore all five subunits traverse the cell membrane The central ion channel pore is opened by the binding of 2 acetylcholine molecules to the 2 a - proteins

Location of other ligand-acetycholine receptors The nicotinic acetylcholine receptor is related to a ligand (acetylcholine)-gated ion channel found not only in the neuromuscular

junction, It also found at all autonomic ganglia and in the central nervous system (CNS).

Process of recptor-ligand binding Opening of the ion channel increases the conductance for small cations (Na+ and K+) across the postjunctional membrane, Therefore , there it depolarising the membrane potential of the cell. It result in electrical potential

Neuromuscular transmission

Ach bind to the a-subunits Both a-subunit of the acetylcholine receptors must be occupied for receptor activation The binding of 1 a-subunits facilitate the binding of other a-subunit

Process of ligand-receptor activation ACH bind to nicotinic cholinergic receptor The binding of ACH to a-subunit causes a conformational change in the receptor It causes opening of central ion channel >

allows the flux of small cations (Na+, K+, Ca++) via the channel The result in generation of action potential

Mechanism of Transmission

AP to axon action potential (AP) reaches the axon terminals, the axon membrane is depolarised, The voltage-gated Ca2+-channels are transiently activated. This causes Ca2+ to flow down its concentration gradient from the outside The increased in nerve [Ca++] also increases the calmodulin & synapsin I The influx of Ca2+ at the release zones causes the vesicles to fuse with the axon membrane, The vesicle empty acetylcholine into the synaptic cleft

ACH crossing the synaptic cleft ACh diffuses across the synaptic cleft to endplate ~ 60 nm

ACH binding to receptor acetylcholine binds to its receptor protein on the muscle cell membrane. 2 x ACh combine with each specific ACh receptor

ACH-receptor activation Activation of voltage gated Na channel “activated” receptor increases membrane conductance of gNa+ & gK+ that result in influx of Na+ The influxes of Na+ depolarise the endplate temporarily, the transient depolarization is termed the endplate potential (EPP).

Generation of end-plate potential The EPP dies away when acetylcholine is hydrolysed to acetate and choline by the enzyme, acetylcholinesterase. The EPP has a large safety margin, as a single action potential in the motor axon will produce an EPP that always reaches the

threshold potential in the muscle fibre.

Generation of muscle action potential Muscular contraction

The acetylcholine binding at the motor endplate increases endplate conductance and generates an action potential (AP) in all directions from the end plate

The generated muscle action potential travel along the whole length of muscle fibers into the small, transverse tubules

Muscle contraction The electrical excitation of the sarcolemma and the transverse tubules (T-tubules) during the AP triggers - by an unknown mechanism

causes the sarcoplasmic reticulum to release a pulse of Ca2+ This Ca2+ diffuses to the adjacent myofilaments, where they bind strongly to troponin C on the active filament, The binding of Ca to troponin c abolish the blockade by the troponin-tropomyosin blockade. This enables cyclic crossbridges to work as long as the high [Ca2+] is maintained, Thus the muscle contraction occurs.

End of muscle contraction An active Ca2+-pump returns Ca2+ to the sarcoplasmic reticulum, and another Ca2+-pump in the cell membrane also reduces

sarcoplasmic [ Ca2+] . The Ca2+ is withdrawn from its troponin C, It result the troponin-tropomyosin-blockade is re-established and relaxation ensues.

Margin of safety of neuromuscular function.overview

this term describe the minimum post-junctional acetycholine receptor that has to be occupied by acetycholine for effective & adequate neuromuscular function

~ 30% Ach receptors (post-J) required for margin of safety of NM transmission The EPP has a large safety margin, a single action potential in the motor axon will produce an EPP that always reaches the threshold potential in the muscle fibre. the blockade is not seen until > 70% receptor occupied by the non-depolarising , and about 25-30 % of receptor occupied by

depolarizing

Mechanism of action of neuromuscular

Overview blockade of neuromuscular transmission can be achieved by depolarizing neuromuscular blockade: suxamethonium and non-

depolarizing neuromuscular blockade

Depolarizing muscle relaxant Sch attaches to one or both alpha subunit of ACH receptors it bind to the receptor for 1 msec before dissociating at this point ach is metabolised in synaptic cleft sux repeatedly act with receptor causing opeining of channel , continous depolarisation This will result in prolonged depolarization of the muscle motor end plate at the post-junctional membrane These continous depolarization at the end plate will result in prolonged relaxation. Known as phase 1 block The sustained opening of receptors ion channels ---depolarization of post-junctional membrane Leakage of potassium from intracellular to extracellular increased the serum potassium

Effect of single large dose, repeated dose or prolonged infusion The administration result in depolarising phase 11 blockade The blockade is due to receptors desensitization , ion channels blockade and the entry of sux into cytoplasm of skeletal muscles

Non-depolarizing muscle relaxant Act as ACH receptors agonist This agent bind to ACH receptors but not activate the receptors Therefore there is no conformational changes that necessary for ions channel opening Drug compete with ach for the binding site at alpha subunits No end plate potential being generated These agent will prevent the natural ACH from binding to the receptors At high dose bind directly to ion receptors channels Also act at pre-junctional receptors Therefore there is failure of neuromuscular transmission resulting in muscle relaxation when 80-90% receptors are blocked

Q. Explain the phenomenon known as fade and post titanic facilitation associated with the use of neuromuscular blocking agentOverview Fade is the term that describe the progressive decrease in electrical and mechanical response to repetitive

nerve stimulation

Mechanism of fade Indicate during partial competitive block ie when the non-depolarising start to cause depression When the muscles is given repeated stimuli-- for example by train of four---result in reduction of twitch height

with each subsequent stimuli

Significant Only non-depolaring drug show fade Fade indicate the partial competitive blockade characteristic of NDMR blockade or phase II blockade)

Monitoring of fade Fade is monitored by using TOF and double burst During TOF, the last response and first response are compared to 4 successive stimuli administered at 0.5 sec

interval ie 2 hz, rule of 4 divide by 2, 4/2 = 2 hz = 2/ 2= ½= 0.5 sec With fade, the repetitive stimuli during the partial NMDA result in progressive decrease of twitch height

Clinical Fade between two contraction during double burst stimulation indicate TOF of 0.6 Absence of fade to DBS indicate clinically significant NDMB the presence of TOF fade after the use of succinylcholine signifies the onset of phase II blockade

Mechanism of fade Fade in tetanic stimulation is presynaptic event fade is believed to be due to depletion of readily available stores of ACh As the stores becomes depleted, the rate of release becomes decrease until equilibrium is reach between

release and synthesis at equilibrium, the rate of release of ACH is equal to the rate of mobilisation

in the absence of neuromuscular blockade, the muscle response is usually maintained due to the large safety factor for transmission

Competitive inhibition by postsynaptic non-depolarising muscles relaxant result in decrease in safety factors the decrease in ach release produce fade in the muscle response begin The prejunctional nicotinic receptors are blocked with decrease in ACH production

Factors affect fade fade also depends on the frequency and the duration of applied stimulation

Post-tetanic facilitation/potentiationoverview increase evoked response in the subsequent twitch after tetanic stimulation Features of nondepolaring blockade after tetanic contraction

Mechanism Tetanic stimulation of the nerve-motor unit result in diminished ach release per stimulus Howewver , there is enhanced synthesis with temporary mobilisation of ACH vesicle into prejunctional area Therefore , after the end of tetanic stimulus----the ACH output increased and the postsynaptic responsiveness

is potentiated When, there is single supramaximal stimulus given after a delay of three seconds that result in increased in

twitch height This occur due to large release of Ach-----displace the drug in receptors site-----evoke the higher twitch

Clinical significant it show partial non depolarizing neuromuscular blockade blockade

Mechanism during partial competitive block there is post-tetanic facilitation of transmission due to compensatory increased

mobilization of Ach

PTC not the same as PTFspecial note The PTC do not occur in depolaring blockade because the tetanic response is well sustained PTC usually is used after TOF of O The PTC give 15 tetanic stimulation and if usually all 15 will give contraction It show the estimated time for the TOF to appear

Q. Describe the effect of hepatic and renal disease to non-depolarising neuromuscular blockade drug

Hepatic Disease

a minor role in the elimination of most muscle relaxants, Exception are rocuronium and tubocurarine that depend on hepatic metabolism therefore, hepatic disease does not influence their use to the same extent as does renal disease Hepatic disease can causes increase in volume of distribution, therefore ,reductions in the plasma clearances thus it increase the duration of action of rocoronium repeated dose or prolonged IV > prolongation of action increased requirements of dTC have been reported in patients with elevated gamma globulins, eg. hepatic disease & biliary cirrhosis

Renal disease

non-depolarising from benzylquinolone group such as mivacurium , atracurium and cisatracurium doesn’t dependent on renal function for elimination of the drugs

aminosteroid group such as rocoronium , vecuronium and pancuronium depend on renal function for elimination of the drugs

Elimination halflife (Minutes)Normal 1-3 21 87 22-30 50-110 130

Renal failure Unknown Slightly unchanged 18-25

Moderately prolonged 97

Slightly unchanged 25-34

Severely prolonged 80-150


Liver failure Unknown Unchanged 20-25 Moderately prolonged 97

Unchanged 21

Moderately prolonged 49-198


Excretion

urine excretion 5% ( <10%) excreted unchanged in urine ,


10-25% excreted unchanged in urine

NS urine excretion

15-25 % excreted unchanged in urine


biliary excretion

NS in bile NS in bile 50-70 % excreted unchanged in bile

NS bile excretion

40-75% excreted unchanged in bile

5-10% excreted unchanged in bile

Animal studies : > 50% excreted unchanged in bile

Renal excretion may be more than 30%

80 eliminated unchanged , 40-60% in bile , 30 % in urine

Iipid solubility enhanced excretion

Renal disease Prolonged DOA


Prolongation of elimination half life of of vecuronium and 3-DAV

Decrease clearance

Increase plasma cctn of 3-DAV

persistent muscle paralysis after prolonged infusion

Decrease plasma clearance by 33-50%

Hepatic disease Total bilairy obstruction , cirrhosis

Significant decrease in metabolism by decerase in plasma pseudocholinesterase

Increased in Vd

therefore, longer DOA especially with repeated dose or prolonged IV

Organ indepence clearance

With 0.1 mg/kg > No difference in elimination half life

With 0.2 mg/kg > prolonged t1/2beta

Prolonged DOA in cirrhosis

Increased Vd

Decreased plasma clearance

Prolonged T1/2beta

Q. Describe the pharmacokinetic of the non-depolarising muscle relaxant and the role of prejunctional receptors as well as effect of renal and hepatic disease

Overview

NMB is quartenary ammonium compound that are highly ionized , water soluble compound at physiological pH

Dose and administration the pharamacokinetic of non-depolarising NMB are calculated after rapid IV the rate of dissaperance of long acting non-depolarising NMB from plasma is chracaterized by rapid initial decline via distribution to

tissue , follwed by initial decline ( clearance)

absorbtion ineffective orally because it cannot be reabsorbed from GIT ephitelial due to its higly ionized drug

Distribution Volume of distribution

volume of distribution is limited , Vd similar as ECF volume 200 ml/kg neuromuscular blocking agent cannot easily cross BBB , renal bular ephitelium, placenta therefore : do not produce central nervous system effect , minimal tubular reabsorbtion, and maternal administration does affect fetus

Protein binding less protein binding , only up to 50 % however , the plasma protein binding or changes in protein binding has significant effect on renal excretion atracurium has 80%-albumin protein binding

Effect of co-morbidity age, presence of volatile , presence of hepatic and renal disease affect the plasma clearance, Vd, elimination half life of non-depolarising drug

Metabolism

eliminationmivacurium

elimination mainly by enzymatic hydrolysis by plasma cholinesterase , no non-specific esterases

the metabolism produced quaternary alcohol and a quaternary monoester metabolite.

Pharmacological studies in cats and dogs have shown that the metabolites possess insignificant neuromuscular, autonomic or cardiovascular activity at concentrations higher than seen in man.

atracurium The duration of neuromuscular blockade produced by atracurium does not correlate with plasma pseudocholinesterase levels Duration of action : not altered by the absence of renal function. eliminated in in plasma via two nonoxidative pathways: 1. ester hydrolysis, catalysed by non-specific esterases; and 2. Hofmann

elimination, a nonenzymatic chemical process which occurs at physiological pH and body temperature. The rate of Hofmann elimination, principal route of elimination for atracurium, is increased at a higher pH or at higher temperatures,

and reduced at a lower pH or lower temperatures.

Rocoronium

eliminate by the body by hepatic metabolism and also excreted in bile

vecuronium

The extent of metabolism of vecuronium is relatively low.

In humans, a 3-OH derivative having approximately 50% less neuromuscular blocking potency than vecuronium could be demonstrated in the urine and bile as a metabolite of NORCURON.

In patients not suffering from renal nor hepatic failure, the plasma concentration of this derivative is below the limit of detection, and does not contribute to the neuromuscular block occurring after administration of NORCURON.

Biliary excretion is the main elimination route.

It is estimated that within 24 hours after intravenous administration of NORCURON, 40 to 80% of the dose administered is excreted into the bile as monoquaternary compounds.

Approximately 95% of these monoquaternary compounds is unchanged vecuronium and 5% is 3-hydroxy vecuronium.

Renal elimination is relatively low.

pancuronium eliminate by liver metabolism and renal elimination large fraction of pancuronium is excreted in the urine therefore, the duration of neuromuscular blockade is prolonged in patients with renal failure and the dose should be reduced.

In patients with impaired hepatic function, prolonged distribution and elimination half-lives result in a higher initial dose to be given

and longer duration of action respectively.

Prejunctional receptors

overview the prejunction nACHrs located on motor nerve endings these receptor influence the release of neurotransmitter

Effect of non-depolarising drugs some non-depolarising drug block the prejunctional sodium ion channel but not calcium ion channel therefore, the drug interefere with mobilization of acetylcholine from synthesis site to release site thus, the intereference with release of acetycholine that depend on calcium channel do not occur

Drugs Mivacurium Atracurium Rocoronium Cisatracurium Vecuronium Pancurunoium

Usual intubating dose(mg/kg )

0.25 0.4-0.5 0.6-1.2 0.1 0.08-0.1 0.1

ED95mcg/kg

0.08 0.25 0.3 0.05 0.05- 0.06 0.06-0.07

Onset(minutes)

slow onset 2-3

moderate onset 3-5

Fast onset1-2

Moderate3-5

Moderate onset3-5

Moderate onset3-5

Duration(Minutes)

shorter duration 12-20

20-35 20-35 20-35 20-35 60-90

tissue distribution Some placental transfer occurs in humans.

Distribution half life 1.2- 1.4

Vdl/kg

0.2 0.3 0.2 0.27 0.26

Protein binding less than 20% 82% less than 20% less than 20%Metabolism

Overview Not dependent on liver degradation

Unknown liver metabolism


Not dependent on liver degradation


10% dependent on liver degradation

Undergo plasma hydrolysis






hydrolysis plasma pseudocholinesterase

Metabolites; quartenary alcohol and quartenary acid






No effect of pseudocholinesterase Hoffman degradation >broken down to tertiary amine laudanosine


little hepatic


35% urine




Hoffman elimination at physiological pH and temperature

Form laudanosine and monoquartenary acrylate that

undergo hoffman elimination

70 % eliminated by hoffman

Metabolites are inactive at NMJ

Mainly hepatic metabolism deacylation to 3-desacetylvecuronium , 17, desaacetylvecuronium and 3,17-desacetylvecuronium the 3-

desacetylvecuronium 50% potency of parents compoundit rapidly converted 3,17 desacetylvecuronium

3,17-DAV and 17-DAV : 1/10 potency to parent compound

Extensive hepatic uptake > rapid decrase in plasma concentration , short duration of action

10-40% undergo hepatic deacetylation to 3-desacetylpancuronium, 17-desacetylpancuronium3,17-desacetylpancuronium 3-

desacetylpancuronium is 50% as potent as parent compound

Metabolites : alcohol and quartenary

monoester are inactive at NMJ




Metabolites are inactive at NMJ

Metabolites has 50% activity

Clearance Ml/min/kg

5.5 5.5




4.0


4.7-5.3




5.2


1.8

clearance dependence on renal function and modestly hepatic function

Overview of elimination

Unknown dependency on renal function

Unknown dependency on hepatic function

Not dependent on renal function

Not dependent on liver function

Dependent on renal function

Dependent on liver function

Not dependent on renal function

Not dependent on liver function


Dependent on liver function


Moderately dependent on liver function

Elimination halflife (Minutes)

Normal

Renal failure

Liver failure

1-3

Unknown

Unknown

21


Unchanged 20-25

87



22-30


Unchanged 21

50-110


Moderately prolonged 49-198

130

Severely prolonged 240-1050Severely prolonged 208-270

Excretion 5% ( <10%) excreted unchanged in urine , NS in bile

10% excreted unchanged in urine NS in bile



NS urine excretionNS bile excretion

15-25 % excreted unchanged in urine 40-75% excreted unchanged in bile

80 eliminated unchanged , 40-60% in bile , 30 % in urineIpid solubility enhanced excretion

80% excreted unchanged in urine 5-10% excreted unchanged in bile

Renal disease Minor excreted in urine 7% of total


Prolonged DOA


Prolongation of elimination half


dose

Insignificant prolongation of the action of miva in anephritic patient

But not due to renal failure per-se , due to decrase in plasma esterase activity cause by renal failure



life of of vecuronium and 3-DAV

Decrease clearance

Increase plasma cctn of 3-DAV > persistent muscle paralysis after prolonged infusion

Hepatic disease Total bilairy obstruction , cirrhosis

Significant decrease in metabolism by plasma pseudocholinesterase

Increased in Vd> longer DOA especially wirh repeated dose or prolonged IV

Organ indepence clearance

With 0.1 mg/kg > No difference in elimination half life With 0.2 mg/kg > prolonged t1/2betaProlonged DOA in cirrhosis

Increased VdDecreased plasma clearanceProlonged T1/2beta

Q. Explain the factors that determine the onset of neuromuscular blockade Overview

speed of onset of muscle relaxant is the time from the injection to onset of maximal single twitch of depression

Factors affecting onset Physicochemical properties of drug Dose of muscle relaxant Potency of agent Effect of cardiac output

Other factor speed of onset between depolarising and non-depolarising speed of onset between different muscle group speed of onset between different route of administration Priming of non-depolarising before depolarizing agent age interaction disease state gender

Physicochemical properties of drugPreparation -additives

the stable agent prior to administration result in normal onset of action compared to agent that unstable and degraded in vivo

example atracurium is prepared +as solution with addition of sodium besylate to provide water solubility and adjust the pH to 3-3.5

therefore , it minimize the spontaneous in vitro degradation thus atracurium should not be mixed in alkaline drugs such as barbiturate or exposed to solution with

more alkaline pH

pharmacokinetic Dose of muscle relaxant

the higher the dose of muscle relaxant by multiple ED95 result in the faster the speed of onset example : ED95% of vecuronium is 0.05 mg/kg, twice this dose >onset time 2-3 minutes faster, but clinical duration is prolonged 30-40 minutes

Usual intubating dose(mg/kg )

0.25 0.4-0.5 0.6-1.2 0.1 0.08-0.1 0.1

Potency of agent the more potent agent has slower speed of onset compared to equivalent dose of a less potent agent the potency of agent is describe as effective dose to depress single twitch of depression by 95% or ED95 The ED95 of rocoronium is 0.3 mg/kg that is less potent than ED95 of vecuronium 0.05 mcg/kg which is

more potent Why?- according to fick law of diffusion , the higher the dose , the faster diffusion to the effect site----the

faster the speed of onset Does concentration and dose are not the same

ED95mg/kg

0.08 0.25 0.3 0.05 0.05- 0.06 0.06-0.07

2-3 3-5 Onset faster--because more molecular weight compared to cistracurium

1-2 3-5 Onset slower than atracurium because more potent

3-5 3-5

Volume of distribution increase in volume of distribution > slow onset decrease in volume of distribution or increase protein binding > faster onset of muscle blockade

Vdl/kg

0.2 0.3 0.2 0.27 0.26

Cardiac output the onset of action is faster with high cardiac output and increase muscle blood flow disease that cause decrease the cardiac output and blood flow to the muscle decrease delivery to muscle

and NMJ, decrease absorbtion > slower onset

Type of agent the speed of onset depolarising agent is faster than non-depolarising

Type of muscle in individual muscles , the speed of onset is faster on small, rapidly moving muscle such as eyes ( orbicularis

oculi ) , digits ( adductor policis ), before large muscle such as trunk and abdomen the blockade is more rapid at the laryngeal muscle than peripheral muscle ie adductor pollicis this reflect the type of fiber , ie fast fiber in thyroparetenoid muscle of glottis , than adductor pollicis , slow

fiber this is due to higher density of ACH receptor at the fast fiber than slow fibers however, the recovery occur first in diaphragm Howewver ,

Route of adminsitartion IV route result in faster onset than IM route due to rapid intravascular delivery to NMJ example IV rocoronium the onset of action is 1-2 minute , compared to IM

Priming the dose of the speed of onset of intermediate acting nondepolarising may be accelerated by priming of subparalyzing

dose of approximately 10 % of the drug ED95, followed by approximately 4 minutes before large 2/3 x ED95 of the drug

the concept: the initial small dose will occupy the spare receptor that produce no blockade , then the large dose will eventually occupy the 70 % receptor for deepening of blockade

thus rapid onset after second large dose , conceptually :the subparalyzing dose will decrease the safety margin of transmission

Q. Describe the characteristics of depolarising and non depolarising block on nerve stimulator

Depolarizing block overview

depolarising block is type of neuromuscular blockade that is cause by normal intubating dose of suxamethonium

Characteristic of depolarizing block ilicited by peripheral nerve stimulatorSingle nerve stimulus

decreased contraction in response to single twitch stimulation

Train of four decrease amplitude but sustained response to continous stimulation TOF ratio > 0.7

Tetanic stimulation absence of post-tetanic potentiation augmentation of neuromuscular blockade after an administration of an anticholinesterase ( the difference )

Non-depolarising blockade overview

the non-depolarising blockade can be cause by non-depolarising agent or with single, large dose > 2 mg/kg, repeated dose of depolarisng agent such as sux

characteristic of non-depolarising neuromuscular blockade single nerve stimulus

the decrease twitch response to single stimulus muscle contraction is all or none event each muscle fiber either contract maximally or dosent contract a all therefore , when the twitch response decerase , then some fibers will contract normally and some will completely blocked ( none )

Trial of four the presence of fade or unsustained response during the continuous stimulation TOF ratio < 0.7 some fiber are more susceptible to be blocked by neuromuscular blocking agent thus it need a greater sustained release of acetylcholine to trigger their response

Tetanic stimulation showed post-tetanic potentiation

Fade some fiber are more susceptible to be blocked by neuromuscular blocking agent thus it need a greater sustained release of acetylcholine to trigger their response

Fade in response to tetatnic stimulation indicate the presynaptic event This occur , when the start of tetanic stimulation there is burst of ACH release from the store of nerve terminal as the tetanic stimulation continue , the stores become depleted the rate of ACH release decreasing until the equilbirum between ACH synthesis and ACH release is achieved when , the number of free cholinergic receptor ( margin of safety of neuromuscular transmission ) is decrease by the non-

depolarsing , with the decrease in number of ACH release occur during tetatnic stimulation , then fade occur

Q. Describe the post-junctional receptorsPost junctional receptors Post-junctional nicotinic receptors is ligand -gated ion channels Located on the muscle cell membrane at the endplate is folded in junctional folds or crypts Found in pairs

Acetylcholine Receptor

It is a nicotinic receptor

Type of receptor fetal recptors adult receptors

Molecular structure Pentamer structures , composed of two a-subunits and 3 other subunit, beta , gamma, delta (for fetal ) and epsilon ( for mature) Each alpha subunits has a MW ~ 40,000 daltons, The internal channels has an outer vestibule The constriction deep in membrane bilayer The receptors has the outer structures that protrudes out and the inner structures that lies 2 nm deep in the cytoplasm of skeletal muscles

cells The subunits surrounds a central ion channel pore in a rosette form The channel is opened by the binding of 2 acetylcholine molecules to the 2 a - proteins

Sublocation of receptor on NMJ The receptor is fixed into the postjunctional membrane, whereas acetylcholinesterase is loosely attached to the surface of postjunctional membrane .

Type of ion channels Ligand gated ion channels Not voltage-gated ion channels that located on cardiac and skeletal muscle cell membranes.

Fetal receptors consist of 5 subunits, alpha , beta, gamma and delta Pentamer structures composed of two a-subunits and 3 other subunit, beta , gamma delta The opening of channels result in influx of Na, Ca and outflux of K on skeletal muscle membrane down its chemical gradient the fetal receptor has long open period compared to mature adult receptor these allow single acetylcholine quantal to elicit action potential

Adult receptor consist of 5 subunits , alpha , beta, gamma and epsilon adult receptor presence when the fetal receptor dissappear during synapse maturation of junctional and extrajunctional receptor these mature receptor , has shorter open period and higher conductance of sodium , potassium and calcium ions

Q. Describe the systemic side-effect of muscle relaxant Overview

The systemic side effect of muscles relaxant are that due to can be due depolarising and nondepolarising

Side effect of depolarising neuromuscular block

Overview

The adverse effect that accompany sux are subdivided into common side effect and rare side effect

Common side effect neuromuscular induction

Fasciculations

intraop rhamdomyolysis Myoglobinuria myoglobinaemia, elevated creatine phosphokinase, hypertonia.

post-op post-operative muscle Pains

CVS Cardiac arrythmia

electrolyte Mild hyperkalaemia ~ 0.5 mmol/l

CNS Increased intracranial pressure ~ 15-20 mmHg

Special senses Increased intraocular pressure

GIT Increase intragastric pressure increased gastric acid secretion increased bowel movements

Respiratory Increased bronchial secretion Increased salivation

Rare electrolyte

Severe hyperkalaemia

Resp Prolonged apnoea

Muscle Malignant hyperpyrexia Masseter spasm

Endocrine porphyria

Immunology Anaphylaxis Anaphylactoid reactions Hypersensitivity reactions including circulatory collapse, flushing, rash, urticaria, bronchospasm and shock, which may lead to death

CVS Pulmonary oedema Sinus arrest / asystole

Note The administration of non-paralysing dose of nondepolarising can attenuate and prevent the occurrence of side effects

Cardiac arrhythmias Overview

Suxamethonium can cause sinus bradycardia , junctional rhythm,and sinus arrest

Mechanism suxamethonium has cholinomimetic actions, Sux may act at, parasympathetic & sympathetic autonomic ganglia causing ganglionic stimulation M2 receptors of the heart causing effect of ach

CVS effect the CVS effects are variable, adults who have received premedication with antimuscarinic drugs frequently develop tachycardia and increased BP children may show bradycardia or sinus arrest, especially if antimuscarinic premedicant has been omitted

Sinus bradycardia the incidence of sinus bradycardia or a junctional rhythm is greater after a second dose It occur approximately 5 minutes after first dose Mechanism ; possibly due to metabolites of sux (succinylmonocholine and choline) that produce bradycardia steolting : Administration of atropine doesn't prevent the slowing of heart after second dose

Sinus tachycardia The effect of sux on autonomic ganglia > increases in heart rate and systemic blood pressure The action of sux on autonomic ganglia is similar as physiological effect of ach in autonomic ganglia

Muscle Pains Overview

common side effect due to the widespread fasciculations

Mechanism Possible ; unsynchronized contraction of skeletal muscles fibres a/w generalised depolarisation

Incidence most commonly affect the neck, shoulder girdle and chest

Clinical administration their incidence may be reduce with a “priming” dose of non-depolarising agent this will also decrease the incidence, or severity of rise in intraocular and intragastric pressure increases in plasma creatinine phosphokinase and myoglobin will also be reduced

Hyperkalaemia Overview

Suxamethonium that causes depolarisation normally produces a small rise in the serum [K+] ~ 0.5 mmol/l

Hyperkalemia In the condition where denervation has occurred, or where neural activation is significantly reduced, ACh receptors spread from the

neuromuscular junction Therefore , suxamethonium can result in dangerous hyperkalaemia,

Condition that predisposed to hyperkalemia Denervation that lead to muscles atrophy Burns , unhealed third degree - which is most common causes Severe skeletal muscles trauma neurologic disease & trauma severe sepsis renal failure cerebrovascular accidents or upper motor neurone lesions

Onset of hyperkalemic response this predisposition does not tend to occur immediately The excessive potassium release develop within 96 hours after denervation , persist for 6 month it may persist for 2-3 months following burns

Hyperkalemia and denervation injury Sux may cause leak of potassium from the extrajunctional cholinergic receptors that proliferate during denervation injury

Hyperkalemia and head injury case report of hyperkalaemia following a closed head injury However this should not prevent its use in this closed head injury however, a hyperkalaemic response is possible

Hyperkalemia and renal failure the evidence to support renal failure as a predisposing factor for hyperkalemia has recently been disputed providing the initial serum K+ << 5.5 mmol/l there is no increased risk Stoelting ; preexisting hyperkalemia > 5.5 mmol a/w renal failure in absence of skeletal muscles paralysis is not associated with

increased risk of hyperkalemia after intubating dose of sux (studies 2002)

Use of sux in children Some clinician avoid use in children Reason; possiblity of undiagnosed myopathy that can causes rhabdomyolyisi, hyperkalemia , cardiac arrest

Clinical condition suxamethonium may actually be the agent of choice because of its lack of reliance on renal excretion

Malignant Hyperpyrexia can trigger malignant hyperthermia in genetically susceptible individuals rare hypermetabolic process of skeletal muscle Early premonitory signs -muscle rigidity, tachycardia, tachypnoea unresponsive to increased depth of anaesthesia, evidence of increased oxygen requirement and carbon dioxide production, rising temperature and metabolic acidosis ~ 70% of whom will display elevated creatine phosphokinase levels in the resting, fasted state

Myoglobinuria Sux in pediatric patients can causes damage to skeletal muscles > myoglobinuria Mechanism ; fasciculation Myoglobinuria not occur in adult

Increased intragastric pressure Overview

Suxamethonium causes increased in intragastric pressure

Mechanism Fasciculation causes increased intragastric pressure due to effect on skeletal muscles

Complications Increased intragastric pressure (> 28 mmhg) > open the gastroesophageal sphinters > aspirations of gastric fluid to lung

Clinical Prevented by use of non-paralysing dose of nondepolarising

Increased intraocular pressure Overview

Suxamethonium > increased in pressure 2- 4 minutes after administration Effect is transient/ last 5-10 minutes

Mechanism Unknown Possible ; contraction of extraocular pressure with distortion and compression of globe Current possible ; cycloplegic action of suxamethonium with deepening of anterior chamber and increased resistance to outflow, plus

slight increase in choroidal blood volume and cvp

Clinical Current believe ; avoid in open eye injury > extrusion of global content

Increase intracranial pressure Stoelting ; increased icp a/w sux is not consistent observation

Sustained skeletal muscles contraction Incomplete jaw relaxation and masseter jaw rigidity not uncommon in children Effect ; interfere with ventilation of lung

Side effect of non-depolarising

Critical illness myopathy Overview

It is skeletal muscles weakness on the recovery in patients receiving drug-induced paralysis to facilitate mechanical ventilation for prolonged duration of time > 6 days

Clinically Moderate / severe quadriparesis with/ without areflexia Normal sensory function Onset / duration ; unpredictable time course, may persist for weeks , months despite discontinuation of nmb

Mechanism Unknown

Causes Commonly occur in patients with aminosteroid nondepolarising nmb; pancuronium and vecuronium However , may occur with atracurium Increase risk of myopathy with administration of corticosteroid

Cardiovascular effect Overview

Nondepolarising NMB that causes the release of histamine or vasoactive substance affect muscarinic cardiac receptors or nicotinic ach receptors at autonomic ganglia

Degree of cardiovascular effect The degree of circulatory effect varies from patients to patients Depend on underlying autonomic nervous activity, preoperative medications , maintainance drug

Autonomic margin of safery It is the difference between dose of neuromuscular agent that produce neuromuscular blockade and circulatory effect The narrow autonomic margin of safety result in more CVS side effect Example ; the ED95 of pancuronium that produce neuromuscular blockade is likely to cause circulatory effect Therefore , the autonomic margin is narrow Example ; the ED95 of vecuronium , rocoronium , cisatracurium wide autonomic margin of safety ED95 for circulatory effect is less than dose that affect circulation

Q. Give detailed account of pharmacology of suxamethonium including its undesirable properties

Overview Short acting depolarising neuromuscular blockade

Physicochemical properties Solubility; solubilize in wate Sterility; solubilize in sterile water Presentation; Injection solution: a clear, colourless, particle-free solution containing

50 mg/mL suxamethonium chloride Shelf-Life with Polyamps: 15 months at 2° - 8°C Storage Conditions-Store between 2°- 8°C. REFRIGERATE - DO NOT FREEZE

Clinical uses ultra short-acting depolarising type neuromuscular blocking agent.

Structure activity relatioship Chemical compound

Suxamethonium consist of two ACh molecules The two ach molecules are joined through the acetate methyl groups The methyl groups are attached to their quartenary head ie the N with 4 bonds The methyl group are separated from each other by 1.2 to 1.4 nm distance The methyl group are joined with their non-quartenary ends through acetyl group ie

CH2CO

Formula structure of suxamethonium

Formula structure of acetylcholine

Pharmacokinetic Absorbtion Dose and administration

Route; can be given via IV and IM route Iv route ;1- 1 .5mg/kg I'm route IM dose for adults and children may be up to 2.5 mg/kg but the total dose

should not exceed 150 mg.

onset/ duration IV Onset ; 30-60 second IV Duration of action; 3- 5 minutes , dissipating effect over 10 minutes IM Onset ; 2-3 minutes ED90 , after thiopental , and maintain with nitrous oxide = 0.27 mg/kg Special; the onset and duration of action is influence by pseudocholinesterase

activity on hydrolyzing the sux before and after it reach endplate

Distribution can crosses the placenta, generally in small amounts

Metabolism metaboliser

rapidly broken down in the plasma by butyrylcholinesterase, or “pseudocholinesterase”, to the monocholine form

metabolites this has ~ 0.05 times the potency of the dicholine parent this is then further metabolised to acetate & choline

Reaction Reaction ;sux broken down to monocholine, monocholine then broken down to choline and acetate, occur in plasma , Enzyme ; plasma pseudocholinesterase or butylcholinesterase Metabolites; the metabolites has 0.05 times potency than parent compound Activity of metabolites; 5% activity ,then parents

Elimination Plasma pseudocholinesterases hydrolyses SUXAMETHONIUM to succinylmonocholine

(relatively inactive) and choline termination of action - by dissociation & diffusion of sux from the receptor

there is no pseudocholinesterase at the endplate

elimination half life tb½ ~ 5 min The rate of hydrolysis result in only a small fraction of the administered dose reaches

the motor endplate pseudocholinesterase therefore controls the duration of suxamethonium blockade by

determining the amount which reaches the endplate

effect of pseudocholinesterase defieciency prolonged effect with both congenital and acquired enzyme abnormalities

Mechanism of action sux bind to one or both alpha subunits of nicotinic receptors It mimic the action of Ach ( partial agonist ) Suxamethonium activates the postjunctional membrane and result in depolarisation

of the membrane, however, the hydrolysis of sux is slow , therefore > sustained depolarization

( opening ) of the receptor ion channel the effects are manifest first as muscle twitching and fasciculation, which are

followed by the onset of blockade neuromuscular blockade occur develop because the depolarized membrane cannot

respond to ACH The depolarisation persists and neuromuscular blockade occur until the drug diffuses

away Note

the above mechanism of neuromuscular blockade = phase 1 blockade Sux also has presynpatic effect but of minor significant than postsynaptic action sustained opening of receptor ion channel > leakage of K from intracxellular to

extracellular > increase serum K+ level by 0.5 mmol/l has no direct action on smooth muscle structures, including the uterus.

Excretion Elimination half life tb½ ~ 5 min Form of excretion; excreted in urine with 10 % unchanged form

Effect of co-morbidity Liver disease

with liver disease and a reduction of enzyme activity to ~ 20%, the duration of succinylcholine increased from ~ 3 to ~ 9 minutes

Interaction inhalational anesthetic

inhaled anaesthetics (cyclopane, diethylether, halothane and nitrous oxide) may increase the incidence of dysrhythmias (especially bradycardia), apnoea and the occurrence of malignant hyperthermia in susceptible persons.

Inhaled anaesthetics have little effect on the usual depolarising neuromuscular blockade of sux

but may enhance the Phase II block (nondepolarising) that may be produced by repeated dosage of sux

intravenous agent Severe bradycardia and asystole have occurred when sux is used in anaesthetic

regimens with propofol and opioids such as fentanyl.

Local anethesia lignocaine and procaine may increase effect of suxamethonium

antibiotic non-penicilin antibiotic- streptomycin , kanamycin , tobramycin , amikacin ,

gentamycin- may prolong and enhance effect of sux

CVS drugs beta blockers, trimethaphan - may prolong and enhance effect of sux

anti-epileptic phenytoin , carbamazepine - may prolong and enhance effect of sux

anti-depressant lithium carbonate - may prolong and enhance effect of sux

anti-histamine cimitidine - may prolong and enhance effect of sux

bronchodilator terbutaline - may prolong and enhance effect of sux

steroid high dose corticosteroid - may prolong and enhance effect of sux

diuretic amphotericin B and thiazide - may prolong and enhance effect of sux secondary to

electrolyte imbalance

anti-cholinesterase Inhibitors of plasma cholinesterases such as neostigmine pyridostigmine bromide,

rivastigmine, donepezil, metoclopramide, physostigmine and phospholine iodide can considerably prolong the depolarising action of sux

recommended that long-acting anticholinesterase inhibitor (ecothiopate) eye drops, should be discontinued several months prior to administration of sux

low plasma pseudocholinesterase

Recovery may occassionally be delayed possibly due to a low serum pseudocholinesterase level;

may occur in patients suffering from severe liver disease, cancer, malnutrition, severe dehydration, collagen diseases, severe anaemia, myxoedem, burns, pregnancy and the puerperium, severe infections, myocardial infarction, renal impairment and abnormal body temperature.

exposure to neurotoxic insecticides or weed killers, antimalarial or anti-cancer agents, monoamine oxidase (MAO) inhibitors, the contraceptive pill, pancuronium, chlorpromazine, ecothiopate or neostigmine may result in low levels of pseudocholinesterase.

sux administered with extreme caution and in reduced doses in such patients.

If low pseudocholinesterase concentration is suspected , give slow administration of a small test dose of suxamethonium (5 to 10 mg as a 0.1% solution)

Q. Compare and contrast vecuronium and pancuronium

Vecuronium Pancurunoium


long acting non-depolarizing muscle relaxant

physicochemical properties vecuronium presented as citrate-

phosphate buffered freeze-dried white to off-white dry cake or powder. No preservative has been added.

vecuronium need to be reinstituted with water before injection to make

pancuronium presented as sterile solution containing in each mL: Pancuronium Bromide 2mg, Sodium Acetate 2mg, Sodium Chloride 8mg in Water for Injections B.P.

clear isotonic solution with pH of 4

therefore, vecuronium has non-ideal properties in which it has to be prepared before use


overview vecuronium is an monoquartenary

aminosteroid the molecular structure is smilar with

pancuronium but without the quartenary methyl group

compound vecuronium is an monoquartenary

aminosteroid the molecular structure is similar with

rocoronium

specific chemical structure Resemble the pancuronium Difference : no quaternary methyl

group at A-ring of steroid nucleus The absence of this structure result

in less acetylcholine like activity , with decrease vagolytic properties

Lipid solubility Monoquartenary structure > increase

in lipid solubility Unstable in solution and need to be

lyphophiliaed in water

overview pancuronium is bisquatenary aminosteroid the molecular structure is similar with

vecuronium but with quartenary methyl group

specific chemical structure has a fragment of molecules----------

resemble the acetylcholine therefore ----------- fragment that bind to

alpha subunit , account for neuromuscular blockade and

its plasma cholinesteasre inhibiting action

Both compound are aminosteroid and has nearly similar molecular structure


intubating dose

0.08-0.1 0.1

ED95

0.005- 0.06 0.006-0.007

Vecuronium is more potent than pancuronium because it need less drug to block 95% contraction on single twitch stimulation

Onset of action

Moderate onset3-5

Moderate onset3-5

Both vecuronium and pancuronium has similar onset of action

Duration of action

20-35 60-90

vecuronium is intermediate acting compared to pancuronium which is long acting muscle relaxant



Elimination

eliminated both by hepatic metabolism and renal excretion more lipid soluble , more entry to

eliminated manly by renal clearance with modest hepatic elimination less lipid soluble , therefore less hepatic

hepatocyte , more hepatic metabolism 20-30% dependent on liver degradation

metabolism 10% dependent on liver degradation

No plasma hydrolysis No plasma hydrolysis

20-30% undergo hepatic deacylation to 3-desacetylvecuronium , 17, desaacetylvecuronium and 3,17-desacetylvecuronium

the 3- desacetylvecuronium 50% potency of parents compound

rapidly converted 3,17 desacetylvecuronium


Extensive hepatic uptake > rapid decrease in plasma concentration , short duration of action

10-40% undergo hepatic deacetylation to 3-desacetylpancuronium, 17-desacetylpancuroniumand 3,17-desacetylpancuronium

3-desacetylpancuronium is 50% as potent as parent compound

less hepatic uptake > slow decrease in plasma concentration , long duration of action

Clearance

5.2 ml/min/kg


1.8 ml/min /kg

clearance dependence on renal function and modestly hepatic function

Elimination


Dependent on renal functionModerately dependent on liver function


50-110Severely prolonged in renal failure

130Severely prolonged in renal failure

80-150 Moderately prolonged inn hepatic failure 49-198

240-1050Prolonged in hepatic failure 208-270

Excretion

15-25 % excreted unchanged in urine 40-75% excreted unchanged in bile 80 eliminated unchanged , 40-60% in bile , 30 % in urineIipid solubility enhanced excretion

80% excreted unchanged in urine 5-10% excreted unchanged in bile



Decrease clearance





Increased VdDecreased plasma clearanceProlonged T1/2beta

CVS effect

vencuronium exerts no vagolytic nor ganglion blocking activity within the clinical dosage range

no cardiovascular effects within the clinical dosage range,

it does not attenuate bradycardia that may occur due to the use of some types of anaesthetics and opiates or due to vagal reflexes during surgery

Pancuronium causes moderate increases in heart rate with an attendant increase in cardiac output and blood pressure;

no effect on systemic vascular resistance.

little or no histamine release and no ganglionic blockade,

therefore does not cause hypotension or bronchospasm

Q. Compare and contrast vecuronium and rocuronium

Vecuronium Rocoronium


intermediate acting non-depolarising from the monoquaternary aminosteroid


intermediate acting non-depolarising agent from the Monoquartenary aminosteroid

physicochemical properties

Presentation vecuronium presented as citrate-

phosphate buffered freeze-dried white to off-white dry cake or powder.

additive No preservative has been added. freeze dried powder containing citric

acid monohydrate, disodium phosphate dihydrate, mannitol (E421), sodium hydroxide and phosphoric acid (for pH correction).

preparation vecuronium need to be reinstituted

with water before injection to make clear isotonic solution with pH of 4

Presentation rocoronium presented as a clear, aqueous

solution for intravenous injection

additive the solution contain sodium acetate,

sodium chloride, acetic acid and water for injections.

No preservative has been added.

therefore, vecuronium has non-ideal properties in which it has to be prepared before use


compound vecuronium is an monoquartenary

aminosteroid the molecular structure is similar with

rocoronium

specific chemical structure Resemble the pancuronium Difference : no quaternary methyl

group at A-ring of steroid nucleus The absence of this structure result

compound rocoronium is monoquartenary

amminosteroid resemble vecuronium with the presence of

acetyl group on the A-ring of steroid nucleus

in less acetylcholine like activity , with decrease vagolytic properties

Lipid solubility Monoquartenary structure > increase

in lipid solubility Unstable in solution and need to be

lyphophiliaed in water

Both compound are aminosteroid and has nearly similar molecular structure


intubating dose

0.08-0.1 0.6- 1.2

ED95

0.05- 0.06 0.3

Vecuronium is more potent than rocoronium because it need less drug to block 95% contraction on single twitch stimulation The ED90 (dose required to produce 90% depression of the twitch response of the thumb to stimulation of the ulnar nerve) during intravenous anaesthesia

Onset of action

Moderate onset3-5

Moderate onset1-2

Rocoronium has faster onset than vecuronium

Duration of action

20-35 20-35

Both vecuronium and rocoronium is moderate acting muscle relaxant



Elimination

eliminated both by hepatic metabolism and renal excretion more lipid soluble , more entry to hepatocyte , more hepatic metabolism 20-30% dependent on liver degradation

eliminated both by hepatic metabolism and renal excretion less lipid soluble , therefore less hepatic metabolism 10-20% dependent on liver degradation

No plasma hydrolysis No plasma hydrolysis

Mainly hepatic metabolism deacylation to 3-desacetylvecuronium , 17, desaacetylvecuronium and 3,17-desacetylvecuronium the 3-

desacetylvecuronium 50% potency of parents compoundit rapidly converted 3,17 desacetylvecuronium


Extensive hepatic uptake > rapid decrase in plasma concentration , short duration of action

Metabolites has 50% activity

little hepatic


35% urine




Clearance

5.2 ml/min/kg


4.0 ml/min/kg


Elimination




50-110Severely prolonged in renal failure 80-150 Moderately prolonged inn hepatic failure 49-198

87Moderately prolonged in renal failure97Moderately prolonged in liver failure 97

Excretion

15-25 % excreted unchanged in urine 40-75% excreted unchanged in bile 80 eliminated unchanged , 40-60% in bile , 30 % in urineIipid solubility enhanced excretion





Decrease clearance


Prolonged DOA




Increased in Vd> longer DOA especially wirh repeated dose or prolonged IV

CVS effect

vencuronium exerts no vagolytic nor ganglion blocking activity within the clinical dosage range

no cardiovascular effects within the clinical dosage range,

it does not attenuate bradycardia that may occur due to the use of some types of anaesthetics and opiates or due to vagal reflexes during surgery

may produced reflex bradycardia in patinet undergo procedure that associated with vagal stimulation ( laparoscopy , opthalmic)


May produce slight vagolytic effect that is not occur with other aminosteroid

Useful in procedure that associated with vagal stimulation

Q. Describe the onset and offset of neuromuscular block at the diaphragm , larynx and adductor pollicis after administration of 2.5 x ED95 dose of vecuronium. Comment on the differences observed. What are clinical implications of the differences?

Decribe onset and offset of neuromuscular agent

Diaphragm and larynx has small density of ach receptors , therefore its is less sensitive to non-depolarising drugs compared to adductor pollicis But the blood flow to diaphragm and larynx is greater than adductor pollicis Therefore , the onset is more rapid in larynx and diaphragm , and slow in adductor

pollicis The speed of onset is faster in diaphragm , followed by larynx Adductor pollicis has the slowest speed of onset ED95 is the effective dose of nondepolaring neuromuscular blocker that depress the

contraction of adductor pollicis on the single stimulation At the time of twitch depression of AP, the diaphragm and larynx is maximally

blocked and begin to recover Therefore , after 2.5 x ED95, the recovery from neuromuscular blockade is started

with diaphragm , larynx . Adductor pollicis is the last muscles to recover due to it slower blood flow

Clinical implication Onset

Onset of neuromuscular block and timing for intubation

duration of action Offset of neuromuscular blockade

neuromuscular reversal Assessment of adequacy of recovery from neuromuscular blockade Monitoring of extent of neuromuscular blockade at AP Predictions of block at AP, larynx , diaphragm

Q. Appraise different methods to monitor neuromuscular junctionOverview Several different methods Basicly before giving the muscles relaxant , need to give initial threshold current

Basic principle neuromuscular function is monitored by evaluating the response of a muscle to supramaximal stimulation of a peripheral motor nerve, a single muscle fibre response in all or none event the response is the sum of all individual fibres that activated by the nerve stimulator therefore, the response of the muscle depend on 1. number of muscle fibre activated 2. the intensity of stimulus

Characteristic of stimulus the supramaximal stimulus is used

This electrical stimulus is large to ensure all muscle fibre is stimulated

usually it above ~ 20-25x maximal response and painful in awake patient

the stimulus should not very low---d/t overestimate degree of paralysis

Current The current is 2.5 x ICT

Placement of electrode The negative (black) electrode is attached as near as possible to a nerve, The other positive electrode(white-proximal ) can be placed anywhere else along the line of the nerve, the ulnar nerve is commonly used and the strength of adductor pollicis brevis adduction ulnar nerve- located flexor carpi ulnaris ( ulnar side/ medial side) and ulnar artery ( radial site/ lateral side) proximal electrode ( positive electrode ) on distal one third of ulnar nerve or commonly on half way along the forearm. distal electrode ( negative electrode ) placed on the skin crest of the wrist on lateral side of FCU tendon skin over the course of nerve is applied with stimulator Other nerves are-

Characteristic of stimulus

electrical stimulus ~ 20-25x > maximal response

the impulse is monophasic & rectangular

Monophasic is used rather than biphasic

Reasons; biphasic pulse may initiate a burst of action potentials and increase the response to stimulation Optimum pulse duration is 0.2- 0.3 ms a pulse duration > 0.5 ms may result in direct muscle stimulation, or initiate repetitive firing of the nerve pulse delivery should be at a constant current, cf. voltage, as stimulation is current dependent

Patterns of Nerve Stimulation

Single-Twitch Stimulation ST

Overview

The simplest methods

stimulus

single stimuli are applied at rates from 0.1 to 1.0 Hz The stimuli - known as a square wave stimulus

Basic principle of action the muscle response to single twitch stimulation The neuromuscular function depends on the frequency of stimulation

Response The amount of movement in response to a supra maximal stimulus before any relaxant is given is known as the 'Control Twitch Height. Successive twitches are often reported as a percentage of this control height. If more than 80% of the receptors are blocked then there will be a decrease in the height of the twitch or no twitch at all.

Relationship between twitches and clinical finding patient can have his neuromuscular blocking drugs reversed when his first twitch reaches 20% of control.

Graph

Advantage Simple to monitor No need expensive monitor

Disadvantage First need to have a control twitch measured before any relaxant has been given. This is done when the patients is awake and has not receive any relaxant ie before induction In emergency cases you have to give the relaxant as soon as the patient is asleep. This can be quite unpleasant.

Second Need to remember how high the first twitch was. This is not possible unless you are using expensive equipment to actually measure the twitch.

Train of Four Stimulation TOF

Overview This is a method for measuring magnitude and type of neuromuscular blockade, It is based upon the ratio of the amplitude of the fourth evoked mechanical response to the first one, when four supramaximal 2-Hz

electrical currents are applied for 2 seconds to a peripheral motor nerve.

Stimulus four supramaximal stimuli are delivered at 2 Hz (1 per 0.5 sec)- 4 stimulus – 2 hz---total duration is 2 second each train of stimulation is separated by 12-20 seconds

Assessment of response the degree of competitive neuromuscular blockade may be assessed by, a. the ratio of the 4th to the 1st response

b. the number, or TOF count

Clinically , the stimulator give 4 stimulus of 50 mA, for 2 hz

Then pressed on TOF,

The monitor give how many twitches it , example it maybe read as 0 twitch or 2 twitches , 3 twitches

If the machine get 4 twitches , then it give the ratio of 4th twitch to the 1st twitch- it ma be read as 20%, 50% or 90%

this enables assessment of transmission in the absence of baseline data

Pattern of response of train of fourpattern before induction for normal response non-paralyzed : if the 4:1 ratio ~ 1.0, that means all four response or thumb movement are the same

TOFC1----90-95% blockade

TOFC4-----70% blockade

Pattern after administration of non-depolarising

the ratio decreases, or “fades”, in relation to the degree of blockade

the number of TOF initially show percentage , then giving the count

Pattern with depolarising

It showed partial non-competitive blockade :

the ratio of TOF count remains ~ constant, but the twitch height uniformly

Pattern with TOF fade after depolarising the presence of TOF fade after the use of succinylcholine signifies the onset of phase II blockade

Pattern with recovery from complete paralysis ,

the T1 return first followed by T2, T3, T4

during recovery, once four responses can be elicited, it is difficult even for experienced observers to estimate the TOF ratio above ~ 0.4

Pattern to start surgical procedure

With complete absence of response on mechanical stimulation indicate adequate surgical relaxation

Usually need TOF of 0-1 for deep block for surgery

TOFC 1---equal to 90-95% receptors blockade

For minimum requirements of return of muscles tone post-surgery ; 0.7 ie T4 to T1- 70%

Principal of use Each successive twitch height becomes lower as the Acetyl choline in the nerve terminal is depleted. After a pause of 30 seconds the Acetyl choline in the nerve terminal will have built up again Therefore ,the test can be repeated. As well as estimating the 'fade' of twitches in the 'Train of 4' it is also useful to simply count the twitches. Fewer stimuli make it across the neuromuscular junction as the block becomes deeper. For most general surgery a block down to 2 twitches is adequate. When only one twitch is visible the patient may still be able to move slightly. If you give relaxant until no twitches are visible you no longer whether you are giving a little bit to much or a lot too much. Deep block is consider as 0 or 1

Advantages

No need for baseline or refference response

Less painful than tetanus

Doesn't affect the level of blockade

Double burst stimulation Overview

nerve stimulus- 2 minitetanic burst of 50 hz separated by 750 msec each of the minitetatnic burst has duration of 2 msec and cotain 2-4 impulse

Double – 2 stimulus- Burst pie-O 50 hz- steamy sex 750 sec

Pattern of DBS fade between 2 contraction equivalent to TOF 0.6 absence of fade with DBS – clinically significant neuromuscular blockade

Advanatage can appreciate the fade with DBS easier than TOF

Fade in response to tetatnic stimulation indicate the presynaptic event This occur , when the start of tetanic stimulation there is burst of ACH release from the store of nerve terminal as the tetanic stimulation continue , the stores become depleted the rate of ACH release decreasing until the equilbirum between ACH synthesis and ACH release is achieved when , the number of free cholinergic receptor ( margin of safety of neuromuscular transmission ) is decrease by the non-depolarsing ,

with the decrease in number of ACH release occur during tetatnic stimulation , then fade occur

Post-tetanic count Overview

this method use during deep muscle relaxation of when TOF is 0 stimulus- it give 5 secs 50 hz tetanus stimulus followed after 3 secs with repetitive stimulus at frequency of 1 hz

Clinical uses use to estimate the time return of first twitch with TOF

Pattern if the PTC give 4 count with use of actracurium , then it show that the first TOF will appear in 4 minutes if the PTC give 4 count with use of pancuronium , then it estimate the first twitch will appear in 4 minutes if PTC give 1 count , then it indicate very deep block if PTC between 2- 8, it indicate moderately deep block if PTC more than 15 , it indicate the TOFC of 1 , then means 1 twitch ilicited with TOF for surgery , TOF count of 1 is adequate for surgery and it indicate there is 90-95% return of neuromuscular blockade

Clinical use of nerve stimulator time for PTC 1 to TOFC 1 for pancuronium 0.1 mg/kg is 37 minutes vecuronium 0.1 mg/kg 7-8 minutes atracurium 0.5 mg/kg 7- 8 minutes

for surgery need TOFC the reversal can be given when TOFC greater than 2 ( 2 thumb movement with TOF) with TOFC is 1 , reversal may take 30 minutes for long acting but 15 minutes for intermediate acting with TOFC of 0 , the block is not reversible with drugs with TOFC of 4, even the long acting take 10 minutes for reversal however , can still give reversal even if TOFC is 4 because respiratory muscle easily fatique

Q. Outline possible reasons for prolongation of paralysis imduced by an intravenous dose of 1 mg/kg of suxamethonium. Briefly indicate the consequences of such prolonged block.

Overview 1 mg/kg is normal intubating dose of suxamethonium Therefore , phase 11 block is unlikely Thus the factors that may prolongation the effect of suxamethonium is the abnormalities

in the metabolism of suxamethonium Suxamethonium is metabolised by pseudocholinesterase Therefore , the alteration in concentration and activity of the enzymes ----result--

prolongation of effect of suxamethonium

Acquired enzymes deficiencyOverview Causes Liver disease Pregnancy Drugs interaction

But However, the acquired enzymes defieciency is not often clinically significant causes

Inherited enzymes defieciency Overview Overview

dibucaine number, the percentage inhibition of plasma cholinesterase produced by a standard titre of dibucaine = 10-5 mmol/l

Function the degree of inhibition of hydrolysis by dibucaine allow one to differentiate between

normal patinet and patient with atypical pseudocholinesterase enzyme

Implication if abnormalities are found, the entire family should be tested

Mechanism Plasma of healthy that experienced prolonged response with suxamethonium

contained abnormal enzymes The atypical enzyme able to hydrolysis the test substance but unable to hydrolyse

suxamethonium Local anesthesia chichocaine ( dibucaine ) able to inhibit hydrolysis of benzocholine

Definition A test for differentiation of one of several forms of atypical pseudocholinesterases

that are unable to inactivate succinylcholine at normal rates; based on the percentage of inhibition of the enzymes by dibucaine,

Result normal enzyme has a DN of at least 75 and higher, heterozygous atypical enzyme has a DN of 40–70, homozygous atypical enzyme has a DN of less than 20

Pharmacodynamic drugs interactionOverview

hypokalemia hypermagnesemia hypothermia

? Drugs ? Mechanism of interaction

Clinical consequences 1. Continue ventilation 2. Closed observation 3. Monitoring of neuromuscular function 4. Possible treatment 5. Investigation of patients 6. Investigation for family7. Implication for future anesthesia

Q. Classify muscle relaxants.

Clinical classification drugsDepolarizing (non-competitive)

Succinylcholine

Nondepolarising (competitive)

Short acting Mivacurium

Intermediate acting AtracuriumRocoronium Vecuronium

Long acting Pancuronium

chemical classification aminosteroid Rocoronium

Vecuronium Pancuronium

benzylisoquinolone tubocurarineMivacurium Atracurium cistaracurium

quaternary amines gallamine

Q. Compare and contrast the depolarising and non-depolarising blockade Pharmacodynamic effect

Depolarizing muscle relaxant preceded by fasciculation in contrast with nondepolaring that has no muscles fasciculation

Monitoring Non-depolarising show fade, in contrast with depolarising that has no fade Non-depolarising show post-tetanic potentiation, in contrast with depolarising that has no post-tetanic

potentiation

Interaction with anticholinesterase Anticholinesterase augment the neuromuscular blockade produced by depolarising nruromuscular

blockade anticholinesterase compete with non-depolarising neuromuscular blockade for nicotinic receptors binding

site , thus terminating the neuromuscular blockade

Chemical structures This agents resembles ACH,

mechanism of action non-depolarising agent antagonise the depolarising block by combining with ach receptor and block the

depolarisation of the post-junctional membrane differ therefore, the non-depolarising antagonise the effect of depolarizing neuromuscular block this is diffrent with depolarizng block that produce block by causing prolong depolarizination of the post-

junctinal membrane

tachyplaxis depolarising blockade show tachyplaxis or decrease maximum response after successive doses of

suxamethonium , diffrent with non-depolarisng blockade in which the administration of drug lead to increase in duration of

action and prolonged the blockade

depolarising phase 11 block depolarising blockade with suxamethonium can produce phase 11 block with prolonged infusion, large

bolus of depolarising during these blockade the ion channel remain open for prolonged time the phase 11 block doesn’t occur with non-depolarising blockade

Q. Describe the reversal of neuromuscular blockade

Overview

NMBA are dangerous agents narrow drug safety margin residual effects of NMBA cause respiratory depression, morbidity & mortality significant inter-individual variability- ethnic, age, gender, disease states interaction between NMBA with other drugs The adequacy of reversal of block is assess clinically, tactile and visual , by mean of

nerve stimulator

Assessment of blockade by neuromuscular stimulator Neuromuscular stimulation of NMJ can be done by DBS or TOF double-burst stimulation is better than TOF DBS TOF

clinical assessment Assessment of maximal inspiratory pressure and airway reflex

Degree of residual blockade is assed by quantifying the maximal inpiratory pressure Assessment of maximal inspiratory pressure (MIP) has the following advantages, can be obtained in uncooperative patients quantitative assessment of respiratory muscle strength relatively unaffected by obstructive/restrictive lung disease gives an estimate of respiratory reserve Therefore ;if MIP > -25 cmH2O required for spontaneous ventilation

Airway protection these muscles of upper airway are more sensitive to blockade than the respiratory

muscles spontaneous ventilation, ability to swallow and protect the airway are usually present

at MIP > -45 cmH2O NB: following extubation, the patients ability to protect their airway should be

reassessed

Assessment on muscular strength a voluntary sustained head-lift > 5 seconds is most sensitive clinical test of reversal this correlates with a MIP > - 55 cmH2O

DBS clinically : the absence of fade on DBS usually means significant residual

neuromuscular blockade is absent

TOF serial of 4 successive twitches in 2 seconds

- 0.2 msec in duration each- 2 Hz

assess the ratio 1st & 4th responses: if the 4th (75%); 3rd (80%); 2nd (90%); 1st (>95%) NDMR - responses fade as relaxation increases TOF at least 0.9 – readiness for extubation

For reversal of neuromuyscular blockade atropine 0.01- 0.02 mg/kg with max 1.2 mg given , followed by neostigmine 0.03-

0.07 mg/kg after 5 minutes the reversal is given after 20-30 minutes after full intubating doses of relaxant the reversal given after: 1. efficinet tidal volume , return of cough reflex , absence of

tracheal tug , return of jaw tone , ability to protrude tongue , head lift for 5 seconds these correspond to 75% recovery from neuromuscular blockade TOFC of 4 – means recivery phase reversal of neuromuscular blockade need , TOFC of 2 or greater

pharmacology- muscle relaxant saq

Documents