pharmacology- muscle relaxant saq

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Q. Compare and contrast atracurium and cisatracurium atracurium cisatracurium

y y

Intermediate acting non-depolarizing muscle relaxant intermediate acting non-depolarising agent from the Bissquaternary benzylisoquinolone

y y

intermediate acting non-depolarizing muscle relaxant intermediate acting non-depolarising agent from the benzylquinolone group

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

presentation y pale y yellow y greenish solution y PYG additive y no antimicrobial preservative

pH of solution y solubilized in benzenesulfonic acid

y

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

structure activity relationship

y y y

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

y y y

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

cis- atracurium 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 onset 3-5 slow onset 3- 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

y y y

y y y

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

y

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

y

y

Rapidly broken by spontaneous chemical reaction ie hoffman elimination

y y

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

y

y

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

5.5 ml/kg/min organ independence clearance

Organ independence clearance non-plasma esterases doesnt involve Therefore can be administered in renal and hepatic dysfunction Therefore can be administered in renal and hepatic dysfunction

Absence of cumulative effect Thus , good as infusion

Absence of cumulative effect Thus , good as infusion

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 Excretion 10% excreted unchanged in urine NS in bile

22- 30 min 25 min 21

5% ( broken down to tertiary amine laudanosine Biologicall metabolism >monoquartenary alcohol and monoquartenary acid

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.

y

y

y

y

y

y

y y

y y

y

Metabolites: laudanosine Metabolites not active at NMJ

Metabolites : alcohol and quartenary monoester are inactive at NMJ

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

5.5

Organ independence clearance

clearance dependence on plasma hydrolysis

Therefore can be administered in renal and hepatic dysfunction Absence of cumulative effect Thus , good as infusion Elimination

Not dependent on renal function Not dependent on liver function

unknown

Elimination half life

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

1-3 min Unknown Unknown

Excretion 10% excreted unchanged in urine NS in bile 5% ( histamine release Decrease blood pressure by 13-18% More pronounced effect on hypertensive patient Uncommon = 1/1,000 and < 1/100 (=0.1% and broken down to tertiary amine laudanosine Biologicall metabolism >monoquartenary alcohol and monoquartenary acid

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 metabolites activity Metabolites: laudanosine Metabolites not active at NMJ

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

4.0 ml/min/kg

Organ independence clearance

clearance dependence on renal function and hepatic function

Therefore can be administered in renal and hepatic dysfunction Absence of cumulative effect Thus , good as infusion Elimination

Not dependent on renal function Not dependent on liver function

Dependent on renal function Dependent on liver function

Elimination half life

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

87 Moderately prolonged in renal failure 97

Moderately prolonged in liver failure 97

Excretion 10% excreted unchanged in urine NS in bile Animal studies : > 50% excreted unchanged in bile Renal excretion may be more than 30% 10-25% excreted unchanged in urine 50-70 % excreted unchanged in bile

Effect of renal disease No effect on elimination Prolonged DOA Renal excretion > 30 % in 24 hours

Efffct of hepatic disease total bilairy obstruction , cirrhosis No effect on elimination Increased in Vd> longer DOA especially wirh repeated dose or prolonged IV

CVS effect

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

No histamine induced CVS effect even with rapid, large dose May produce slight vagolytic effect that is not occur with other aminosteroid

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

rocoronium is useful in procedure that associated with vagal stimulation

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 Respiratory effect

Bronchospasm y Histamine induce CVS effect

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 Atracurium m

Rocoroni um

Cistaracuri um

Vecuronium

Pancuroniu m

Dose

Minimal CVS effect at 2 x ED95 3 x ED95 over 1015 seconds > histamine release

2 x ED95 during nitrous oxide/fentany l and isoflurane No histamine induce CVS effect even with rapid administration 3 x ED95 with presence of nitrous/fenta nyl increase the heart rate and decrease MAP

No histamine induced CVS effect even with rapid, large dose

No histamine induced CVS effect with rapi