2000B16 Compare and contrast the pharmacology of atracurium and cisatracurium.

 

List:

·      PC

·      PK

·      PD

 

Physicochemical:

 

Atracurium

Cisatracurium

Molecule

Quaternary amine

4 chiral centres

10 stereoisomers (n2 = 16 but some identical)

15% cisatracurium = 50% activity

Quaternary amine

1Rcis-1R’cis stereoisomer of atracurium

R: stereochemistry of the benzyltetrahydroisoquinoline rings

Cis: geometry of the bulky methoxy at C1 and 2-alkylester at N1

 

Needs reconstitution

(i.e. easy use)

N

N

Needs refrigeration

Y 2-8°C

Y 2-8°C

Life at room temp (accept 90% potency)

3/12?

3/12?

Compatibility

No precipitation

pH 4

No precipitation

pH 4

 

Pharmacokinetics:

 

Atracurium

Cisatracurium

Admin:

 

 

ED95

0.25mg/kg

0.05mg/kg

Route

IV only

Same

Infusion rate

5-10mcg/kg/min

1-2mcg/kg/min

Time course:

 

 

-Onset 2x ED95

95% ↓twitch height

3 mins?

5 mins?

-Duration 2x ED95 (mins)

30-40mins

20-30mins

Absorption:

 

 

 

IV only

IV only

Distribution:

 

 

-VDSS

0.15L/kg

0.15L/kg

-%PPB

15

15

Metabolism:

 

 

-rate

Cl 5mL/kg/min

t1/2β 20 mins (faster offset after long infusion)

Cl 6mL/kg/min

t1/2β 30 mins

-Hoffman elimination

30%

80%

-Ester hydrolysis

60%

15%

-Active metabolites

Laudanosine: glycine antagonist -> seizure

Tiny amount in man

Renally cleared

Same

-↓temp

↓Ester hydrolysis

↓Hoffman elim

Same

-↓pH

↑Ester hydrolysis

↓Hoffman elim

(Less impairment)

Same

(more impairment)

-Liver failure

Minimal effect on parent (unlikely to ↓esterase level)

Same

-Age

Minimal effect on parent

Same

Excretion:

 

 

-% excreted unchanged

10%

5%

-Renal failure

Minimal effect on parent

Accumulate laudanosine (rarely significant)

Same

 

Pharmacodynamics:

 

Atracurium

Cisatracurium

Effects:

 

 

Action at NMJ type nAChR

Competitive antagonist

Competitive antagonist

Reversal by AChEi

Y

Y

Side effects:

 

 

-Histamine release -> bronchospasm, hypotension, rash

Y

↑Methoxy groups = ↑potency, ↓histamine release
(e.g. mivacurium 2, atracurium 4, doxacurium 6)

↓risk if slow injection

↓risk with repeat injection

Rare (↑potency -> ↓dose for 2xED95)

Factors prolonging effect

Phys: ↑Mg2+, ↓K+, ↓temp, resp acidosis

Pharm: e.g. volatile anaesthetic

Path: e.g. myasthaenia gravis

Same

 

 

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