L2i: Pharmacology of NDMR
Pharmaceutics
Atracurium
Cisatracurium
Pancuronium
Vecuronium
Rocuronium
Use
Atracurium
Cisatracurium
Pancuronium
Vecuronium
Rocuronium
Paralysis
Chemical
Atracurium
Benzylisoquinolinium
Cisatracurium
Benzylisoquinolinium
Cis-cis isomer of atracurium
4xpotent
so given at smaller dose & onset is longer
Pancuronium
Vecuronium
Rocuronium
Aminosteroid
Roc is x8 less potent than Vec
Can be given at much higher dose
Presentation
Atracurium
Clear, colourless, 10mg/ml
Fridge
Cisatracurium
Clear, colourless,
5mg/ml
Fridge
Pancuronium
Clear, colourless, 2mg/ml
Fridge
Vecuronium
Powder
Diluted w water
Room temp
Rocuronium
Clear, colourless, 10mg/ml
Fridge 4C
Dose
Atracurium
0.6mg/kg
Cisatracurium
0.15mg/kg
Pancuronium
0.1mg/kg
Vecuronium
0.1mg/kg
Rocuronium
0.6mg/kg
1.2mg/kg RSI
Onset
Atracurium
2mins
Cisatracurium
2mins
Pancuronium
3-6min
Vecuronium
2mins
Rocuronium
60 sec RSI
Offset
Atracurium
Intermediate
Cisatracurium
Intermediate
Pancuronium
Long > 50min
Vecuronium
Intermediate
Rocuronium
Intermediate
Pharmacodynamics
Atracurium
Cisatracurium
Pancuronium
Vecuronium
Rocuronium
MoA
Atracurium
Cisatracurium
Pancuronium
Post-junctional competitive inhibition nAChR
Vecuronium
Rocuronium
Pre & post –junctional inhibition of nAChR
CVS
Atracurium
Cisatracurium
Pancuronium
No histamine
Direct vagolytic effect
Sympathomimetic – NA release
↑HR, CO, BP
Vecuronium
No histamine
No CVS effect
Rocuronium
Mild vagolysis
Resp
Atracurium
Cisatracurium
Pancuronium
Vecuronium
Rocuronium
Apnoea
Pharmacokinetics
Atracurium
Cisatracurium
Pancuronium
Vecuronium
Rocuronium
D
Atracurium
82%PPB
Cisatracurium
Small
Large MW
V polar
Pancuronium
30% PPB
Vd 0.15L/kg
Vecuronium
90% PPB
Rocuronium
30% PPB
Vd 0.27L/kg
M
Atracurium
Hoffman degradation & ester hydrolysis
Cisatracurium
Hoffman degradation
Pancuronium
30% hepatic metabolism
Vecuronium
Liver deacetylation, active metabolites
Rocuronium
No metabolites
E
Atracurium
Cisatracurium
Metabolites in urine & feces
Pancuronium
40% unchanged in urine
prolonged w renal impairment
Vecuronium
20% unchanged urine
25% unchanged bile
prolonged w renal impairment
Rocuronium
40% unchanged bile
35% unchanged urine
A/E
Atracurium
Histamine release
Cisatracurium
Hypotension
Pancuronium
Vecuronium
Rocuronium
Anaphylaxis
Structure
- All NDMR are quaternary ammonium compounds
- All structurally related to ACh which has quaternary nitrogen group (N+(CH3)3)
- The positive Nitrogen atom of NDMR is attracted to the a-subunit of nAChR
- 2 quaternary ammoniums (bisquaternary) are more powerful than monoquaternary;
- Bis – Succinylcholine, pancuronium, atracurium
- Mono – Rocuronium, vecuronium
- Monoquaternary have one quaternary cation + one tertiary amine
- If pH becomes acidic, the tertiary amine can become protonated ∴ +vely charged
- This ↑potency of monoquaternary NDMR in acidic conditions
MoA
Competitive antagonism of nAChR
Dynamic binding – repeated association & deassociation
Block causes gradual decline in EPP until it fails to reach threshold
To produce complete block requires 92% receptor occupancy
Some NDMR also block pre-junctional nAChR → these receptors act in +ve fdbk to increase ACh release during high frequency stimulation
Classification
Benzylisoquinolinium
Atracurium
Mivacurium
Cisatracurium
2 quaternary ammonium groups joined by thin methyl chain
More likely to release histamine
Methyl chain contains >1 chiral atom → stereoisomers of drug
Aminosteroid
Rocuronium
Pancuronium
Vecuronium
Require organ function for elimination