2015A05 Sevoflurane and fentanyl are a common anaesthetic drug combination.
Discuss pharmacological reasons why it is useful to use them together.

 

List:

·      Summary

·      Drug effects

·      PD

·      PK

·      PC

 

Summary:

Pharmacodynamic (PD)

Complementary and synergistic -> ↓dose -> ↓side effects

Pharmacokinetic (PK)

Synergy -> ↓dose -> ↓accumulation

No interference

Pharmaceutics (PC)

No incompatibility

 

Drug effects:

 

Sevoflurane (SF)

Fentanyl (F)

Amnesia

MAC 0.25

Unreliable even at high Ce

Hypnosis

MAC 0.3

Immobility

MAC 1

No

Analgesia

No

Yes

CVS side effects

↓HR, ↓contractility, ↓SVR, ↓mAP

↓SNS output -> ↓HR, ↓SVR, ↓mAP

Resp side effects

↓RR, ↓TV

↓RR, ↓TV

Other

PONV

↑Uterine blood flow +/- PPH

↑Cerebral blood flow +/- ICP

PONV

Sedation

 

Pharmacodynamics:

Complementary

·   SF: anaesthesia

·   F: analgesia

Synergistic

·   Combined effect exceeds sum of individual effects

·   Represented by isobologram (or response surface)

·   Mechanism: ? F reduces nociceptive activation of ascending reticular activating system (ARAS)

Implications of synergism

·   ↓SF % for hypnosis and immobility

·   ↓MAC standard deviation -> ↓variability

·   ↓SF side effects

·   ↓Need for paralysis

Quantification of interaction

 

SF alone

SF + F 3ng/mL

MACBAR

4.15%

↓80%

MAC

1.85%

↓60%

MACawake

0.6%

↓25%

Standard deviation

0.1MAC

<0.1MAC (not from this stud

https://www.ncbi.nlm.nih.gov/pubmed/9447851

https://www.ncbi.nlm.nih.gov/pubmed/?term=fentanyl+sevoflurane+somatic+1999

 

 

Pharmacokinetics:

Lack of interference

·   Plasma protein binding sites:

o Fentanyl to AAG > albumin

o Sevoflurane uptake to proteins, lipids, RBCs

·   Metabolism:

o SF -> liver CYP2E1 (only 2-5%)

o F -> liver CYP3A4 (almost 100%)

·   Excretion:

o SF via lungs

o F metabolites via urine

Implications of synergism

·   For a given desired effect, ↓[SF] and ↓[F]

·   ↓compartmental concentrations

·   ↓total dose, ↓accumulation

·   ↓time to emergence (since MAC awake less affected)

 

Pharmaceutics:

Compatibility

None: F intravenous, SF inhaled

Efficiency

Synergism -> ↓total dose -> ↓cost

 

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