2019B06 Propofol and remifentanil TCI are often given together as a TIVA technique.
Discuss pharmacological reasons why this is a useful combination.

 

List:

·     Summary

·     Drug effects

·     PD

·     PK

·     PC

·     Applications

 

Summary:

Pharmacodynamic (PD)

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

Pharmacokinetic (PK)

·   Ideal properties of each

·   No interference

·   Synergistic -> ↓dose -> ↓accumulation

Pharmaceutic (PC)

·   Compatible

 

Drug effects:

 

Propofol (PPF)

Remifentanil (RF)

Usual Cet

2-6mcg/mL

2-6ng/mL

Amnesia

Ce50 1-2mcg/mL

Unreliable even at high Ce

Hypnosis

Ce50 2-3mcg/mL

Immobility

Ce50 16mcg/mL (N.B. ↑↑)

No

Analgesia

No

Yes

CVS side effects

↓HR, ↓contractility, ↓SVR, ↓mAP

↓SNS output -> ↓HR/arrest, ↓SVR, ↓mAP

Resp side effects

↓RR, ↓TV

↓RR, ↓TV, chest wall rigidity

 

Pharmacodynamics:

Complementary

·   PPF: anaesthesia

·   RF: analgesia

Synergistic

·   Combined effect exceeds sum of individual effects

·   Represented by isobologram (or response surface)

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

Implications of synergism

·   ↓PPF Cp50 for hypnosis and immobility

·   ↓Ceγ -> ↓PPF Cp50 variability (?)

·   ↓PPF side effects

·   ↓Need for paralysis

 

Pharmacokinetics:

PPF ideal features

·   Rapid onset:

o Small

o High lipid solubility

o >99% unionized

o t1/2ke0 2.6 minutes

·   Rapid offset by distribution:

o ? due to similar factors

o t1/2α fast 2 mins

·   Rapid metabolism:

o Cl 30-60mL/kg/min

o Phase 1 (CYP) and phase 2

o No active metabolites

RF ideal features

·   Rapid onset:

o 20x more lipid soluble than morphine

o 68% unionized cf. morphine 23%

o t1/2ke0 1.4 mins (cf. morphine 7)

·   Rapid offset by metabolism:

o Cl 40mL/kg/min

o Non-specific esterases especially muscle

o Max context sensitive half time (CSHT) 10 mins

o No active metabolites

Lack of interference

·   No competition for plasma protein binding sites

o PPF albumin

o RF: AAG > albumin

·   No competition for metabolic pathways

o PPF liver CYP2B6/2C9/3A4

o RF non-specific esterases

·   No competition for excretion (renal for both)

Implications of synergism

·   ↓Ce for given clinical effect

·   ↓Infusion rate

·   ↓total dose

·   ↓compartmental concentrations

·   ↓time to emergence

 

Pharmaceutics:

Precipitation

No

Miscible

No (need separate syringes)

 

Indications for TIVA:

Medical

·   Malignant hyperthermia (absolute indication)

·   ↑ ICP (PPF decreases CMRO2 and CBF, but preserves coupling ratio)

·   PHx PONV (PPF 5HT3 antagonist hence antiemetic; cf. volatiles pro-emetic)

·   Avoid paralysis (e.g. muscular dystrophy (RF -> ETT tolerance)

·   Sinus surgery (PPF ↓mAP -> ↓bleeding)

Logistical

·   Airway surgery precluding volatile use (absolute indication)

·   Field anaesthesia

·   Transport

 

 

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