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

Reliable

Unreliable

Hypnosis

Reliable (Cpt 2.7mcg/mL)

Unreliable

Immobility

Unreliable (Cp50 15mcg/mL)

Variable

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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