2019B Question 06
Propofol and remifentanil TCI are often given together as a TIVA technique. Discuss pharmacological reasons why this is a useful combination.
Examiner Report
91.1 % of candidates achieved a pass in this question.
In order to pass, an answer needed to convey an understanding of the pharmacodynamic and pharmacokinetic principles that support propofol and remifentanil as a useful combination for total intravenous anaesthesia.
When discussing pharmacodynamics, some idea of clinically appropriate plasma and effect site concentrations and how remifentanil reduced that of propofol was valuable. Good answers acknowledged important side effects of each drug and discussed how the combination of these two drugs might minimise these.
Pharmacokinetics can be split into two parts; the general kinetics of the drugs (with an emphasis on synergism and onset and offset profile) and the advantages that a target controlled infusion might provide. Lists of pharmacokinetic values for half life, Keo, volume of distribution, pKa, ionised fractions etc without explaining their relevance did not attract marks.
With regard to pharmaceutics, the only point of note is that remifentanil and propofol are compatible and do not precipitate.
Pharmacologic principles that explained application of this combination to specific indications also distinguished some answers.
Model Answer
Structure:
- Summary
- Drug effects
- PD
- PK
- PC
- Applications
Summary
| Factor | Details |
|---|---|
| Pharmacodynamic | - Complementary and synergistic → ↓ Dose → ↓ Side effects |
| Pharmacokinetic | - Ideal properties of each - No interference - Synergistic → ↓ Dose → ↓ Accumulation |
| Pharmaceutic | - Compatible |
Drug Effects
| Propofol (PPF) | Remifentanil (RF) | |
|---|---|---|
| Usual Cet | 2-6μg/mL | 2-6ng.mL-1 |
| Amnesia | Ce50 1-2μg/mL | Unreliable even at high Ce |
| Hypnosis | Ce50 2-3μg/mL | |
| Immobility | Ce50 16μg.mL-1(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
| Factor | Details |
|---|---|
| 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
| Factor | Details |
|---|---|
| PPF Ideal Features | - Rapid onset: - Small - High lipid solubility - >99% unionized - t1/2ke0 2.6 minutes - Rapid offset by distribution: - ?Due to similar factors - t1/2α fast 2 mins - Rapid metabolism: - Cl 30-60mL.kg-1.min-1 - Phase 1 (CYP) and phase 2 - No active metabolites |
| RF Ideal Features | - Rapid onset: - 20x more lipid soluble than morphine - 68% unionized cf. morphine 23% - t1/2ke0 1.4 mins (cf. morphine 7) - Rapid offset by metabolism: - Cl 40mL.kg-1.min-1 - Non-specific esterases especially muscle - Max context sensitive half time (CSHT) 10 mins - No active metabolites |
| Lack of interference | - No competition for plasma protein binding sites - PPF albumin - RF: AAG > albumin - No competition for metabolic pathways - PPF liver CYP2B6/2C9/3A4 - 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
| Factor | Details |
|---|---|
| Precipitation | Yes |
| Miscible | No |
Indications for TIVA
| Factor | Details |
|---|---|
| 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 |