18A05: Exam Report

Compare and contrast the pharmacokinetic and pharmacodynamics of IV fentanyl and IV remifentanil (60 marks). Discuss the concept of context sensitive half-time using these drugs as examples (40 marks)

66% of candidates passed this question.

Well-constructed answers were presented in a table to compare pharmacokinetics and pharmacodynamics with a separate paragraph to discuss the concept of context sensitive half-time. Important pharmacokinetic points included: the differences in lipid solubility, ionised fractions and onset, and differences in metabolism. Marks were awarded for a definition of context-sensitive half-time. A discussion of these two drugs’ context-sensitive half-times should have included the differences in re-distribution into other compartments and rates of elimination.

Bvi / 18A05: Compare and contrast the pharmacokinetic and pharmacodynamics of IV fentanyl and IV remifentanil (60 marks). Discuss the concept of context sensitive half-time using these drugs as examples (40 marks)

Remifentanil

Fentanyl

Chemical

Remifentanil

Rapid onset, ultrashort acting
Synthetic selective µ agonist of PHENYLPERIDINE CLASS

Fentanyl

Synthetic opioid of PHENYLPIPERIDINE CLASS

Rapid acting, intermediate duration

PD

Remifentanil

CNS – analgesia no effect on ICP/IOP

CVS – ↓HR, ↓BP

MSK – muscle rigidity at high dose

Immuno – no histamine release

Resp – potent resp depression

Fentanyl

CNS – Analgesia

CVS – ↓HR more common cf. M

RESP – respiratory depression  most marked of all opioids. POTENT ANTITUSSIVE & chest wall rigidity

GI – less N&V

IMMUNO –histamine release

PK

Remifentanil

A

IV administration only.  100% bioavailability

D

VD 0.4L/kg

Very small

Low lipid solubility

PPB 70%

M

Rapid ester hydrolysis

Non-specific plasma & tissue esterases

Into remifentanil acid x 5000 less potent cf. remi

E

Inactive metabolites

Renally excreted

Fentanyl

A

IV.  100% bioavailability

D

4L/kg

Larger cf. Remi

↑lipid solubility = rapid & extensive tissue penetration

PPB 80%

Tissue affinities

  • Lungs → large, inactive storage site; 75% dose = pulmonary uptake

Fat & skeletal m. → redistribution sites

M

Liver

N-Demethylation

  • To norfentanyl
  • Less potent cf. F

High HER

∴depends on HBF

E

Norfentanyl excreted by kidneys

10% unchanged

(Given in renal failure as metabolites are not pharmacologically active)

Context Sensitive Half Time

CSHT = the time taken for plasma [  ] to fall 50% following cessation of a drug infusion of specific duration

  • “Context” refers to the duration
  • Based on a multi-compartment model
  • DETERMINANTS
    • Duration of infusion
    • Distribution to + from central/peripheral compartments
    • Clearance
  • Distinct from elimination half-life of a drug
  • Elim t ½ = time taken for plasma [ ] of drug to fall by 50% during the elimination phase
    • After a single bolus
    • Based on Single Compartment Model

DETERMINANT: Clearance

\(  \textbf{t ½ = }  \frac{\text{ VD x 0.693}}{\text{Clearance}}  \)

 

When SS is reached → CSHT = Elim t ½

@ SS; C5HT = Elim t ½

→ Otherwise CSHT is always less owing to redistribution (because it’s cleared & redistributed from central compartment)

CSHT of Remi v CSHT of Fentanyl

Remifentanil

Fentanyl

Cl

Remifentanil

High, Instant clearance

40 – 60ml/kg/min

Fentanyl

15mL/kg/min

VD

Remifentanil

0.4L/kg

Fentanyl

4L/kg

Elim t ½

Remifentanil

3 mins

Fentanyl

250 mins (6hr)

300 mins (9hr)

CSHT

Remifentanil

0.1 hrs – regardless of infusion duration

Fentanyl

5 hrs

Comments

Remifentanil

Remi has low lipid solubility + Low VD ∴ rapidly equilibrates with peripheral tissue → rapidly metabolised

Fentanyl

F = highly lipid soluble

∴rapid onset + large VD → basic drug, sequestered to pulmonary circulation

∴long CSHT

As duration of infusion exceeds 2hrs, it saturates the ‘inactive sites’(lungs, fat, skeletal m)

So when an infusion is terminated, the plasma [  ] cannot ↓ by redistributing to these sites

→ for plasma F to ↓ it must be eliminated by hepatic metabolism