24A09: Exam Report
(a) Describe the pharmacokinetics of intravenous fentanyl and intravenous remifentanil (40% of marks). (b) Explain how these features create contrasts between the two drugs (20% of marks). (c) Discuss the concept of context sensitive half-time using these drugs as examples (40% of marks).
31% of candidates passed this question.
This question is essentially a compare and contrast question.
It was worded specifically to encourage candidates to describe the pharmacokinetics of the drugs in question (in particular the relative lipid solubilities, volume of distribution, pka / ionisation, plasma protein binding, and metabolism) and then use these features to discuss the clinically relevant implications.
In part (c) a brief definition of what is meant by the context sensitive half time followed by how these pharmacokinetic differences influence the CSHT of each was required.
K4ii / 24A09: (a) Describe the pharmacokinetics of intravenous fentanyl and intravenous remifentanil (40% of marks).
(a) Describe the pharmacokinetics of intravenous fentanyl and intravenous remifentanil (40% of marks).
ADME - Distribution
Pharmacokinetic Parameter
Fentanyl
Remifentanil
Vdss (L/kg)
4
0.3
Vdc (L/kg)
0.4-1
.06-0.08
Relative lipid solubility (morphine = 1)
600x
20x
Protein binding
84%
70-80% (a1 acid glycoprotein)
pKa
8.4 (<10% unionized at pH 7.4)
7.1 (67% unionized at pH 7.4)
ADME - Metabolism
Pharmacokinetic Parameter
Fentanyl
Remifentanil
Metabolism mechanism(s)
- Hepatic CYP3A4 via demethylation into norfentanyl, which is inactive
- Lung via 1st pass pulmonary endothelial uptake
- Non-specific plasma and tissue esterases via ester hydrolysis to carboxylic acid metabolite (GI90291 – clinically negligible effect/inactive)
- Tissue esterases are located primarily in muscle and intestines, with the lungs, liver, kidneys, and blood each contributing minimally to the clearance of remifentanil
ADME - Elimination
Pharmacokinetic Parameter
Fentanyl
Remifentanil
Elimination Mechanism
- Renal elimination of norfentanyl
- 10% eliminated unchanged in urine
- Renal elimination of GI90291
T1/2a (minutes)
1-2
0.5-1.5
T1/2b (minutes)
190
10
Protein binding
84%
70-80% (a1 acid glycoprotein)
Clearance (mL/kg/min)
13
40
Remifentanil’s clearance is several times more rapid than normal hepatic blood flow, consistent with widespread extrahepatic metabolism
ADME - Times
Pharmacokinetic Parameter
Fentanyl
Remifentanil
Onset (seconds)
< 30
< 20
Peak effect (minutes)
3.6
(t½ke0 = 4.7 minutes)
1.6
(t½ke0 = 1.3 minutes) 0.5-1.5
Duration
- Variable
- Context-sensitive – dose and duration (see below)
- Largely independent of duration of infusion
- Context-insensitive
- Determined by metabolism NOT redistribution
- (see below)
(b) Explain how these features create contrasts between the two drugs (20% of marks).
Time to peak effect and clinical onset
- Remifentanil t½ke0 3 minutes → peak effect 1.6 minutes
- Fentanyl t½ke0 7 minutes → peak effect 3.6 minutes
- A remifentanil infusion is therefore more titratable and new steady-state effect site concentrations occur within 5 minutes after changes in infusion rate
- Determinants of t½ke0:
- pKa
- Lower pKa → more unionized → faster equilibration
- pKa remifentanil = 7.1; pKa fentanyl = 8.4
- Protein binding
- Higher protein binding → slower equilibration
- Fentanyl protein binding = 84%; Remifentanil protein binding 70%
- Lipid solubility
- Higher lipid solubility → faster equilibration
- Fentanyl lipid solubility >>>> Remifentanil but offset due to effects above
- pKa
Time to offset and administration techniques
- Remifentanil is rapidly cleared by non-specific esterases, with a clearance of 40mL/kg/min and t1/2b of ~10 minutes. Thus remifentanil requires a continuous infusion to maintain clinical effect.
- Fentanyl’s time to offset is dependent on duration of infusion (see below on context-sensitive half time) and whether or not a bolus dose was given. These characteristics can be exploited and thus intermittent doses and/or PCAs may be appropriate.
Context-sensitive half time – See below part (c)
- In brief, remifentanil is context-insensitive and recovery of effect is independent of duration of drug administration, due to its rapid elimination processes.
- This is in contrast to fentanyl’s duration of effect which is context-sensitive and is very much dependent on the duration of infusion. This is due to its slow elimination processes, low tissue metabolism, high lipid solubility, and high volume of distribution
Organ independent metabolism
- Remifentanil is cleared by organ-independent processes via non-specific esterases
- Fentanyl is metabolised by both the liver. Thus severe hepatic dysfunction can be assumed to reduce the clearance of fentanyl
(c) Discuss the concept of context-sensitive half-time using these drugs as examples (40% of marks).
- Terminal elimination half-life does not accurately predict time to clinical offset of a drug
- For drugs described by single compartment models, context-sensitive half time is the same as the half-life and the duration of infusion is irrelevant.
- Context-sensitive half times properly incorporate the multicompartmental behaviour of intravenous anaesthetics, and more accurately predict clinical drug offset times
Context-sensitive half-time (CSHT)
“The time required for the plasma drug concentration to decrease by 50% after the cessation of an infusion that maintains a constant plasma concentration (ie at steady state). The “context” is the duration of infusion”
Determinants of CSHT using fentanyl and remifentanil to illustrate
CSHT Determinant - Distribution and redistribution (K12 and K21)
Factors that determine
How determinant changes CSHT
Fentanyl vs Remifentanil
Lipid solubility (major factor)
Increase distribution to peripheral compartment → increasing CSHT
Fentanyl is more lipid soluble, thus increased distribution to peripheral compartments and increased CSHT (relative lipid solubilities 600 vs 20)
Protein binding
High (tissue) protein binding → increase CSHT
Fentanyl 84% vs remifentanil 70%
Ratio of distribution : redistribution
k12:k21 >>>> 1 → CSHT increases
k12:k21 <<<< 1 → CSHT decreases
Fentanyl has increased k12 compared to remifentanil mainly due to fentanyl’s high lipid solubility.
Also, more tissue binding of fentanyl reduces k21 (Thus k12:k21>>1) → slower redistribution from peripheral to central compartment → increased CSHT
CSHT Determinant - Clearance K10
Factors that determine
How determinant changes CSHT
Fentanyl vs Remifentanil
Organ-dependent clearance of drug
Ie hepatic and pulmonary endothelial
Low clearance rate → increased CSHT
Hepatic demethylation and lung endothelial uptake for fentanyl. Fentanyl has negligible peripheral tissue metabolism.
VS
—
—
Organ-independent and widespread clearance
Ie non-specific esterases
Low tissue metabolism → increased CSHT
Widespread non-specific esterases for remifentanil, which are present in peripheral tissues
Fentanyl clearance (13mL/kg/min) is much less than remifentanil (40mL/kg/min)
CSHT Determinant - Volume & Time
Factors that determine
How determinant changes CSHT
Fentanyl vs Remifentanil
Volume – Vdss
- Increased Vdss → increased CSHT
- Increased Vdss acts as a peripheral drug volume reservoir which slowly redistributes back into the central compartment, maintaining the drug plasma concentration
- Note: Vdss only really important for drugs with low clearance from the central compartment ie fentanyl
- Fentanyl has huge Vdss (4L/kg). With its slow clearance from the central compartment, this contributes to fentanyl’s long CSHT.
- Even though remifentanil’s Vdss is significantly much smaller (0.3L/kg), it doesn’t impact remifentanil’s CSHT anyway due to its rapid clearance from the central compartment
Time
Increased infusion times → increased CSHT
Increasing infusion times will have MUCH MORE of an affect on fentanyl’s CSHT due to the above factors
As shown in the above figure, remifentanil’s context-insensitivity maintains a relatively unchanged CSHT, even with increasing infusion times. This is in contrast to fentanyl, which is very context-sensitive and has a rapidly increasing CSHT with increasing infusion times.
Author: Andrew Yates