Significance Of Pharmacokinetic Data For Practical

While terminal elimination half-life (t 1/26) is only a single variable based on the beta slope of only the decay curve of an agent, it does not take into account redistribution and compartment kinetics (Table III-6). Time course of anesthesia related to intravenous bolus use is far less than the time course for terminal halflife. One would expect effects and recovery within seconds and minutes not hours. Anesthesia intravenous bolus time frame is determined by redistribution and mixed kinetics phase. Therefore elimination half-life is irrelevant in discussing effects of i.v. boluses within anesthesia. In the literature, the guidelines doses for i.v. boluses are based on volumes of distribution, overdose limits, peak effect concentrations but not necessarily duration considerations. It is therefore necessary to balance between side effects of overdose and duration of desired effects to choose a bolus dose.

Table III-6. Classical phramacokinetics of different opioid agonists as they are often described in the literature

Opioid

Rapid

Slow

Elimination

distribution

distribution

half-time

half-time

half-time

(hours) t1/2ß

(mm) ti/2„

(min)

Morphine

1.2-25

9-13.3

7.2-22

Pethidine (meperidine)

4-17

?

3.2-7.9

Fentanyl

1.0-17

13-28

3.1-7.9

Alfentanil

1.4

17.7

2.7

Sufentanil

0.7-35

8.2-16.8

1.2-1.9

For example, why is alfentanil shorter acting and faster than fentanyl. Looking at traditional elimination half-life, one would explain this phenomenon by stating that this was due to alfentanil's shorter elimination half-life. Not so! Notice alfentanil and fentanyl's decay curves are almost identical until after 90min. But we are explaining phenomena within the 3-10 min range. The fact is that alfentanil peaks earlier at a higher percentage of the initial plasma concentration Cp. Alfentanil effect is more rapid due to its smaller volume of distribution and rapid uptake into the effect compartment. Therefore, the clinician needs relatively less drug to get the same effect.

Therefore, the clinician underdoses alfentanil relative to fentanyl and sufentanil to get the same effect, and its duration of effect is shorter since less drug needs a shorter time decay to achieve subapnea levels. This shows that elimination half-life is a poor predictor of describing drug disposition in time frames relevant to anesthesia where redistribution and mixed kinetics are more relevant. Alfentanil's rapid onset and shorter duration of effect is due to distribution kinetics and not due to elimination kinetics only. When using a bolus dose of an agent, three different scenarios can be created:

1. Only one huge dose is given in order to cover the projected procedure time. This necessitates a very large initial overdose, creating both a prolonged elimination and recovery time.

2. A single bolus for rapid short-term effect is given, which rapidly redistributes and falls below the therapeutic target window allowing quick recovery.

3. Repeated boluses are given to maintain an effect-site concentration within the therapeutic window frame, however, creating a seesaw effect with repeated boluses with possible subsequent build-up of the drug and a prolongation of effects.

Since the key points of any injection is that the effect-site concentration, and not the plasma concentration, determines drug effect. Since a three-compartment model best describes most intravenous drugs, the terminal elimination half-life is not the basis for comparing durations of effect of i.v. boluses, especially since i.v. boluses balance overdose with duration.

Table III-7. Approximate opioid loading doses (bolus) and maintenance infusion rates for total intravenous anesthesia (TIVA)

Drug

Loading dose (|g/kg)

Maintenance dose (| g/kg/min)

Alfentanil

50-150

0.5-1.0

Fentanyl

5-15

0.33-0.1

Sufentanil

1-3

0.01-0.05

Remifentanil

0.5-1.0

0.1-0.4

Ketamine

1500-2500

25-75

Propofol

1000-2000

50-150

Mivacron

50-150

0.25-1.5

Methohexital

1500-2500

50-150

Adapted from [79]

Adapted from [79]

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