Liver
8.4 Loading doses
8.4.1 Loading dose where drugs are treated as occupying one compartment
In Figure 8.3, the useful therapeutic range of a drug is between 3 and 5 mg/L and this is indicated by shading. Concentrations below or above this range are likely to be either ineffective or toxic respectively. With a simple infusion (indicated as ‘No loading dose’) the patient will achieve an inadequate therapeutic effect for approximately the first six hours of treatment.
With some drugs this might be tolerable. However, with an anti-asthmatic drug such as theophylline (which may be given by infusion) we certainly could not leave the patient unable to breathe properly for such a long time.
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Pharmacokinetics Constant intravenous infusion
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
0 10 20 30 40 50 60
No loading dose With loading dose
Time (h)
Conc(mg/L)
Ineffective up to this time
Figure 8.3 The purpose of supplementing an infusion with a loading dose
The solution to this problem is to precede the infusion with a ‘Loading dose’. This is a single i.v. bolus dose calculated to bring blood levels immediately into the therapeutic range and then the infusion acts to maintain those levels. This is shown in the upper trace labelled ‘With loading dose’.
‘Loading doses’ are used to achieve effective blood levels of drug rapidly, without having to wait for the drug to accumulate.
We have already seen the simple, general relationship:
Concentration = Dose / V This can be re-arranged to:
D = C x V
A loading dose (LD) is just a specific example of a dose and there is a target concentration we wish to achieve, so:
LD = Target x V.
For an i.v. infusion, bioavailability is not an issue; F is automatically equal to 1.0. However, we will meet loading doses in other settings, where drugs are administered orally and then F does have to be incorporated. To avoid having two separate equations for loading dose, we will include F, but remember that for i.v. infusion this simply takes the value 1.0.
The general equation is:
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Pharmacokinetics Constant intravenous infusion
LD = Target x V / F
The other potential complication is that the drug may be given as a salt (e.g. theophylline administered as aminophylline), in which case the salt factor must also be included:
LD = Target x V / (F x S) 8.4.2 An example
A patient weighs 60Kg and is to receive a loading dose plus infusion of aminophylline. The target concentration range for theophylline is 10-20mg/L. Aminophylline contains 70% (w/w) of theophylline. The population mean volume of distribution and clearance of theophylline are 0.48L/Kg and 0.04L/h/Kg respectively.
Target = midrange = 15mg/L V = 0.48L/Kg x 60Kg = 28.8L
Cl = 0.04L/h/Kg x 60Kg = 2.4L/h
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Pharmacokinetics Constant intravenous infusion
LD = Target x V / (F x S)
= 15mg/L x 28.8L / (1.0 x 0.7) = 617mg
Css = Rinf / Cl
Rinf (theophylline) = Css x Cl = 15mg/L x 2.4L/h = 36mg/h
Rinf (aminophylline) = 36mg/h / S = 36mg/h / 0.7 = 51mg/h
8.4.3 Loading dose where we have to recognize two compartments
The method of calculation of a loading dose shown above, works fine if the drug can be considered as occupying one compartment. However, some drugs have to be recognized as occupying two compartments and then there is a potential problem. Figure 8.4 shows the situation. Both the loading dose and the continuing infusion act as inputs.
Pharmacokinetics Constant intravenous infusion
LD Rinf
V
1V
2Eliminated
Figure 8.4 Infusion accompanied by a loading dose with a two compartment system.
The formula for calculating a loading dose takes account of the volume of distribution. But that raises the question, which volume? Should we use just V1 or the complete volume of the system Vss (i.e. V1 + V2)?
If we use the total, V1 + V2, we will arrive at a dose large enough to raise the concentration of the whole system to the target concentration. However, that dose will initially find itself constrained within just V1 and therefore the initial concentration will be much higher than the target. The loading dose will eventually redistribute throughout the complete volume and drug concentrations will decline. Whether the initially high levels are a real problem depends upon how quickly the loading dose disperses and the potential of the drug to cause toxicity over the period prior to re-equilibration.
For some drugs such as lidocaine, the problem is perfectly real and a loading dose calculated using the complete volume of the system would risk toxicity.
If alternatively, we calculate the loading dose using just V1, then the initial concentration in the first compartment (including blood levels) should match the target concentration. This is shown in Figure 8.5, where it is assumed that the target concentration is 4mg/L and that the shaded area (3-5mg/L) is the acceptable concentration range. Immediately after the injection, there will be a marked disequilibrium, with the whole dose in the first compartment and drug will move out of the first into the second compartment. This will cause the drop in concentrations shown in the early part of the graph.
After a while enough drug will have moved over to the second compartment to achieve an equilibrium. Distributional loss of drug from the first compartment will then cease and the infusion will be able to return the concentration to Css.
Pharmacokinetics Constant intravenous infusion
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
0 10 20 30 40
Conc (Plus LD) Conc (No LD)
Time (h)
Conc(mg/L)
Rapid loss to second compartment
Second compartment
equilibrated
Figure 8.5 A loading dose calculated to provide enough drug to raise the concentration in the first compartment to the target level.
This approach may therefore lead to a temporary loss of adequate drug effect. If it is likely that this would cause real clinical problems, then there are two possible approaches:
- Give a small, additional loading dose a short time into the infusion when the dip in concentrations is anticipated.
- Use a rate of infusion higher than would generally be required during the period when the dip would otherwise occur and then revert to the normal rate for the rest of the infusion.