Describe the calculations involved in determining the loading dose and maintenance dose for an intravenous infusion (50% of marks). What factors may affect these values in the critically ill (50% of marks)?

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College Answer

Main points for a pass included the equations for determining the loading and maintenance doses. Points were awarded for explaining the rationale for giving a loading dose and for relevant diagrams. Answers to the second part of the question often lacked detail. Candidates should have mentioned alterations in volume of distribution, plasma proteins, renal & hepatic function. Examples of drugs illustrating an understanding of pharmacokinetics attracted extra marks.
Syllabus II 2 f
Reference: Rang Ritter Dale p120-123

Discussion

For IV drugs given by infusion,

  • Dose rate (mg/hr) = dose (mg) divided by dosing interval (hrs)
  • Maintenance dose rate (mg/hr) = desired peak concentration (mg/L) × clearance (L/hr)
  • Loading dose = desired peak concentration (mg/L) × volume of distribution (L)

For drugs not given IV, these doses need to be divided by the bioavailability.

The rationale for giving a loading dose is to achieve steady state sooner than would otherwise be achievable with continuous infusion or intermittent dosing. The counter-argument is that this is not always practical, wg. with drugs which have extremely large volumes of distribution (and which would require absurdly large loading doses).

A "relevant diagram" would probably a fusion of different concentration/time diagrams, and would closely resemble that which is offered in Birkett et al (2009). Here is that diagram, reproduced with zero modifications and with no permission whatsoever:

Birkett et al infusion maintenance and loading dose

The graph represents a drug being given intermittently (b), with the dosing rate equal to the half-life of the drug. There is also the same dose rate given as infusion (a) with the hourly dose rate equivalent to that of the intermittent dosing. Lastly, there is an example of a loading dose which is twice the normal maintenance dose (c). This graph can be found in its original state at www.nps.org.au, where the old (pre-textboook, pre-famous) 1996 versions of Birkett's articles are still hosted.

Following from the above, the following factors are determinants of dosing design which are affected by critical illness:

  • Volume of distribution
  • Clearance rate
  • Bioavailability

The following table lists these factors, and the ways in which critical illness influences them:

Factors which Influence Maintenance Dose and Loading Dose
Factor involved Effects of critical illness  Impact on loading dose and maintenance dose

Volume of distribution

Increased Vd (due to fluid overload) 

Increased loading dose and maintenance dose or dose rate

Decreased Vd (due to hypovolaemia)

Decreased loading dose and maintenance dose or dose rate

     

Clearance

Decreased renal clearance (due to decreased renal blood flow or renal parenchymal damage)  ​​​​​​

Decreased maintenance dose or dose rate; also possibly increased dosing interval.

Loading dose could remain unchanged

Increased renal clearance (hyperdynamic states, eg. early sepsis)

Increased maintenance dose or dose rate; also possibly dencreased dosing interval

Loading dose could remain unchanged

Decreased hepatic clearance (decreased hepatic blood flow or inhibited liver enzyme function)

Decreased maintenance dose or dose rate; also possibly increased dosing interval.

IV loading dose could remain unchanged

Oral loading dose would need to be decreased to accommodate for the decreased first pass metabolism

 

Increased hepatic clearance (increased hepatic blood flow or hepatic parenchymal clearance)

Increased maintenance dose or dose rate; also possibly decreased dosing interval.

IV loading dose could remain unchanged

Oral loading dose would need to be increased to accommodate for the increased first pass metabolism

Bioavailability

Decreased protein binding (due to lower levels of protein)

Increased free unbound fraction of the drug, which gives rise to increased clearance and increased drug effect.

Decreased gut absorption (due to decreased splanchnic blood flow and/or decreased peristalsis)

Variable and inconsistent absorption of an otherwise correctly calculated oral loading dose

 

Competition for protein binding (eg. where bilirubin competes for albumin binding sites)

Increased free unbound fraction of the drug

The following memorable illustrative examples could be retrieved from storage as "examples of drugs illustrating an understanding" etc...

  • Theophylline:  a drug which is dosed every half-life (300mg every 8 hours), which is equivalent to a dose rate of 37.5mg/hr, which is in turn equivalent to an infusion rate of 37.5mg/hr.
  • Phenobarbitone:  a drug with a vast volume of distribution, where the loading dose would be massive and toxic
  • Morphine:  a drug which is poorly orally bioavailable; an example of how the oral loading dose is affected by bioavailability (i.e. 
  • Phenytoin: a drug which is highly protein-bound, and which is highly affected by the low plasma albumin associated with critical illness (thus, with low total drug levels the levels of  free unbound drug may still be therapeutic)
  • Gentamicin: a drug which is cleared rapidly by the kidneys, a clearance which is significantly affected by poor renal function. It is an example of how the loading or maintenance dose should remain unchanged; instead the dosing interval should be extended.
  • Vancomycin and β-lactams: examples of drugs which are subject to increased renal clearance in the context of hyperdynamic circulatory states, for example in early sepsis

References

References

Birkett, D. J. "Pharmacokinetics made easy 11 designing dose regimens." Australian Prescriber 19.3 (1996).

Blot, Stijn I., Federico Pea, and Jeffrey Lipman. "The effect of pathophysiology on pharmacokinetics in the critically ill patient—concepts appraised by the example of antimicrobial agents." Advanced drug delivery reviews 77 (2014): 3-11.

Ebert, Steven C., and William A. Craig. "Pharmacodynamic properties of antibiotics: application to drug monitoring and dosage regimen design." Infection Control & Hospital Epidemiology 11.6 (1990): 319-326.

Wysocki, Marc, et al. "Continuous versus intermittent infusion of vancomycin in severe staphylococcal infections: prospective multicenter randomized study." Antimicrobial agents and chemotherapy 45.9 (2001): 2460-2467.