Viva B(vi )

This viva is relevant to parts from Section B(vi) of the 2017 CICM Primary Syllabus, which expects the exam candidate to "explain clinical drug monitoring with regard to peak and trough concentrations, minimum therapeutic concentration and toxicity"

What are the determinants of steady state concentration during drug maintenance therapy, and how long does it take to achieve this?
  • The steady state concentration is determined only by two major factors, the dose rate and the clearance rate.
  • Steady state is achieved when clearance rate and dose rate are equal
  • The time taken to achieve this  steady state in continuous infusion is 3-5 half lives, and 5 half-lies for regular maintenance dosing.
  • This is because increasing drug concentration usually results in a more rapid rate of elimination
What is the purpose of a loading dose?

A loading dose rapidly achieves the peak concentration necessary to compete with clearance, so that the desired effect is achieved and maintained sooner.

How do you calculate the loading dose?

Loading dose is calculated by multiplying the desired peak concentration by the volume of distribution of the drug

If the dosing interval is the same as the half-life of the drug, the loading dose should be twice the maintenance dose (i.e. after one half-life the drug concentration will have dropped by half, and "topping up" with another maintenance dose will bring it back to the same peak concentration as the loading dose).

What are the effects of oral dosing on maintenance and loading dose calculations?
  • All the loading doses and maintenance doses have to be adjuested to bioavailability (i.e. divided by the bioavailability fraction) - this increases the required dose if the drug is not 100% bioavailable
  • The slower intestinal absorption of the drug  has a "smoothing" effect on the peaks of concentration, which has the effect of decreasing concentration-dependent adverse effects.
Which factors influence the dosing interval?
  • Elimination half-life:  most of the time, one does not wait for all of the drug to be eliminated before the next dose, as it is important to maintain a certain level of plasma concentration. 
  • Generally speaking, for most drugs, the dosing interval is approximately one half life.
  • Therapeutic index: in other words, how widely would you allow the drug concentration to fluctuate between doses?
  • Convenience: inconvenient dosing intervals translate into poor compliance.
How does critical illness affect maintenance dose and loading dose calculations?
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

What is the rationale for monitoring drug levels?
  • The drug may have unpredictable pharmacokinetics.
  • The therapeutic index may be narrow (and one wishes to avoid toxicity).
  • There may be significant variability in pharmacogenetics, i.e many patients may metabolise or eliminate the drug in some sort of unusual way.
  • There may be a well-defined therapeutic goal level which the drug needs to achieve to be effective
  • The therapeutic effect of the drug may be subtle, or somehow difficult to monitor (in which case it might be a good idea to monitor drug levels and from these infer that the drug must be doing its job). A classical example of this is lithium, where clinical titration to effect would require serially re-determining how stable the patient's mood is.  
  • The drug is being administered prophylactically, i.e. rather than titrating to positive effect one is titrating the dose to the absence of some unpleasant outcome
  • The drug is being taken .. irresponsibly, and there is a need to monitor drug levels in order to monitor compliance. Classically, one might make this argument for monitoring of cocaine and cannabinoid levels.
What are the limitations of drug level monitoring?
  • There is little evidence that targeting plasma concentrations improve the therapeutic outcome (Vozeh, 1987)
  • It is often difficult or impossible to define appropriate therapeutic ranges; they are usually derived from small groups and point measurements of questionable reliability
  • The greatest benefit from monitoring is to specialised or at-risk populations, but therapeutic ranges are frequently designed without these groups in mind
  • Obsession with monitoring may lead people to treat drug levels rather than the patient (Sjoqvist,, 1985), i.e. the clinical monitoring of effects may give way to remote monitoring of plasma concentrations
  • The availability of monitoring may give rise to pointless routine monitoring, which would be irresponsible and costly.
Which factors are relevant to the interpretation of drug concentration measurements?
  • Pharmacokinetic factors:
    • Measurement assay: the measurement of the drug level may be 
    • Protein binding: the total plasma drug levels may not be reflective of the drug activity, as in the case of phenytoin and hypoalbuminaemia (i.e. with a low total level there is still enough free unbound drug around to have a significant therapeutic effect). Even if you manage to monitor free drug levels, the situation is made more complicated by the fact that the drugs bind variably depending on pH and competition for binding sites (which may not be well represented in the cooled and centrifuged blood sample)
    • Relationship of plasma concentration to effect site concentration:  if the drug penetrates variably and incompletely, it is difficult to relate the robust serum levels to effect site levels. One example of this is vancomycin being administered to treat ventriculitis, where high plasma levels are no guarantee of bactericidal CSF levels  (Moelering et al, 1981)
    • Factors which influence plasma concentration:  these include the volume of distribution, tissue binding, sites of metabolism, rate of clearance, and organ-independent biotransformation (which my carry on inside the blood sample tube and then inside the measurment apparatus, leaving one to measure the metabolic breakdown products instead of the parent drug).
    • Timing of the sampling in relation to the dosing:  most drug levels are trough levels, which makes it important to collect them before the next dose rather than at some arbitrary point in the dosing regimen (particularly for drugs with short half-lives). The trough is generally viewed as the least variable point in the dosing regimen because the drug concentration is changing the least over time - in contrast, after the peak the concentration would be changing (falling) rapidly.
    • Steady state concentration: most intermittently dosed drugs will achieve the steady state after 3-5 half-lives, and any drug levels collected before this point will need to be interpreted accordingly.
  • Pharmacodynamic factors:
    • Relationship of the plasma concentration to clinical drug effect: in some cases, there is no such relationship, making it pointless to measure drug level (eg. in the case of levitiracetam).
    • Active metabolites:  the presence of chemically distinct daughter molecules which have their own therapeutic (or adverse) effect makes it difficult to relate measured drug levels to the clinical effect.
    • Individual variability in drug response: there may be groups in the population who have a satisfactory response to therapy at plasma levels which are below the expected "low" concentration threshold, and there may be those who experience toxicity below the "high" threshold.
  • Clinical and pragmatic factors:
    • Simplicity of the assay:  there is often no point in measuring drug levels if the measurement requires such equipment and expertise as to take weeks.
    • Convenience of sample collection, eg. whether the blood sample needs to be handled in some carefully ritualised manner before being transferred to the laboratory (on ice, on dry ice, in liquid helium, etc)
    • Accuracy of the measurements:  the assay may be accurate, but it may be interfered with by other factors, rendering it uninterpretable
    • Cost and benefit of the assay, i.e. it may be inefficient to measure drug levels if they be expensive and will not alter the design of the dosing regimen and prevent the administration of the expensive drug, or if it cheaper and equally effective to titrate the drug to some sort of clinical effect.
    • Therapeutic range misalignment when the population in whom the therapeutic ranges were first defined may be completely mismatched to the scenario in which the drug is being monitored - i.e. it may be inappropriate to relate adult therapeutic ranges to the drug levels measured in the neonate
    • Relationship of the therapeutic range to the clinical situation, i.e. where the therapeutic range which is quoted does not represent the clinical scenario - for instance, the therapeutic plasma levels quoted for an antibiotic may be well above or well below the MIC for the organism being targeted

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