Viva C(i)

This viva is relevant to the objectives of Section C(i) from the 2017 CICM Primary Syllabus, which expects the exam candidate to "define and explain dose-effect relationships of drugs, including dose-response curves with reference to... graded and quantal response"

What is a graded dose-response relationship? What is meant by saying that it is "graded"?
  • Graded dose-response relationship describes a drug effect which increases in proportion to increasing drug dose.
  • A graded response to a drug is seen in an individual, and increases with dose.
  • Graded dose-response graphs plot the response to a drug against its concentration
What is a quantal dose-response relationship?
  • Quantal dose-response relationship describes a drug effect which is binary (either present or absent), for example death.
  • A quantal response to a drug is observed in a population, and is either present or absent in any single individual.
  • Quantal dose-response graphs plot the rate of an outcome occurrence in a population against the drug dose.
What is an ordered dose-response relationship?
  • an Ordered dose-response relationship is a sequence of quantal dose-response relationships which represent several quantal response end-points which are seen when dose is increased.
  • There is not necessarily any ordinal relationship between these separate quantal end-points (i.e. there is an ordered progression of endpoints with increasing dose but you cannot use them as grading of the response)
Can you draw a quantal dose-response curve?

One should produce something like this:

quantal dose-response curve reconstructed from bell curve

What is the definition of the median effective dose (ED50)? How about the median toxic dose (TD50) and the median lethal dose (LD50)?
  • The median effective dose is the dose at which 50% of individuals exhibit the specified quantal effect
  • The median toxic dose is the dose required to produce a defined toxic effect in 50% of subjects
  • The median lethal dose is the dose required to kill 50% of subjects

The trainee should at this stage be encouraged to demonstrate these on the quantal dose-response curve they just drew:

quantal dose-response curve with ED50 TD50 LD50

What is the "therapeutic index"?

It is "the ratio of the TD50 to the ED50 for some therapeutically relevant effect" (Katzung)

or:

"Therapeutic index is most commonly defined as the ratio of the median lethal dose (LD50) to the median effective dose (ED50), as determined in preclinical animal studies, [which] reflects the selectivity of a drug to elicit a desired effect rather than toxicity"

What is the therapeutic range or "window"?
  • The therapeutic window is the range between the minimum toxic dose and the minimum therapeutic dose, or the range of doses over which the drug is effective for most of the popuation and the toxicity is accceptable.

therapeutic index

What is the use of the therapeutic index?
  • It is a numeric measure of the selectivity of the drug for its desired effect. The larger the value, the safer the drug, one could crudely say.
  • It guides the need for therapeutic level monitoring. Drugs with a narrow therapeutic index should be monitored more closely. 
  • It guides the dosing interval. Or rather, it theoretically could. The drug with a narrow index would need to be given more frequently and in smaller doses.

References

Dimmitt, Simon, Hans Stampfer, and Jennifer H. Martin. "When less is more–efficacy with less toxicity at the ED50." British journal of clinical pharmacology 83.7 (2017): 1365-1368.

Neubig, Richard R., et al. "International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on terms and symbols in quantitative pharmacology." Pharmacological reviews 55.4 (2003): 597-606.

Abughazaleh, R. D., & Tracy, T. S. (2014). Therapeutic Index. Wiley StatsRef: Statistics Reference Online.doi:10.1002/9781118445112.stat07121. Originally published online in 2007 in Wiley Encyclopedia of Clinical Trials, © John Wiley & Sons, Inc. and republished in Wiley StatsRef: Statistics Reference Online, 2014.

Trevan, John William. "The error of determination of toxicity." Proc. R. Soc. Lond. B 101.712 (1927): 483-514.

Zhou, Jian-Xin, et al. "The efficacy and safety of intravenous emulsified isoflurane in rats." Anesthesia & Analgesia 102.1 (2006): 129-134.