Viva B(ii)a

This viva is theoretically relevant to something in Section B of the 2017 CICM Primary Syllabus, even though that document does not explicitly mention routes of administration. One might stretch the wording of the syllabus to bring these topics under the objective, "describe absorption and factors that will influence it". 

List the routes of administration available for medications.


  • Oral
  • Enteric coated
  • Controlled release


  • Intravenous
  • Subcutaneous
  • Intramuscular
  • Intra-arterial
  • Intrathecal
  • Epidural


  • Transdermal
  • Mucosal, eg. sublingual or nasal
  • Rectal
  • Vaginal
  • Eluted locally (eg. coronary stent)


  • Nebulised
  • Vapourised / gaseous
Define "bioavailability". 
  • Bioavailability is the fraction of the dose which reaches systemic circulation as intact drug.
How do you calculate the bioavailable fraction?

Oral bioavailability (F) can be described by the following equation:

simple bioavailability equation

What is Dost's Law of Corresponding Areas?
  • Dost's law states, ""The ratio of the area beneath the blood level-time curves after oral administration to that following intravenous administration of the same dose is a measure of the absorption of the drug administered."
  • It is a mathematical concept used to determine the absorption of a drug from the area under the curve which is described by its serum concentration measurements over time.
    illustration of Dosts Law of Corresponding Areas
  • i.e. if the area under the oral concentration curve covers 50% of the area covered by the IV curve, the law dictates that the drug is 50% bioavailable.
Define "absolute bioavailability"

Using concentration/time curves, the absolute bioavailability is the dose-corrected area under curve (AUC) for non-intravenous route, divided by AUC of the intravenous route. 

bioavailability equation for equal oral and IV doses

(where F is the absolute bioavailability fraction)

 Define "relative bioavailability"

Whereas absolute bioavailability compares the drug formulation to an equivalent IV dose, relative bioavailability compares it to another similar non-IV formulation

Define the term "bioequivalence".

Bioequivalence is a clinical definition referring to two formulations of a drug. Drugs are considered bioequivalent if the extents and rates of absorption of drug from them are so similar that there is likely no clinically important difference between their effects.

Bioequivalence rests on the assumption that the measured drug concentration is related to its clinical effect

What factors influence bioavailability?
Factors which Influence Drug Bioavailability

Generic influences on drug bioavailability

  • Drug concentration at site of administration
  • Surface area of the absorptive site
  • Drug pKa
  • Drug molecule size
  • pH of the surrounding fluid

Factors affecting first pass metabolism

  • Drug absorption from the gut
  • Drug metabolism in the gut
  • Metabolism in the gut wall
  • Metabolism in bloodstream (eg. plasma esterases)
  • Hepatic blood flow
  • Hepatic enzyme activity
  • Spontaneous drug degradation

Factors affecting gastrointestinal absorption

  • Gastric motility
  • Intestinal motility
  • Splanchnic perfusion
  • Tablet disintegration
  • Mode of transport
  • Intestinal content
  • Bile and bile salt content
  • Enterohepatic recirculation
  • Metabolism by gut bacteria
  • Metabolism in the intestinal wall
  • Drug on drug interactions in the gut
  • First pass metabolism

Bioavailability via transdermal and mucosal routes of administration

  • Mucosal blood flow
  • Drug lipophilicity
  • Factors affecting membrane penetration, eg. molecule size, pKa, etc
  • pH of the mucosal fluid
What are the effects of shock states on bioavailability?
Factor Effects of shock

Factors affecting gastrointestinal absorption

  • Gastric motility
Gastric motility and gastric emptying is decreased; the latter has the effect of decreasing absorption rate. The importance of gastric drug absorption becomes greater.
  • Intestinal motility
Intestinal motility is decreased, which slows gut transit. On one hand this has the effect of decreasing the rate of drug absorption because the delivery of the drug to absorptive surfaces is slowed. On the other hand, the increased duration of exposure to gut surfaces may increase the overall absorption of orally administered drugs, particularly in the context of overdose with a large bezoar of sustained release formulation tablets.
  • Splanchnic perfusion
Decreased splanchnic perfusion is a part of stereotypic shock response (and we make it worse by giving the patients noradrenaline). The ultimate effect is decreased drug transport from the gut wall to the systemic circulation. 
  • Metabolism by gut bacteria
Gut bacteria may metabolise more drugs if there is intestinal stasis and they have plenty of time to work on the drug in the dilated paralysed bowel loops. Alternatively, drug metabolism by bacteria may be completely abolished by the wholesale slaughter of these bacteria in the wake of high dose broad spectrum antibiotics. Colonic transit may also be increased by gut ischaemia and diarrhoea, resulting in less exposure time. 
  • Metabolism in the intestinal wall
An ischaemic intestine will not be metabolising anything. A poorly perfused shocked intestine will also be likely to downregulate its brush border enzymes, focusing on survival and self-preservation.
  • Intestinal surface area
This will be diminished in the wake of ischaemia as the villi are shed and the brush border denuded. A decrease in the intestinal surface area will be the result. 

Factors affecting first pass metabolism

  • Hepatic blood flow
This is sacrificed in shock, and drug metabolism will be slowed proportionally (particularly where the enzymes are not particularly saturable and blood flow determines the rate of metabolism)
  • Hepatic enzyme activity
The activity of hepatic enzymes may be downregulated (as in the case of CYP enzymes during septic shock) or abolished completely (as in the case of ischaemic hepatitis)
  • Shunts
In shock states with poor cardiac output and hepatic congestion (eg. cardiogenic shock) portosystemic shunts may open, allowing drugs to bypass first pass metabolism

Factors influencing absorption from other sites

  • Decreased mucosal perfusion
Buccal, rectal, vaginal absorption - these will be diminished or erratic becayse blood flow to these regions is usually sacrificed
  • Altered muscle and subcutaneous blood flow
Typically shock states decrease cutaneous and muscle blood flow, leading to mottling. This will result in decreased bioavailability of intramuscular and subcutaneously administered drugs. The only exception to this rule is anaphylaxis, where systemic vasodilation leads to excellent intramuscular absorption.
  • Tachypnoea
Increased respiratory rate and higher tidal volumes may improve the bioavailability of nebulised drugs and gaseous agents, or - instead - decrease it, if the patient is taking shallow peri-arrest breaths

Factors affecting the bioavailability of already absorbed drugs

  • Decreased protein binding
Most of the proteins which are expected to bind drugs will have their production downregulated during the acute phase response (eg. the hypoalbuminaemia of acute illness). Drug bioavailability will be increased by this if the drug is highly protein-bound.
  • Decreased plasma metabolism
The synthesis of plasma esterases and proteases will be decreased during an acute phase response, leading to diminished drug clearance by these enzymes.


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Dost, F. H. "Absorption, Transit, Occupancy und Availments als neue Begriffe in der Biopharmazeutik." Journal of Molecular Medicine 50.8 (1972): 410-412.

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