Viva B(ii)c

This viva is relevant to Section B(ii) of the 2017 CICM Primary Syllabus, which expects the exam candidate to "Describe absorption and factors that will influence it".

Which drug properties influence the absorption of drugs from the gastrointestinal tract?

Drug factors: 

  • Concentration

A large drug dose will be absorbed more rapidly because of the high concentration gradient

  • Molecule size

Small molecules diffuse more easily

  • pKa

Weak acids are better absorbed; lipophilic drugs are better absorbed

  • Tablet disintegration

Stability of the tablet determines the dispersion rate of the drug, and therefore the rate of absorption. This is manipulated intentionally in slow release formulations

  • Particle size

The smaller the particles, the greater the surface area from which the drug will be eluted

Which gastrointestinal factors influence drug absorption?
Gastrointestinal factors

Gastric emptying is the major determinant of absorption

  • Intestinal motility

Intestinal motility can increase or decrease absorption (eg. slow gut transit can ensure complete absorption of a drug bezoar)

  • Splanchnic perfusion

Gut perfusion is a rate-limiting step in drug absorption only for rapidly absorbed drugs, but as perfusion slows it also becomes more important for all other drugs.

  • Surface area

Surface area of the small intestine is massive (usually, tens of square metres) and this increases absorption. Factors which decrease intestinal surface area (eg. denuded villi due to gastroenteritis, or surgacal short gut) will decrease drug absorption

  • Mode of transport

Drugs can be transported by passive diffusion (either paracellular or transcellular); some are actively transported out of the gut lumen, and others may be actively excreted back into it by efflux pumps.

  • Intestinal content

Interaction with other drugs and food substances (eg. tetracycline chelating intestinal calcium from milk, thereby forming an insoluble complex which defeats absorption) 

  • Bile and bile salts

The emulsifying effect of bile is critical to the absorption of fat-soluble vitamins and steroids

  • Enterohepatic recirculation

Some drugs may be eliminated in the bile only to be reabsorbed in the jejunum

  • Gut bacteria

Gut bacteria may either deactivate drugs (by metabolisng them) or activate drugs (by metabolism of an inactive precursor). 

  • Metabolism in the intestinal wall

Enterocytes may metabolise drugs before they undergo first-pass metabolism. Injured enterocytes (eg. after ischaemia) may lose their metabolic function.

Where does most drug absorption take place, and why?

Pretty much all drug absorption occurs in the small intestine. This is because:

  • Drugs spend longer in the small intestine
  • The small intestine has a larger surface area
What is the importance of gastric motility on drug absorption?
  • Gastric emptying rate is one of the main determinants of oral drug bioavailability and gastrointestinal drug absorption, because there is so little gastric drug absorption.
  • Theoretically the low pH of the gastric fluid should render all but the most acidic drugs into a lipid-soluble nonpolar form, which would favour absorption.
  • However:
    • The stomach lining is coated with a thick protective mucus which makes diffusion difficult.
    • The stomach has a fairly small surface area when compared to the small bowel.
  • The consequences of this are that the stomach participates minimally in drug absorption
Which drug characteristics favour gastric drug absorption?

To be well absorbed in the stomach, a drug would need to be:

  • A small molecule
  • Weakly acidic (pKa higher than the pH of stomach acid)
  • Highly concentrated (i.e. a large dose of drug)

Additional caveats in the ICU environment:

  • The drug may be highly concentrated because of overdose
  • The gastric pH may be high because of routine use of proton pump inhibitors
  • The gastric mucus layer may be thin because of critical illness
  • Bypassing the stomach altogether (jejunal administration, gastric sleeve or bypass surgery etc)
Name some examples of drugs which are well-absorbed in the stomach
  • Ethanol
  • Aspirin
  • Paraquat
  • Thiopentone
  • Caffeine
  • Warfarin
  • Phenytoin
  • Theophylline
What factors influence gastric emptying?

In brief summary, gastric emptying can be affected by:

  • Food in the stomach (especially fat)
  • Viscosity of the stomach content
  • Size of the tablet or capsule 
  • Sedation 
  • Mobility
  • Abdominal compartment pressure
  • Gastric perfusion
  • Autonomic and hormonal activity
  • Anticholinergic drugs
How does drug absorption occur in the small intestine?

Drug absorption in the intestine can occur by three possible ways:

  • Passive diffusion of lipophilic drugs, though the membrane
  • Passive diffusion of hydrophilic drugs, through pores and gap junctions
  • Active transport of larger molecules by transport proteins

For most drugs, the main mechanism of absorption is by passive diffusion through the cell membranes. Paracellular junctions account for less than 0.01% of the total surface area, and these junctions become less and less permeable as one progresses from jejunum to colon.

What drug characteristics favour the active transport of drugs from the small intestine? Give examples.

Drugs will be transported actively if they resemble some "natural" substrate chemically. Eg.  methyldopa substitutes for L-dopa, and 5-fluorouracil substitutes for uracil.

GIT transporters and their substrates - Martinez, 2002

Describe the time course of drug absorption from the gastrointestinal tract.
  • In the normal population, intestinal transit time is usually quite consistent and largely unaffected by gastric emptying. For most people it will be some 2-6 hours.
  • Peak effect is usually in 30 minutes
What are the problems with drug absorption from the colon?
  • Surface area is small (5m2)
  • Solid stool make diffusion difficult
  • Concentration is usually low, as most of the drug has already been absorbed
  • Gut bacteria are more numerous, and transit time is slower (i.e. bacterial metabolism is more prevalent)
How does gut microflora affect drug absorption? Give examples.
  • Decreased availability or deactivation of the drug, by...
    • Metabolism into inactive metabolites
    • Sequestration in bacterial organisms
    • Chelation by bacterial wall components
    • Competition for intestinal absorption with bacterial metabolites
  • Increased availability or activation of the drug, by...
    • Metabolism of inactive precursor into active metabolites
    • Change of ambient pH to enhance absorption
    • Metabolism into more easily absorbed forms

Sulphasalazine as a good example. The drug itself is completely inactive, but is metabolised by gut bacteria to produce sulphapyridine and 5-amino salicylic acid (which have a therapeutic effect).

What is "enterohepatic recirculation"?
  • In the liver, a drug may be conjugated directly with glucuronic acid or sulphate.
  • This conjugate is excreted in the bile.
  • In the colon, the gut bacteria possess both glucuronidase and sulphatase enzymes.
  • These bacteria split the conjugate from the drug molecule, thus liberating the unchanged drug
  • The liberated drug can now be absorbed by the 5m2 surface of the colon.

References

Welling, Peter G. "Influence of food and diet on gastrointestinal drug absorption: a review." Journal of Pharmacokinetics and Biopharmaceutics 5.4 (1977): 291-334.

Levine, Ruth R. "Factors affecting gastrointestinal absorption of drugs." Digestive diseases and sciences 15.2 (1970): 171-188.

Prescott, L. F. "Pathological and physiological factors affecting drug absorption, distribution, elimination, and response in man." Concepts in Biochemical Pharmacology. Springer Berlin Heidelberg, 1975. 234-257.

Martinez, Marilyn N., and Gordon L. Amidon. "A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals." The Journal of Clinical Pharmacology 42.6 (2002): 620-643.

Chillistone, Shruti, and Jonathan G. Hardman. "Factors affecting drug absorption and distribution." Anaesthesia & Intensive Care Medicine 18.7 (2017): 335-339.

Hogben, C. Adrian M., et al. "Absorption of drugs from the stomach. II. The human." Journal of Pharmacology and Experimental Therapeutics 120.4 (1957): 540-545.

Schanker, L. S. "Absorption of drugs from the gastrointestinal tract." Concepts in Biochemical Pharmacology. Springer Berlin Heidelberg, 1971. 9-24.

BERGGREN, SVEN M., and LEONARD GOLDBERG. "The Absorption of Ethyl Alcohol from the Gastro‐Intestinal Tract as a Diffusion Process." Acta Physiologica 1.3 (1940): 246-270.

Schanker, Lewis S., et al. "Absorption of drugs from the stomach I. The rat." Journal of Pharmacology and Experimental Therapeutics 120.4 (1957): 528-539.

Mitra, Amitava, and Filippos Kesisoglou. "Impaired drug absorption due to high stomach pH: a review of strategies for mitigation of such effect to enable pharmaceutical product development." Molecular pharmaceutics 10.11 (2013): 3970-3979.

Masaoka, Yoshie, et al. "Site of drug absorption after oral administration: assessment of membrane permeability and luminal concentration of drugs in each segment of gastrointestinal tract." European journal of pharmaceutical sciences 29.3 (2006): 240-250.

Orme, M. "Drug absorption in the gut." BJA: British Journal of Anaesthesia56.1 (1984): 59-67.

El-Kattan, Ayman, and Manthena Varma. "Oral absorption, intestinal metabolism and human oral bioavailability." Topics on drug metabolism. InTech, 2012.

Welling, Peter G. "Influence of food and diet on gastrointestinal drug absorption: a review." Journal of Pharmacokinetics and Biopharmaceutics 5.4 (1977): 291-334.

Levine, Ruth R. "Factors affecting gastrointestinal absorption of drugs." Digestive diseases and sciences 15.2 (1970): 171-188.

Prescott, L. F. "Pathological and physiological factors affecting drug absorption, distribution, elimination, and response in man." Concepts in Biochemical Pharmacology. Springer Berlin Heidelberg, 1975. 234-257.

Martinez, Marilyn N., and Gordon L. Amidon. "A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals." The Journal of Clinical Pharmacology 42.6 (2002): 620-643.

Chillistone, Shruti, and Jonathan G. Hardman. "Factors affecting drug absorption and distribution." Anaesthesia & Intensive Care Medicine 18.7 (2017): 335-339.

Hogben, C. Adrian M., et al. "Absorption of drugs from the stomach. II. The human." Journal of Pharmacology and Experimental Therapeutics 120.4 (1957): 540-545.

Schanker, L. S. "Absorption of drugs from the gastrointestinal tract." Concepts in Biochemical Pharmacology. Springer Berlin Heidelberg, 1971. 9-24.

BERGGREN, SVEN M., and LEONARD GOLDBERG. "The Absorption of Ethyl Alcohol from the Gastro‐Intestinal Tract as a Diffusion Process." Acta Physiologica 1.3 (1940): 246-270.

Schanker, Lewis S., et al. "Absorption of drugs from the stomach I. The rat." Journal of Pharmacology and Experimental Therapeutics 120.4 (1957): 528-539.

Mitra, Amitava, and Filippos Kesisoglou. "Impaired drug absorption due to high stomach pH: a review of strategies for mitigation of such effect to enable pharmaceutical product development." Molecular pharmaceutics 10.11 (2013): 3970-3979.

Masaoka, Yoshie, et al. "Site of drug absorption after oral administration: assessment of membrane permeability and luminal concentration of drugs in each segment of gastrointestinal tract." European journal of pharmaceutical sciences 29.3 (2006): 240-250.

Orme, M. "Drug absorption in the gut." BJA: British Journal of Anaesthesia56.1 (1984): 59-67.

El-Kattan, Ayman, and Manthena Varma. "Oral absorption, intestinal metabolism and human oral bioavailability." Topics on drug metabolism. InTech, 2012.