Viva B(y)a

This viva is relevant to the objectives of Section C from the 2017 CICM Primary Syllabus, which expects the exam candidate to develop "A general understanding of how drugs work, ... including ... drug interactions". .

What are the possible effects of drug-drug interactions on drug absorption?

Formation of insoluble complexes

  • The decreased bioavailability of bisphosphonates when calcium is co-administered

Inhibition of active transporters

  • Inhibition of metformin uptake by repaglinide interfering with the organic cation transporter OCT1

Inhibition of efflux transporters

  • The effect of verapamil on the P-glycoprotein efflux pump reduces the efflux of digoxin; ergo the concentration of digoxin increases
  • The effect of rifampicin on the P-glycoprotein efflux pump increases its activity, thereby increasing gut clearance of cyclosporine 
What are the possible effects of drug-drug interactions on drug distribution?

Competition for transport protein binding sites

  • Phenytoin and valproate compete for the same protein binding sites, which tends to displace phenytoin (Perucca et al, 1980)
What are the possible effects of drug-drug interactions on drug metabolism?

Competition for the same CYP450 enzymes

  • Macrolides, inhibiting the metabolism of warfarin (and about half of all other medically interesting drugs) by competing for CYP450 3A4

Inhibition or induction of metabolic enzymes

  • The effect of carbamazepine, which increases the rate of warfarin and oral contraceptive metabolism 
  • The inhibition of metabolic pathways can also paradoxically decrease the bioavailability if those enzymes convert a prodrug into the active from (eg. tamoxifen)
What are the possible effects of drug-drug interactions on drug elimination?

Competition for active transport

  • The effect of probenecid is to decrease the actve secretion of β-lactams and  cephalosporins

Interference with solubility

  • Increased ion trapping of salicylate in alkaline urine due to the use of acetazolamide

References

Palleria, Caterina, et al. "Pharmacokinetic drug-drug interaction and their implication in clinical management." Journal of research in medical sciences: the official journal of Isfahan University of Medical Sciences 18.7 (2013): 601.

Huang, Shiew-Mei. "Drug-drug interactions." Applications of Pharmacokinetic Principles in Drug Development. Springer, Boston, MA, 2004. 307-331.

Snyder, Ben D., Thomas M. Polasek, and Matthew P. Doogue. "Drug interactions: principles and practice." Australian prescriber 35.3 (2012): 85-8.

Perucca, E., et al. "Interaction between phenytoin and valproic acid: plasma protein binding and metabolic effects." Clinical Pharmacology & Therapeutics 28.6 (1980): 779-789.