Question 3

Created on Thu, 07/20/2017 - 06:44
Last updated on Thu, 02/08/2018 - 20:49
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Classify and describe the mechanisms of drug interactions with examples.

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College Answer

Candidates with a well organised answer scored highly. A list of drug interactions was not sufficient to pass, as the question asked to 'describe' the mechanism of drug interactions. Some candidates described the interaction but did not give examples. Common mistakes included using incorrect examples for a particular mechanism and describing the mechanism of action of drugs instead of drug interactions

Discussion

This answer should probably be separated into some combination of pharmacokinetic and pharmacodynamic drug-drug effects. A sensible-sounding classification system and some examples are listed here. 

Pharmacokinetic Drug-Drug Interactions
Mechanism Examples
Absorption interactions

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 
Distribution interactions

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)
Metabolic interactions

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)
Interactions influencing 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
Pharmacodynamic Drug-Drug interactions
Mechanism Examples

Homodynamic: Binding to the same receptor site

  • Antagonism of opioids and naloxone (both compete for the same receptor site)
  • Antagonism of ibuprofen and aspirin (both compete for the same receptor site) 

Allosteric modulation: binding to the same receptor, but at different sites

  • Agonist  effect of barbiturates (which are GABA receptor agonists) and benzodiazepines (which are positive allosteric modulators of the same receptor) 

Heterodynamic: Binding to different receptors, but affecting the same second messenger system

  • Antagonist effect of glucagon upon the cyclic AMP second messenger effects of β-blockers

Second messenger effects: Binding to different receptor/messenger systems, but having effect on the same physiological process

  • The synergistic effect of sedative agents upon the decrease in the level of consciousness (eg. the combination of benzodiazepines and propofol)
  • The antagonist effect of acetylcholinesterase inhibitors on neuromuscular blockade beffects of non-depolarising agents

Additive or opposing physiological effects: different receptor systems and physiological mechanisms, all acting on the same clinical effect

  • The opposing physiological effects of vasopressors and vasodilators. An excellent (and incomprehensible) example is the routine use of GTN at the same time as noradrenaline, for patients recovering from CABG.

Interference with the control mechanism of a physiological process which is the target of another drug

  • Effect of NSAIDs on the local prostaglandin E2 synthesis in the renal circulation tends to decrease glomerular perfusion and therefore increase the secretion of renin, thereby antagonising the antihypertensive effects of ACE-inhibitors (Fournier et al, 2012)

References

Hinder, Markus. "Pharmacodynamic drug–drug interactions." Drug discovery and evaluation: methods in clinical pharmacology. Springer Berlin Heidelberg, 2011. 367-376.

Rodrigues, A. David, ed. Drug-drug interactions. CRC Press, 2008.

Rowland, Malcolm. "Introducing pharmacokinetic and pharmacodynamic concepts." DRUGS AND THE PHARMACEUTICAL SCIENCES 179 (2008): 1.

Cascorbi, Ingolf. "Drug interactions—principles, examples and clinical consequences." Deutsches Ärzteblatt International109.33-34 (2012): 546.

Fournier, Jean-Pascal, et al. "Non-steroidal anti-inflammatory drugs (NSAIDs) and hypertension treatment intensification: a population-based cohort study." European journal of clinical pharmacology 68.11 (2012): 1533-1540.

Abdel-Magid, Ahmed F. "Allosteric Modulators: An Emerging Concept in Drug Discovery." (2015). ACS Med. Chem. Lett., 2015, 6 (2), pp 104–107

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.