Mechanisms of Pharmacodynamic Drug-drug Interactions

Created on Mon, 02/05/2018 - 20:17
Last updated on Tue, 02/06/2018 - 03:44

This chapter is vaguely related to the learning 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". In short, interactions between drugs can be classified as pharmacokinetic and pharmacodynamic, Of the former, the subdivisions would naturally have to include absorption, distribution, metabolism and elimination. As such, these interactions have no business being discussed in the revision section on pharmacodynamics, and a separate chapter exists elsewhere which deals with them. The pharmacodynamic interactions of drug-on-drug can be divided into three broad groups: interference with drug effects on receptor function, interference with a physiological control process, and additive or opposing physiological effects. To elaborate on these is the objective of this chapter.

This topic does not appear to hold much interest for the examiners. Of the past paper SAQs, it has only ever appeared once - in Question 3 from the first paper of 2017, which asked the candidates to "classify and describe the mechanisms of drug interactions with examples." The examiners in their (very short) comment on the question mentioned that having a structure and giving (correct) examples was essential to a good answer. 

Of the published peer-reviewed works which might be helpful for last-minute revision, the best reference is probably Hinder (2011). It is unfortunately not available to the freegan, as it is Chapter C.3 in the first edition of Vogel Maas and Gebauer's Drug Discovery and Evaluation: Methods in Clinical Pharmacology. For these destitute poor, the material presented in these revision notes represents a summary of the main points made by Hinder and his references. Good free articles include Ingolf Cascorbi's 2012 paper from the mellifluously titled Deutsches Ärzteblatt International.  For additional reading which extends well beyond what might be considered sane or reasonable, the exam candidate with infinite time resources can be referred to the extensive Drug-Drug Interactions (2nd ed) by A.D Rodriques, 2008.

Pharmacodynamic vs. pharmacokinetic drug-drug interactions

This definition quoted from Rowland et al (2008) is probably the shortest and best:

Pharmacodynamic interactions occur when one drug modifies the pharmacodynamic response to the same concentration of another. 

To clarify, pharmacodynamic drug-drug interactions do not involve any absorption, distribution, metabolism or excretion processes directly. There may still be some sort of indirect effect. For example, one might say that the use of noradrenaline interacts with the pharmacokinetics of orally available medications by decreasing their absorption from the gut, via the mechanism of interfering with the perfusion thereof.

Pharmacodynamic drug-drug interactions can take several forms, and can lead to either enhanced activity (synergism) or decreased activity (antagonism). This is only one of the ways to classify them. In order to simplify revision, these are listed here in a table, together with some examples.

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