Interactions

Definition

When two or more drugs are combined, they may affect each other. This is especially true with regard to their pharmacokinetics (ADME) and effects and adverse effects (pharmacodynamics). This phenomenon is called interaction and drug-drug interaction. Interactions are usually undesirable because they can lead to, for example, loss of efficacy, side effects, poisoning, hospitalization, and organ rejection. Deaths have also been reported. Because of their potential for interaction, several drugs have had to be withdrawn from the market in the past. However, interactions can also be desirable, for example, in HIV treatment, Parkinson’s therapy, or combination therapies. A distinction is made between pharmacokinetic and pharmacodynamic interactions.

Pharmacokinetic interactions

Pharmacokinetic interactions occur at the level of release, absorption, distribution, metabolism, and elimination (ADME):

  • Influence on gastric emptying, alteration of gastric pH.
  • Interactions with food
  • Reduction of absorption in the intestine due to mutual binding and inactivation (e.g., minerals, activated charcoal, bisphosphonates).
  • Inhibition or induction of metabolic enzymes (e.g. CYP450, UGT).
  • Inhibition or induction of drug transporters (e.g., P-glycoprotein, BCRP, OAT, OATP).
  • Displacement from protein binding

Pharmacodynamic interactions

Pharmacodynamic interactions involve onset of action, duration of action, potency of action, and adverse effects:

  • Additive: an identical mechanism of action leads to an enhancement of effects and adverse effects. Sometimes two drugs with the same active ingredient are also inadvertently administered simultaneously.
  • Antagonistic: cancellation of the effects of a drug due to opposite mechanisms of action.
  • The effect of a drug can increase sensitivity to adverse effects. For example, potassium depletion increases susceptibility to cardiac arrhythmias.

A pharmacodynamic effect may exert an influence on pharmacokinetics. For example, inhibition of gastric acid secretion affects the release of another drug.

Food, beverages, stimulants, and intoxicants.

Interactions can occur not only between drugs, but also between drugs and foods or beverages. The best-known example is alcohol. It should not be combined with centrally depressant or liver-toxic agents. Together with disulfiram, an intolerance reaction occurs. Grapefruit juice inhibits the metabolic enzyme CYP3A4 in the intestine and thus can enhance the effects and side effects of corresponding substrates. Other fruit juices may also cause interactions. Many foods have an effect on the absorption and oral bioavailability of drugs. These include, for example, milk, black tea, coffee, mineral water and eggs. For this reason, instructions regarding the timing of intake can be found in the product information and package insert. Foods containing vitamin K, such as leaf spinach and broccoli, can influence the effect of vitamin K antagonists. It should be noted that even seemingly innocuous therapeutic agents such as herbal remedies (phytopharmaceuticals such as hyperforin-rich St. John’s wort extracts) or dietary supplements can cause interactions. It also does not matter whether the drugs are prescription or not. Recreational drugs such as tobacco smoking and intoxicants are also common triggers for interactions. Smoking induces the metabolic enzyme CYP1A2.

Desirable interactions

Pharmacokinetic boosters are agents that improve the pharmacokinetic properties of another agent, thereby increasing its bioavailability or plasma concentration, for example. They can be effective at different levels (ADME). They are often inhibitors of CYP450 isozymes or inhibitors of transporters. Typical examples are ritonavir and cobicistat. Also desirable are synergistic pharmacodynamic effects, for example, when different analgesics are combined.

Clarification of interactions

Before initiation, it is important to check whether the combination is possible with the drugs already administered.Due to the complexity, the clarification must be carried out by a specialist. At the same time, medications that are no longer needed should be discontinued. On the one hand, it can be carried out with the help of previous knowledge, literature and specialist drug information. On the other hand, digital tools and applications are available that perform this check automatically. In German-speaking countries, the ABDA database plays an important role. Online applications (examples):

  • Drugs.com – Free interaction check (English).
  • Medscape – Drug Interaction Checker (English).
  • MediQ – Well-founded, professional system developed in many countries (fee required).
  • Interaction check Free interaction check, Apotheken-Umschau.

The response to interactions depends on their clinical relevance. Weak interactions can be accepted under certain circumstances. In some cases, a dose adjustment is sufficient. Alternatively, blood concentrations can be determined. However, there are combinations that are explicitly contraindicated. For high-risk patients on many medications, well-tolerated and low-risk agents are available for some indications.

Appendix: examples of drug-drug interactions