Drug-Drug Interactions

Introduction

In a dream, my lecturer was showing a long list of medications. He asked, do you know what is the most prominent drug interaction that you can identify. I tried my best but I could not recognize the drug name. He answered, it would be interaction with MONEY.

Yes, it is bit off topic here.

Drug Interactions

Two or more drugs given at the same time can exert their effects independently or they can interact. Interactions may be beneficial or may cause you to experience an unexpected side effect or reduced efficacy.

Drug-drug interactions can be broadly classified as being either pharmacokinetic or pharmacodynamic.

• Pharmacokinetic - occur when one drug alters the absorption, distribution, metabolism or excretion of another.
• Pharmacodynamic - might be due to competition at receptor sites or occur between drugs acting on the same physiological system.

Potentially harmful drug interactions may occur in only a small number of patients, but the true incidence is often hard to establish. Furthermore, the severity of a harmful interaction is likely to vary from one patient to another. When a patient is elderly and on polypharmacy, you will probably expect few drug-drug interactions, especially if the patient is on a drug that interacts with many drugs such as antacids, warfarin, digoxin, lithium, phenytoin and rifampicin.

Regardless, the main concern remains, is the drug-drug interaction clinically significant. Depending on the levels of severity of the drug-drug interaction, the recommended management varies.

• No action needed,
• Monitor therapy,
• Modify therapy, or
• Avoid combination

Another hand-in-hand consideration is when one of the interacting drug is being adjusted or discontinued by prescriber, the relevant drug dose adjustment should be initiated. Personally, I have seen a patient is on quetiapine XR 1000 mg ON when the patient is also on phenytoin.

• Quetiapine dose increases to as much as 5 times the regular dose may be required to maintain therapeutic benefit during chronic treatment (e.g. greater than 7 to 14 days) with a strong CYP3A4 inducer. The dose should be titrated based on the clinical response and tolerability of the individual patient. The quetiapine dose should be reduced to the previous/regular dose within 7 to 14 days of discontinuation of the CYP3A4 inducer.

NOTE: There is also

• Drug-food interactions
• Certain drugs absorption is affected by presence of food.
• Cranberry may enhance the anticoagulant effect of warfarin.
• The interaction between tyramine in some foods and MAOIs.
• The interaction between grapefruit juice and CCBs or simvastatin).
• Drug-herb interactions
• Herbal extracts containing coumarin-like constituents include alfalfa (Medicago sativa), angelica (Angelica archangelica), dong quai (Angelica polymorpha, A. dahurica, A. atropurpurea), chamomile, horse chestnut and red clover (Trifolium pratense), which can potentially lead to interactions with warfarin.
• Herbal products with antiplatelet properties include borage (Borago oficinalis), bromelain (Ananas comosus), capsicum, feverfew, garlic, ginkgo (Ginkgo biloba) and turmeric, amongst others.
• Other examples of drug–herb interactions include enhancement of hypoglycaemic (e.g. Asian ginseng) and hypotensive (e.g. hawthorn) effects, and lowering of seizure threshold (e.g. Shankhapushpi).
• Drug-condition interactions

Reference

During provisional registered year, one of my batchmates had a habit of including all drug-drug interactions in her case presentation, even minor ones. This is a raw yet practical learning method.

• In fact, drug-drug interactions should always be considered when introducing a new drug in patient pharmacotherapy management.

One of the world's most comprehensive and authoritative international drug interactions reference is Stockley's Drug Interactions.

Having said that, in my day-to-day work, I normally use mobile drug interaction checker application when needed since it is fast and quick. Some mobile applications include:

• British National Formulary
• Epocrates
• Lexicomp
  
• Medscape
  
• Micromedex Drug Interactions

However, some drug-drug interactions may be only identified in one reference, but not the others.

• Apart from formal study, interactions could be based on either a single case report or a limited number of case reports OR are predicted based on sound theoretical considerations.
• Over times, more drug interactions are being identified.

Case Scenario

Mr X is a 45-year-old HIV-positive man who has been taking tenofovir-emtricitabine and efavirenz for many years. One day, he developed a cough and shortness of breath, and was diagnosed with penicillinosis, a fungal infection of the lungs.

Based on National Antimicrobial Guideline, the preferred regimen for mild acute infection is itraconazole.

• However, efavirenz is a moderate CYP3A4 inducer and will decrease the serum contration of itraconazole and its active metabolite. The concurrent use should be avoided.

As a result, the doctor decided to start Mr X on fluconazole (alternative regimen) for his penicillinosis.

Key Reminders

Drugs with a narrow therapeutic window are more likely to result in more significant interactions.

Certain drugs used together can have additive risk, e.g. multiple nephrotoxins increasing the risk of acute kidney injury (e.g. NSAIDs, gentamicin, vancomycin, ACE inhibitors), particularly in the setting of dehydration/sepsis.

Be alerted to check drug interactions when introducing new drug as medical management.

Some Examples

ACE Inhibitors and Metformin

ACE inhibitors may enhance the adverse effects of metformin such as the risk of hypoglycaemia or lactic acidosis. Hence, monitor therapy.

ACE Inhibitors and NSAIDs

The combination may result in a decrease in renal function. NSAIDs may diminish the antihypertensive effects of ACE inhibitors. Hence, monitor therapy.

ACE Inhibitors and Potassium-Sparing Diuretics

The combination may lead to hyperkalaemia Hence, monitor therapy.

Amiodarone and Digoxin

Amiodarone may increase the serum concentration of cardiac glycosides. Reduce the dose of cardiac glycosides by 30% to 50% or reduce the frequency of administration when initiating concomitant amiodarone therapy. Monitor for increased serum concentrations and toxic effects (e.g. gastrointestinal symptoms, visual disturbances, cardiac arrhythmias) of cardiac glycosides.

Azathioprine and Allopurinol

Allopurinol may increase serum concentrations of the active metabolite(s) of azathioprine. More specifically, allopurinol may increase mercaptopurine serum concentrations and promote formation of active thioguanine nucleotides. Hence, reduce the azathioprine dose to one third to one quarter of the usual dose if used concomitantly with allopurinol, and monitor closely for systemic toxicity (particularly hematologic toxicity, nausea and vomiting).

Calcium Channel Blockers and Calcium Salts

Calcium salts may diminish the therapeutic effect of calcium channel blockers. Hence, monitor therapy.

Clopidogrel and Omeprazole/Esomeprazole

Clopidogrel prescribing information recommends avoiding concurrent use with omeprazole or esomeprazole, due to the possibility that combined use may result in decreased clopidogrel effectiveness. Rabeprazole or pantoprazole may be lower risk alternatives to omeprazole or esomeprazole.

Metoclopramide and Prochlorperazine

Avoid combination due to the potential risk of extrapyramidal reactions (e.g. tardive dyskinesia) or neuroleptic malignant syndrome.

Phosphodiesterase 5 Inhibitors and Nitrates

PDE 5 inhibitors may enhance the vasodilatory effects of nitrates. Based on the elimination half-lives of the PDE5 inhibitors, nitrate doses should not be given within at least 24 hours of sildenafil or vardenafil and at least 48 hours of tadalafil.

Serotonin Toxicity

Drugs that can cause serotonin toxicity include antidepressants (SSRIs, SNRIs, MAOIs, TCAs), fentanyl, pethidine, tramadol, dextromethorphan, St John's wort, lithium, phentermine and amphetamines.

Simvastatin and Amlodipine

Daily adult simvastatin greater than 20 mg should be avoided in amlodipine treated patient. Consider to modify therapy (lower the simvastatin dose or change to alternative statins).

Statins and Gemfibrozil

Gemfibrozil may enhance the myopathic (rhabdomyolysis) effect of statins. Hence, avoid combination.

Statins and Warfarin

Some statins (e.g. simvastatin, rosuvastatin, pravastatin) may increase the anticoagulant effect of warfarin. INR should be monitored.

NOTE: May refer to Appendix 1 of British National Formulary or any related references for more examples.

Summary

The problem arises when an interacting drug is added to or ceased from a previously stable drug regimen.

External Links

• Medicines Learning Portal - Interactions
  
• Drug Interactions-Principles, Examples and Clinical Consequences, 2012
  
• 10 Drug Interactions Every Pharmacist Should Know, 2002
  
• Clinically Significant Drug Interactions, 2000