In veterinary practice, many of our patients are on multiple medications, from the young cat struggling with recurrent urethral obstructions to the ancient shih tzu with a novel for a medical record. The more drugs our patients are on, the greater the risk for toxicity and drug interactions.
While most of our knowledge of drug interactions comes from human patients, many of the same interactions likely occur in veterinary patients. With this in mind, here’s a look at the top 10 drugs likely to be involved in drug interactions that have been studied in dogs and cats.1
1. Cimetidine
In humans, this histamine (H2) blocker is a potent inhibitor of several families of cytochrome P450 enzymes and also affects renal transporters. It decreases the clearance of many drugs and can increase the risk for toxicity of metronidazole, lidocaine, theophylline, diazepam, and propranolol. It may also decrease the efficacy of ketoconazole, itraconazole, and iron supplements in humans.
While it seems to be a much weaker inhibitor of P450 enzymes in dogs, its effects on renal transporters have not been well studied. Given the potential risk, it may be worth choosing an alternative H2 blocker that doesn’t inhibit P450 at therapeutic concentrations, such as ranitidine, famotidine, or nizatidine.
2. Clomipramine
Potentially fatal serotonin syndrome can occur when this tricyclic antidepressant is combined with other drugs that increase serotonin, like trazodone, tramadol, fluoxetine, and selegiline.
Selective serotonin reuptake inhibitors (SSRIs) can also increase plasma clomipramine concentrations and cause cardiac conduction disturbances. Ketoconazole and itraconazole slow the metabolism of clomipramine and can increase the risk of adverse effects of clomipramine.
3. Cyclosporine
This immunomodulatory drug is a substrate for cytochrome P450 enzymes and p-glycoprotein: a transporter in the intestine, kidney, and biliary tree, and a component of the blood-brain barrier.
Diltiazem, clarithromycin, ketoconazole, and other azole antifungals inhibit P450 enzymes and p-glycoprotein, decreasing the clearance of cyclosporine and leading to potential toxicity. Saint-John’s-wort has also been shown to speed the elimination of cyclosporine and decrease drug concentrations.
4. Fluoroquinolone antibiotics
Fluoroquinolone antibiotics inhibit the clearance of theophylline and can increase the risk of theophylline toxicosis. Sucralfate and iron and calcium supplements decrease the absorption of some fluoroquinolones, which can lead to loss of efficacy.
Fluoroquinolones delay the elimination of flunixin meglumine, potentially leading to adverse effects of flunixin. But flunixin can also lower enrofloxacin concentrations and diminish its efficacy,2 demonstrating that drug interactions can be complex.
5. Furosemide
This loop diuretic can lead to dehydration and pre-renal azotemia, which decreases the renal clearance of drugs such as digoxin. Furosemide can also cause hypokalemia and hypomagnesemia, both of which worsen the cardiac toxicity of digoxin.
Furosemide enhances the nephrotoxicity of aminoglycosides such as amikacin and gentamicin. High doses of furosemide may have additive effects when combined with ACE inhibitors and lead to hypotension and acute kidney injury. Monitoring the patient’s blood pressure, hydration, and renal function is important.
6. Ketoconazole
Ketoconazole inhibits the cytochrome P450 enzyme family and is also an inhibitor of p-glycoprotein. It can decrease the bioavailability and/or clearance of many drugs and has a high potential for drug-to-drug interactions.
Ketoconazole may increase the risk for toxicity of cyclosporine, ivermectin, digoxin, amitriptyline, cisapride, clomipramine, and midazolam. Since it’s best absorbed at an acidic pH, ketoconazole won’t work as well when combined with drugs that increase pH, like omeprazole, H2 blockers, and other acid-modulating drugs.
7. Metoclopramide
This prokinetic and anti-emetic agent shortens gastric emptying time and can increase the absorption of acetaminophen and aspirin from the small intestine, increasing the risk for toxicity.
Metoclopramide can potentially cause extrapyramidal side effects (tremors) when combined with acepromazine or SSRIs like fluoxetine.
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8. Omeprazole
This proton pump inhibitor decreases the clearance of diazepam, midazolam, warfarin, and carbamazepine in humans by inhibiting some cytochrome P450 enzymes. Omeprazole can also lead to digoxin toxicosis in humans, but this hasn’t been evaluated in dogs or cats.
All proton pump inhibitors decrease gastric acidity and can decrease the absorption of drugs that are absorbed best at an acidic pH, like ketoconazole and itraconazole.
9. Phenobarbital
Phenobarbital is a major inducer of cytochrome P450 enzymes in humans and dogs but not in cats. It increases the metabolism of many drugs in humans, including glucocorticoids, clonazepam, lidocaine, theophylline, and digoxin. Dogs on phenobarbital that are being treated for hyperadrenocorticism can require higher doses of mitotane.
Phenobarbital can decrease the efficacy of other anticonvulsants like zonisamide and levetiracetam, so dose adjustments may be necessary in dogs requiring more than one anticonvulsant.
10. Sucralfate
Sucralfate binds many drugs in the gastrointestinal tract, where it decreases absorption by forming insoluble complexes. For example, when doxycycline was given with sucralfate suspension, it decreased the absorption of doxycycline to 20%.3
Sucralfate also inhibits the absorption of theophylline, digoxin, and azithromycin in humans, and this likely occurs in dogs and cats as well.
Preventing medication interactions with a drug interaction checker
We face the potential for drug interactions like these every single time we prescribe more than one medication.
While we all want to safeguard our patients, it’s impossible to rely on memory alone to remember all the potential interactions we may encounter. We’re also busier than ever, so most of us don’t have the time to flip back and forth between drug monographs to double-check potential drug interactions.
That’s why relying on a drug interaction checker for support is so invaluable. But human-specific drug interaction tools don’t typically list veterinary drugs or use species-specific data, leaving potentially dangerous information gaps.
The drug interaction checker in Plumb’s™ is a continually updated interactive tool that gives you veterinary-specific guidance. Enter all your patient’s medications at once to see how each drug interacts with the others based on current evidence in veterinary patients.
Classifications are color-coded and range from contraindicated to no known interaction, with three levels of caution in between: major, moderate, and minor.
Plumb’s™ interaction checker is available in seconds from any internet-connected device, so you can safely and quickly prescribe.
When you use the Plumb’s™ drug interaction checker, you can be confident you’re doing all you can to safeguard your patients against drug interactions.
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Further Reading
- Reinhart JM, Trepanier LA. Top ten potential drug interactions in small animal medicine. Eur J Companion Anim Pract. 2016;26(4):9-19.
- Ogino T, Mizuno Y, Ogata T, Takahashi Y. Pharmacokinetic interactions of flunixin meglumine and enrofloxacin in dogs. Am J Vet Res. 2005;66(7):1209-1213. doi:10.2460/ajvr.2005.66.1209
- KuKanich K, KuKanich B. The effect of sucralfate tablets vs. suspension on oral doxycycline absorption in dogs. J Vet Pharmacol Ther. 2015;38(2):169–173.