Top 5 Commonly Missed Drug Interactions

Awareness of the risks of polypharmacy and possible drug interactions, especially when starting or changing therapy, is critical. Drug interactions can occur in many ways, including through inactivation of one or more chemical structures, production of sub- or supratherapeutic drug levels over time, and development of life-threatening syndromes.

The following list, although not comprehensive, provides insight on possible types of drug interactions in veterinary medicine.

1. Chelation of Fluoroquinolones & Tetracyclines With Heavy Metals

Chelation is a process in which an ionic molecule (ie, ligand) forms multiple single bonds with a heavy metal that has multiple positive charges (Figure). These bonds render the ligand essentially inert, preventing the drug from exerting its intended effect on the body.

FIGURE Example of chelation illustrated by complexation of an enrofloxacin molecule with iron. Image partially created with use of the Chemical Sketch Tool (see Suggested Reading)¹¹

Chelation can be used as a medical treatment (eg, for heavy metal toxicosis), but chelation of fluoroquinolones or, to a lesser extent, tetracyclines can prevent achievement of clinically effective levels in the blood. Aluminum- and magnesium-containing antacids, fortified nutritional supplements, and dairy products are common chelators of fluoroquinolones.¹ Lanthanum chloride, sevelamer hydrochloride, and D-penicillamine are also chelators with clinical applications. To reduce the risk for antibiotic inactivation, administration of fluoroquinolones or tetracyclines should ideally occur 1 to 2 hours before or after administration of possible chelators.

2. Serotonin-Affecting Drugs & Serotonin Syndrome

Serotonin syndrome is an infrequent but potentially fatal condition characterized by a dangerously elevated level of serotonin in the CNS and is often directly related to concomitant use of serotonergic drugs. Serotonin syndrome most frequently occurs when a new serotonergic medication is added to an existing serotonergic therapy or when doses are changed.

Trazodone, selegiline, tramadol, mirtazapine, metoclopramide, fluoxetine, ondansetron, and clomipramine are common drugs known or thought (based on human data) to cause serotonin syndrome in veterinary patients.^2,3 For patients receiving serotonergic drugs, caution should be used when new therapies are added or existing doses are adjusted. Pet owners should be instructed on how to report potential signs of serotonin syndrome (see Clinical Signs of Serotonin Syndrome).

3. Induction or Autoinduction of Cytochrome P450 by Phenobarbital

Phenobarbital is a substrate and an inducer of cytochrome P450 (CYP450) enzymes in humans and veterinary patients. Phenobarbital can increase the metabolism of other drugs, and its metabolism can be altered by the presence of other drugs that share the same substrate. Many drugs interact with phenobarbital; of note, phenobarbital can decrease serum concentrations of some other antiepileptic medications (eg, levetiracetam, topiramate, zonisamide), which may lead to breakthrough seizures and inability to accurately predict and treat epilepsy.

In addition, phenobarbital induces the CYP450 enzyme responsible for its own metabolism (ie, autoinduction). Phenobarbital doses therefore may need to be continuously evaluated and/or increased; other antiepileptics may be considered.

4. Theophylline & Cytochrome P450 1A2

Theophylline, a commonly used bronchodilator, is highly metabolized via CYP450 pathways. In humans and dogs, this process occurs mainly via cytochrome P450 1A2 (CYP1A2).^4-7

Phenobarbital and rifampin may induce theophylline metabolism, decreasing bioavailability. Omeprazole and lansoprazole are inducers of CYP1A2 but have not demonstrated an ability to alter theophylline metabolism.^8,9 Conversely, enrofloxacin, chloramphenicol, some macrolide antibiotics (eg, erythromycin), and cimetidine may inhibit theophylline metabolism.¹⁰ Significant reductions in the theophylline dose (30%-50%) may be warranted in patients receiving enrofloxacin or chloramphenicol to reduce the risk for adverse effects.

In addition to the potential for drug interactions, expression of CYP1A2 in dogs has high polymorphic variability. Theophylline administration should be closely monitored in certain breeds, including beagles and Irish wolfhounds, particularly when other drugs are initiated or discontinued.

5. Cisapride & Other Drugs That Can Inhibit P-Glycoprotein

P-glycoprotein is a primary efflux pump that helps keep toxic chemicals, including drugs, out of areas of the body where they are unwanted. A naturally occurring multidrug sensitivity gene (MDR1 gene, also known as ABCB1 gene) mutation (also known as ABCB1-1delta) most commonly found in breeds like Australian shepherds, collies, and Shetland sheepdogs can cause an inefficiency in P-glycoprotein expression that leads to elevated and potentially dangerous levels of substrate drugs (eg, some macrolides [eg, ivermectin, eprinomectin], cyclosporine, ketoconazole, digoxin, rivaroxaban, acepromazine). P-glycoprotein can also be inhibited by certain medications, which can cause increased (potentially toxic) levels of drugs that would otherwise be efficiently pumped out of the brain. The substrates listed above, along with spironolactone, spinosad, and cisapride, may competitively inhibit P-glycoprotein activity. Although the extent of P-glycoprotein inhibition is likely variable, caution should be used when administering cisapride in conjunction with P-glycoprotein substrates, particularly in dogs with the MDR1 gene mutation. Cisapride is primarily metabolized via the CYP450 pathway that is shared with many of the same P-glycoprotein substrate drugs. Thus, drugs clinically impacted by cisapride can simultaneously increase the cardiotoxic effects of cisapride.