Top ten drug interactions in dogs and cats (Proceedings)

In humans, the risk of adverse drug interactions multiplies as the number of administered drugs increases. Interactions can occur during IV drug administration, during oral absorption, at the target site, or during hepatic or renal elimination, and may lead to loss of efficacy or increased toxicity. Although most of our knowledge of drug interactions is from data in humans, many of these interactions are likely to occur in dogs and cats as well.

Cimetidine

Cimetidine is a major P450 enzyme inhibitor, and decreases the clearance of many drugs, which may lead to drug toxicity:

     • Chloramphenicol: dose-dependent leukopenia

     • Metronidazole: neurologic side effects

     • Lidocaine: GI and neurologic side effects

     • Theophylline and aminophylline: theophylline toxicity

     • Warfarin, propranolol, diazepam, midazolam, many others....

Because of many potential cimetidine interactions, alternative H2 blockers such as ranitidine, famotidine, or nizatidine (which are not P450 inhibitors at therapeutic concentrations), should be chosen over cimetidine for patients treated with multiple drugs. Ranitidine and nizatidine have the added advantage of prokinetic effects, which may counteract gastric atony in clinically ill patients.

Sucralfate

Aluminum-containing drugs such as sucralfate can form complexes with many other drugs in the GI tract, markedly decreasing drug absorption:

     • Fluoroquinolones: poor bioavailability even 6 hours after sucralfate in humans

     • Tetracycline and doxycycline: marked inhibition of oral absorption by sucralfate

     • H2 blockers: sucralfate delays, but does not decrease the extent of, the absorption of H2 blockers; therefore staggering of dosing is probably NOT required for sucralfate and H2 blockers

     • Theophylline, aminophylline, digoxin, azithromycin: sucralfate may decrease efficacy

     • This is a physicochemical interaction that is likely to occur in dogs and cats as it does in humans.

Ketoconazole

Ketoconazole and itraconazole are best absorbed at acidic pH; therefore, do not combine these drugs with:

     • Omeprazole, H2 blockers, or other antacids

     • Interestingly, increased gastric pH does not affect the absorption of fluconazole 1

Ketoconazole inhbits a cytochrome P450 enzyme, CYP3A, with a wide substrate range and high potential for drug-drug interactions. Ketoconazole is also an inhibitor of p-glycoprotein, an important drug efflux transporter in the intestine, kidney, and biliary tree. Ketroconazole can therefore decrease the bioavailability and/or clearance of many drugs:

     • Cyclosporine: a favorable interaction; ketoconazole can allow lower doses of cyclosporine.

Recommended dosages: cyclosporine, 5 mg/kg once to twice daily, depending on disease being treated; ketoconazole, 10 mg/kg/day. Monitor ALT and clinical response. Whole blood cyclosporine can be measured at steady state (by one week). Target levels for immunosuppression in humans are 400-600 ng/ml.

     • Digoxin: ketoconazole can lead to digoxin toxicity

     • Amitriptyline, midazolam: ketoconazole could increase sedation

     • Warfarin: ketoconazole may prolong its toxicity

Note: Itraconazole, like ketoconazole, also inhibits the P450 metabolism of the same drugs in humans.

Fluoroquinolones

The absorption of oral fluoroquinolones is markedly impaired by drugs that contain divalent or trivalent cations, such as:

     • Sucralfate, aluminum hydroxide, aluminum carbonate

     • Calcium carbonate

     • Oral iron, oral zinc

In humans and dogs, fluoroquinolones inhibit the CYP1A2 metabolism, of theophylline. This has lead to theophylline toxicity in humans. In dogs, enrofloxacin leads to higher plasma theophylline concentrations by about 30-50%.2

Metoclopramide

As a dopaminergic (D2) antagonist and prokinetic agent, metoclopramide has several important drug interactions:

     • Enhanced absorption of acetaminophen, aspirin, and alcohol overdoses via increased gastric emptying (shown in humans).

     • Enhanced extrapyramidal side effects (tremor) in combination with phenothiazines (e.g. chlorpromazine, acepromazine) or selective serotonin reuptake inhibitors (e.g. fluoxetine), or with renal insufficiency.

     • Metoclopramide reduces the amount of propofol needed for anesthetic induction in humans by 20-25% (mechanism unknown).

It has been suggested that metoclopramide may antagonize the effects of dopamine on renal hemodynamics. However:

     • Metoclopramide has no effect on low dose dopamine-induced increases in GFR or effective renal plasma flow in humans.

     • Dopamine increases urine output in cats 3 as in humans, but this is not inhibited by dopamine antagonists. 4

Cisapride

Like ketoconazole, cisapride is a substrate of CYP3A. High plasma concentrations of cisapride can lead to potentially fatal cardiac arrhythmias in humans. Drugs that inhibit CYP3A may increase cisapride concentrations and increase the risk of cardiac side effects in humans:

     • Clarithromycin, erythromycin (but not azithromycin)

     • Fluconazole, itraconazole, ketoconazole

     •Note: in one study in dogs, erythromycin did not alter cisapride pharmacodynamics.5

Furosemide

Several drug combinations with furosemide can lead to enhanced toxicity:

     • Amikacin and gentamicin: nephrotoxicity is enhanced by furosemide; mannitol may be preferable to furosemide for treatment of acute renal failure due to aminoglycosides.

     • Enalapril, benazapril: may cause hemodynamic changes leading to acute renal failure, when given with high doses of furosemide. Use conservative initial doses of ACE inhibitors when also starting furosemide, and monitor clinical status and renal function over the first 1-2 weeks.

     • Digoxin: furosemide increases serum digoxin levels (independent of dehydration). Furosemide can also lead to hypokalemia and hypomagnesemia, both of which exacerbate the cardiac toxicity of digoxin. In addition, furosemide can lead to pre-renal azotemia, leading to decreased digoxin excretion. All of these interactions can lead to digoxin toxicity unless serum digoxin levels are monitored.

     • Renal function and serum electrolytes should be routinely evaluated in all patients on furosemide.

Other drug combinations with furosemide can affect efficacy:

     • Lidocaine: hypokalemia secondary to furosemide can blunt the antiarrhythmic effects of lidocaine. Serum potassium should be evaluated in patients with ventricular arrhythmias, and potassium supplementation should be considered if patients do not respond to lidocaine.

     • Bromide: furosemide administration will increase the renal loss of bromide, and lower serum bromide concentrations, which may lead to seizure breakthrough

Omeprazole

Omeprazole is an inhibitor of some P450's in humans, and may inhibit the metabolism, and possibly increase the toxicity, of:

     • Diazepam, midazolam

     • Warfarin

As an inhibitor of gastric acid secretion, omeprazole can also decrease the absorption of:

     • Iron supplements

     • Ketoconazole and itraconazole (but not fluconazole, which does not require an acidic pH for absorption)

Phenobarbital

Phenobarbital is a major P450 enzyme inducer in humans and dogs. Phenobarbital speeds the metabolism of many drugs in dogs, including:

     • Glucocorticoids

     • Mitotane – phenobarbital can lead to higher mitotane dosage requirements in dogs being treated for hyperadrenocorticism

     • Ketoconazole

     • Clomipramine

     • Chloramphenicol – conversely, chloramphenicol is a major inhibitor of phenobarbital clearance, and can lead to sedation in dogs on phenobarbital

     • Lidocaine

     • Etodolac

     • Theophylline

     • Digoxin, propranolol, and many others...

However, phenobarbital causes minimal cytochrome P450 enzyme induction in the cat, 6,7 and therefore these P450-mediated drug interactions are unlikely in the cat.

Clomipramine

As a tricyclic antidepressant that inhibits norepinephrine reuptake, clomipramine can have pharmacologic interactions with monoamine oxidase inhibitors (which decrease the breakdown of norepinephrine and serotonin)

     • L-deprenyl (selegiline): MAO inhibitors like L-deprenyl used in combination with clomipramine or amitriptyline can lead to "serotonin syndrome" (twitching, tremor, seizures) in humans

     • Amitraz: an MAO inhibitor found in tick dips and collars; potential for interaction with tricyclic antidepressants like clomipramine

The metabolism of clomipramine can be inhibited by:

     • Fluoxetine (Prozac): can lead to increased clomipramine levels and cardiac conduction disturbances in humans

     • Ketoconazole, itraconazole

Drug interactions in humans that may also affect dogs and cats

Cited references

Zimmermann, et al. The influence of gastric pH on the pharmacokinetics of fluconazole: the effect of omeprazole. Int J Clin Pharmacol Ther 1994;32:491-496.

Intorre, et al. Enrofloxacin-theophylline interaction: influence of enrofloxacin on theophylline steady-state pharmacokinetics in the beagle dog. J Vet Pharmacol Ther 1995;18:352-356.

Wassermann, et al. Dopamine-induced diuresis in the cat without changes in renal hemodynamics. Naunyn Schmiedebergs Arch Pharmacol 1980;312:77-83.

Wright, et al. Pharmacokinetics of gentamicin after intravenous and subcutaneous injection in obese cats. J Vet Pharmacol Ther 1991;14:96-100.

Al-Wabel, et al. Electrocardiographic and hemodynamic effects of cisapride alone and combined with erythromycin in anesthetized dogs. Cardiovasc Toxicol 2002;2:195-208.

Maugras, et al. The hepatic cytochrome level in the cat (Felis catus): normal value and variations in relation to some biological parameters. Comp Biochem Physiol B 1979;64:125-127.

Truhaut, et al. [Induction of cytochrome P 450 by phenobarbital in cats]. C R Acad Sci Hebd Seances Acad Sci D 1978;286:371-373.