Top 8 Drug Interactions for Orally Administered Medications

Drug interactions, particularly those associated with orally administered drugs, can significantly impact pharmacokinetics and pharmacodynamics. Interactions can affect pH, chelation, absorption, and cytochrome P450 (CYP450) enzymes and may lead to degradation, formation of insoluble complexes, issues with bioavailability, and increased or decreased drug concentrations.

Consideration of these potential interactions is critical for maintaining appropriate plasma concentrations and avoiding significant adverse effects.

1. Cimetidine

Cimetidine, a histamine₂-receptor antagonist (H2RA) used to reduce gastric acid production, is a CYP450 enzyme inhibitor that decreases the clearance of many drugs, most notably metronidazole, chloramphenicol, lidocaine, and theophylline.^1-5 Decreased clearance can lead to increased risk for toxicosis associated with these medications. Alternatives to cimetidine include famotidine and ranitidine, where available.^1-5 Ranitidine was removed from most markets globally in 2020.⁶

2. Sucralfate & Other Aluminum-Containing Preparations

Sucralfate, an aluminum-containing GI mucosal protectant, reacts with hydrochloric acid in the stomach to form an insoluble paste-like aluminum moiety–containing complex.⁷ This aluminum moiety can bind with tetracyclines, fluoroquinolones, and ursodiol and may lead to a reduction in absorption and efficacy.^1-5 Administering sucralfate 2 hours after these medications may help reduce the impact on absorption, with the exception of fluoroquinolones, as poor bioavailability has been noted up to 6 hours between administration of fluoroquinolones and sucralfate in humans.^4,5

3. Ketoconazole

Ketoconazole, an imidazole antifungal, is a CYP450 enzyme inhibitor (specifically CYP3A) and a P-glycoprotein substrate and inhibitor that can decrease drug metabolism, leading to higher concentrations of cyclosporine, ivermectin, digoxin, tricyclic antidepressants (TCA), cisapride, and midazolam.^3-5 Ketoconazole can lower the required cyclosporine dose by 33% to 50%,^1,2,8 which can help offset the cost of cyclosporine. Ketoconazole requires an acidic environment for appropriate absorption and must be administered with food. Absorption of ketoconazole is enhanced in an acidic environment, so concomitant use of drugs that can increase GI pH (eg, antacids, H2RAs, proton pump inhibitors, sucralfate) should be avoided.^1-5

4. Fluoroquinolones

Fluoroquinolone (eg, enrofloxacin, marbofloxacin) absorption is reduced in the presence of divalent or trivalent cations.^1,2,4,5 Concomitant administration should be avoided, or administration should be separated by at least 2 hours for drugs containing aluminum (eg, sucralfate), calcium, iron, magnesium, zinc, or phosphate-binding agents (eg, lanthanum, sevelamer).^1-5

Fluoroquinolones can increase serum concentrations of theophylline due to inhibition of metabolism via CYP1A2, which can reduce clearance of theophylline by 30% to 50% in dogs.^4,5

5. Metoclopramide

Metoclopramide, a dopamine antagonist, is used as a prokinetic agent. This drug alters gastric emptying time, which can increase absorption in the small intestine for drugs like acetaminophen and aspirin and can contribute to alcohol toxicity in humans. Activity on dopamine receptors can lead to extrapyramidal signs (eg, tremors) in patients with renal insufficiency or when combined with other drugs that block dopamine receptors (including acepromazine) or drugs that inhibit the metabolism of metoclopramide (eg, selective serotonin reuptake inhibitors [SSRIs]).^3-5

6. Furosemide

Loop diuretics (eg, furosemide) can lead to hypotension, electrolyte derangements, and renal impairment when combined with aminoglycoside antibiotics (eg, gentamicin, amikacin), angiotensin-converting enzyme inhibitors (eg, benazepril, enalapril), and angiotensin receptor blockers (eg, telmisartan).^3-5 Furosemide can also result in dehydration and prerenal azotemia, which decreases clearance of digoxin. Electrolyte derangements caused by furosemide increase the potential for digoxin toxicity.^3-5 Diuresis with furosemide increases renal loss of bromide, resulting in the need for adjustments of bromide dosages.^4,5

7. Phenobarbital

Phenobarbital, a barbiturate antiepileptic, is a CYP450 enzyme inducer that can increase clearance and decrease plasma concentration of glucocorticoids, zonisamide, levetiracetam, ketoconazole, clomipramine, lidocaine, propranolol, digoxin, and mitotane.^1,3,4,5 Dose adjustments may be needed for patients treated with >1 antiepileptic medication because of increased metabolism and clearance of drugs like zonisamide and levetiracetam. Phenobarbital can autoinduce its metabolism, requiring dosage adjustments for patients given phenobarbital long-term.^1,3-5

8. Clomipramine

TCAs (eg, clomipramine) can cause serotonin syndrome when combined with other medications that have serotonergic activity, including SSRIs, serotonin and norepinephrine reuptake inhibitors (SNRIs), tramadol, trazodone, mirtazapine, and ondansetron.^3,4 Concomitant use with monoamine oxidase inhibitors (MAOI; eg, selegiline, amitraz) is contraindicated, and a washout period of at least 14 days between administration of MAOIs and TCAs is necessary.^3-5