Drug interactions in small animal medicine

Introduction

Some drug-drug interactions cause unwanted morbidity and mortality within small animal medicine. 

Several drug-to-drug interactions are incompatible with each other as they can result in a lack of a therapeutic effect or toxicity within the patient. 

There are two ways to mix drugs:

• Mixing drugs in vitro, such as within a syringe
• Mixing drugs in vivo, by administering multiple drugs for the patient to ingest without considering interactions

What can mixing drugs do to animals?

Pharmaceutical drug interactions are drug interactions that occur before the administration or absorption of a drug. This can occur from the addition of drugs to intravenous fluid preparations within critical care environments. Besides drug mixing, degradation can also occur from changes in temperature or exposure to ultraviolet radiation. This mixing can cause fluctuations in environment and pH thereby leading to the formation of precipitate and the disruption of drug structure and stability. 

Pharmacokinetic drug interactions occur within the body of the patient. These interactions occur when one drug alters the disposition of another drug, thereby changing the way it is absorbed, distributed, metabolised and eliminated from the patient. These changes can interfere with hepatic drug clearance,  the activity of cytochrome P-450, and many other pathways thereby causing overdosage or decreased pharmaceutical effects from medication. 

The most common drug interactions to look out for:

Antibiotics

One of the leading examples of drug-to-drug interactions is the interactions of antibiotics, such as ampicillin, tetracyclines, chloramphenicol, penicillins and amphotericin B when mixed with other drugs. 

Aminoglycosides, such as gentamicin and tobramycin when mixed with most other drugs result in the inactivation of both drugs’ pharmaceutical effects. 

Fluoroquinolones

Fluoroquinolones notoriously can chelate with metallic compounds. Mineral and vitamin supplements, such as Lixotinic, contain a significant concentration of iron and calcium, which decreases fluoroquinolone concentration by approximately 50%. 

Intravenous fluoroquinolones should never be mixed with cation-containing fluid solutions. Cation-containing fluid solutions include:

• Calcium (Ca2+): Calcium carbonate
• Aluminium (Al3+): Aluminium hydroxide, Aluminium carbonate
• Magnesium (Mg2+)
• Iron (Fe3+): Oral Iron supplmenets
• Zinc
• Sucralfate, which consists of aluminium hydroxide and sulphated sucrose

Antacid compounds

Antacid compounds or H2 compounds such as Cimetidine can suppress stomach acidity. Many oral drugs require a low pH of stomach acidity to become activated. Therefore, in combination with H2 blockers many oral drugs will have decreased absorption, these include antifungal drugs such as ketoconazole and itraconazole. 

Cimetidine 

Cimetidine decreases the activity of Cytochrome P-450, which can potentially lead to overdosage involving drugs that utilise this enzyme to be cleared. This effects:

• Chloramphenicol: risk of developing dos-dependent leukopenia
• Metronidazole: risk of developing neurological side effects
• Lidocaine: risk of developing enhanced gastrointestinal and neurological side effects
• Theophylline and Aminophylline: risk of developing theophylline toxicity
• [5] Warfarin: Risk of developing delay in Prothrombin time
• [6,7,8] Propranolol, Diazepam & Midazolam: Risk of developing heart complications

It is recommended that H2 blockers are used over cimetidine for patients treated with multiple drugs. 

Sucralfate

Sucralfate belongs to an aluminium-containing drug group. Within this group, they can form complexes with other drugs in the gastrointestinal tract, thereby decreasing their pharmaceutical effects. This effects:

• Fluoroquinolones: Decreases bioavailability
• Tetracycline and doxycycline: Inhibited if ingested orally
• H2 blockers: Delays the absorption of H2 blockers
• Theophylline, aminophylline, digoxin, and azithromycin: all have decreased efficacy 

Ketoconazole

Ketoconazole and itraconazole are a part of a group of drugs that are activated within acidic pH environments, thereby it is not advised to combine these with:

• Omeprazole
• H2 blockers
• Antacids

Ketoconazole also inhibits cytochrome P450 enzyme alongside p-glycoprotein, which decreases the bioavailability and clearance of many drugs. This effects:

• Digoxin: risk of developing digoxin toxicity
• Amitriptyline, and midazolam: can increase sedation
• Warfarin: risk of prolonging Warfarin toxicity 

The benefit of drug mixing with Ketoconazole:

Cyclosporine can be used alongside Ketoconazole for favourable interactions by interaction with Cyclosporine to lower its dosage in vivo.  

Metoclopramide

Metoclopramide is a dopaminergic antagonist and a prokinetic agent, thereby increasing GI motility. This interacts with:

• Acetaminophen, aspirin: Enhanced absorption by increased gastric emptying
• Phenothiazines, such as Chlorpromazine and acepromazine: Enhanced extrapyramidal side effects, as seen with unpurposeful movements such as tremors

Cisapride

Cisapride is a substrate of CYP3A enzymes, as such, drugs that inhibit CYP3A may increase cisapride concentration which can lead to fatal cardiac arrhythmias. Drugs that inhibit CYP3A include:

• Clarithromycin and erythromycin
• Fluconazole, itraconazole and ketoconazole

Furosemide

Several drug combinations can lead to enhanced furosemide toxicity. These drug combinations include:

• Amikacin and gentamicin: Nephrotoxicity is enhanced
• Enalapril, benazepril: Can cause hemodynamic changes if given with a full dose of furosemide
• Digoxin: In combination, it increases serum digitoxin levels. 
• Lidocaine: In combination, it can blunt the antiarrhythmic effect of lidocaine. 
• Bromide: Increases the renal loss of bromide

Omeprazole

Omeprazole is an inhibitor of P450 enzymes, as such, it may increase the toxicity, of:

• Diazepam and midazolam
• Warfarin

Omeprazole can also decrease the absorption of:

• Iron supplements
• Ketozonazole and itraconazole

Phenobarbital

Phenobarbital is a major P450 inducer in dogs. It increases the metabolism of:

• Glucocorticoids, ketoconazole, clomipramine, chloramphenicol, lidocaine, etodolac, digoxin and propranolol: Decreases pharmaceutical effects 

Phenobarbitol causes minimal disturbances to cytochrome P450 in cats, therefore drug-to-drug interactions are minimal in cats. 

Clomipramine

Clomipramine can have interactions with monoamine oxidase inhibitors. As such, they interact with:

• L-deprenyl
• Amitraz: an MAO inhibitor 

The metabolism of clomipramine can be inhibited by:

• Fluoxetine (Prozac): Leads to increased clomipramine levels and cardiac conduction disturbances
• Ketoconazole and intraconazole

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Nonsteroidal anti-inflammatory drugs can interact with:

• Furosemide: Decreasing its efficacy 
• Metoclopramide: can cause enhanced GI absorption via increased gastric emptying (specifically Aspirin)
• Warfarin: Increases risk of bleeding
• ACE inhibitors: increased risk of kidney failure
• ACE inhibitors, Beta-blockers and Diuretics: Can oppose the pharmaceutical effects
• Other NSAIDs or Corticosteroid medications: increase the risk of gastrointestinal ulceration or bleeding

Conclusion

When prescribing medication for a patient, it is always vital to double-check what medications they are already on and how these drugs may potentially affect other medications, efficacy and toxicity. Hampering processes within a patient's body can lead to overdosage of medication or decreased pharmaceutical effects, leading to unwanted consequences for the client and clinic. To help with drug-to-drug interactions find below a simplified table introducing drug-to-drug interactions that may affect small animals. 

Courtesy of Lauren A,. et.al. by School of Veterinary Medicine in Wisconsin-Madison

References:

Drug Interactions in Animals: What Happens When We Mix Drugs? - WSAVA2007 - VIN. (2023). Vin.com. https://www.vin.com/apputil/content/defaultadv1.aspx?id=3860837&pid=11242&

Top Ten Potential Drug Interactions in Dogs and Cats - WSAVA2008 - VIN. (2023). Vin.com. https://www.vin.com/apputil/content/defaultadv1.aspx?pId=11268&catId=32736&id=3866571

Pitman, Hoang, Wi, Alsheikh, Hiner, & Percival. (2019). Revisiting Oral Fluoroquinolone and Multivalent Cation Drug-Drug Interactions: Are They Still Relevant? Antibiotics, 8(3), 108. https://doi.org/10.3390/antibiotics8030108

Deaton, J. G., & Nappe, T. M. (2022, July 18). Warfarin Toxicity. Nih.gov; StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK431112/#:~:text=Acute%20overdose%20of%20warfarin%20has,to%20clinical%20signs%20and%20complications.

Beta-blockers. (2022, April). Pet Poison Helpline. https://www.petpoisonhelpline.com/poison/beta-blockers/#:~:text=Overdose%20can%20result%20in%20heart,and%20secondary%20acute%20kidney%20failure.

Easton, D. (2020, March 6). Diazepam - American College of Veterinary Pharmacists. American College of Veterinary Pharmacists. https://vetmeds.org/pet-poison-control-list/diazepam/#:~:text=Signs%20and%20symptoms%20of%20toxicity,and%20very%20low%20body%20temperature.

Easton, D. (2020, March 6). Midazolam - American College of Veterinary Pharmacists. American College of Veterinary Pharmacists. https://vetmeds.org/pet-poison-control-list/midazolam/#:~:text=Signs%20and%20symptoms%20of%20toxicity,and%20very%20low%20body%20temperature.

Health. (2021). Medications - non-steroidal anti-inflammatory drugs. Vic.gov.au. https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/medications-non-steroidal-anti-inflammatory-drugs#drug-interactions-with-nsaids