Drug interactions:understanding, predicting and managing

Why should you do this module? There are many situations in which you might use several medicines at the same time in a companion animal – for example, to treat chronic diseases or multiple conditions in older animals; to achieve broad parasite protection; in anaesthetic protocols; and when anaesthetising animals on long-term drug treatment.  This module covers: the principles of interactions and their potential consequences; interactions with herbal medicines and nutraceuticals; where to find information about interactions and what to do with it; and practical tips on predicting, avoiding and managing drug interactions.

Why should you do this module?

There are many situations in which you might use several medicines at the same time in a companion animal – for example, to treat chronic diseases or multiple conditions in older animals; to achieve broad parasite protection; in anaesthetic protocols; and when anaesthetising animals on long-term drug treatment. 

This module covers: the principles of interactions and their potential consequences; interactions with herbal medicines and nutraceuticals; where to find information about interactions and what to do with it; and practical tips on predicting, avoiding and managing drug interactions.

A drug interaction is an alteration in the magnitude or duration of the pharmacological effects of one drug caused by another drug, a food or any other substance. If the interaction causes an increase in the effects of the drug the outcome can be harmful because of an increased likelihood of adverse effects. A reduction in efficacy due to an interaction can also be harmful. Occasionally, an interaction can be beneficial, such as the deliberate use of an antihypertensive drug together with a diuretic in order to gain antihypertensive effects not achievable with either drug alone; and the use of adrenaline to slow the systemic absorption of lidocaine and prolong its analgesic effect. There are three main categories of drug interaction – pharmacokinetic, pharmacodynamic and pharmaceutical.

Pharmacokinetic interactions are the most common type. They occur if one drug increases or decreases the concentration of another drug in the system by altering its absorption, distribution, metabolism or excretion (Waller 2014). This can lead to an increased risk of adverse effects or reduced efficacy of one or more drugs (Kennedy 2016). The effects can be complicated and difficult to predict because the interacting drugs often have unrelated actions.

Effects on drug absorption

These interactions occur because of a change in intestinal blood flow or motility, an alteration in gut bacteria, a change in stomach acidity or because of binding (Kennedy 2016; Davis 2011; Kukanich 2014). The following are examples:

  • delayed absorption of a drug from the small intestine because of delayed gastric emptying caused by an opioid.
  • reduced absorption of itraconazole and ketoconazole (which have pH-dependent solubility) because of altered pH in the stomach by proton pump inhibitors.
  • reduced absorption of tetracycline due to chelation in the stomach by calcium-containing solutions (such as milk).
  • reduced absorption of doxycycline due to chelation by aluminium ions from sucralfate.

Effects on drug distribution

Protein binding interactions can affect distribution. A drug (such as warfarin or phenytoin) that binds to plasma proteins, such as albumin, in the bloodstream can be displaced from its binding site by another with greater binding affinity (Kennedy 2016). This type of interaction is usually short lived because metabolism of the affected drug usually increases in parallel with the increased concentrations of unbound drug (Davis 2011).

Effects on drug metabolism

Important interactions can occur when one drug induces or inhibits the enzymes involved in the metabolism of another drug, such as enzymes in the cytochrome P450 system in the liver (Waller 2014). This can affect systemic clearance of a drug and also, after oral dosage, first-pass metabolism (Waller 2014). Many drugs are metabolised by CYP450 enzymes, so these are common pharmacokinetic interactions (Sasaki 2015; Waller 2014; Court 2013; Palmerio 2013; Trepanier 2006). Most interactions due to enzyme inhibition occur relatively quickly and the effects are usually short-lived once the inhibitor has been stopped. Interactions due to enzyme induction need new enzymes to be formed, so can take up to 1–2 weeks to develop, and at least a week to disappear (Kennedy 2016).

  • Drugs that have been shown to induce CYP450 enzymes, and so increase the metabolism of other drugs, in dogs include barbiturates, omeprazole and rifampin (rifampicin) (Sasaki 2015).
  • Drugs that have been shown to inhibit CYP450 enzymes, and so reduce the metabolism of other drugs, in dogs include fluoroquinolones, azole antifungals, cimetidine, fluoxetine, loperamide, vincristine and ciclosporin (Sasaki 2015; Trepanier 2006). In this way, chloramphenicol reduces the metabolism of barbiturates causing prolonged sedation and increased toxicity (Martin-Jiminez 2011).

There has been little work done in cats on CYP450 enzyme interactions (Trepanier 2006), but inhibition with fluoroquinolones and ketoconazole has been demonstrated (Sasaki 2015).

Effects on drug elimination

A relatively small reduction in renal elimination can cause a disproportionate increase in drug exposure and toxicity. For example:

  • aminoglycoside antibiotics can reduce glomerular filtration rate, which leads to increased levels in the body as well as accumulation of other drugs that are mainly excreted by the kidneys, such as digoxin (Kennedy 2016).
  • competition for renal tubular excretion can also cause a drug interaction between, for example, NSAIDs and methotrexate.

P-glycoprotein (P-gp) is a protein involved in drug transport across cell membranes. It is a product of the MDR-1 gene and is thought to fulfil a protective function, by actively pushing substances and drugs out of cells. It can be involved in absorption, distribution and elimination interactions. Drug interactions occur because some drugs can induce the expression of P-gp (and so increase the amount of P-gp), or inhibit its activity (Kennedy 2016; Mealey 2013; Mealy &Fidel 2015; Stockley 2011). In dogs, interactions involving P-gp can enhance the toxicity of many drugs including some anticancer drugs, antibiotics, antihistamines, ciclosporin and ketoconazole (Mealey 2015; Davis 2011).

Pharmacodynamic interactions occur when the effect of one drug is changed by the presence of another drug acting at the same biochemical or molecular site (such as a drug receptor), on the same target organ, or on a different target but one that is associated with a common physiological process. The effect can be synergistic (when the effect of the two drugs together is greater than the sum of their separate effects), additive (when the drug's effect is increased), or antagonistic (when the drug's effect is decreased) (Joint Formulary Committee 2017; Kennedy 2015; Davis 2011; Martin-Jiminez 2001; Stockley 2011; Veterinary Prescriber 2016). 

Examples of pharmacodynamics effects

Synergistic interactions:

  • beta-lactam antibiotics and aminoglycosides (when one antibiotic increases penetration of another antibiotic).
  • sulfonamides and dihydrofolate reductase inhibitors (e.g. methotrexate), which act at difference places in the same biochemical pathway.
  • pyrantel and febantel (a pro-drug of fenbendazole) are anthelmintics with different modes of action. They are commonly included together in anthelmintic products.

Additive effects:

  • barbiturates and benzodiazepines – increased sedation
  • opioids and NSAIDs – increased analgesia
  • NSAIDs and corticosteroids – increased risk of gastrointestinal ulceration
  • NSAIDs and aminoglycosides – increase risk of nephrotoxicity
  • NSAIDs and heparins – increased risk of bleeding
  • telmisartan and ACE inhibitors – increased risk of hyperkalaemia.

Antagonistic interactions:

  • buprenorphine (a partial opioid agonist) antagonising the effects of morphine (a full agonist).
  • pyrantel and piperazine are anthelmintics with opposing pharmacological actions. Pyrantel paralyses worms by depolarising the neuromuscular junctions whereas piperazine causes paralysis by hyperpolarising the neuromuscular junctions.

Pharmaceutical interactions are uncommon (Kennedy et al. 2016). They can occur when two drugs with incompatible pHs are mixed (for example, in a syringe) and one is precipitated out (Davis 2011). They can also occur between a drug and a carrier (solvent), container or the environment – for example, diazepam can adsorb to plastic or glass containers (Davis 2011; Zoff et al 2016).

Herbal medicines and nutraceuticals are widely used in cats and dogs (Davis 2011; Goodman 2005). Often, they are bought over the counter or online by the pets’ owners and, as with non-prescription medicines, may be used without the vet’s knowledge. There is even less known about interactions between herbal medicines and other drugs in dogs and cats than there is about drug–drug interactions (Davis 2001). However, risks can be estimated from reports in human medicine (Davis 2011; Goodman 2010; Wynn 2006; Zoff et al 2016).

  • Vitamin E at very high doses (400IU/day) can have an effect on coagulation, and has caused severe coagulopathy in dogs when given with warfarin.
  • Mineral supplements containing calcium, magnesium and other multivalent cations can decrease the absorption of drugs such as the fluoroquinolones, penicillamine and tetracycline.
  • Mineral electrolytes, such as chloride and potassium, can interact with drugs – for example, the anticonvulsant bromide and dietary chloride in dogs.
  • St. John's wort induces the expression of CYP450 and P-gp in humans, which can lead to a decrease in plasma concentrations of drugs which are substrates.
  • In humans, gingko biloba induces some CYP450 enzymes and inhibits others, and may also inhibit P-gp in the intestine. It may also increase the risk of bleeding with other drugs that affect platelets, such as non-specific cyclo-oxygenase inhibitors, because it affects platelet function in humans.
  • Asian ginseng inhibits platelet aggregation and some investigators recommend against using it in combination with NSAIDs, warfarin, or heparin. Ginseng has been shown to reduce the analgesic effect of opioids.
  • Garlic may interact with anticoagulant and antiplatelet drugs to increase the risk of bleeding.

For many drugs there is a shortage of robust evidence on drug-drug interactions, particularly in relation to veterinary use (Davis 2011). The available data on interactions in human medicine vary widely in quality and reliability. While some have come from controlled clinical trials, they more usually come from sources such as pharmacovigilance reporting mechanisms and case reports (Stockley 2011). Some listed interactions are known while others are theoretical or speculative. Currently, the Veterinary Medicines Directorate does not explicitly encourage reporting of suspected interactions involving veterinary medicines, although it does look for trends or patterns in data from adverse event reports which might indicate a drug interaction issue.

Interactions noted in human medicine might give an indication for potential drug interactions in animals, and some of the veterinary sources below include them. But it may not always be appropriate to extrapolate between humans and animals or between animal species or even breeds. In human medicine, information on drug interactions has been integrated into prescribing systems but this is yet to happen in veterinary medicine.

The following resources include information on drug interactions. For more on prescribing information, see our module on quick-reference sources.

The clinical significance of drug interactions is difficult to predict in individual patients because it is influenced by many factors, such as the size and frequency of the dose, route of administration, treatment duration, species, breed, age, and renal and hepatic function (Martin-Jiminez 2011; Toutain 2010; Stockley 2011). Nevertheless, some idea of the probable outcome of using drugs together can be based on what has been reported: the stronger the evidence, the firmer the predictions (Stockley 2011).

When deciding the possible first-time use of any two drugs in a particular patient, you need to consider the information about interactions available in the context of the characteristics of the patient (breed, age, disease and so on) so that what you decide to do is well thought out and soundly based. It may not be possible to know all the facts, so an initial conservative approach is often the safest. The use of two interacting drugs together is not necessarily contraindicated, but there is a need to weigh the potential risks and perform additional monitoring when appropriate.

For example, using two parasiticide products, each containing a macrocyclic lactone (e.g. moxidectin and milbemycin), potentially increases the risk of adverse effects, the risk of which is higher in Collie-type dogs because of a genetic difference (MDR-1 mutation) affecting their ability to metabolise drugs in this class.

It is impossible to remember all the known clinically important interactions and how they occur, but there are several ways to reduce the risk.

  • Use reliable and up-to-date reference resources when prescribing. It’s a good idea to use several resources.
  • Be on the alert for drugs that have a narrow therapeutic window or drugs for which it is necessary to keep serum levels at or above a suitable level (e.g. antidiabetic drugs, antiepileptics, anti-infectives, anticancer drugs, immunosuppressants).
  • Be aware of drugs that are key enzyme inducers (e.g. phenytoin, barbiturates) or enzyme inhibitors (e.g. azole antifungals, erythromycin, SSRIs).
  • Think about the basic pharmacology of drugs so that obvious problems (e.g. increased risk of bleeding, sedation) are not overlooked, and try to think of what might happen if drugs that affect the same receptors are used together. Bear in mind that many drugs affect more than one type of receptor. It is easier to do this if you use or think of generic drug names when prescribing.
  • Keep in mind that older animals are at risk because of reduced liver and kidney function, on which drug clearance depends.
  • Adjust doses and monitor the animal closely when there is a possibility of an interaction.
  • Comprehensive drug histories are essential. Ask owners about any herbal or non-prescription medicines or supplements they are giving their pet.
  • Report suspected drug interactions to the Veterinary Medicines Directorate.

Prescribers need to be familiar with the principles of drug interactions and know where to find reliable information about interactions. Ideally, people working in veterinary medicine and owners should be encouraged to report suspected drug interactions to the Veterinary Medicines Directorate. Producers of veterinary prescribing software should consider whether to include information on drug interactions. More research is necessary to determine the effects herbal medicines and nutraceuticals have on drugs in veterinary medicines.

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References

Court MH. Canine cytochrome P-450 pharmacogenetics. Vet Clin Small Anim 2013; 43: 1027-38.

Davis JL. Drug-drug interactions (Proceedings). DVM 360 2011. [Accessed 19 June 2017].

Goodman L, Trepanier L. Potential drug Iinteractions with dietary supplements. Compendium 2005; 27. [Accessed 19 June 2017].

Hunter RP, Isaza R. Polypharmacy in zoological medicine. Pharmaceutics 2017; 9: 10; doi:10.3390/pharmaceutics9010010.  [Accessed 19 June 2017].

Joint Formulary Committee. British National Formulary. London: BMJ Group and Pharmaceutical Press.  [Accessed on 14 May 2017].

Kennedy C et al. Drug interactions. Clin Pharmacol 2016; 44: 422-6.

KuKanich K, KuKanich B. The effect of sucralfate tablets vs. suspension on oral doxycycline absorption in dogs. J Vet Pharmacol Therap 2014; 38: 169-73.

Martin-Jiminez T. Understanding drug interactions (Proceedings). DVM 360 2011.  [Accessed 19 June 2017].

Mealey KL. Adverse drug reactions in veterinary patients associated with drug transporters. Clin Small Anim 2013; 43: 1067–78.

Mealey KL, Fidel J. P-glycoprotein mediated drug interactions in animals and humans with cancer. J Vet Intern Med 2015; 29: 1-6.

Palmeiro BS. Cyclosporine in veterinary dermatology. Vet Clin Small Anim 2013; 43: 153-71.

Sasaki K, Shimoda M. Possible drug-drug interaction in dogs and cats resulted from alteration in drug metabolism: a mini review. J Adv Res 2015; 6: 383-92.

Stockley’s Drug Interactions, 11th edition. Claire Preston (Ed.) London: Pharmaceutical Press, 2011.

Toutain P-L et al. Species differences in pharmacokinetics and pharmacodynamics. In: Cunningham F et al (eds). Comparative and Veterinary Pharmacology, Handbook of Experimental Pharmacology 199. Berlin: Springer-Verlag, 2010.

Trepanier LA. Top ten drug interactions in dogs and cats (Proceedings). DVM360 2010 (online). [Accessed 19 June 2017].

Trepanier LA. Cytochrome P450 and its role in veterinary drug interactions. Vet Clin Small Anim 2006; 36: 975-85.

Waller DG, Sampson T. Medical Pharmacology and Therapeutics, Fourth edition. London: BMA, 2014.

Telmisartan for chronic kidney disease in cats. Veterinary Prescriber 2016. [Accessed 19 June 2017].

Wynn SG, Fougère B. Veterinary Herbal MedicineSt. Louis, Missouri: Moseby Elsevier, 2007.

Zoff A et al. Anaesthesia and drug interactions in dogs and cats. In Practice 2016; 38: 167-75.