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If a drug is used at the same time as another drug, or is taken with food, there may be an interaction, depending on the substances involved. Sometimes two interacting drugs are used deliberately for an advantage, but some interactions can have bad consequences. This module covers the general principles about drug interactions and their potential consequences. It focuses on interactions involving parasiticides. By doing this module you will:

  • Know the definition of a drug interaction
  • Understand how drug interactions can occur
  • Be aware of interactions that involve parasiticides
  • Know what to check to avoid adverse interactions.

A drug interaction is a change in the size or duration of the effects of one drug caused by another drug or a food or other substance.

If an animal is receiving one drug treatment and then another is added, or two or more drugs are started at the same time, there may be an interaction. There are several possible results depending on the drugs involved and the mechanism of interaction:

  • the effects (benefits and harms) of one of the drugs are increased
  • the effects (benefits and harms) of one of the drugs are decreased
  • the beneficial effects of each drug are added together
  • the adverse effects (harms) of each drug are added together.

You can see from this that an interaction is not always a bad thing. Sometimes two drugs with similar effects are used together deliberately to increase the overall treatment effect. An example of this in human medicine is when two or more drugs that lower blood pressure are used to treat high blood pressure. 

There are two main types of drug interactions: pharmacokinetic and pharmacodynamic

A pharmacokinetic interaction occurs if one drug increases or decreases the concentration of another drug in the body by affecting how much of the drug is absorbed, or the extent to which it is distributed in the body, or by affecting how the drug is broken down in the body or eliminated from the body. Pharmacokinetic interactions can be complicated and difficult to predict. Foods, food supplements and herbal medicines can also interact with drugs in this way. Pharmacokinetic interactions are the most common type overall but they are not often associated with non-prescription medicines. The following are examples of pharmacokinetic interactions.

  • Foods containing calcium (e.g. milk) can bind with certain drugs (e.g. tetracyclines) to reduce their absorption from the stomach. 
  • Some drugs are broken down in the body by liver enzymes. An added drug that either stimulates or inhibits the liver enzymes can therefore affect the amounts of the first drug circulating in the body. Phenobarbitone, which is used to treat epilepsy is known to interact with many other drugs through its effects on liver enzymes.
  • Grapefruit juice can stimulate an enzyme in the body that is involved in breaking down certain cholesterol-reducing drugs. This can lead to increased amounts of the drug in the body and therefore a greater likelihood of adverse effects. People on this type of drug are advised to avoid drinking large amounts of grapefruit juice.
  • The amount of a drug eliminated from the body can be changed by another drug or substance that affects blood flow to the kidneys or that changes the acidity of the urine.

A pharmacodynamic interaction occurs when two or more drugs are used that have similar effects, or that have opposite effects.  This type of interaction is easier to predict than pharmacokinetic interactions. Over-the-counter pain medications for humans give some good examples of this type of interaction:

  • paracetamol + ibuprofen  – a useful interaction

Paracetamol and ibuprofen both reduce pain, but they do this through different mechanisms. So, if paracetamol is not reducing pain sufficiently on its own (at the maximum recommended dose), adding ibuprofen is a reasonable option, to get an additional pain-relieving effect. 

  • ibuprofen + naproxen – a harmful interaction

Ibuprofen relieves pain and inflammation. So does naproxen. But both drugs belong to the same class of drugs (called non-steroidal anti-inflammatory drugs [NSAIDs]) and so they have the same mechanism of action and also the same adverse effects. This means that if ibuprofen is not sufficiently effective (at the maximum recommended dose), naproxen should not be added to increase the pain-relieving or anti-inflammatory effects. If this is done, it is unlikely there will be any added benefit, but there is a risk that the adverse effects of each drug will be added together. Gastric bleeding is an adverse effect of this type of drug and so using two together is potentially dangerous. 

  • codeine and alcohol

Both these substances can cause drowsiness. Taken together, the likelihood of becoming drowsy, and for driving performance to be affected, is greater than with either alone. 

febantel pyrantel – additive effects

Many non-prescription wormers for dogs contain febantel and pyrantel together. They include Anthelmin Plus and Drontal Plus. Both drugs are effective against roundworms.

Febantel itself is inactive. After absorption from the stomach it is converted to fenbendazole and oxfendazole. (Drugs that are inactive until they are converted to active forms in the body are known as pro-drugs). Both of these are active against roundworms. They interfere with the body functions of worms, particularly glucose uptake.The parasite dies after exhaustion of its energy reserves, which occurs after a few days.

Pyrantel acts by paralysing susceptible worms which are then expelled from the intestines by peristaltic activity. 

The two drugs have the same effect (killing roundworms) and so the combination may be more effective overall than either drug alone. But because they work in different ways, they are unlikely to have additive adverse effects. This is a beneficial interaction.

pyrantel and piperazine – opposite effects

Pyrantel is in ingredient in several non-prescription wormers, e.g. Drontal, Anthelmin, and as discussed above, it is included in many products in combination with febantel

Piperazine is the active ingredient in Beaphar and Johnson’s wormers. 

Both drugs are active against roundworms. But the two drugs work in opposite ways: pyrantel causes a spastic paralysis whereas piperazine causes a flaccid paralysis and so their effects might be expected to cancel each other out. This is a theoretical drug interaction and there is no evidence that they cancel out each other’s effects in practice and in reality there is no good reason to use products containing these drugs at the same time. 

A drug interaction can occur when two products with the same or similar ingredients are used together. It’s important to be aware of the potential for this sort of interaction, because it can sometimes occur accidentally. 

Different brands – same drug

The pain-relieving drug paracetamol is an ingredient in many over-the-counter brands for humans. For example, Hedex; Nurofen; Night Nurse. Sometimes people use more than one brand at the same time, not realising that there is paracetamol in each one. This is very important because even though paracetamol is a very safe drug when used at recommended doses, too much can be dangerous.

Similar mistakes can occur with veterinary medicines because many different brands are available containing similar active ingredients. For example, there are many different brands containing the ectoparasiticide fipronil (Amflee, Broadline, Duoflect, Frontline, to name a few); another example is the ectoparasiticide imidacloprid, which is an ingredient in Seresto collar and in Advocate spot-on. The brand name does not always give a clue to the active ingredients. Using two products with the same ingredient could lead to a higher risk of adverse effects.

Different brands – similar drugs

Using two or more products with active ingredients in the same drug group can lead to a greater risk of adverse effects. Among the prescription-only parasiticides there are four different macrocyclic lactone drugs: eprinomectinmilbemycinmoxidectin and selamectin. These drugs are active against fleas and worms. Using two products, each containing a different macrocyclic lactone would be the same as using two products containing the same drug – it would mean an increased risk of adverse effects.

Sometimes in veterinary practice two different macrocyclic lactone products are used (e.g. Advocate, which contains moxidectin and Milbemax, which contains milbemycin) without adverse effect. In general it is not necessary to do this. It is important to take care in herding breeds of dog (particularly Collies and Australian Shepherds) because they have a genetic difference (called MDR-1 mutation) that affects their ability to break down drugs in the macrocyclic lactone group. It is fine to use this type of drug at the usual recommended dose in these susceptible breeds, but they may not tolerate higher than recommended doses as well as other breeds.

The place to check for drug interactions is the medicine’s summary of product characteristics (SPC), which is available on the Veterinary Medicine Directorate’s product database, or the product data sheet.

It is worth knowing that sometimes the information on different products is inconsistent. If you look at the SPC or data sheet for products containing pyrantel, you will see that there is a warning against use together with products containing piperazine. However, the information accompanying products containing piperazine does not mention any interaction. The reason for this anomaly is that pyrantel-containing products were licensed more recently and so more information on drug interactions has been required as part of the licensing process.

To help avoid harmful interactions:

  • check the active ingredients of the products you are supplying;
  • ask pet owners if they are using any other products to treat the animal. These might be products they have bought or that have been prescribed by a vet.

Podcast

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Test yourself

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References

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

Goodman L, Trepanier L. Potential drug interactions 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].

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

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

Mealey K et al. Breed distribution of the ABCB1-1∆ (multidrug sensitivity) polymorphism among dogs undergoing ABCB1 genotyping. J Am Vet Med Assoc 2008; 233:921–4.

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].

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