Clinically significant drug interactions are rarely reported in veterinary medicine, however the incidence is probably far
greater than is reported. With the introduction of more and more veterinary drugs, as well as the use of more human drugs
in animals, the incidence is likely to increase in the next few years. Additionally, the practice of 'polypharmacy' or having
animals on multiple medications causes a logarithmic increase in the risk of drug-drug interactions. It is the veterinarian's
responsibility to be aware of any potential drug interactions between drugs being used on veterinary patients, and to recognize
the potential dangers involved with drug combinations.
There are three categories of drug interactions that can occur. Pharmaceutical, pharmacokinetic and pharmacodynamic interactions
can all be present. These may result in harmful consequences, additive or synergistic beneficial effects, or inactivation
of some drugs, resulting in therapeutic failure. The following presentation will define these categories of interactions,
and present specific examples of drug interactions in veterinary medicine.
Types of drug interactions
Pharmaceutical interactions: These interactions commonly occur due to mixing of two drugs with incompatible pH, and usually
result in a visible precipitate. Examples of this include meperidine and thiopental, which have a pH of 3.5 and 10.8, respectively.
In some instances, the interaction occurs not between two drugs, but between the drug and the container, or a drug and its
vehicle, particularly with compounded drugs. Diazepam and the highly lipophilic drug itraconazole have been known to adsorb
to plastic or glass containers. Drugs with strong chelating abilities can be inactivated if they are combined with vehicles
containing cations. Fluoroquinolones can be inactivated in solutions with calcium (such as lactated Ringer's solution) or
iron (lixotinic). However, physical inactivation can also occur for other reasons, and may or may not cause a visible precipitate.
A good example of this is the combination of aminoglycosides and penicillins in vitro. Although no visible change occurs,
the drugs become inactivated, which results in lower concentrations of active drugs, and potential therapeutic failure in
the patient. When these drugs are given in vivo, this interaction does not occur, however, as the drugs are sufficiently
diluted in the patient's blood to prevent the interaction. Pharmaceutical interactions can occur in vivo, however and this
fact can be manipulated pharmacologically in the form of an antidote. Protamine sulfate is an antidote for heparin toxicosis.
It works by combining with heparin in the body to form a stable, inactive salt formulation with heparin.
Pharmacodynamic interactions: Pharmacodynamic interactions can occur in a variety of different ways. They can cause synergism
between two drugs, resulting in a greater than expected increase in the action of one or both drugs. This occurs with combinations
of β-lactam antibiotics and aminoglycosides, and sulfonamides and dihydrofolate reductase inhibitors. Additive effects are
reported using combinations of barbiturates and benzodiazepines in producing sedation/hypnosis, and combinations of opioids
and NSAIDs for analgesia. Pharmacodynamic effects are the basis of the use of reversal agents. Good examples of this in
veterinary medicine include atipamezole and metdetomidine, and opioids and naloxone. Pharmacodynamic interactions can also
lead to increased toxicity, if both drugs adversely affect the same organ system. For example, co-administration of NSAIDs
and steroids increases the risk of gastrointestinal ulceration. Also, concurrent administration of 2 nephrotoxic drugs, such
as an NSAID and an aminoglycoside, may increase the chance of nephrotoxicity.
Pharmacokinetic interactions: Pharmacokinetic drug interactions are common in humans and can be a result of changes in drug
absorption, distribution, metabolism or excretion.
Changes in drug absorption can occur following pharmaceutical interaction in the stomach or small intestine. The classis
example of this is tetracycline chelation in the stomach by calcium containing solutions, such as a milk diet in newborns.
Cation containing drugs or solutions, such as antacids and sucralfate, can also bind tetracyclines and fluoroquinolones.
Drug interactions can also occur with drugs that alter the pH of the stomach, when they are co-administered with drugs that
have a pH dependent solubility. For example, proton pump inhibitors have been shown to reduce the oral absorption of the
azole antifungal drugs itraconazole and ketoconazole, by decreasing their solubility. Some drugs also alter gastric emptying
and intestinal motility, which may affect drug absorption by delaying delivery of the drug to the site of absorption, which
is typically the proximal small intestine. Opioid drugs and the anticholinergic drugs, such as atropine or butylscopolamine,
alter gastric motility to the extent that orally administered drugs may exhibit delayed absorption. Alteration of absorption
may also occur following intramuscular or subcutaneous routes. Epinephrine added to local anesthetics delays drug absorption
from the injection site, resulting in prolonged effects. Two inhalant gases administered together can alter the rate of uptake
at the alveolar level.