Drug-drug interactions (Proceedings)
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 interactionsPharmaceutical 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.