Drug interactions: expecting the unexpected! (Proceedings)

Often, the concurrent administration of more than one drug is necessary to achieve therapeutic goals. When two or more drugs are administered concomitantly, the pharmacological activity (primary (therapeutic) and secondary (toxic)) of one or all of these drugs may be modified by the presence of one another. Possible outcomes of drug interactions include increased chance of therapeutic failure, drug toxicity or therapeutic success, or may have no clinical significance at all. Unlike in human medicine, the incidence of clinically significant drug interactions is not that common in veterinary medicine since most of the drugs used have a wide therapeutic window and a wide margin of safety. Hence, drug interactions may occur in veterinary patients but may go undetected. Having said that however, there are important drug interactions reported in companion animals which may be either pharmaceutical, pharmacokinetic (PK) or pharmacodynamic (PD) in nature. These three types of pharmacological drug interactions are discussed during this presentation in order to help the veterinarian expect the unexpected!

Objectives

1. Provide the practitioner with a general understanding of the three types of pharmacological factors that may influence drug disposition.

2. Provide the practitioner with examples of drug interactions specific to each type.

3. Provide the practitioner with ways to avoid drug interactions in their patients.

4. Provide the practitioner with tools to recognize and manage drug interactions when they occur.

Recalling important drug interactions

1. Pharmaceutical interactions occur before the drug is absorbed. Pre-absorption incompatible reactions may be due to changes in the drug pH (e.g., precipitation and loss of stability of lidocaine hydrogen chloride (acid salt) mixed with sodium bicarbonate (alkaline solution)), binding of drugs with different charges (e.g., calcium and sodium bicarbonate or heparin and β-lactam antibiotics), changes in temperature (e.g., freezing increases degradation of ampicillin, crystallization of furosemide and precipitation of insulin) or exposure to light (e.g., diazepam or furosemide) for intravenous preparations. Pharmaceutical interactions can also change the diffusibility, dissolution rate and particle size of orally administered drugs affecting their absorption. Examples of drugs that bind to and prevent the absorption of other drugs are sucralfate, aluminum hydroxide and kaopectate.

2. Pharmacokinetic interactions occur when one drug affect the drug disposition of another drug during absorption, distribution, metabolism or excretion.

a. Absorption: The absorption of a drug may be hindered by another drug due to several reasons including changes in the integrity of the biological membranes, regional blood flow, and gastric motility, and the induction or inhibition of P-glycoproteins (efflux pumps) of enterocytes. Chloramphenicol, tetracyclines and neomycin are examples of drugs that cause malabsorption whereas a-adrenergics, -agrenergics and cimetidine decrease regional blood flow to major organs. Drugs that may alter the rate of absorption by altering gastric motility are listed in Table 1. Drug interactions causing clinical significant alteration in drug absorption mostly involve slow-release formulations and/or antacids.

Table 1. Drugs that may alter the rate of absorption of other drugs when administered concomitantly

b. Distribution: Drug interactions causing changes in distribution may occur when two drugs compete for one protein binding site. The clinical significance of plasma protein binding displacement in veterinary medicine is still controversial as in most cases, increased hepatic clearance of the unbound drug counter the increased plasma drug concentration, resulting in a non detectable drug interaction. This is especially true for orally administered drugs at steady-state. So when might plasma protein binding displacement be clinically significant? For drugs with a slow clearance, a narrow therapeutic ratio and a small volume of distribution, a temporary increase in plasma drug concentration and the increased variation within a dosing interval may be clinically significant. Examples of drugs with these characteristics are warfarin, phenytoin and tolbutamide.

In the case of a highly protein bound, rapid clearance drug (e.g., lidocaine), a clinically significant interaction from plasma protein binding displacement is possible as both bound and unbound drug is already available for elimination.

c. Metabolism: The most common drug interaction results from modulation of oxidative metabolism by the hepatic metabolizing enzymes, cytochrome P450. Some drugs may induce these enzymes, while others may inhibit them (Table 2). In general, a drug that induces cytochrome P450 enzymes increases the clearance of other drugs normally metabolized by the liver, thereby decreasing their pharmacological activity (therapeutic and toxic). Having said that however, toxicity may be enhanced when the formation of active metabolites is increased through induction (e.g., cyclophosphamide and phenobarbital) or as it is the case for pro-drugs (e.g. diazepam, ACE inhibitors). Enzyme induction is important in the pathogenesis of hepatotoxicity and/or therapeutic failure auto-induced by anticonvulsants.

Drug-induced hepatic enzyme inhibition often reflects competition for the same enzyme and usually occurs more rapidly than drug-induced enzyme induction. Hepatic clearance impairment of theophylline by enrofloxacin is an example of when enzyme inhibition results in toxicity whereas decreased hepatic metabolism of cyclosporine by ketoconazole is financially beneficial.

Lastly, the clearance of highly metabolized drugs may also be altered by drugs that change hepatic blood flow (e.g., propranolol), however clinical significance for current veterinary drugs is usually low. Table 2 lists drugs that may alter the metabolism of other drugs when administered concomitantly.

Table 2. Drugs that may alter the metabolism of other drugs

Excretion: Drug-induced modulation of excretion result from changes in glomerular filtration, competition between drugs for active tubular secretion or alteration of urinary pH and tubular reabsorption. This drug interaction is often used to either prolong the pharmacological activity of a drug (e.g., probenicid and penicillin) or hasten excretion to avoid further toxicity (e.g., urinary acidifier and aminoglycoside). P-glycoproteins located at the level of the biliary interface promote excretion of certain drugs into the bile. Drugs that induce or inhibit these P-glycoproteins will enhance or delay drug excretion, respectively.

3. Pharmacodynamic interactions can either enhance the response of a drug due to additive or synergistic effects at the same receptor, intracellular site or different sites but with the same physiological reaction, or they may decrease the response of some drugs through direct or indirect competitive antagonism. Some examples of beneficial synergistic or additive PD drug-induced interactions include balanced combined neuroleptanalgesia, diltiazem and digoxin, phenobarbital and potassium bromide, and clavulanic acid and amoxicillin. A few examples of beneficial antagonistic drug-induced PD interactions include reversal of oxymorphone or xylazine with naloxone or atipamezole, respectively, or decreased toxicity of organophosphate with the administration of atropine. In veterinary medicine however, PD interactions that increase toxicity are common such as NSAIDs with aminoglycosides, ACE inhibitors or glucocorticoids (nephrotoxicity and/or gastrointestinal ulceration), digoxin with furosemide (hypokalemia and cardiac arrhythmias), and clindamycin with aminoglycosides (neuromuscular blockade).

Avoiding detrimental drug interactions – Expecting the unexpected!

The incidence of interaction increases with the number of drugs administered (polypharmacy) and/or with the duration of treatment, and is clinically significant for drugs with steep dose-response curves or a narrow therapeutic ratio, particularly in a critical care environment where multiple drugs are generally administered concomitantly. Furthermore, when drug elimination occurs through a single metabolic pathway and/or when one of the drugs administered is a potent CYP450 enzyme inhibitor or inducer, careful patient monitoring should be implemented as drug-interactions should be expected. However, a recognized or potential drug interaction is not necessarily a contraindication for concomitant use of a specific drug combination but requires a benefit-risk ratio assessment for that individual patient. Cytochrome P450 enzyme activity is not uniform between species and often differs within a species, depending on age, gender and breed.

Recognizing and managing drug interactions

The predictability of a drug interaction and whether or not this interaction will produce an adverse effect or not, depend on the presence or absence of predisposing factors such as the type of the disease, organ function and dosage regimen (dose, frequency and duration), and awareness on the part of the prescriber for the particular drug, so that preventative measures and appropriate monitoring can be taken.

Summary and conclusion

There are three types of drug-induced interactions that have the potential to either increase or decrease pharmacological activity of co-administered drugs. These include pharmaceutical, pharmacokinetic and pharmacodynamic interactions. The veterinarian's knowledge in the clinical significance of potential drug-interactions and careful patient monitoring greatly help avoid or manage therapeutic failures and toxicities in veterinary patients. Individual variability between species and within species makes drug-induced interaction predictability a constant challenge.

References

Novotny, MJ. 2001. Clinical pharmacology: Principles of therapeutics. Chapter 4 in Veterinary Pharmacology and Therapeutics. Ed. H. Richard Adams. 8th edition. pp57-57.

Boothe, D.M. 2001. Factors affecting drug disposition and extrapolation of dosing regimens. Chapter 2 in Small Animal Clinical Pharmacology and Therapeutics. W.B. Saunders Company. Pp18-25.

Katzung, BG. 2001. Important drug interactions and their mechanisms. Appendix II in Basic and Clinical Pharmacology. pp1110-1111.