Polypharmacy is increasingly common in the prevention and treatment of diseases in animals. Drug-drug interactions represent one common event associated with multidrug therapy that may interfere with optimal clinical outcome.
Polypharmacy is increasingly common in the prevention and treatment of diseases in animals. Drug-drug interactions represent one common event associated with multidrug therapy that may interfere with optimal clinical outcome. Mechanisms whereby drugs may interact during concurrent treatment are well established for many drug combinations. However, the incidence and clinical relevance of interactions are difficult to determine with accuracy because of the many factors involved and because there is very little clinical data to validate in vitro findings. Therefore, the need for clarification of the clinical relevance of potential interactions has become crucial, since clinicians are faced with the difficult task of evaluating both qualitatively and quantitatively the risk of drug interactions in their patients in order to make sound therapeutic decisions. An understanding of the role of pharmacokinetics, pharmacodynamics, and the factors that alter these processes are vital in the clinician's process of decision making.
1. To briefly review common mechanisms of drug-drug interactions.
2. To discuss sources of uncertainty in the clinical setting.
3. To review some relevant interactions in small animals.
1. Most of the published information refers to in vitro experiments that provide very valuable mechanistic information and can be used to make reasonable predictions about the clinical relevance, time course, and methods used to avoid the interaction or palliate its clinical consequences.
2. Many factors influence the clinical significance of drug-drug interactions; these include size and frequency of dose, duration of treatment, time-course of the interaction, drug therapeutic index, disease status, pharmacokinetic differences between interacting drugs, status of the immune system, inter-animal variability, etc.
3. Pharmacokinetic interactions may occur that affect the absorption, distribution or elimination of concurrently administered drugs. Interactions affecting absorption or elimination are the most likely to be of clinical consequence. The exposure of an animal to a drug (as represented by the area under the drug concentration-time profile in plasma) changes in proportion to variations in clearance and/or systemic availability. This is more likely to be of clinical significance when the affected drug has a narrow therapeutic index and when the size and duration of the change in exposure are of enough magnitude.
4. The gastrointestinal (GI) absorption of one agent may be affected by other agent that alters GI pH or motility, chelates other chemicals, or affects active transporters such as P-glycoprotein. While both rate and extent of absorption may be altered, interactions that affect the systemic availability of drugs are more likely to be of clinical importance. A common type of drug interaction affecting absorption is the chelation of an antibiotic by concurrently administered metal ions, which may be present in food or antacid medications. Separating the administration times of the antibiotic and the chelating agent may reduce the extent of interaction. A reasonable approach is to leave 2-4 hours of separation between both.
5. The distribution of concurrently administered drugs may be affected by competitive displacement from plasma and tissue binding sites or alteration of active tissue transporters (e.g. blood-brain barrier), with the latter being more likely to result in clinically relevant consequences.
6. The elimination of concurrently administered drugs can be altered through mechanisms affecting metabolism, secretion, or excretion. Induction or inhibition of cytochrome P450 isozymes in the liver may result in increased or decreased drug clearance, respectively. For example, chloramphenicol is known to inhibit cytochrome P450 enzymes in the liver of dogs resulting in prolonged barbiturate sedation and potential for toxicity1-6. On the other hand, phenobarbital is a well known inducer of enzymes involved in Phase I and Phase II drug metabolism, and as such it decreases the plasma concentration of drugs like chloramphenicol7,8 or doxycycline9. One of the most commonly P450 enzymes involved in metabolic drug-drug interactions is CYP3A4, which represents the primary route of metabolism for many of the drugs used in domestic animals. In practice, the clinician has to consider the time course of these processes, for while enzyme inhibition occurs relatively quickly, enzyme induction commonly requires more time. It takes approximately 1-2 weeks for the maximum inductive effect to occur and about the same time for it to cease once drug administration has stopped. Rifampin may be an exception to the rule given that it may elicit enzyme induction just after a few doses. The elimination half-life of the drug is another important factor, since it will take about 3-5 half-lives for a drug with changed clearance to reach a new steady state concentration.
7. Pharmacodynamic interactions may result in additive, synergistic or antagonistic effects on the receptor systems where the drugs act.
8. In general, a synergistic effect can be expected when the mechanisms of action are complementary, for example, when drugs act at different places of the same biochemical pathway (sulfonamides and diaminopyrimidine), or when the presence of one antibiotic increases the bacterial penetration of another (beta-lactams and aminoglycosides). For example, synergism has been reported to occur between flouroquinolones and either aminoglycosides, 3rd generation cephalosporins, extended-spectrum penicillins, carbapenems, vancomycin, or trimethoprim against some bacterial pathogens, including Pseudomonas aeruginosa (e.g. ciprofloxacin and amikacin or imipenem), Staphylococcus aureus (e.g. levofloxacin and oxacillin) Enterococcus spp. (e.g. ciprofloxacin and amikacin)10 and Escherichia coli (e.g. trimethoprim and ciprofloxacin)11.
9. On the other hand, antibiotic combinations characterized by overlapping mechanisms of action or suppression of important efficacy elements (e.g. lack of active bacterial growth) may result in antagonism characterized by the clinical efficacy of the drug combination being less than that of the individual agents.
10. However, neither in vitro synergy nor antagonism can be assumed to straightforwardly occur in vivo. The predictive value of common in vitro tests for efficacy of antibiotic combination therapy is often poor.
11. For antibiotics, in vitro/in vivo PKPD models currently provide the most promising approach to unveil clinically meaningful pharmacodynamic interactions.
1. Sanders JE, Yeary RA, Fenner WE, et.al. Interaction of phenytoin with chloramphenicol or phenobarbital in the dog. J Am Vet Med Assoc 1979;175(2):177-180.
2. Teske RH, Carter GG. Effect of chloramphenicol on pentobarbital-induced anesthesia in dogs. J Am Vet Med Assoc 1971;159(6):777-780.
3. Adams HR, Dixit BN. Prolongation of pentobarbital anesthesia by chloramphenicol in dogs and cats. J Am Vet Med Assoc 1970;156(7):902–905.
4. Houston DM, Chochrne SM, Conlon P. Phenobarbital toxicity in dogs concurrently treated with chloramphenicol. Can Vet J 1989;30:598.
5. Adams RH, Isaacson EL, Masters BS. Inhibition of hepatic microsomal enzymes by chloramphenicol. J Pharmacol Exp Therap 1977;203(2):388-396.
6. Campbell CL. Primidone intoxication associated with concurrent use of chloramphenicol. J Am Vet Med Assoc 1983;182(9):992-993.
7. Palmer DL, Despopoulos A, Rael ED. Induction of chloramphenicol metabolism by phenobarbital. Antimicr Ag Chemother 1972;1(2):112-115.
8. Graham RA, Downey A, Mudra D et al. In vivo and in vitro induction of cytochrome P450 enzymes in beagle dogs. Drug Metab Dispos 2002;30(11):1206–1213.
9. Neuvonen PJ, Penttilä. Interaction between doxycycline and barbiturates. Br Med J 1974;1:535-536.
10. Pillai SK, Moellering RC, Eliopoulos GM. Antimicrobial Combinations. In: Lorian V, ed. Antibiotics in Laboratory Medicine, 4th ed. 1996; Williams and Wilkins.
11. Huovinen P, Wolfson JS, Hooper DC. Synergism of trimethoprim and ciprofloxacin in vitro against clinical bacterial isolates. Eur J Clin Microb Infect Dis 1992;11:255-257.
12. Trepanier LA. Cytochrome P450 and its role in veterinary drug interactions. Vet Clin North Am Small Anim Pract 2006;36:975-985.
13. Mandsager RE, Clarke CR, Shawley RV, et.al. Effects of chloramphenicol on infusion pharmacokinetics of propofol in greyhounds. Am J Vet Res 1995;56(1):95–99.
14. Hay Kraus BL, Greenblatt DJ, Venkatakrishnan K, et.al. Evidence for propofol hydroxylation by cytochrome P4502±1 in canine liver microsomes: breed and gender differences. Xenobiotica 2000;30(6):575-588.
15. Hirt RA, Teinfalt M, Dederichs D, et.al. The effect of orally administered marbofloxacin on the pharmacokinetics of theophylline. J Vet Med A Physiol Pathol Clin Med 2003;50(5):246–250.
16. Intorre L, Mengozzi G, Maccheroni M, et.al. Enrofloxacin-theophylline interaction: influence of enrofloxacin on theophylline steady-state pharmacokinetics in the beagle dog. J Vet Pharmacol Ther 1995;18(5):352–356.
17. Regmi NL, Abd El-Aty AM, Kuroha M, et.al. Inhibitory effect of several fluoroquinolones on hepatic microsomal cytochrome P-450 1A activities in dogs. J Vet Pharmacol Ther 2005;28(6):553-557.
18. Ogino T, Mizuno Y, Ogata T, et.al. Pharmacokinetic interactions of flunixin meglumine and enrofloxacin in dogs. Am J Vet Res 2005;66(7):1209-1213.
19. Kumar N, Singh SD, Jayachandran C. Pharmacokinetics of enrofloxacin and its active metabolite ciprofloxacin and its interaction with diclofenac after intravenous administration in buffalo calves. Vet J 2003;165:302-306.
20. Rahal A, Kumar A, Ahmad AH, et.al. Pharmacokinetics of diclofenac and its interaction with enrofloxacin in sheep. Res Vet Sci 2008;84(3):452-456.
21. Lehto P, Kivistö. Effect of sucralfate on absorption of norfloxacin and ofloxacin. Antimicr Ag Chemother 1994;38:248–251.
22. Jaehde U, Sörgel F, Stephan U, et.al. Effect of an antacid containing magnesium and aluminum on absorption, metabolism, and mechanism of renal elimination of pefloxacin in humans. Antimicr Ag Chemother 1994;38(5):1129-1133.
23. Sadowski DC. Drug interactions with antacids. Mechanisms and clinical significance. Drug Safety 1994;11(6):395-407.
24. Al-Wabel NA, Strauch SM, Keene BW, et.al. Electrocardiographic and hemodynamic effects of cisapride alone and combined with erythromycin in anesthetized dogs. Cardio Toxicol 2002;2(3):195-208.
25. Busch DF, Sutter VL, Finegold SM. Activity of combinations of antimicrobial agents against Bacteroides fragilis. J Infect Dis 1976;133(3):321-328.
26. Fish DN, Choi MK, Jung R. Synergic activity of cephalosporins plus flouroquinolones against Pseudomonas aeruginosa with resistance to one or both drugs. J Antimicr Ther 2002;50:1045-1049.
27. Miranda-Novales G, Leaños-Miranda BE, Vilchis-Pérez M, et.al. In vitro activity effects of combinations of cephalothin, dicloxacillin, imipenem, vancomycin and amikacin against methicillin-resistant Staphylococcus spp. strains. Ann Clin Microb Antimicr 2006;5:25-29.
28. Paul M, Benuri-Silbiger I, Soares-Weiser K, et.al. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials. Br Med J 2004;328:668-672.
29. Snyder RJ, Wilkowske CJ, Washington JA 2nd. Bacetericidal activity of combinations of gentamicin with penicillin or clindamycin against Stretococcus mutans. Antimicr Ag Chemother 1975;7(3):333-335.
30. Klastersky J, Meunier-Carpentier F, Prevost JM. Significance of antimicrobial synergism for the outcome of gram negative sepsis. Am J Med Sci 1977 Mar-Apr;273(2):157-167.