Case Presentations: Managing Drug Interactions
ACVIM 2008
Patricia M. Dowling, DVM, MSc, DACVIM, DACVCP
Saskatoon, SK, Canada

Introduction

As veterinary internal medicine advances, small animal patients are more likely to receive multiple drug therapies for acute and chronic diseases. As the number of drugs administered increases, the potential for clinically significant drug-drug interactions increases. Drug interactions are a well-known problem in human medicine. In the 1990's patients experienced serious cardiac toxicity after taking antihistamines or prokinetic drugs concurrently with macrolide antimicrobials or azole antifungals. Subsequently, terfenidine, astemizole and cisapride were removed from the human market due to these serious drug interactions. Most recently, the prokinetic drug tegaserod was withdrawn due to similar interactions and resulting cardiac toxicity. Drug interactions continue to be identified as new drugs are approved and metabolic enzymes and transporters are identified.

Concurrently administered drugs can interfere with one another's efficacy or safety. The object drug is the medication affected by the interaction and the precipitant drug is the medication responsible for the interaction. The effect may either be a pharmacokinetic (PK) effect and/or a pharmacodynamic (PD) effect. The clinical importance of a drug interaction depends on drug, patient and administration-related factors. Generally, interaction that causes a doubling or more in plasma drug concentration has the potential for enhanced adverse or beneficial drug response. Less pronounced PK interactions may still be clinically important for drugs with a steep dose-response curve or narrow therapeutic index.

Pharmacokinetic Drug Interactions

A PK effect results from changes in the drug's absorption, distribution, metabolism or elimination profile. Absorption interactions generally occur in the gastrointestinal tract. Drugs that have pH-dependent dissolution can be affected by antacids, proton pump inhibitors, and histamine H2-blockers. Cephalosporin prodrugs, such as cefpodoxime proxetil, have reduced oral bioavailability when administered with H2-blockers and the absorption of fluoroquinolones and tetracyclines is reduced by concurrent administration with antacids.1 Interactions causing changes in drug distribution are mainly caused by alterations in transport proteins. The most studied is P-glycoprotein, which is an efflux transporter that effects gastrointestinal absorption and distribution of substrate drugs across the blood-brain barrier (see Dr Katrina Mealey's proceedings for further information on these interactions). Drug interactions due to competitive protein binding and subsequent drug displacement are only rarely of clinical significance, despite numerous references to the contrary.2

The majority of clinically significant drug interactions occur because of interactions in metabolism. Drug metabolic pathways are divided into Phase I and Phase II reactions. Phase I reactions typically add functional groups to the drug molecule necessary for Phase II reactions. Phase II reactions typically include conjugation reactions which increase the water solubility of the drug, facilitating excretion from the body. Species differences in drug metabolism are the primary sources of variation in drug activity and toxicity. Cats have a poor ability to glucuronidate drugs, pigs are deficient in sulfate conjugation and dogs are relatively poor acetylators.

Figure 1. Phases of drug metabolism.
Figure 1. Phases of drug metabolism.

 

A precipitant drug can induce, inhibit, or be a substrate for these reactions. Among the reactions catalyzed by drug metabolism enzymes, the Cytochrome P450 (CYPs) mixed function oxidase system is the most intensively studied. This system catalyses the hydroxylation of hundreds of structurally diverse drugs, whose only common characteristic is high lipid solubility. Many precipitant drugs are capable of inducing enzyme activity, thereby increasing the rate of metabolism and hepatic clearance of concurrently administered drugs, typically resulting in a decreased pharmacological effect. Enzyme induction typically occurs slowly, requiring several weeks to reach maximum effect. Induction is accompanied by increased hepatic RNA and protein synthesis and increased hepatic weight. Enzyme induction is important in the pathogenesis of hepatotoxicity and therapeutic failure of many drugs. Phenobarbital is a potent enzyme inducer, known for hepatotoxicity and for inducing its own metabolism.

Precipitant drug induced enzyme inhibition can be reversible or irreversible. Reversible inhibition occurs when drugs compete for the same catalytic site (competitive inhibition) or bind to another site on the enzyme and alter enzyme binding to object drug (non-competitive inhibition). The degree of reversible inhibition depends on concentrations around the enzyme and the affinity of the precipitant to the enzyme. Mechanism based inhibition is the irreversible inhibition of an enzyme due to catalysis of the reaction of an artificial substrate (also called 'suicide inhibition').3 Synthesis of new enzyme is necessary before activity is restored. The consequences of mechanism-based inhibition include auto-inhibition of the clearance of the precipitant drug itself and prolonged inhibition of the clearance of other drugs that share the same enzyme, which greatly increases the risks of serious or even fatal toxicity.4 Screening of new compounds for mechanism-based enzyme inhibition is now standard practice within the pharmaceutical industry. In contrast to induction, inhibition occurs rapidly. Ketoconazole and cimetidine are two of the most potent enzyme inhibitors known, while rifampin is one of the most potent inducers. For compounds that both inhibit and induce CYPs, predicting the net effect in vivo is particularly challenging.

Enzyme Inducers

 Chlorinated hydrocarbons

 Griseofulvin

 Omeprazole

 Phenobarbital

 Phenytoin

 Rifampin

Enzyme Inhibitors

 Chloramphenicol

 Cimetidine

 Dexamethasone

 Erythromycin

 Fluoroquinolones

 Ketoconazole

 Phenobarbital

 Phenylbutazone

 Prednisolone

 Quinidine

PK drug interactions can also occur during renal excretion. Such interactions are usually the result of competitive interactions involving active tubular secretion of drugs. The organic anion transport (OAT) proteins of the kidney facilitate the renal excretion of many antimicrobial drugs such as the penicillins, cephalosporins and fluoroquinolones. Probenecid is the classic inhibitor of this system and concurrent administration decreases the renal clearance of OAT substrate drugs. During WWII, when penicillin was in short supply, probenecid was used to reduce the amount of penicillin required to treat wounded soldiers.

There is significant interindividual variability in drug interactions, due to patient-specific factors such as the disease condition, other concurrent medications, and genetics. We are only just now beginning to appreciate "pharmacogenomics" in the canine breed-related P-glycoprotein deficiency that causes sensitivity to ivermectin (amongst other drugs). There are hundreds of CYP enzymes; currently they are only partially characterized in dogs and almost no work has been done in cats.5

Pharmacodynamic Drug Interactions

A PD drug interaction is associated with a change in efficacy or safety of the object drug, with or without a change in its pharmacokinetics. There are many well known examples of PD drug interactions. The cardiac effects of digoxin are increased when concurrent furosemide reduces plasma potassium concentrations. Pre-treatment with buprenorphine reduces the antinociceptive efficacy of intra-operative sufentanil, presumably from buprenorphine activity at kappa opioid receptors, which is antagonistic to mu receptor effects.6 The diuretic effects of furosemide or angiotensin-converting enzyme inhibitors are decreased with concurrent NSAID use.7,8 Concurrent administration of nonsteroidal anti-inflammatory drugs and corticosteroids is associated with adverse renal, hemostatic and gastrointestinal effects.9 For antimicrobials, PD interactions can cause synergy or antagonism. The combination of ampicillin and an aminoglycoside in the treatment of human enterococcal endocarditis is one of the few documented clinical examples of antimicrobial synergism. Antagonism between tetracyclines and beta-lactam antibiotics in the treatment of Streptococcus pneumoniae supports the general admonition that bacteriostatic and bactericidal antimicrobials should not be used concurrently.

Clinical Case Presentations

A 4-year-old FS Golden retriever with idiopathic epilepsy is well controlled on phenobarbital and potassium bromide. She presents to a relief veterinarian on duty at her regular clinic, with severe otitis externa and a head tilt. In additional to topical therapy, the relief veterinarian prescribes a 10 day course of chloramphenicol (50 mg kg, PO, q 8 hr). What do you predict will happen?

A 10-year-old FS Beagle with a history of chronic bronchitis was maintained on aminophylline (10 mg/kg, PO q 8 hr) and prednisone (5 mg, PO q 48 hr). She presented for hematuria and inappropriate urination. A urinalysis revealed 4+ gram-negative rods, so presumably she has an E coli urinary tract infection. She is prescribed 5 mg/kg of enrofloxacin q 24 hr for 10 days. What do you predict will happen?

References

1.  Pai MP, et al. Med Clin North Am 2006;90: 1223-1255;

2.  Toutain PL, et al. J Vet Pharmacol Ther 2002;25: 460-463;

3.  Regmi NL, et al. J Vet Pharmacol Ther 2005;28: 553-557;

4.  Dresser GK, et al. Clin Pharmacokinet 2000;38: 41-57;

5.  Trepanier LA. Vet Clin North Am Small Anim Pract 2006;36: 975-985, v;

6.  Goyenechea Jaramillo LA, et al. Vet Anaesth Analg 2006;33: 399-407;

7.  Elliott WJ. J Clin Hypertens (Greenwich) 2006;8: 731-737;

8.  Herchuelz A, et al. J Pharmacol Exp Ther 1989;248: 1175-1181;

9.  Narita T, et al. J Vet Med Sci 2007;69: 353-363.

Speaker Information
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Patricia Dowling, DVM, MSc, DACVIM, DACVCP
University of Saskatchewan
Saskatoon, SK, Canada


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