A Guide To Drug-Drug Interactions In Podiatry

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Understanding How Drugs Affect Enzymes

The major group of enzymes in the liver responsible for metabolizing drugs can be isolated in a sub-cellular fraction termed the “microsomes.” Cytochrome P450 is a “superfamily” of enzymes that are the terminal oxidases of this oxidation system. “Cytochrome” means colored cells. These enzymes contain iron and give the liver its red color. The name “P450” comes from the observation that the enzyme absorbs a very characteristic wavelength (450 nm) of ultraviolet light when it is exposed to carbon monoxide.

These enzymes are named according to families that are defined by the similarity of their amino acid sequence. These P450 iso-enzymes are denoted with the following numbers and letters: CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4.10-12 More than 50 percent of currently used medications that are metabolized undergo CYP3A4 metabolism.

The CYP3A subfamily is of particular interest because it is responsible for the metabolism of a large number of clinically important drugs in humans.11 The CYP3A4 isozyme accounts for over 25 percent of hepatic CYP450 content and is responsible for over half of all CYP450-mediated drug metabolisms. About 14 percent of the adult liver contains a substantial proportion of CYP3A5. However, it is proportionally more important in intestinal tissue and is the primary CYP3A enzyme in the kidney.11,12

A drug that is metabolized by a particular isoenzyme is a substrate for that enzyme. A drug can be a substrate for several different isoenzymes or an active metabolite can be a substrate for a different isoenzyme to the parent drug. These pharmacokinetic drug interactions affecting metabolism are often clinically significant and can involve induction (increased metabolism) or inhibition (reduced metabolism) of enzymes. Competition between two drugs for cytochrome P450 isozymes will occur. This competition may result in one drug interfering with the metabolism of another drug.

Medications metabolized by CYP3A4 or CYP2C9 are particularly susceptible to enzyme induction. Drugs known as “enzyme inducers” are capable of increasing the activity of drug metabolizing enzymes, resulting in a decrease in the effect of certain other drugs. For therapeutic agents that undergo extensive first-pass metabolism by CYP3A in the gut wall and liver, the reduction in serum concentrations of object drugs by enzyme inducers (precipitant drugs) can be profound. Enzyme inducers can increase the formation of toxic metabolites and increase the risk of hepatotoxicity as well as damage to other organs.

Robert G. Smith, DPM, MSc, RPh, CPed

NSAIDs And Drug Interactions: What You Should Know

All NSAIDs, with the possible exception of nabumetone (Relafen, GlaxoSmithKline), affect platelet aggregation and can increase bleeding, thereby affecting anticoagulant therapy. The interaction between warfarin and NSAIDs is considered pharmacodynamic in nature with an additive risk of bleeding related to the antiplatelet effects and gastrointestinal erosion associated with NSAIDs and the anticoagulant effect of warfarin.

   Some NSAIDs also alter the pharmacokinetics of warfarin. One should avoid concurrent warfarin and NSAID therapy, including celecoxib (Celebrex, Pfizer), when possible. Acetaminophen may alter the warfarin response but the effect is relatively small. Antiplatelet therapy with aspirin primarily increases the risk of minor bleeding. Finally, opioid analgesics are not known to interact with warfarin.

   While most interactions between NSAIDs and other drugs are pharmacokinetic, NSAID-related pharmacodynamic interactions may be considerably more important in the clinical context. For a list of selected NSAID-related adverse drug interactions, see “A Guide To Potential Drug Interactions With NSAIDs” at the right. When it comes to NSAIDs, one can reduce the risk of adverse drug interactions by rational prescribing and careful monitoring of drugs and therapy periods, particularly for high-risk patients.22

   Prescribing NSAIDs is relatively contraindicated for patients on oral anticoagulants due to hemorrhage and for patients taking high dose methotrexate (Trexall, Barr Laboratories) due to bone marrow toxicity, renal failure and hepatic dysfunction.23 The podiatric physician should consider the use of either aspirin or sulindac (Clinoril, Merck) in the presence of lithium or antihypertensives. He or she should also monitor the patient’s blood pressure and lithium level for toxicity. Avoid indomethacin (Indocin, Merck) and triamterene (Dyrenium, WellSpring Pharmaceutical) due to the risk of renal failure.

   The concurrent administration of amiodarone (Cordarone, Pfizer) with fluconazole, itraconazole or ketoconazole has caused increased plasma levels of amiodarone and possible toxicity.24 Desethylamiodarone is a major metabolite of amiodarone and has exhibited more potent inhibitory effects on human CYP activities.25

Pertinent Pointers On Drug-Food Interactions

Sometimes when patients take medications with food, they can have less of an effect than if patients took the drugs on an empty stomach. Food can speed up or slow down the action of a drug. Medications may alter how the body uses nutrients.

   As foods are a complex mixture of different constituents, the potential exists to alter the pharmacodynamic, pharmacokinetic and clinical response obtained with a medication.26 The podiatric physician should realize that food can act as a physical barrier and thereby prevent drug access to the absorptive surface of the gastrointestinal mucosa.27 Food and drug interactions can happen with both prescription and over-the-counter medications.

   The acidity of fruit juice may decrease the effectiveness of antibiotics such as penicillin. Dairy products may blunt the infection fighting effects of tetracycline and fluoroquinolones by decreasing the absorption of these drugs. Fluoroquinolones can inhibit the clearance of xanthine derivatives, including theophylline and caffeine, which may result in seizures. Antidepressants, specifically monoamine oxidase inhibitors (MAOIs), are dangerous when mixed with foods or drinks that contain tyramine (i.e., beer, red wine and some cheeses). Linezolid (Zyvox, Pfizer) is a reversible, non-selective inhibitor of monoamine oxidase and has the potential for interacting with adrenergic and serotonergic agents as well as tyramine.

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