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.

Author(s): 
Robert G. Smith, DPM, MSc, RPh, CPed

Given the likelihood that one of your patients is already taking a prescription drug, it is critical to be aware of potential interactions between medications. In addition to reviewing pertinent pharmacology principles, this author offers insights on azole antifungals, NSAIDs and a variety of other medications, and how to reduce the risk of harmful interactions.

   Prescription medications are vital to preventing and treating illness, and can help avoid more costly medical problems.1 The use of prescription medications to treat chronic medical conditions is particularly prevalent among older individuals. Almost 40 percent of older Americans take five or more therapeutic agents monthly.2 Moreover, the most recent data from a sample population survey of United States civilian households reveals 50 percent of the population consumes at least one or more prescription drugs a month while one out of 10 Americans use five or more prescription drugs each month.2

   The term “drug misadventure” is used to define the phenomena associated with negative drug experiences.3 Further, Mannasse simplifies drug misadventures to mean: “when something goes wrong with drug therapy and is unexpected.”4 Kelly reports that one category of drug misadventures is drug interactions.5 Given the aforementioned statistics, a potential for drug-drug interactions exists for at least 10 percent of Americans.

   Some drugs interact with other prescription medications, over-the-counter medications, food or drink, tobacco products, alcohol consumption, and botanical or herbal products. The literature has not well defined the ability of the clinician to accurately identify and manage potential drug-drug interactions. Many healthcare providers may overlook or are unaware of specific potential drug interactions.

   Given that a large number of drugs are introduced every year and new interactions between medications are increasingly reported, it is important that clinicians be knowledgeable of the existence of pharmacological interactions that are either beneficial or harmful within a patient’s medication regimen. While it is not possible for the healthcare provider to recognize all clinically significant drug interactions, it is possible to understand the scientific principles and mechanisms involved.

   Accordingly, let us take a closer look at drug-drug interactions in the context of frequently prescribed medications and their possible altered effects within the scope of the lower extremity.

What You Should Know About Pharmacology Principles And Drug Interactions

Understanding observed physiological effects specific to both pharmacodynamic and pharmacokinetic principles is essential when discussing drug-drug interactions. Patients need to maintain drug concentrations within the appropriate target range for efficacy. When it comes to drug interactions, the drug affected by the interaction is the “object drug” and the drug causing the interaction is the “precipitant drug.”

   The science of pharmacology encompasses both pharmacokinetics, which is the science that describes the body’s action on a medicinal agent, and pharmacodynamics, which is the scientific description of the medicinal agent’s action on the body’s systems.

   Pharmacokinetics involves four major body functions: absorption, distribution, metabolism and excretion. Drug absorption occurs at different sites along the gastrointestinal tract, including the stomach and the small and large intestines. Factors affecting absorption include: change in gastrointestinal pH, drug binding in the gastrointestinal tract, change in gastrointestinal flora, change in gastrointestinal motility and malabsorption caused by other drugs. Most interactions result in a reduced absorption rather than increased absorption from the gut.

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