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

   Grapefruit juice contains various bioflavonoids that have the ability to inhibit CYP450 isoenzymes. Grapefruit juice inhibits cytochrome P-450 3A4 in the wall of the small intestine. This impairs the oxidative metabolism of some drugs. The dose of grapefruit juice will markedly affect the magnitude of the interaction. Eating grapefruit pulp also reportedly inhibits CYP3A4. Grapefruit juice inhibition of CYP3A may last for up to 24 hours after a single dose and up to 72 hours after multiple doses.28 Finally, a number of selected drugs are known to interact with grapefruit juice to cause adverse reactions (see “Which Drugs Are Significantly Affected By Grapefruit Juice?” below.28

What About Medication Interactions With Cigarettes And Illegal Drugs?

Cigarette smoke and alcohol may interact with medications through pharmacokinetic or pharmacodynamic mechanisms. Engaging in both of these social activities can reduce the effectiveness of certain drugs or can make drug therapy unpredictable.

   The analgesic effects of hydrocodone (Vicodin, Abbott Laboratories), oxycodone (Oxycontin, Purdue Pharma) and codeine acetaminophen (Tylenol, McNeil) combination products are decreased with cigarette smoking.29 With cigarette smoking, the subcutaneous absorption of insulin is lower and an increase in warfarin clearance occurs.29 Concurrent beta-blocker use and cigarette smoking have caused pronounced decreases in heart rate and blood pressure. Finally, a decrease in sedation has occurred with zolpidem (Ambien, Sanofi Aventis) and lorazepam (Ativan, Pfizer) in cigarette smokers.29

Key Pointers On Interactions With Illegal Drugs

As podiatric physicians become more familiar with the subject of drug-drug interactions, they can avoid life-threatening events and improve patient outcome. Both pharmacokinetic and pharmacodynamic interactions of illicit drugs may occur with a range of drug types.30

   Drug interactions involving illicit drugs fall into three categories. The first category involves substances described as psychostimulants that include amphetamines, methamphetamine, ecstasy (MDMA) and cocaine.30 The second category involves cannabis.30 The last category involves illicit drugs that cannot be grouped with the other two categories.30

   All psychostimulants can increase blood pressure and may counteract the therapeutic effect of antihypertensive medications.30 Cannabis pharmacokinetic interactions occur because cannabinoids are highly protein bound. They will compete with other protein bound substances like warfarin and increase the availability of warfarin and thus increase warfarin's therapeutic effect on the body to interact with various receptors.30 The addition of methamphetamine and/or cocaine to concomitant serotonergics have the potential to cause serotonin toxicity. Central nervous system effects are additive if patients taking heroin also take a medication with central nervous system depressant properties.30

Management Strategies For Avoiding Drug-Drug Interactions

One can prevent drug interactions by avoiding concomitant administration of interacting substances or possibly employing alternative therapeutic strategies. Regularly updated reference manuals of drug interactions and computerized programs can be useful to the podiatric physician. In order to minimize drug-drug interactions involving mechanism-based CYP inhibition, it is necessary to choose safe drug combination regimens, adjust drug dosages appropriately and conduct therapeutic drug monitoring for drugs with narrow therapeutic indices.31

   One management option to control potential dangerous drug-drug interactions includes avoiding the drug-drug combination entirely, given that with some drug interaction, the risk always outweighs the benefit. It is possible to give two interacting drugs safely as long as one appropriately adjusts the dose of the object drug.

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