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.
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.
Precipitant drugs that act as binding agents, such as cholestyramine (Questran, Bristol-Myers Squibb) and colestipol (Colestid, Pfizer), can impair the bioavailability of object drugs. Thus, an impairment of the bioavailability of the object drug results in a reduction of therapeutic effect of the object drug. The amount of a medication that is absorbed from the gut may be increased or decreased by drugs that increase stomach pH. Interactions affecting the rate of absorption are generally insignificant unless the patient must achieve therapeutic plasma levels quickly as in the case of analgesics. Conversely, interactions affecting the extent of absorption may affect the efficacy of a drug.
Once absorbed, most drugs bind to plasma proteins that are specific for some aspect or structural feature of the drug. The term, volume of distribution, commonly describes the extent of drug distribution to tissues relative to the plasma volume.
Drug metabolism refers to enzyme-mediated structured modification to a drug that changes its biological activity and/or water solubility. Drug metabolism occurs as a result of enzymatic reactions on the medications that result in metabolites that may be active or rendered inactive. The gastrointestinal wall, lungs, liver and blood possess enzymes that metabolize drugs.6-8
Metabolism via the smooth endoplasmic reticulum of the liver is the first step in the elimination of many drugs.6,8 Drug metabolism by the liver occurs through one or both biotransformation reactions that are classified as either Phase I or Phase II reactions.7 Phase I reactions modify the drug by using oxidation, hydrolysis and reduction. These modifying reactions create a more polar and highly water-soluble drug molecule for elimination by the kidneys.
Phase II reactions modify the drug pharmacologically to an inactive form via conjugation resulting in glucuronides, acetates and sulfates. This occurs via the formation of a covalent linkage between a functional group appearing on the parent drug as a result of phase I metabolism and endogenously derived glucuronic acid, sulfate, glutathione, amino acids or acetate.6,9 The kidneys may now eliminate this new drug metabolite.
Some important preventable drug interactions are due to their effects on drug metabolizing enzymes, resulting in either reduced activity of the enzyme or increased activity of the enzyme referred to as enzyme induction (see “Understanding How Drugs Affect Enzymes” at the right).
Metabolism and elimination are responsible either separately or together for drug inactivation. Without these two pharmacokinetic functions, drugs would continuously circulate through our bodies, interacting with various body receptors and interrupting important physiological processes.13 Drugs are either eliminated directly or converted into metabolites that are subsequently excreted.
Removal of a drug from the body may occur by a number of routes, the most important being through the kidney into the urine. Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus. Drugs that have the same active transport mechanism can compete for excretion in the kidney tubules. Active secretion into the renal tubules is an important route of elimination for some drugs. Other routes of elimination for drugs from the body include sweat, tears, breast milk or expired air. Some drugs are excreted in the bile as water-soluble conjugates. Bacteria in the gut can break down these conjugates to liberate the free drug, which can then be reabsorbed.
Pharmacodynamic interactions are due to competition at receptor sites or activity of the interacting drugs on the same physiological system. There is no change in plasma concentrations of interacting drugs. When patients concurrently take medications with similar pharmacodynamic effects, this may result in an additive pharmacologic excessive response and possible drug toxicity. Conversely, drugs with opposing pharmacodynamic effects may reduce the response to one or both drugs. The pharmacodynamic consequences precipitated by drug-drug interactions may or may not closely follow pharmacokinetic drug changes.
A person’s genetic makeup can alter the response to a medication. Genetics affect both pharmacokinetics and pharmacodynamics. Two terms describe genetic variations in drug metabolism. Pharmacogenomics applies to the entire spectrum of genes. The focus of pharmacogenomics is on individualized drug and dosage for a specific disease. When it comes to pharmacogenetics, the focus is on metabolizing enzymes and and how they are transported. Pharmacogenomics is the broader application of genomic technologies to new drug discovery and further characterization of older drugs. Pharmacogenetics is generally regarded as the study or clinical testing of genetic variation, which gives rise to different responses to drugs.
The scientific field of drug-drug interactions is relatively new. Forty years ago, the first major symposium on drug interactions took place in Britain.14 McInnes and Brodie advise clinicians to appreciate drug interactions by combining a practical knowledge of the pharmacological mechanisms involved with an awareness of the most vulnerable patients.15
The relatively recent discoveries of cytochrome P-450 isozymes and ATP binding cassette transporters have revolutionized the field. Podiatric physicians are encouraged to have a sound knowledge of drug-induced, mechanism-based cytochrome P450 drug interactions.
Nonsteroidal anti-inflammatory drugs (NSAIDs) and antibiotics such as rifampin (Rifadin, Sanofi Aventis) are common precipitant drugs that podiatrists prescribe. Drugs with a narrow therapeutic range or low therapeutic index are more likely to be the objects for serious drug interactions. Warfarin (Coumadin, Bristol-Myers Squibb), fluoroquinolones, antiepileptic drugs, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and oral contraceptives are common object drugs.
It is important for the podiatric physician to remember that even if a drug is not metabolized by a specific cytochrome P450 isozyme, the drug can affect the metabolism of other drugs through the cytochrome P450 pathway. However, even given all the scientific knowledge describing cytochrome P450 isozymes and the adenosine triphosphate-binding cassette transporters, the discovery of new drug interactions still occurs through careful assessment of case reports.
Many potential drug-drug interactions are clinically inconsequential. In terms of a general rule, a drug-drug interaction may be clinically relevant when the administration of another substance alters the efficacy or toxicity of a medication. Drug interactions are never straightforward because not all patients will experience the same effect to the same degree. For a ready reference source, see “A Primer On Potentially Serious Drug Interactions” (see table below).
When a patient is stabilized on either lovastatin (Zocor, Merck) or simvastatin (Mevacor, Merck) and one adds “azole antifungal agents” to the regimen, there may be increased serum concentrations of simvastatin/lovastatin as a result. Azole antifungal agents include itraconazole (Sporanox, Janssen Pharmaceuticals), ketoconazole (Nizoral, McNeil-PPC), posaconazole (Noxafil, Schering Plough), voriconazole (Vfend, Pfizer), fluconazole (Diflucan, Pfizer). There is also a risk of myopathy/rhabdomyolysis because of the inhibition of simvastatin/lovastatin metabolism by CYP3A4.
In these cases, the podiatric physician should consider alternative antifungal agents like terbinafine (Lamisil, Novartis) or ciclopirox nail lacquer (Penlac, Sanofi Aventis).
If alternative agents are not appropriate, then one should monitor the patient for evidence of myopathy (muscle pain or weakness) and myoglobinuria (dark urine). Temporarily stopping simvastatin/lovastatin during the short-term itraconazole therapy is a reasonable alternative as long as patients keep their primary care providers informed of the drug regimen. Alternative statin agents like fluvastatin (Lescol, Novartis), rosuvastatin (Crestor, AstraZeneca) or even pravastatin (Pravachol, Bristol-Myers Squibb) may prove beneficial in patients who need long-term therapy of itraconazole.
All “azoles” inhibit the CYP3A4 isoenzyme.16 Yu and colleagues reported the potential fluconazole drug interactions were very frequent among hospitalized patients on systemic azole antifungal therapy, but they had few apparent clinical consequences.17 The authors reported that among the 4,185 admissions who took azole agents (fluconazole, itraconazole or ketoconazole), 2,941 (70.3 percent) admissions experienced potential azole–drug interactions. This included 2,716 (92.3 percent) patients who experienced fluconazole interactions.
The most frequent interactions with potential moderate to major severity were co-administration of fluconazole with prednisone (25.3 percent), midazolam (Dormicum, Roche) (17.5 percent), warfarin (14.7 percent), methylprednisolone (Medrol, Pfizer) (14.1 percent), cyclosporine (Gengraf, Abbott Laboratories) (10.7 percent) and nifedipine (Adalat, Bayer HealthCare) (10.1 percent).17 Fluconazole causes an increase of phenobarbital (Solfoton) and phenytoin (Dilantin, Pfizer) levels in the blood when patients take it concurrently with these anti-seizure agents.18
Itraconazole appears to increase the bioavailability of digoxin (Lanoxin, GlaxoSmithKline) and/or reduce the renal and non-renal clearance of digoxin by inhibiting P-glycoprotein (PGP). Digoxin toxicity may occur when one uses it in combination with itraconazole.19 P-glycoprotein is an efflux transporter found in the small intestine, kidney, liver and brain. To manage this interaction, the preferred management strategy is to use an alternative antifungal that does not inhibit P-glycoprotein.
Digoxin toxicity may occur when one uses it in combination with clarithromycin (Biaxin, Abbott Laboratories). Clarithromycin, a macrolide, enhances the absorption of digoxin and/or reduces its elimination by inhibiting PGP transport of digoxin.20 To manage this interaction, the preferred management strategy is to use an alternative antibiotic, preferably an anti-infective that does not inhibit PGP.
Warfarin is an anticoagulant racemic mixture of S- and R-warfarin enantiomers. The metabolism of these enantiomers is by different CYPs. S-warfarin is primarily metabolized by CYP2C9 and R-warfarin is metabolized by CYP1A2, CYP2C19 and CYP3A4. Fluconazole causes a dose-related inhibition of the metabolism by CYP2C9 and increases warfarin concentration and bleeding risk.21
Monitor carefully for an altered warfarin response if the patient starts on an interacting “azole antifungal,” stops taking it or changes dosage. Inhibition of warfarin metabolism by CYPC9 and resulting bleeding risk can occur with sulfamethoxazole/trimethoprim (Bactrim, Roche) and metronidazole (Flagyl, Pfizer).21 Researchers have reported that quinolones and macrolides increase the anticoagulant effects of warfarin.21 Oral penicillin, amoxicillin (Amoxil, GlaxoSmithKline), ampicillin, oral cephalosporins and penicillins have not been shown to interact with warfarin. These agents are considered preferred alternatives. In those cases when alternatives are not appropriate, carefully monitor the international normalized ratio (INR) and check for signs of bleeding.
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
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.
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
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
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
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.
Another drug-drug management option is to space the dosing times of each interacting drug to avoid the interaction. This option allows for the object drug to be absorbed into the circulation before the precipitant drug. Always provide information on patient risk factors that increase the chance for an adverse outcome to the patient or patient caretaker so the patient avoids the adverse effects of drug-drug interactions. Computerized drug interaction screening systems are helpful tools that the podiatric physician may use but improvement in these systems is necessary.
One can predict the potential for important drug interactions based on the properties of the causative agent and the interacting agent. The majority of drug-drug interactions have known factors grounded in science. However, many healthcare providers rely solely on inductive reasoning based on personal clinical experience as a guide to the clinical importance of most drug-drug interactions.
Published clinical evidence does exist for many of the reported drug-drug interactions that cause serious adverse reactions. Therefore, podiatric physicians should consider the results of published literature as well as their own clinical experience when making decisions on the potential for drug interactions in their patient population.
Dr. Smith is in private practice at Shoe String Podiatry in Ormond Beach, Fla.
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