I t’s 9 a.m., and do you know what your patient might be doing? It’s very possible that any of the three scenarios is occurring right now: 1. One of your patients, who’s undergoing treatment for acne, has ingested her morning dose of tetracycline (Sumycin) along with a vitamin-mineral supplement that has been promoted at a health food store to help her lose weight. 2. Another one of your patients, who is undergoing treatment for an infected leg ulcer, has just taken his morning dose of ciprofloxacin (Cipro) 10 minutes after he ingested an antacid that was recommended by his pharmacist to reduce “heartburn.” 3. A third patient, a female undergoing treatment for rosacea, consistently takes her oral tetracycline along with her morning meal of yogurt because she read in a health publication that yogurt reduces the risk of vaginal yeast infection in women taking antibiotics. In all three cases, good intentions have likely been thwarted by the ability of various mineral ions to reduce drug absorption. Here, I’ll discuss important perspectives regarding the impact of interactions between specific prescription drugs and various minerals found in high content in certain foods and over-the-counter (OTC) supplements or antacids. In addition, I’ll highlight selected interactions based on the high likelihood of their significance in clinical practice. Defining and Recognizing Interactions Drug interactions have classically been defined based on their underlying mechanism. They may occur from alterations in gastrointestinal absorption, metabolism or excretion. A more conceptual approach is to view a drug interaction based upon its pharmacokinetic and pharmacodynamic impact. • Pharmacokinetic interaction. This term refers to whether or not serum levels and bioavailability parameters are affected. For example, when ciprofloxacin is ingested within 10 minutes of an aluminum/magnesium containing antacid, the bioavailability of ciprofloxacin is reduced by up to 85%. • Pharmacodynamic effect. The potential result of this interaction is a decrease in antimicrobial effect, reduced drug efficacy and continuation of infection. It’s possible that although pharmacokinetic interactions occur as a result of many reported drug interactions, in only some cases is the impact significant enough to produce a clinically apparent pharmacodynamic effect. In this example, if ciprofloxacin is habitually ingested too close to antacid administration, the patient has a high likelihood of treatment failure related to the marked decrease in ciprofloxacin absorption. When the Patient Experiences Toxicity The pharmacodynamic effect of a drug interaction is much more likely to be suspected when a patient experiences toxicity. For example, say the patient experiences an unexplained increase in cyclosporin serum levels resulting in elevated blood pressure. This event may prompt the clinician to ask the patient whether he or she habitually takes cyclosporin along with grapefruit juice instead of water. Grapefruit juice has been shown to increase cyclosporin bioavailability by inhibiting intestinal cytochrome P450 3A4, the enzyme involved in cyclosporin metabolism in the gastrointestinal tract. However, a drug interaction is less likely to be suspected when there is a lack of clinical response. For example, in the case described, where ciprofloxacin absorption is reduced significantly by concommitant antacid use, the clinician may suspect that ciprofloxacin was not effective, overlooking the fact that lack of efficacy occurred solely as a result of impaired drug absorption. Had the patient been ingesting the ciprofloxacin with water 2 hours before antacid intake, the infection would’ve likely responded. When discussing interactions, I’ll focus on three classes of drugs that we commonly use in dermatology. These include the following: 1. quinolones 2. tetracyclines (especially tetracycline) 3. some cephalosporins. With regard to these drug classes, I’ll review several seemingly innocuous agents that patients use — specifically antacids, dairy products, grapefruit juice, vitamins and minerals — to discuss some of the dramatic subtherapeutic events that can result when these agents are used in conjunction with specific drugs. Interactions with Antacids Antacids significantly vary in composition, resulting in variable impact on the gastrointestinal absorption of specific medications. Let’s look at some examples of their effects on commonly prescribed therapies. • Quinolones. Several studies have established the correlation between a decrease in gastrointestinal absorption of several oral quinolones secondary to co-administration with antacids containing aluminum/magnesium (ie. Maalox, Mylanta), calcium carbonate (ie. Tums, Rolaids) and bismuth subsalicylate (ie. Pepto-Bismol). What happens to cause decreased gastrointestinal absorption? The reported mechanism of action involves functional groups of the quinolone structural nucleus. Certain metal ions in antacids bind with the structural nuclei of the quinolone. When this occurs, it causes the formation of insoluble chelates that aren’t absorbed through the gastrointestinal mucosa. Reduced quinolone bioavailability appears to be greatest with antacids containing aluminum and magnesium. Another important factor is timing. The time at which a patient ingests an aluminum/magnesium antacid greatly affects the bioavailability of a drug such as ciprofloxacin (Cipro). (For more specifics, see the table on page 52.) Other studies have reported the following decreases in bioavailability of specific quinolones: • ofloxacin (Floxin) — 48% to 69% • norfloxacin (Noroxin) — 23% to 97% • levofloxacin (Levaquin) — 45%. Comparing Different Antacids Intake of ciprofloxacin 5 minutes before calcium carbonate antacid administration has been reported to reduce the ciprofloxacin bioavailability by 41%. Calcium carbonate antacid ingestion has also been shown to reduce the bioavailability of norfloxacin by 63% and levofloxacin by only 3%. Bismuth subsalicylate appears to produce a lesser effect on quinolone gastrointestinal absorption, reducing the relative bioavailability of ciprofloxacin by 16%. Because the antibacterial effect of quinolone antibiotics is concentration-dependent, significant reduction in gastrointestinal absorption can profoundly reduce clinical efficacy. What Are The Alternatives? Since the mechanism of interaction between several antacids and quinolone antibiotics is drug chelation rather than increased gastric pH, possible alternatives to antacid therapy include the following: • H2 Receptor Antagonists. Examples include cimetidine (Tagamet), ranitidine (Zantac) and famotidine (Pepcid). • Proton Pump Inhibitors. Drugs in this category include rabeprazole (Aciphex), lansoprazole (Prevacid), omeprazole (Prilosec), pantoprazole (Protonix) and esomeprazole (Nexium). Also, it’s important to remember that some patients utilize antacid products containing calcium carbonate as calcium supplements rather than for their antacid properties. In order to obviate the adverse effect of antacids on quinolone absorption and bioavailability, recommend to your patients that they take a prescribed quinolone antibiotic with water 2 hours before or at least 6 hours after an antacid. •Tetracyclines. Multiple antacid formulations have been shown to significantly reduce the gastrointestinal absorption of several tetracycline antibiotics, including tetracycline and doxycycline. Although drug chelation by metal ions is the predominant interaction mechanism, other interactions can occur as well. There are also reports of increased gastric pH with antacids when co-administration with some tetracyclines occurs. In addition, in some cases the antacid has absorbed the tetracycline so that less of the antibiotic is bioavailable. Ingestion of magnesium/aluminum hydroxide-containing antacids with tetracycline has been shown to reduce tetracycline absorption, resulting in up to 90% reduction in tetracycline serum levels. A significant reduction in doxycycline absorption has also been reported with co-administration of an aluminum hydroxide-containing antacid. Bismuth subsalicylate also reduces the gastrointestinal absorption of both tetracycline and doxycycline, with a 50% reduction in doxycycline serum levels reported. Some reports have indicated that sodium bicarbonate ingestion can reduce tetracycline absorption by up to 50%. Reduction in absorption of tetracycline when co-ingested with calcium carbonate has also been reported. Although kaolin-pectin preparations (ie. Kaopectate) are not technically antacids, they’re commonly used for “stomach upset” and diarrhea. Kaolin-pectin ingestion with tetracycline reduces the absorption of the antibiotic by 50%. When given 2 hours before or after tetracycline, the absorption of tetracycline was reduced by 20%. In fact, if gastrointestinal upset or diarrhea occurs during tetracycline therapy, it’s best to discontinue tetracycline use if clinically feasible and explore a possible relationship between the gastrointestinal symptoms and tetracycline use. Dairy Dilemmas Studies evaluating the impact of milk ingestion on the absorption of tetracyclines suggest a decrease in gastrointestinal absorption of 50% with tetracycline and 20% to 30% with doxycycline or minocycline. It’s recommended that patients take tetracycline antibiotics 1 to 2 hours before antacids. With regard to milk or dairy products, including yogurt and cheeses, patients should wait at least 2 hours after taking tetracycline before they eat or drink dairy products. The small amounts of milk used in coffee or tea don’t appear to significantly impair tetracycline absorption. • Cephalosporins. Concurrent ingestion of antacids may decrease the absorption of cefdinir (Omnicef). A retrospective evaluation of patients treated for cellulitis has suggested concomitant acid suppression therapy as a risk factor for therapeutic failure with cephalexin (Keflex). Due to significant reduction in cefdinir absorption, co-administration with ferrous sulfate and other iron salts should also be avoided. This is likely due to chelation of cefdinir by iron. Interactions with Minerals Several reports have demonstrated significant reductions in the absorption of quinolone and tetracycline antibiotics when co-administered with certain mineral supplements, including calcium, iron and zinc. • Quinolones. The impact of calcium ingestion on quinolone absorption was discussed above under the section on antacids. Several studies have confirmed decreased quinolone bioavailability after co-administration with preparations containing ionic iron, including ferrous sulfate, ferrous gluconate and ferrous fumarate. Reductions in ciprofloxacin maximum serum levels of 30% to 80% and reduced total absorption (area under the curve) have been reported due to co-administration with iron supplements and vitamin-mineral supplement preparations (for example, Centrum Forte). Significant reduction in gastrointestinal absorption of other quinolones has also been reported, including norfloxacin and levofloxacin. Although zinc has less of an impact than iron on quinolone absorption, significant interaction may also occur. Recommend to your patients that they take quinolones at least 2 hours before calcium supplements, iron supplements, zinc supplements and vitamin-mineral preparations containing significant quantities of these minerals. Keep in mind that certain “fortified” foods (i.e. cereals, juices) may contain significant quantities of minerals. For example, a breakfast containing 8 ounces of calcium-fortified orange juice and one serving of Total cereal exceeds the amount of calcium contained in two Tums-EX antacid tablets. • Tetracyclines. The concurrent administration of ferrous sulfate (200 mg) and tetracycline has been shown to reduce tetracycline serum levels by 40% to 50% and doxycycline by 80% to 90%. Other ferrous salts (ie. gluconate, fumarate) also produce significant reductions in tetracycline bioavailability. Reduction in tetracycline serum concentrations below minimum inhibitory antibacterial concentrations has been reported. An additional study demonstrated a reduction in absorption of tetracycline of 81% and minocycline of 77% due to co-administration of ferrous sulfate (300 mg). Interestingly, chelation of tetracycline by iron has also been shown to adversely reduce iron absorption by 37% to 78% in normal subjects and 40% to 65% in iron-depleted individuals. When iron is administered 3 hours before or 2 hours after administration of tetracycline, serum levels of tetracycline aren’t significantly reduced. However, in one report, when iron was administered 11 hours after ingestion of doxycycline, serum concentrations of doxycycline remained reduced by 20% to 45%. Multiple studies have demonstrated reductions in tetracycline absorption ranging from 30% to >50% due to chelation by co-administered zinc sulfate. In one study, the reduction in serum zinc levels was found to be negligible. (Bismuth may also reduce tetracycline absorption.) As with iron, administration of tetracycline and zinc supplements should be separated by 2 to 3 hours. • Cephalosporins. Co-administration of cefdinir with ferrous sulfate and other iron salts should be avoided. It’s believed that cefdinir is chelated by iron. Grapefruit Juice Interaction Grapefruit juice may seem like an unlikely culprit to intervene with medications, but there are a few situations to be wary of. • Cephalosporins. Reports have confirmed that co-administration of cyclosporin and grapefruit juice increases cyclosporin absorption. Mean trough levels of cyclosporin have been reported to increase by approximately 25%. Grapefruit juice ingestion with cyclosporin has been shown to increase total cyclosporin absorption (area under the curve) by 16% to 200% compared with water or orange juice. Peak serum levels of cyclosporin were 24% higher in patients ingesting the drug 90 minutes after intake of grapefruit juice as compared to ingestion with water. In patients who previously ingested cyclosporin with grapefruit juice, taking the drug with water resulted in lowering cyclosporin serum levels. Because cyclosporin is a drug that’s titrated within a “therapeutic window,” patients should just avoid taking this drug with grapefruit juice. In fact, because grapefruit juice can affect the absorption of other drugs, it’s best to just have your patients avoid taking it with any medication just to be safe. Safety First Many of you may not have been aware of these potential interactions of seemingly harmless, everyday agents that our patients could easily be taking with their medications. I hope I’ve provided you with some information to help avoid interactions that could render your patients’ therapies ineffective.
Avoiding Prescribing Pitfalls
I t’s 9 a.m., and do you know what your patient might be doing? It’s very possible that any of the three scenarios is occurring right now: 1. One of your patients, who’s undergoing treatment for acne, has ingested her morning dose of tetracycline (Sumycin) along with a vitamin-mineral supplement that has been promoted at a health food store to help her lose weight. 2. Another one of your patients, who is undergoing treatment for an infected leg ulcer, has just taken his morning dose of ciprofloxacin (Cipro) 10 minutes after he ingested an antacid that was recommended by his pharmacist to reduce “heartburn.” 3. A third patient, a female undergoing treatment for rosacea, consistently takes her oral tetracycline along with her morning meal of yogurt because she read in a health publication that yogurt reduces the risk of vaginal yeast infection in women taking antibiotics. In all three cases, good intentions have likely been thwarted by the ability of various mineral ions to reduce drug absorption. Here, I’ll discuss important perspectives regarding the impact of interactions between specific prescription drugs and various minerals found in high content in certain foods and over-the-counter (OTC) supplements or antacids. In addition, I’ll highlight selected interactions based on the high likelihood of their significance in clinical practice. Defining and Recognizing Interactions Drug interactions have classically been defined based on their underlying mechanism. They may occur from alterations in gastrointestinal absorption, metabolism or excretion. A more conceptual approach is to view a drug interaction based upon its pharmacokinetic and pharmacodynamic impact. • Pharmacokinetic interaction. This term refers to whether or not serum levels and bioavailability parameters are affected. For example, when ciprofloxacin is ingested within 10 minutes of an aluminum/magnesium containing antacid, the bioavailability of ciprofloxacin is reduced by up to 85%. • Pharmacodynamic effect. The potential result of this interaction is a decrease in antimicrobial effect, reduced drug efficacy and continuation of infection. It’s possible that although pharmacokinetic interactions occur as a result of many reported drug interactions, in only some cases is the impact significant enough to produce a clinically apparent pharmacodynamic effect. In this example, if ciprofloxacin is habitually ingested too close to antacid administration, the patient has a high likelihood of treatment failure related to the marked decrease in ciprofloxacin absorption. When the Patient Experiences Toxicity The pharmacodynamic effect of a drug interaction is much more likely to be suspected when a patient experiences toxicity. For example, say the patient experiences an unexplained increase in cyclosporin serum levels resulting in elevated blood pressure. This event may prompt the clinician to ask the patient whether he or she habitually takes cyclosporin along with grapefruit juice instead of water. Grapefruit juice has been shown to increase cyclosporin bioavailability by inhibiting intestinal cytochrome P450 3A4, the enzyme involved in cyclosporin metabolism in the gastrointestinal tract. However, a drug interaction is less likely to be suspected when there is a lack of clinical response. For example, in the case described, where ciprofloxacin absorption is reduced significantly by concommitant antacid use, the clinician may suspect that ciprofloxacin was not effective, overlooking the fact that lack of efficacy occurred solely as a result of impaired drug absorption. Had the patient been ingesting the ciprofloxacin with water 2 hours before antacid intake, the infection would’ve likely responded. When discussing interactions, I’ll focus on three classes of drugs that we commonly use in dermatology. These include the following: 1. quinolones 2. tetracyclines (especially tetracycline) 3. some cephalosporins. With regard to these drug classes, I’ll review several seemingly innocuous agents that patients use — specifically antacids, dairy products, grapefruit juice, vitamins and minerals — to discuss some of the dramatic subtherapeutic events that can result when these agents are used in conjunction with specific drugs. Interactions with Antacids Antacids significantly vary in composition, resulting in variable impact on the gastrointestinal absorption of specific medications. Let’s look at some examples of their effects on commonly prescribed therapies. • Quinolones. Several studies have established the correlation between a decrease in gastrointestinal absorption of several oral quinolones secondary to co-administration with antacids containing aluminum/magnesium (ie. Maalox, Mylanta), calcium carbonate (ie. Tums, Rolaids) and bismuth subsalicylate (ie. Pepto-Bismol). What happens to cause decreased gastrointestinal absorption? The reported mechanism of action involves functional groups of the quinolone structural nucleus. Certain metal ions in antacids bind with the structural nuclei of the quinolone. When this occurs, it causes the formation of insoluble chelates that aren’t absorbed through the gastrointestinal mucosa. Reduced quinolone bioavailability appears to be greatest with antacids containing aluminum and magnesium. Another important factor is timing. The time at which a patient ingests an aluminum/magnesium antacid greatly affects the bioavailability of a drug such as ciprofloxacin (Cipro). (For more specifics, see the table on page 52.) Other studies have reported the following decreases in bioavailability of specific quinolones: • ofloxacin (Floxin) — 48% to 69% • norfloxacin (Noroxin) — 23% to 97% • levofloxacin (Levaquin) — 45%. Comparing Different Antacids Intake of ciprofloxacin 5 minutes before calcium carbonate antacid administration has been reported to reduce the ciprofloxacin bioavailability by 41%. Calcium carbonate antacid ingestion has also been shown to reduce the bioavailability of norfloxacin by 63% and levofloxacin by only 3%. Bismuth subsalicylate appears to produce a lesser effect on quinolone gastrointestinal absorption, reducing the relative bioavailability of ciprofloxacin by 16%. Because the antibacterial effect of quinolone antibiotics is concentration-dependent, significant reduction in gastrointestinal absorption can profoundly reduce clinical efficacy. What Are The Alternatives? Since the mechanism of interaction between several antacids and quinolone antibiotics is drug chelation rather than increased gastric pH, possible alternatives to antacid therapy include the following: • H2 Receptor Antagonists. Examples include cimetidine (Tagamet), ranitidine (Zantac) and famotidine (Pepcid). • Proton Pump Inhibitors. Drugs in this category include rabeprazole (Aciphex), lansoprazole (Prevacid), omeprazole (Prilosec), pantoprazole (Protonix) and esomeprazole (Nexium). Also, it’s important to remember that some patients utilize antacid products containing calcium carbonate as calcium supplements rather than for their antacid properties. In order to obviate the adverse effect of antacids on quinolone absorption and bioavailability, recommend to your patients that they take a prescribed quinolone antibiotic with water 2 hours before or at least 6 hours after an antacid. •Tetracyclines. Multiple antacid formulations have been shown to significantly reduce the gastrointestinal absorption of several tetracycline antibiotics, including tetracycline and doxycycline. Although drug chelation by metal ions is the predominant interaction mechanism, other interactions can occur as well. There are also reports of increased gastric pH with antacids when co-administration with some tetracyclines occurs. In addition, in some cases the antacid has absorbed the tetracycline so that less of the antibiotic is bioavailable. Ingestion of magnesium/aluminum hydroxide-containing antacids with tetracycline has been shown to reduce tetracycline absorption, resulting in up to 90% reduction in tetracycline serum levels. A significant reduction in doxycycline absorption has also been reported with co-administration of an aluminum hydroxide-containing antacid. Bismuth subsalicylate also reduces the gastrointestinal absorption of both tetracycline and doxycycline, with a 50% reduction in doxycycline serum levels reported. Some reports have indicated that sodium bicarbonate ingestion can reduce tetracycline absorption by up to 50%. Reduction in absorption of tetracycline when co-ingested with calcium carbonate has also been reported. Although kaolin-pectin preparations (ie. Kaopectate) are not technically antacids, they’re commonly used for “stomach upset” and diarrhea. Kaolin-pectin ingestion with tetracycline reduces the absorption of the antibiotic by 50%. When given 2 hours before or after tetracycline, the absorption of tetracycline was reduced by 20%. In fact, if gastrointestinal upset or diarrhea occurs during tetracycline therapy, it’s best to discontinue tetracycline use if clinically feasible and explore a possible relationship between the gastrointestinal symptoms and tetracycline use. Dairy Dilemmas Studies evaluating the impact of milk ingestion on the absorption of tetracyclines suggest a decrease in gastrointestinal absorption of 50% with tetracycline and 20% to 30% with doxycycline or minocycline. It’s recommended that patients take tetracycline antibiotics 1 to 2 hours before antacids. With regard to milk or dairy products, including yogurt and cheeses, patients should wait at least 2 hours after taking tetracycline before they eat or drink dairy products. The small amounts of milk used in coffee or tea don’t appear to significantly impair tetracycline absorption. • Cephalosporins. Concurrent ingestion of antacids may decrease the absorption of cefdinir (Omnicef). A retrospective evaluation of patients treated for cellulitis has suggested concomitant acid suppression therapy as a risk factor for therapeutic failure with cephalexin (Keflex). Due to significant reduction in cefdinir absorption, co-administration with ferrous sulfate and other iron salts should also be avoided. This is likely due to chelation of cefdinir by iron. Interactions with Minerals Several reports have demonstrated significant reductions in the absorption of quinolone and tetracycline antibiotics when co-administered with certain mineral supplements, including calcium, iron and zinc. • Quinolones. The impact of calcium ingestion on quinolone absorption was discussed above under the section on antacids. Several studies have confirmed decreased quinolone bioavailability after co-administration with preparations containing ionic iron, including ferrous sulfate, ferrous gluconate and ferrous fumarate. Reductions in ciprofloxacin maximum serum levels of 30% to 80% and reduced total absorption (area under the curve) have been reported due to co-administration with iron supplements and vitamin-mineral supplement preparations (for example, Centrum Forte). Significant reduction in gastrointestinal absorption of other quinolones has also been reported, including norfloxacin and levofloxacin. Although zinc has less of an impact than iron on quinolone absorption, significant interaction may also occur. Recommend to your patients that they take quinolones at least 2 hours before calcium supplements, iron supplements, zinc supplements and vitamin-mineral preparations containing significant quantities of these minerals. Keep in mind that certain “fortified” foods (i.e. cereals, juices) may contain significant quantities of minerals. For example, a breakfast containing 8 ounces of calcium-fortified orange juice and one serving of Total cereal exceeds the amount of calcium contained in two Tums-EX antacid tablets. • Tetracyclines. The concurrent administration of ferrous sulfate (200 mg) and tetracycline has been shown to reduce tetracycline serum levels by 40% to 50% and doxycycline by 80% to 90%. Other ferrous salts (ie. gluconate, fumarate) also produce significant reductions in tetracycline bioavailability. Reduction in tetracycline serum concentrations below minimum inhibitory antibacterial concentrations has been reported. An additional study demonstrated a reduction in absorption of tetracycline of 81% and minocycline of 77% due to co-administration of ferrous sulfate (300 mg). Interestingly, chelation of tetracycline by iron has also been shown to adversely reduce iron absorption by 37% to 78% in normal subjects and 40% to 65% in iron-depleted individuals. When iron is administered 3 hours before or 2 hours after administration of tetracycline, serum levels of tetracycline aren’t significantly reduced. However, in one report, when iron was administered 11 hours after ingestion of doxycycline, serum concentrations of doxycycline remained reduced by 20% to 45%. Multiple studies have demonstrated reductions in tetracycline absorption ranging from 30% to >50% due to chelation by co-administered zinc sulfate. In one study, the reduction in serum zinc levels was found to be negligible. (Bismuth may also reduce tetracycline absorption.) As with iron, administration of tetracycline and zinc supplements should be separated by 2 to 3 hours. • Cephalosporins. Co-administration of cefdinir with ferrous sulfate and other iron salts should be avoided. It’s believed that cefdinir is chelated by iron. Grapefruit Juice Interaction Grapefruit juice may seem like an unlikely culprit to intervene with medications, but there are a few situations to be wary of. • Cephalosporins. Reports have confirmed that co-administration of cyclosporin and grapefruit juice increases cyclosporin absorption. Mean trough levels of cyclosporin have been reported to increase by approximately 25%. Grapefruit juice ingestion with cyclosporin has been shown to increase total cyclosporin absorption (area under the curve) by 16% to 200% compared with water or orange juice. Peak serum levels of cyclosporin were 24% higher in patients ingesting the drug 90 minutes after intake of grapefruit juice as compared to ingestion with water. In patients who previously ingested cyclosporin with grapefruit juice, taking the drug with water resulted in lowering cyclosporin serum levels. Because cyclosporin is a drug that’s titrated within a “therapeutic window,” patients should just avoid taking this drug with grapefruit juice. In fact, because grapefruit juice can affect the absorption of other drugs, it’s best to just have your patients avoid taking it with any medication just to be safe. Safety First Many of you may not have been aware of these potential interactions of seemingly harmless, everyday agents that our patients could easily be taking with their medications. I hope I’ve provided you with some information to help avoid interactions that could render your patients’ therapies ineffective.
I t’s 9 a.m., and do you know what your patient might be doing? It’s very possible that any of the three scenarios is occurring right now: 1. One of your patients, who’s undergoing treatment for acne, has ingested her morning dose of tetracycline (Sumycin) along with a vitamin-mineral supplement that has been promoted at a health food store to help her lose weight. 2. Another one of your patients, who is undergoing treatment for an infected leg ulcer, has just taken his morning dose of ciprofloxacin (Cipro) 10 minutes after he ingested an antacid that was recommended by his pharmacist to reduce “heartburn.” 3. A third patient, a female undergoing treatment for rosacea, consistently takes her oral tetracycline along with her morning meal of yogurt because she read in a health publication that yogurt reduces the risk of vaginal yeast infection in women taking antibiotics. In all three cases, good intentions have likely been thwarted by the ability of various mineral ions to reduce drug absorption. Here, I’ll discuss important perspectives regarding the impact of interactions between specific prescription drugs and various minerals found in high content in certain foods and over-the-counter (OTC) supplements or antacids. In addition, I’ll highlight selected interactions based on the high likelihood of their significance in clinical practice. Defining and Recognizing Interactions Drug interactions have classically been defined based on their underlying mechanism. They may occur from alterations in gastrointestinal absorption, metabolism or excretion. A more conceptual approach is to view a drug interaction based upon its pharmacokinetic and pharmacodynamic impact. • Pharmacokinetic interaction. This term refers to whether or not serum levels and bioavailability parameters are affected. For example, when ciprofloxacin is ingested within 10 minutes of an aluminum/magnesium containing antacid, the bioavailability of ciprofloxacin is reduced by up to 85%. • Pharmacodynamic effect. The potential result of this interaction is a decrease in antimicrobial effect, reduced drug efficacy and continuation of infection. It’s possible that although pharmacokinetic interactions occur as a result of many reported drug interactions, in only some cases is the impact significant enough to produce a clinically apparent pharmacodynamic effect. In this example, if ciprofloxacin is habitually ingested too close to antacid administration, the patient has a high likelihood of treatment failure related to the marked decrease in ciprofloxacin absorption. When the Patient Experiences Toxicity The pharmacodynamic effect of a drug interaction is much more likely to be suspected when a patient experiences toxicity. For example, say the patient experiences an unexplained increase in cyclosporin serum levels resulting in elevated blood pressure. This event may prompt the clinician to ask the patient whether he or she habitually takes cyclosporin along with grapefruit juice instead of water. Grapefruit juice has been shown to increase cyclosporin bioavailability by inhibiting intestinal cytochrome P450 3A4, the enzyme involved in cyclosporin metabolism in the gastrointestinal tract. However, a drug interaction is less likely to be suspected when there is a lack of clinical response. For example, in the case described, where ciprofloxacin absorption is reduced significantly by concommitant antacid use, the clinician may suspect that ciprofloxacin was not effective, overlooking the fact that lack of efficacy occurred solely as a result of impaired drug absorption. Had the patient been ingesting the ciprofloxacin with water 2 hours before antacid intake, the infection would’ve likely responded. When discussing interactions, I’ll focus on three classes of drugs that we commonly use in dermatology. These include the following: 1. quinolones 2. tetracyclines (especially tetracycline) 3. some cephalosporins. With regard to these drug classes, I’ll review several seemingly innocuous agents that patients use — specifically antacids, dairy products, grapefruit juice, vitamins and minerals — to discuss some of the dramatic subtherapeutic events that can result when these agents are used in conjunction with specific drugs. Interactions with Antacids Antacids significantly vary in composition, resulting in variable impact on the gastrointestinal absorption of specific medications. Let’s look at some examples of their effects on commonly prescribed therapies. • Quinolones. Several studies have established the correlation between a decrease in gastrointestinal absorption of several oral quinolones secondary to co-administration with antacids containing aluminum/magnesium (ie. Maalox, Mylanta), calcium carbonate (ie. Tums, Rolaids) and bismuth subsalicylate (ie. Pepto-Bismol). What happens to cause decreased gastrointestinal absorption? The reported mechanism of action involves functional groups of the quinolone structural nucleus. Certain metal ions in antacids bind with the structural nuclei of the quinolone. When this occurs, it causes the formation of insoluble chelates that aren’t absorbed through the gastrointestinal mucosa. Reduced quinolone bioavailability appears to be greatest with antacids containing aluminum and magnesium. Another important factor is timing. The time at which a patient ingests an aluminum/magnesium antacid greatly affects the bioavailability of a drug such as ciprofloxacin (Cipro). (For more specifics, see the table on page 52.) Other studies have reported the following decreases in bioavailability of specific quinolones: • ofloxacin (Floxin) — 48% to 69% • norfloxacin (Noroxin) — 23% to 97% • levofloxacin (Levaquin) — 45%. Comparing Different Antacids Intake of ciprofloxacin 5 minutes before calcium carbonate antacid administration has been reported to reduce the ciprofloxacin bioavailability by 41%. Calcium carbonate antacid ingestion has also been shown to reduce the bioavailability of norfloxacin by 63% and levofloxacin by only 3%. Bismuth subsalicylate appears to produce a lesser effect on quinolone gastrointestinal absorption, reducing the relative bioavailability of ciprofloxacin by 16%. Because the antibacterial effect of quinolone antibiotics is concentration-dependent, significant reduction in gastrointestinal absorption can profoundly reduce clinical efficacy. What Are The Alternatives? Since the mechanism of interaction between several antacids and quinolone antibiotics is drug chelation rather than increased gastric pH, possible alternatives to antacid therapy include the following: • H2 Receptor Antagonists. Examples include cimetidine (Tagamet), ranitidine (Zantac) and famotidine (Pepcid). • Proton Pump Inhibitors. Drugs in this category include rabeprazole (Aciphex), lansoprazole (Prevacid), omeprazole (Prilosec), pantoprazole (Protonix) and esomeprazole (Nexium). Also, it’s important to remember that some patients utilize antacid products containing calcium carbonate as calcium supplements rather than for their antacid properties. In order to obviate the adverse effect of antacids on quinolone absorption and bioavailability, recommend to your patients that they take a prescribed quinolone antibiotic with water 2 hours before or at least 6 hours after an antacid. •Tetracyclines. Multiple antacid formulations have been shown to significantly reduce the gastrointestinal absorption of several tetracycline antibiotics, including tetracycline and doxycycline. Although drug chelation by metal ions is the predominant interaction mechanism, other interactions can occur as well. There are also reports of increased gastric pH with antacids when co-administration with some tetracyclines occurs. In addition, in some cases the antacid has absorbed the tetracycline so that less of the antibiotic is bioavailable. Ingestion of magnesium/aluminum hydroxide-containing antacids with tetracycline has been shown to reduce tetracycline absorption, resulting in up to 90% reduction in tetracycline serum levels. A significant reduction in doxycycline absorption has also been reported with co-administration of an aluminum hydroxide-containing antacid. Bismuth subsalicylate also reduces the gastrointestinal absorption of both tetracycline and doxycycline, with a 50% reduction in doxycycline serum levels reported. Some reports have indicated that sodium bicarbonate ingestion can reduce tetracycline absorption by up to 50%. Reduction in absorption of tetracycline when co-ingested with calcium carbonate has also been reported. Although kaolin-pectin preparations (ie. Kaopectate) are not technically antacids, they’re commonly used for “stomach upset” and diarrhea. Kaolin-pectin ingestion with tetracycline reduces the absorption of the antibiotic by 50%. When given 2 hours before or after tetracycline, the absorption of tetracycline was reduced by 20%. In fact, if gastrointestinal upset or diarrhea occurs during tetracycline therapy, it’s best to discontinue tetracycline use if clinically feasible and explore a possible relationship between the gastrointestinal symptoms and tetracycline use. Dairy Dilemmas Studies evaluating the impact of milk ingestion on the absorption of tetracyclines suggest a decrease in gastrointestinal absorption of 50% with tetracycline and 20% to 30% with doxycycline or minocycline. It’s recommended that patients take tetracycline antibiotics 1 to 2 hours before antacids. With regard to milk or dairy products, including yogurt and cheeses, patients should wait at least 2 hours after taking tetracycline before they eat or drink dairy products. The small amounts of milk used in coffee or tea don’t appear to significantly impair tetracycline absorption. • Cephalosporins. Concurrent ingestion of antacids may decrease the absorption of cefdinir (Omnicef). A retrospective evaluation of patients treated for cellulitis has suggested concomitant acid suppression therapy as a risk factor for therapeutic failure with cephalexin (Keflex). Due to significant reduction in cefdinir absorption, co-administration with ferrous sulfate and other iron salts should also be avoided. This is likely due to chelation of cefdinir by iron. Interactions with Minerals Several reports have demonstrated significant reductions in the absorption of quinolone and tetracycline antibiotics when co-administered with certain mineral supplements, including calcium, iron and zinc. • Quinolones. The impact of calcium ingestion on quinolone absorption was discussed above under the section on antacids. Several studies have confirmed decreased quinolone bioavailability after co-administration with preparations containing ionic iron, including ferrous sulfate, ferrous gluconate and ferrous fumarate. Reductions in ciprofloxacin maximum serum levels of 30% to 80% and reduced total absorption (area under the curve) have been reported due to co-administration with iron supplements and vitamin-mineral supplement preparations (for example, Centrum Forte). Significant reduction in gastrointestinal absorption of other quinolones has also been reported, including norfloxacin and levofloxacin. Although zinc has less of an impact than iron on quinolone absorption, significant interaction may also occur. Recommend to your patients that they take quinolones at least 2 hours before calcium supplements, iron supplements, zinc supplements and vitamin-mineral preparations containing significant quantities of these minerals. Keep in mind that certain “fortified” foods (i.e. cereals, juices) may contain significant quantities of minerals. For example, a breakfast containing 8 ounces of calcium-fortified orange juice and one serving of Total cereal exceeds the amount of calcium contained in two Tums-EX antacid tablets. • Tetracyclines. The concurrent administration of ferrous sulfate (200 mg) and tetracycline has been shown to reduce tetracycline serum levels by 40% to 50% and doxycycline by 80% to 90%. Other ferrous salts (ie. gluconate, fumarate) also produce significant reductions in tetracycline bioavailability. Reduction in tetracycline serum concentrations below minimum inhibitory antibacterial concentrations has been reported. An additional study demonstrated a reduction in absorption of tetracycline of 81% and minocycline of 77% due to co-administration of ferrous sulfate (300 mg). Interestingly, chelation of tetracycline by iron has also been shown to adversely reduce iron absorption by 37% to 78% in normal subjects and 40% to 65% in iron-depleted individuals. When iron is administered 3 hours before or 2 hours after administration of tetracycline, serum levels of tetracycline aren’t significantly reduced. However, in one report, when iron was administered 11 hours after ingestion of doxycycline, serum concentrations of doxycycline remained reduced by 20% to 45%. Multiple studies have demonstrated reductions in tetracycline absorption ranging from 30% to >50% due to chelation by co-administered zinc sulfate. In one study, the reduction in serum zinc levels was found to be negligible. (Bismuth may also reduce tetracycline absorption.) As with iron, administration of tetracycline and zinc supplements should be separated by 2 to 3 hours. • Cephalosporins. Co-administration of cefdinir with ferrous sulfate and other iron salts should be avoided. It’s believed that cefdinir is chelated by iron. Grapefruit Juice Interaction Grapefruit juice may seem like an unlikely culprit to intervene with medications, but there are a few situations to be wary of. • Cephalosporins. Reports have confirmed that co-administration of cyclosporin and grapefruit juice increases cyclosporin absorption. Mean trough levels of cyclosporin have been reported to increase by approximately 25%. Grapefruit juice ingestion with cyclosporin has been shown to increase total cyclosporin absorption (area under the curve) by 16% to 200% compared with water or orange juice. Peak serum levels of cyclosporin were 24% higher in patients ingesting the drug 90 minutes after intake of grapefruit juice as compared to ingestion with water. In patients who previously ingested cyclosporin with grapefruit juice, taking the drug with water resulted in lowering cyclosporin serum levels. Because cyclosporin is a drug that’s titrated within a “therapeutic window,” patients should just avoid taking this drug with grapefruit juice. In fact, because grapefruit juice can affect the absorption of other drugs, it’s best to just have your patients avoid taking it with any medication just to be safe. Safety First Many of you may not have been aware of these potential interactions of seemingly harmless, everyday agents that our patients could easily be taking with their medications. I hope I’ve provided you with some information to help avoid interactions that could render your patients’ therapies ineffective.
