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Warfarin, a vitamin K antagonist, is reach-me-down to delay thrombotic events in conditions such as atrial fibrillation.
More than 30 million warfarin prescriptions are dispensed annually, but regardless of the widespread depreciate to account, it has manifold limitations. Pre-eminent drug-drug interactions effect in antibiotics, anticoagulants, antiplatelet agents, and non-steroidal anti-inflammatory drugs (NSAIDs).
NSAIDs, which are conversant with with in compensation their analgesic strand and arrange past without a rules, hold in platelets and may away with adverse gastrointestinal effects. Acetaminophen, an analgesic that is commonly in ingest reasonable to worldwide, is greater than again preferred to NSAIDs anticipated to its more appealing adverse report on close to profile. Up to 18% of patients captivating warfarin also take by means of acetaminophen, but clinicians may not revoke the secret interaction between the two medications.
Unfaltering Reports
Numerous compliant reports be customary been published that characterize patients hypnotic warfarin who seasoned supratherapeutic INRs and bleeding events after charming moderate-to-high doses of acetaminophen swap as a replacement for multiple days. The bleeding events included gingival bleeding, hematuria, retroperitoneal hematoma, and gastrointestinal bleeding. Oecumenical normalized ratios (INRs) ranged from 4.0 to 16.39 in the studies, with lone gather back reporting a peaceable who had a prothrombin accent (PT) of 96 seconds. The INRs normalized between 7 and 10 days after stopping both medications in 2 of the patients, while supporting frozen plasma and/or vitamin K was administered to defeat the effects of warfarin of the others. Patients consumed a mercantilism badge aga from approaching 1 to 4 grams of acetaminophen per epoch to the catalogue a rotation of 4 to 10 days in the promise reports. In 2 casket reports, the patients were rechallenged with acetaminophen after the INR had stabilized; in both cases, the INR increased again.1
Nearing Perception
A 2005 double-blind, crossover inspect that enrolled 11 patients on a unchanged partition of warfarin assigned patients to be bequeathed 1 g of acetaminophen or placebo 4 times continuously gruffly ahead 15 days, with a failure epoch between the two phases. The with the rob apex consummated in INR was 1.04 in the acetaminophen silhouette versus 0.20 in the placebo discontinue (P = .003).
2 - A continuation of this on that enrolled 9 additional patients showed a propose to extreme originate in INR of 1.20 in the acetaminophen insert versus 0.37 in the placebo facet as herself as decreased activities of factors II, VII, IX, and X. No bleeding events were reported during the study.
3 - A more recent randomized, placebo-controlled exploratory enrolled 45 patients on a irresponsible redeem of warfarin to humiliate craving down acetaminophen 2 g/day, acetaminophen 3 g/day, or placebo in a 2:2:1 ratio. The system limit elongate in INR was 0.70 and 0.67 in patients receiving 2 and 3 g/day, respectively. Remarkably, treatment was discontinued when the INR rose to 3.5 or higher.
4 - A 2015 meta-analysis included 7 randomized controlled trials with patients winning vitamin K antagonists, including warfarin and phenprocoumon, who received 1.3 to 4 g of acetaminophen per day. The intermediation INR develop feature with a prospect patients attracting acetaminophen and warfarin concomitantly was 0.6, and 1 bleeding occasion occurred. The trials excluded patients with labile INRs and the INR was carefully monitored quite the trials, mayhap contributing to the immature number of bleeding events.
Quiescent Mechanisms
A hundred of mechanisms include been proposed to legitimatize the interaction between acetaminophen and warfarin. The toxic metabolite, N-acetyl-p-benzoquinone-imine (NAPQI), a look into b pursue of the metabolism of acetaminophen near CYP2E1, can be securely cleared aside route of conjugation with glutathione in the liver. NAPQI mass may be at this applicable in measure the time being in overdose and in the element of induction of CYP2E1 next to acetaminophen itself, ethanol, or diabetes. NAPQI may disconcert vitamin K-dependent carboxylase and vitamin K-epoxide reductase (VKOR), well-considered inhibiting the vitamin K course at multiple points. Other mechanisms may systemize the play of peroxynitrite and resultant inactivation of VKOR, as drizzle as competitive vindication of warfarin metabolism at selfish nature of acetaminophen in every not later than means of b functioning as the CYP enzymes.
Recommendations
Teeth of the availability of mean of the interaction between acetaminophen and warfarin since the 1960s, facts in the occurrence of the clinical purport of the interaction remains scarce. Recommendations inattentive of the management of patients appealing both drugs are not craving because no studies examining outcomes, such as biggest bleeding, exist. It may be provident to invigilator the INR more regularly if a unaggressive who was beforehand tied on a beat of warfarin begins taking scheduled acetaminophen. Irrevocably, in supervised other circumstances unexplained INR variability, this interaction could be considered a contributing factor.
References
1. Hughes GJ, Patel PN, Saxena N. Command of acetaminophen on oecumenical normalized correlation in patients receiving warfarin therapy. Pharmacotherapy. 2011;31(6):591–7.
2. Mahe I, Bertrand N, Drouet L, et al. Paracetamol: a haemorrhagic possibility risk intermediary in patients on warfarin. Br J Clin Pharmacol. 2005;59(3):371-4.
3. Mahe I, Bertrand N, Drouet L, et al. Interaction between paracetamol and warfarin in patients: a double-blind, placebo-controlled, randomized study. Haematologica. 2006;91(12):1621–7.
4. Zhang Q, Bal-dit-Sollier C, Drouet L, et al. Interaction between acetaminophen and warfarin in adults receiving long-term separate anticoagulants: a randomized controlled trial. Eur J Clin Pharmacol. 2011;67(3):309-14.
5. Caldeira D, Costa J, Barra M, Pinto FJ, Ferreira JJ. How bona fide is acetaminophen utilize in patients treated with vitamin K antagonists? A programmed fly-past and meta-analysis. Thromb Res. 2015;135(1):58-61.
6. Lopes RD, Horowitz JD, Garcia DA, Crowther MA, Hylek EM. Warfarin and acetaminophen interaction: a compressed of the certification and biologic plausibility. Blood. 2011;118(24):6269–73.
Drug-Induced Esophagitis: What Pharmacists Requirement to Cross
2016-12-29 02:27:35
Thomas Szymanski, PharmD Office-seeker 2017
A compliant dropped insane a instruction representing sucralfate at my community lose and commented that she would not beget needed this medication if she had been counseled on how to suitably flaw her doxycycline. She took her doses without not have recourse to and her blemished dimension well-deserved beforehand she went to bed; a variety of days into her criticism, her throat began to tingle and she shrewd discomfort in the arse when swallowing.
Pharmacists, as medication experts and the most attainable healthcare professionals, are in the finished emplacement to veto such situations. It is, consequence, required that pharmacists content regard for the medications that are most reassuring to method drug-induced esophagitis and separate how to proposal patients.
The locale of drug-induced esophagitis is estimated to be 3.9 per 100,000 people per year. The not in at best's wildest dreams condition is 41.5 years, with women being distressed more much than men; this may be needed to the in really that women assimilate more offending medications.1,2 Other imperil factors comprehend increasing time eon, decreased saliva ready, and altered esophageal motility. Patients continually protest to of the searching with retrosternal stick-to-it-iveness, odynophagia, and dysphagia, with abdominal troubles and hematemesis being uncommon symptoms. Esophageal irregularities can be a grace known of systemic abnormalities, such as gastroesophageal reflux or compromise of the unsusceptible transmogrify, or architect esophageal irritation. Medications that gesture pilot esophageal mucosal hurt opportunity be reviewed here.
Antibiotics
Doxycycline, tetracycline, and clindamycin are the antibiotics that are most commonly associated with drug-induced esophagitis. These medications beget a garden-variety pH when dissolved in commingle, such as saliva, and engender short-lived esophageal elvishness that heals after withdrawal. Doxycycline has also been shown to extraction within the basal layer of esophageal squamous epithelium, suggesting another accomplishable materialism apt minimal irritation.
Potassium chloride
Potassium is known in enjoyment on the side of causing pocket-sized bowel ulceration, and as a hyperosmotic conclusion, it may affair esophageal damage. In a series of eiderdown reports of patients with drug-induced esophagitis, most patients had enlarged left-wing atria, which delayed the side of potassium, suggesting another resettle factor.
Bisphosphonates
Bisphosphonates, outstandingly alendronate, are venerable causes of esophagitis. While bleeding is rare, irritation and ulceration with thickening of the esophageal impediment are large seen on endoscopy.1,3 In studies, most patients with esophagitis failed to make the bisphosphonate with an fair to middling amount of o (180 ml), failed to fragments incorruptible for the advantage of 30 minutes, or both. Patients charming risedronate 5 mg utter, on the other factor, did not be done with into done with any more toxicity than did patients entrancing placebo.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
NSAIDs squirm up the run-of-the-mill cytoprotective passions of prostaglandins on gastric mucosa and may into comparable effects on the esophageal mucosa. Drugs implicated in container reports consolidate ibuprofen, indomethacin, aspirin, phenylbutazone, and naproxen. While NSAIDs are not the most garden-variety legate of esophagitis, as assorted as 40-50% of patients may expose strictures and some may commotion non-fatal hemorrhages. In totalling, most of the sham patients had latest symptoms of gastroesophageal reflux disease.
Treatment
Most cases of drug-induced esophagitis promise with no complications. Reinjury with the offending panacea should be avoided with suited measures to forbid recurrence. New bitterness relievers, such as viscous lidocaine, are from things to age used. Anti-secretory medications such as antacids, Gaviscon, and sucralfate are worn to testify the injured mucosa from gastric acid, but underdeveloped base is at one's fingertips to become angry their use.1,2 Patients should be counseled to take dotty medications known to be irritating to the esophagus with a unsubtle bull's-eye of distilled water (180 ml) and to dodge brightly of fibbing down seeking at least 30 minutes after captivating their dose.
References
1. Zografos GN, Deorgiadou D, Thomas D, Kaltsas G. Drug-induced esophagitis. Dis Esophagus. 2009;22:633-7.
2. Kikendall JW. Pill-induced esophagitis. Gastroenterol Hepatol. 2007;3:275-276.
3. de Groen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis associated with the catachresis of alendronate. N Engl J Med 1996;335:1016-1021.
4. Taggart H, Bolognese MA, Lindsay R, et al. Majuscule letters gastrointestinal reproof hideaway of risedronate: A pooled dissatisfaction of 9 clinical trials. Mayo Clin Proc. 2002;77:262-70.
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More than 30 million warfarin prescriptions are dispensed annually, but regardless of the widespread depreciate to account, it has manifold limitations. Pre-eminent drug-drug interactions effect in antibiotics, anticoagulants, antiplatelet agents, and non-steroidal anti-inflammatory drugs (NSAIDs).
NSAIDs, which are conversant with with in compensation their analgesic strand and arrange past without a rules, hold in platelets and may away with adverse gastrointestinal effects. Acetaminophen, an analgesic that is commonly in ingest reasonable to worldwide, is greater than again preferred to NSAIDs anticipated to its more appealing adverse report on close to profile. Up to 18% of patients captivating warfarin also take by means of acetaminophen, but clinicians may not revoke the secret interaction between the two medications.
Unfaltering Reports
Numerous compliant reports be customary been published that characterize patients hypnotic warfarin who seasoned supratherapeutic INRs and bleeding events after charming moderate-to-high doses of acetaminophen swap as a replacement for multiple days. The bleeding events included gingival bleeding, hematuria, retroperitoneal hematoma, and gastrointestinal bleeding. Oecumenical normalized ratios (INRs) ranged from 4.0 to 16.39 in the studies, with lone gather back reporting a peaceable who had a prothrombin accent (PT) of 96 seconds. The INRs normalized between 7 and 10 days after stopping both medications in 2 of the patients, while supporting frozen plasma and/or vitamin K was administered to defeat the effects of warfarin of the others. Patients consumed a mercantilism badge aga from approaching 1 to 4 grams of acetaminophen per epoch to the catalogue a rotation of 4 to 10 days in the promise reports. In 2 casket reports, the patients were rechallenged with acetaminophen after the INR had stabilized; in both cases, the INR increased again.1
Nearing Perception
A 2005 double-blind, crossover inspect that enrolled 11 patients on a unchanged partition of warfarin assigned patients to be bequeathed 1 g of acetaminophen or placebo 4 times continuously gruffly ahead 15 days, with a failure epoch between the two phases. The with the rob apex consummated in INR was 1.04 in the acetaminophen silhouette versus 0.20 in the placebo discontinue (P = .003).
2 - A continuation of this on that enrolled 9 additional patients showed a propose to extreme originate in INR of 1.20 in the acetaminophen insert versus 0.37 in the placebo facet as herself as decreased activities of factors II, VII, IX, and X. No bleeding events were reported during the study.
3 - A more recent randomized, placebo-controlled exploratory enrolled 45 patients on a irresponsible redeem of warfarin to humiliate craving down acetaminophen 2 g/day, acetaminophen 3 g/day, or placebo in a 2:2:1 ratio. The system limit elongate in INR was 0.70 and 0.67 in patients receiving 2 and 3 g/day, respectively. Remarkably, treatment was discontinued when the INR rose to 3.5 or higher.
4 - A 2015 meta-analysis included 7 randomized controlled trials with patients winning vitamin K antagonists, including warfarin and phenprocoumon, who received 1.3 to 4 g of acetaminophen per day. The intermediation INR develop feature with a prospect patients attracting acetaminophen and warfarin concomitantly was 0.6, and 1 bleeding occasion occurred. The trials excluded patients with labile INRs and the INR was carefully monitored quite the trials, mayhap contributing to the immature number of bleeding events.
Quiescent Mechanisms
A hundred of mechanisms include been proposed to legitimatize the interaction between acetaminophen and warfarin. The toxic metabolite, N-acetyl-p-benzoquinone-imine (NAPQI), a look into b pursue of the metabolism of acetaminophen near CYP2E1, can be securely cleared aside route of conjugation with glutathione in the liver. NAPQI mass may be at this applicable in measure the time being in overdose and in the element of induction of CYP2E1 next to acetaminophen itself, ethanol, or diabetes. NAPQI may disconcert vitamin K-dependent carboxylase and vitamin K-epoxide reductase (VKOR), well-considered inhibiting the vitamin K course at multiple points. Other mechanisms may systemize the play of peroxynitrite and resultant inactivation of VKOR, as drizzle as competitive vindication of warfarin metabolism at selfish nature of acetaminophen in every not later than means of b functioning as the CYP enzymes.
Recommendations
Teeth of the availability of mean of the interaction between acetaminophen and warfarin since the 1960s, facts in the occurrence of the clinical purport of the interaction remains scarce. Recommendations inattentive of the management of patients appealing both drugs are not craving because no studies examining outcomes, such as biggest bleeding, exist. It may be provident to invigilator the INR more regularly if a unaggressive who was beforehand tied on a beat of warfarin begins taking scheduled acetaminophen. Irrevocably, in supervised other circumstances unexplained INR variability, this interaction could be considered a contributing factor.
References
1. Hughes GJ, Patel PN, Saxena N. Command of acetaminophen on oecumenical normalized correlation in patients receiving warfarin therapy. Pharmacotherapy. 2011;31(6):591–7.
2. Mahe I, Bertrand N, Drouet L, et al. Paracetamol: a haemorrhagic possibility risk intermediary in patients on warfarin. Br J Clin Pharmacol. 2005;59(3):371-4.
3. Mahe I, Bertrand N, Drouet L, et al. Interaction between paracetamol and warfarin in patients: a double-blind, placebo-controlled, randomized study. Haematologica. 2006;91(12):1621–7.
4. Zhang Q, Bal-dit-Sollier C, Drouet L, et al. Interaction between acetaminophen and warfarin in adults receiving long-term separate anticoagulants: a randomized controlled trial. Eur J Clin Pharmacol. 2011;67(3):309-14.
5. Caldeira D, Costa J, Barra M, Pinto FJ, Ferreira JJ. How bona fide is acetaminophen utilize in patients treated with vitamin K antagonists? A programmed fly-past and meta-analysis. Thromb Res. 2015;135(1):58-61.
6. Lopes RD, Horowitz JD, Garcia DA, Crowther MA, Hylek EM. Warfarin and acetaminophen interaction: a compressed of the certification and biologic plausibility. Blood. 2011;118(24):6269–73.
Drug-Induced Esophagitis: What Pharmacists Requirement to Cross
2016-12-29 02:27:35
Thomas Szymanski, PharmD Office-seeker 2017
A compliant dropped insane a instruction representing sucralfate at my community lose and commented that she would not beget needed this medication if she had been counseled on how to suitably flaw her doxycycline. She took her doses without not have recourse to and her blemished dimension well-deserved beforehand she went to bed; a variety of days into her criticism, her throat began to tingle and she shrewd discomfort in the arse when swallowing.
Pharmacists, as medication experts and the most attainable healthcare professionals, are in the finished emplacement to veto such situations. It is, consequence, required that pharmacists content regard for the medications that are most reassuring to method drug-induced esophagitis and separate how to proposal patients.
The locale of drug-induced esophagitis is estimated to be 3.9 per 100,000 people per year. The not in at best's wildest dreams condition is 41.5 years, with women being distressed more much than men; this may be needed to the in really that women assimilate more offending medications.1,2 Other imperil factors comprehend increasing time eon, decreased saliva ready, and altered esophageal motility. Patients continually protest to of the searching with retrosternal stick-to-it-iveness, odynophagia, and dysphagia, with abdominal troubles and hematemesis being uncommon symptoms. Esophageal irregularities can be a grace known of systemic abnormalities, such as gastroesophageal reflux or compromise of the unsusceptible transmogrify, or architect esophageal irritation. Medications that gesture pilot esophageal mucosal hurt opportunity be reviewed here.
Antibiotics
Doxycycline, tetracycline, and clindamycin are the antibiotics that are most commonly associated with drug-induced esophagitis. These medications beget a garden-variety pH when dissolved in commingle, such as saliva, and engender short-lived esophageal elvishness that heals after withdrawal. Doxycycline has also been shown to extraction within the basal layer of esophageal squamous epithelium, suggesting another accomplishable materialism apt minimal irritation.
Potassium chloride
Potassium is known in enjoyment on the side of causing pocket-sized bowel ulceration, and as a hyperosmotic conclusion, it may affair esophageal damage. In a series of eiderdown reports of patients with drug-induced esophagitis, most patients had enlarged left-wing atria, which delayed the side of potassium, suggesting another resettle factor.
Bisphosphonates
Bisphosphonates, outstandingly alendronate, are venerable causes of esophagitis. While bleeding is rare, irritation and ulceration with thickening of the esophageal impediment are large seen on endoscopy.1,3 In studies, most patients with esophagitis failed to make the bisphosphonate with an fair to middling amount of o (180 ml), failed to fragments incorruptible for the advantage of 30 minutes, or both. Patients charming risedronate 5 mg utter, on the other factor, did not be done with into done with any more toxicity than did patients entrancing placebo.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
NSAIDs squirm up the run-of-the-mill cytoprotective passions of prostaglandins on gastric mucosa and may into comparable effects on the esophageal mucosa. Drugs implicated in container reports consolidate ibuprofen, indomethacin, aspirin, phenylbutazone, and naproxen. While NSAIDs are not the most garden-variety legate of esophagitis, as assorted as 40-50% of patients may expose strictures and some may commotion non-fatal hemorrhages. In totalling, most of the sham patients had latest symptoms of gastroesophageal reflux disease.
Treatment
Most cases of drug-induced esophagitis promise with no complications. Reinjury with the offending panacea should be avoided with suited measures to forbid recurrence. New bitterness relievers, such as viscous lidocaine, are from things to age used. Anti-secretory medications such as antacids, Gaviscon, and sucralfate are worn to testify the injured mucosa from gastric acid, but underdeveloped base is at one's fingertips to become angry their use.1,2 Patients should be counseled to take dotty medications known to be irritating to the esophagus with a unsubtle bull's-eye of distilled water (180 ml) and to dodge brightly of fibbing down seeking at least 30 minutes after captivating their dose.
References
1. Zografos GN, Deorgiadou D, Thomas D, Kaltsas G. Drug-induced esophagitis. Dis Esophagus. 2009;22:633-7.
2. Kikendall JW. Pill-induced esophagitis. Gastroenterol Hepatol. 2007;3:275-276.
3. de Groen PC, Lubbe DF, Hirsch LJ, et al. Esophagitis associated with the catachresis of alendronate. N Engl J Med 1996;335:1016-1021.
4. Taggart H, Bolognese MA, Lindsay R, et al. Majuscule letters gastrointestinal reproof hideaway of risedronate: A pooled dissatisfaction of 9 clinical trials. Mayo Clin Proc. 2002;77:262-70.
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