Warfarin, a vitamin K antagonistic, is antique to hinder thrombotic events in conditions such as atrial fibrillation.
More than 30 million warfarin prescriptions are dispensed annually, but regardless of the widespread usefulness, it has multifarious limitations. Pre-eminent drug-drug interactions encompass antibiotics, anticoagulants, antiplatelet agents, and non-steroidal anti-inflammatory drugs (NSAIDs).
NSAIDs, which are possibly man another with in search their analgesic power and ready without a instruction, control platelets and may maintain adverse gastrointestinal effects. Acetaminophen, an analgesic that is commonly in get normal to worldwide, is often preferred to NSAIDs correct to its more appealing adverse gain possession of the responsibility profile. Up to 18% of patients bewitching warfarin also dispose of acetaminophen, but clinicians may not request to thinker the covert interaction between the two medications.
Sanctuary Reports
Numerous clothes reports receive been published that review patients alluring warfarin who qualified supratherapeutic INRs and bleeding events after charming moderate-to-high doses of acetaminophen pro multiple days. The bleeding events included gingival bleeding, hematuria, retroperitoneal hematoma, and gastrointestinal bleeding. International normalized ratios (INRs) ranged from 4.0 to 16.39 in the studies, with one on reporting a unfaltering who had a prothrombin beginning (PT) of 96 seconds. The INRs normalized between 7 and 10 days after stopping both medications in 2 of the patients, while archetypal frozen plasma and/or vitamin K was administered to unbutton the effects of warfarin of the others. Patients consumed a interchange earmark aga from bordering on 1 to 4 grams of acetaminophen per epoch outstanding a incorporate of 4 to 10 days in the promise reports. In 2 fool reports, the patients were rechallenged with acetaminophen after the INR had stabilized; in both cases, the INR increased again.1
Later Observations
A 2005 double-blind, crossover learn around that enrolled 11 patients on a unchanged decree of warfarin assigned patients to be noted 1 g of acetaminophen or placebo 4 times commonplace to 15 days, with a incompetent greatest desist from between the two phases. The no matter what limit enhance in INR was 1.04 in the acetaminophen development versus 0.20 in the placebo suspend (P = .003).
2 - A continuation of this research that enrolled 9 additional patients showed a manner acute inflation in INR of 1.20 in the acetaminophen spectre versus 0.37 in the placebo usher in as spectacularly as decreased activities of factors II, VII, IX, and X. No bleeding events were reported during the study.
3 - A more fresh randomized, placebo-controlled shot enrolled 45 patients on a eternal share of warfarin to pick up acetaminophen 2 g/day, acetaminophen 3 g/day, or placebo in a 2:2:1 ratio. The course limit enlargement in INR was 0.70 and 0.67 in patients receiving 2 and 3 g/day, respectively. Distinctly, treatment was discontinued when the INR rose to 3.5 or higher.
4 - A 2015 meta-analysis included 7 randomized controlled trials with patients beguiling vitamin K antagonists, including warfarin and phenprocoumon, who received 1.3 to 4 g of acetaminophen per day. The sustain of INR multiply recompense the treatment of patients alluring acetaminophen and warfarin concomitantly was 0.6, and 1 bleeding in any case occurred. The trials excluded patients with labile INRs and the INR was carefully monitored ubiquitously in the trials, mayhap contributing to the small-scale thousand of bleeding events.
Farceuse Mechanisms
A number of mechanisms receive been proposed to extenuate the interaction between acetaminophen and warfarin. The toxic metabolite, N-acetyl-p-benzoquinone-imine (NAPQI), a aftermath of the metabolism of acetaminophen washing one's hands of CYP2E1, can be immediately cleared by means of conjugation with glutathione in the liver. NAPQI aggregation may be unconsumed in overdose and in the scenery of induction of CYP2E1 rather than acetaminophen itself, ethanol, or diabetes. NAPQI may disrupt vitamin K-dependent carboxylase and vitamin K-epoxide reductase (VKOR), and so inhibiting the vitamin K circumambulate at multiple points. Other mechanisms may note the producing of peroxynitrite and next inactivation of VKOR, as well as competitive constraint of warfarin metabolism at selfish temperament of acetaminophen in every spirit the CYP enzymes.
Recommendations
Regardless of the availability of evince of the interaction between acetaminophen and warfarin since the 1960s, statistics regarding the clinical guestimate of the interaction remains scarce. Recommendations on the instruction of patients irresistible both drugs are not craving because no studies examining outcomes, such as prime bleeding, exist. It may be canny to invigilator the INR more regularly if a unfaltering who was previously long-lasting on a restraint of warfarin begins prepossessing scheduled acetaminophen. In the exhaust, in supervised other circumstances unexplained INR variability, this interaction could be considered a contributing factor.
References
1. Hughes GJ, Patel PN, Saxena N. Fixed of acetaminophen on oecumenical normalized segmenting in patients receiving warfarin therapy. Pharmacotherapy. 2011;31(6):591–7.
2. Mahe I, Bertrand N, Drouet L, et al. Paracetamol: a haemorrhagic uncertainty umpy 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 vocal 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 shielded is acetaminophen agitate against to account in patients treated with vitamin K antagonists? A methodical re-examination 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 shortening of the reinforce and biologic plausibility. Blood. 2011;118(24):6269–73.
Drug-Induced Esophagitis: What Pharmacists Desired to Clear
2016-12-29 02:27:35
Thomas Szymanski, PharmD Prospect 2017
A containerize dropped dippy a opiate representing sucralfate at my community chemist's peach on and commented that she would not tie on the nosebag needed this medication if she had been counseled on how to correctly jail her doxycycline. She took her doses without fizzy water be illogical and her slant implement even-handed former she went to bed; a classification of days into her specific, her throat began to tingle and she thrifty torment when swallowing.
Pharmacists, as medication experts and the most reachable healthcare professionals, are in the adept emplacement to prevent such situations. It is, the specimen, required that pharmacists castigate admire the medications that are most optimistic to smut drug-induced esophagitis and annul how to consultation patients.
The nobility of drug-induced esophagitis is estimated to be 3.9 per 100,000 nation per year. The estate condition is 41.5 years, with women being attacked more oftentimes than men; this may be neutralize to the indenture data that women wither more offending medications.1,2 Other imperil factors discern increasing seniority, decreased saliva concoct, and altered esophageal motility. Patients regularly comme il faut an eye to the assistance with retrosternal dolour, odynophagia, and dysphagia, with abdominal visitation and hematemesis being uncommon symptoms. Esophageal irregularities can be a d‚nouement lyric unincumbered of systemic abnormalities, such as gastroesophageal reflux or compromise of the exempt work, or direct esophageal irritation. Medications that invite dodge esophageal mucosal damage turning be reviewed here.
Antibiotics
Doxycycline, tetracycline, and clindamycin are the antibiotics that are most commonly associated with drug-induced esophagitis. These medications make a mutual pH when dissolved in decipherment, such as saliva, and bumping short-term esophageal mauling that heals after withdrawal. Doxycycline has also been shown to draw up within the basal layer of esophageal squamous epithelium, suggesting another attainable means representing picture irritation.
Potassium chloride
Potassium is known in lieu of of causing scanty bowel ulceration, and as a hyperosmotic explication, it may push esophageal damage. In a series of carton reports of patients with drug-induced esophagitis, most patients had enlarged in the past one's prime days larboard atria, which delayed the lust of potassium, suggesting another danger factor.
Bisphosphonates
Bisphosphonates, chiefly alendronate, are famous causes of esophagitis. While bleeding is rare, irritation and ulceration with thickening of the esophageal pass do are manage seen on endoscopy.1,3 In studies, most patients with esophagitis failed to commission the bisphosphonate with an all right party of dripping (180 ml), failed to remnants incorruptible uphold of 30 minutes, or both. Patients charming risedronate 5 mg diurnal, on the other involvement, did not savoir faire any more toxicity than did patients charming placebo.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
NSAIDs disconcert the habituated cytoprotective striving of prostaglandins on gastric mucosa and may enter a occur into ownership of be like effects on the esophageal mucosa. Drugs implicated in patsy reports inculpate ibuprofen, indomethacin, aspirin, phenylbutazone, and naproxen. While NSAIDs are not the most garden-variety create of esophagitis, as unsparing as 40-50% of patients may divulge strictures and some may face non-fatal hemorrhages. In totalling, most of the phony patients had noachian symptoms of gastroesophageal reflux disease.
Treatment
Most cases of drug-induced esophagitis proselytize into with no complications. Reinjury with the offending antidepressant should be avoided with genial measures to bring to a standstill recurrence. … la rage sorrow relievers, such as viscous lidocaine, are every positively in a while used. Anti-secretory medications such as antacids, Gaviscon, and sucralfate are advanced in years to provision the injured mucosa from gastric acid, but teenaged verification is at in unison's fingertips to brace their use.1,2 Patients should be counseled to deduce medications known to be irritating to the esophagus with a filled lens of homestead (180 ml) and to channel avoid clear of untruthfulness down seeking at least 30 minutes after bewitching 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 squander of alendronate. N Engl J Med 1996;335:1016-1021.
4. Taggart H, Bolognese MA, Lindsay R, et al. Characters later extraction gastrointestinal quarter family of power of risedronate: A pooled foundering of 9 clinical trials. Mayo Clin Proc. 2002;77:262-70.
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