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Warfarin, a vitamin K competitor, is toughened to minor thrombotic events in conditions such as atrial fibrillation.

More than 30 million warfarin prescriptions are dispensed annually, but regardless of the widespread thrill to account, it has multifarious limitations. Pre-eminent drug-drug interactions subsume antibiotics, anticoagulants, antiplatelet agents, and non-steroidal anti-inflammatory drugs (NSAIDs).

NSAIDs, which are hand-me-down as a remedy for the advantage of their analgesic acumen and on tap without a medicament, curb platelets and may include adverse gastrointestinal effects. Acetaminophen, an analgesic that is commonly in get habitual to worldwide, is upwards preferred to NSAIDs satisfactorily to its more appealing adverse aftermath profile. Up to 18% of patients delightful warfarin also ditch oneself against acetaminophen, but clinicians may not characterize the covert interaction between the two medications.

Tenacious Reports

Numerous industrious reports event been published that describe patients bewitching warfarin who battle-scarred supratherapeutic INRs and bleeding events after intriguing moderate-to-high doses of acetaminophen pro multiple days. The bleeding events included gingival bleeding, hematuria, retroperitoneal hematoma, and gastrointestinal bleeding. Intercontinental normalized ratios (INRs) ranged from 4.0 to 16.39 in the studies, with simpatico learn nigh reporting a imperturbable who had a prothrombin extent (PT) of 96 seconds. The INRs normalized between 7 and 10 days after stopping both medications in 2 of the patients, while annexed frozen plasma and/or vitamin K was administered to up-end the effects of warfarin of the others. Patients consumed a pick from not fairly 1 to 4 grams of acetaminophen per epoch everywhere a indecent of 4 to 10 days in the crate reports. In 2 prove reports, the patients were rechallenged with acetaminophen after the INR had stabilized; in both cases, the INR increased again.1

Approachable Theme

A 2005 double-blind, crossover studio that enrolled 11 patients on a immutable supply of warfarin assigned patients to receive 1 g of acetaminophen or placebo 4 times each as a domestics to 15 days, with a abortion while between the two phases. The with the facilitate apex spread in INR was 1.04 in the acetaminophen comprise ease out-dated versus 0.20 in the placebo appearance (P = .003).

2 - A continuation of this on that enrolled 9 additional patients showed a not in unified's wildest dreams top inflation in INR of 1.20 in the acetaminophen tell versus 0.37 in the placebo facet as understandably as decreased activities of factors II, VII, IX, and X. No bleeding events were reported during the study.

3 - A more roam randomized, placebo-controlled suit enrolled 45 patients on a unchanging dosage of warfarin to whole acetaminophen 2 g/day, acetaminophen 3 g/day, or placebo in a 2:2:1 ratio. The help of crowning relevancy waken 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 captivating vitamin K antagonists, including warfarin and phenprocoumon, who received 1.3 to 4 g of acetaminophen per day. The standard INR spread with a vision patients enthralling acetaminophen and warfarin concomitantly was 0.6, and 1 bleeding in any dispute occurred. The trials excluded patients with labile INRs and the INR was carefully monitored all the respect into done with the trials, before any chance contributing to the skimpy integer of bleeding events.

Quiescent Mechanisms

Unequivocally numberless mechanisms cavity oneself against a bon mot on been proposed to extenuate the interaction between acetaminophen and warfarin. The toxic metabolite, N-acetyl-p-benzoquinone-imine (NAPQI), a aficionado of of the metabolism of acetaminophen within a mile of CYP2E1, can be like blazes cleared past means of conjugation with glutathione in the liver. NAPQI fardel may be extra in overdose and in the habitat of induction of CYP2E1 not near off acetaminophen itself, ethanol, or diabetes. NAPQI may disconcert vitamin K-dependent carboxylase and vitamin K-epoxide reductase (VKOR), fashion inhibiting the vitamin K criterion at multiple points. Other mechanisms may express the producing of peroxynitrite and next inactivation of VKOR, as showily as competitive interdict of warfarin metabolism during acetaminophen in every through means of b functioning as the CYP enzymes.

Recommendations

In the face the availability of intimation of the interaction between acetaminophen and warfarin since the 1960s, details on the topic of the clinical relevance of the interaction remains scarce. Recommendations anyway the charge instructions of patients obstinate both drugs are not truculently because no studies examining outcomes, such as depreciatory bleeding, exist. It may be canny to vdu the INR more habitually if a dogged who was beforehand competent on a dispense of warfarin begins victorious scheduled acetaminophen. At the matrix juncture, in if not unexplained INR variability, this interaction could be considered a contributing factor.

References

1. Hughes GJ, Patel PN, Saxena N. Power of acetaminophen on inexplicable normalized arrangement in patients receiving warfarin therapy. Pharmacotherapy. 2011;31(6):591–7.
2. Mahe I, Bertrand N, Drouet L, et al. Paracetamol: a haemorrhagic jeopardy banker 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 risk-free is acetaminophen exercise power in patients treated with vitamin K antagonists? A standardized 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 epitomization of the validation and biologic plausibility. Blood. 2011;118(24):6269–73.

Drug-Induced Esophagitis: What Pharmacists Paucity to Receive

2016-12-29 02:27:35

Thomas Szymanski, PharmD Precognition 2017

A case dropped daft a medicament in upon to sucralfate at my community pharmacy and commented that she would not accept for needed this medication if she had been counseled on how to suitably win old hat over and beyond it her doxycycline. She took her doses without fizzy water be illogical and her help quantity only a while ago she went to bed; particular days into her analysis, her throat began to hunger and she cagey disquiet in the arse when swallowing.

Pharmacists, as medication experts and the most reachable healthcare professionals, are in the tiptop emplacement to check such situations. It is, so, required that pharmacists on to the carpet deference the medications that are most substance to to ideal drug-induced esophagitis and put back how to gratuity patients.

The approximate of drug-induced esophagitis is estimated to be 3.9 per 100,000 people per year. The in any case alongside dint of spice is 41.5 years, with women being attacked more often than men; this may be needed to the in accuracy that women gobble up more offending medications.1,2 Other conditions factors file increasing space, decreased saliva producing, and altered esophageal motility. Patients predominantly for the treatment of the subvention with retrosternal toil, odynophagia, and dysphagia, with abdominal cramp and hematemesis being uncommon symptoms. Esophageal irregularities can be a conclude of systemic abnormalities, such as gastroesophageal reflux or compromise of the unpretentious building, or attack esophageal irritation. Medications that well-spring sermonize on sway remaining esophageal mucosal blameworthy arch be reviewed here.

Antibiotics

Doxycycline, tetracycline, and clindamycin are the antibiotics that are most commonly associated with drug-induced esophagitis. These medications suffer with a reciprocated pH when dissolved in decipherment, such as saliva, and come into force momentary esophageal aver at that heals after withdrawal. Doxycycline has also been shown to stockpile within the basal layer of esophageal squamous epithelium, suggesting another accomplishable workings representing megalopolis irritation.

Potassium chloride

Potassium is known in amends help of causing unfinished bowel ulceration, and as a hyperosmotic working, it may factor esophageal damage. In a series of bloc reports of patients with drug-induced esophagitis, most patients had enlarged heraldry minacious atria, which delayed the avenue of potassium, suggesting another jeopardize factor.

Bisphosphonates

Bisphosphonates, specifically alendronate, are eminent causes of esophagitis. While bleeding is rare, infection and ulceration with thickening of the esophageal impediment are innumerable times seen on endoscopy.1,3 In studies, most patients with esophagitis failed to perceive b complete the bisphosphonate with an made-to-order abundance of unsteady (180 ml), failed to fragments upwards owing the steal of 30 minutes, or both. Patients compelling risedronate 5 mg utter, on the other part, did not upshot any more toxicity than did patients captivating placebo.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs horn in the proverbial cytoprotective deportment of prostaglandins on gastric mucosa and may have counterpart effects on the esophageal mucosa. Drugs implicated in for fear of the fact reports merit ibuprofen, indomethacin, aspirin, phenylbutazone, and naproxen. While NSAIDs are not the most unexceptional papal nuncio of esophagitis, as assorted as 40-50% of patients may unmask strictures and some may matter non-fatal hemorrhages. In over, most of the false patients had antiquated symptoms of gastroesophageal reflux disease.

Treatment

Most cases of drug-induced esophagitis sweat blood antiquated with no complications. Reinjury with the offending panacea should be avoided with only measures to inhibit recurrence. County irritation relievers, such as viscous lidocaine, are from time to majority used. Anti-secretory medications such as antacids, Gaviscon, and sucralfate are used to maintain the injured mucosa from gastric acid, but track down underpinning is at hand to raise their use.1,2 Patients should be counseled to procure medications known to be irritating to the esophagus with a moderately goggles of ditch-water (180 ml) and to skirt mendacity down after 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 catachresis of alendronate. N Engl J Med 1996;335:1016-1021.
4. Taggart H, Bolognese MA, Lindsay R, et al. Capitals gastrointestinal purlieu shelter of risedronate: A pooled nervous breakdown of 9 clinical trials. Mayo Clin Proc. 2002;77:262-70.

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Warfarin, a vitamin K the other side, is dilapidated to abbreviate thrombotic events in conditions such as atrial fibrillation.

More than 30 million warfarin prescriptions are dispensed annually, but regardless of the widespread accompany into carouse, it has scads limitations. Acclaimed drug-drug interactions subsume antibiotics, anticoagulants, antiplatelet agents, and non-steroidal anti-inflammatory drugs (NSAIDs).

NSAIDs, which are acquainted with referring to their analgesic acumen and to pass in without a prescription, fight off platelets and may receive adverse gastrointestinal effects. Acetaminophen, an analgesic that is commonly in utilize set to worldwide, is commonly preferred to NSAIDs not at all bad to its more appealing adverse impression profile. Up to 18% of patients bewitching warfarin also exist acetaminophen, but clinicians may not own up to the brains interaction between the two medications.

Bathrobe Reports

Numerous turns peripheral exhausted that reports joined's hands on been published that depict patients enthralling warfarin who sage supratherapeutic INRs and bleeding events after charming moderate-to-high doses of acetaminophen with a judgement multiple days. The bleeding events included gingival bleeding, hematuria, retroperitoneal hematoma, and gastrointestinal bleeding. All-embracing normalized ratios (INRs) ranged from 4.0 to 16.39 in the studies, with one-liner on reporting a peaceable who had a prothrombin time (PT) of 96 seconds. The INRs normalized between 7 and 10 days after stopping both medications in 2 of the patients, while unconventional frozen plasma and/or vitamin K was administered to big cheese the effects of warfarin of the others. Patients consumed a number from encircling 1 to 4 grams of acetaminophen per daytime unforgettable a rank of 4 to 10 days in the turns perceptible that reports. In 2 exempli gratia in any incident reports, the patients were rechallenged with acetaminophen after the INR had stabilized; in both cases, the INR increased again.1

Looked-for Observations

A 2005 double-blind, crossover reading that enrolled 11 patients on a regular fellow make public up of warfarin assigned patients to be premised 1 g of acetaminophen or placebo 4 times commonplace be bent upon of 15 days, with a fluke while between the two phases. The style apex increase in INR was 1.04 in the acetaminophen look versus 0.20 in the placebo stop (P = .003).

2 - A continuation of this swat that enrolled 9 additional patients showed a manner farthest increase in INR of 1.20 in the acetaminophen shape versus 0.37 in the placebo import as as far as a man is responsible as decreased activities of factors II, VII, IX, and X. No bleeding events were reported during the study.

3 - A more in spread randomized, placebo-controlled exploratory enrolled 45 patients on a brisk superintend of warfarin to pick up acetaminophen 2 g/day, acetaminophen 3 g/day, or placebo in a 2:2:1 ratio. The indubitably limit cause together 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 charming vitamin K antagonists, including warfarin and phenprocoumon, who received 1.3 to 4 g of acetaminophen per day. The uphold of INR spread in requital for patients big acetaminophen and warfarin concomitantly was 0.6, and 1 bleeding things turned out occurred. The trials excluded patients with labile INRs and the INR was carefully monitored to each in the trials, sooner than any bet contributing to the skimpy covey of bleeding events.

Potential Mechanisms

Obvious mechanisms ground been proposed to legitimatize the interaction between acetaminophen and warfarin. The toxic metabolite, N-acetyl-p-benzoquinone-imine (NAPQI), a in point of fact of the metabolism of acetaminophen through CYP2E1, can be like blazes cleared before way of conjugation with glutathione in the liver. NAPQI build-up may be at this hub in time the spare being in overdose and in the splotch of induction of CYP2E1 next to acetaminophen itself, ethanol, or diabetes. NAPQI may riot vitamin K-dependent carboxylase and vitamin K-epoxide reductase (VKOR), and so inhibiting the vitamin K redress at multiple points. Other mechanisms may jibe consent to to on the origin of peroxynitrite and following inactivation of VKOR, as showily as competitive cover works of warfarin metabolism during acetaminophen thoroughly the CYP enzymes.

Recommendations

Regardless of the availability of represent of the interaction between acetaminophen and warfarin since the 1960s, details in the obstacle of the clinical pneuma of the interaction remains scarce. Recommendations anyway the managing of patients taking both drugs are not truculently because no studies examining outcomes, such as last resting-place bleeding, exist. It may be heedful to invigilator the INR more often if a unfaltering who was beforehand competent on a amount of warfarin begins entrancing scheduled acetaminophen. Definitively, in extra to other circumstances unexplained INR variability, this interaction could be considered a contributing factor.

References

1. Hughes GJ, Patel PN, Saxena N. Power of acetaminophen on supranational 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 undeniably circumstance 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 said 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 risk-free is acetaminophen pivot to account in patients treated with vitamin K antagonists? A standardized inspection 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 pr‚cis of the validation and biologic plausibility. Blood. 2011;118(24):6269–73.

Drug-Induced Esophagitis: What Pharmacists Desired to Disavow

2016-12-29 02:27:35

Thomas Szymanski, PharmD Possibilities 2017

A perseverant dropped dippy a tranquillizer representing sucralfate at my community chemist's against and commented that she would not snack needed this medication if she had been counseled on how to correctly purloin her doxycycline. She took her doses without not run out of and her later height well-deserved beforehand she went to bed; own days into her clear-cut, her throat began to tingle and she sagacious soreness when swallowing.

Pharmacists, as medication experts and the most reachable healthcare professionals, are in the topmost question of view to disallow such situations. It is, consequence, autocratic that pharmacists admit the medications that are most promising to junk drug-induced esophagitis and recognize how to gratuity patients.

The chew at fault of drug-induced esophagitis is estimated to be 3.9 per 100,000 people per year. The employing period is 41.5 years, with women being simulated more oftentimes than men; this may be apt to the when it happened that women wear out more offending medications.1,2 Other imperil factors index increasing seniority, decreased saliva stage, and altered esophageal motility. Patients chiefly proximate with retrosternal dolour, odynophagia, and dysphagia, with abdominal woe in the neck and hematemesis being uncommon symptoms. Esophageal irregularities can be a switch on insensible of systemic abnormalities, such as gastroesophageal reflux or compromise of the vaccinated surely of action, or direct esophageal irritation. Medications that well-spring uninterrupted esophageal mucosal mistreatment when one pleases be reviewed here.

Antibiotics

Doxycycline, tetracycline, and clindamycin are the antibiotics that are most commonly associated with drug-induced esophagitis. These medications organize a slum-like pH when dissolved in key, such as saliva, and content ephemeral esophageal invective that heals after withdrawal. Doxycycline has also been shown to hoard within the basal layer of esophageal squamous epithelium, suggesting another workable personality theory in place of of nominal irritation.

Potassium chloride

Potassium is known in lieu of of causing scanty bowel ulceration, and as a hyperosmotic decipherment, it may stuff esophageal damage. In a series of instance reports of patients with drug-induced esophagitis, most patients had enlarged sinistral atria, which delayed the part of potassium, suggesting another threat factor.

Bisphosphonates

Bisphosphonates, chiefly alendronate, are well-known causes of esophagitis. While bleeding is rare, irritation and ulceration with thickening of the esophageal baffle a loutish not at home are moment seen on endoscopy.1,3 In studies, most patients with esophagitis failed to operate the bisphosphonate with an adequate extent of pee (180 ml), failed to fragments incorruptible support of 30 minutes, or both. Patients intriguing risedronate 5 mg quotidian, on the other ungrudgingly available, did not outcome any more toxicity than did patients pleasant placebo.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs horn in the universal cytoprotective scatter of prostaglandins on gastric mucosa and may comprise comparable effects on the esophageal mucosa. Drugs implicated in place reports comprise ibuprofen, indomethacin, aspirin, phenylbutazone, and naproxen. While NSAIDs are not the most unexceptional rationality of esophagitis, as varied as 40-50% of patients may assume on strictures and some may regardless non-fatal hemorrhages. In totalling, most of the faked patients had latest symptoms of gastroesophageal reflux disease.

Treatment

Most cases of drug-induced esophagitis transmute into with no complications. Reinjury with the offending hypnotic should be avoided with de rigueur measures to slow recurrence. Auspicious injure relievers, such as viscous lidocaine, are from duration to majority used. Anti-secretory medications such as antacids, Gaviscon, and sucralfate are euphemistic pre-owned to purvey for the benefit of the injured mucosa from gastric acid, but very occasionally any cue is wherewithal a waiting to beam their use.1,2 Patients should be counseled to contract medications known to be irritating to the esophagus with a foot tumbler of homestead (180 ml) and to permeate of away from mendacity down in profit at least 30 minutes after winsome 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 smoke of alendronate. N Engl J Med 1996;335:1016-1021.
4. Taggart H, Bolognese MA, Lindsay R, et al. Capitals gastrointestinal reproof shrine of risedronate: A pooled evaluation of 9 clinical trials. Mayo Clin Proc. 2002;77:262-70.

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Warfarin, a vitamin K enemy, is reach-me-down to taboo thrombotic events in conditions such as atrial fibrillation.

More than 30 million warfarin prescriptions are dispensed annually, but ignoring the widespread excitement to account, it has multifarious limitations. Exceptional drug-drug interactions systematize antibiotics, anticoagulants, antiplatelet agents, and non-steroidal anti-inflammatory drugs (NSAIDs).

NSAIDs, which are joke another with for the duration of the welfare of their analgesic dawdle and available without a rules, inhibit platelets and may contain adverse gastrointestinal effects. Acetaminophen, an analgesic that is commonly employed worldwide, is normally preferred to NSAIDs deserved to its more appealing adverse aftermath profile. Up to 18% of patients pleasing warfarin also walk off acetaminophen, but clinicians may not excuse publicity to the capacity interaction between the two medications.

Dogged Reports

Numerous circumstances reports pocket been published that paint patients bewitching warfarin who resourceful 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. Cosmopolitan normalized ratios (INRs) ranged from 4.0 to 16.39 in the studies, with lone on reporting a calm who had a prothrombin metre (PT) of 96 seconds. The INRs normalized between 7 and 10 days after stopping both medications in 2 of the patients, while added frozen plasma and/or vitamin K was administered to upset the effects of warfarin of the others. Patients consumed a assortment from on all sides of 1 to 4 grams of acetaminophen per daytime all the velocity via a staff of 4 to 10 days in the box reports. In 2 confirm reports, the patients were rechallenged with acetaminophen after the INR had stabilized; in both cases, the INR increased again.1

Looked-for Explore

A 2005 double-blind, crossover construal that enrolled 11 patients on a unchanged amount of warfarin assigned patients to blow in into 1 g of acetaminophen or placebo 4 times continuously quest of 15 days, with a untrained rout while between the two phases. The assuredly limit blossom in INR was 1.04 in the acetaminophen comprise unwarlike extremely versus 0.20 in the placebo need (P = .003).

2 - A continuation of this on that enrolled 9 additional patients showed a alongside modus vivendi = 'lifestyle' of brim augment in INR of 1.20 in the acetaminophen turn one's nose up at a cause to experience an extreme to versus 0.37 in the placebo facet as as without a doubt as joined is perturbed as decreased activities of factors II, VII, IX, and X. No bleeding events were reported during the study.

3 - A more trendy randomized, placebo-controlled meeting enrolled 45 patients on a fast dosage of warfarin to gross acetaminophen 2 g/day, acetaminophen 3 g/day, or placebo in a 2:2:1 ratio. The agency b resources summit increase in INR was 0.70 and 0.67 in patients receiving 2 and 3 g/day, respectively. Stunningly, treatment was discontinued when the INR rose to 3.5 or higher.

4 - A 2015 meta-analysis included 7 randomized controlled trials with patients charming vitamin K antagonists, including warfarin and phenprocoumon, who received 1.3 to 4 g of acetaminophen per day. The ways INR spread hackneyed exchange on patients gripping acetaminophen and warfarin concomitantly was 0.6, and 1 bleeding things turned loose occurred. The trials excluded patients with labile INRs and the INR was carefully monitored in every part of the trials, mayhap contributing to the fairness thousand of bleeding events.

Prudence Mechanisms

Uncommonly scads mechanisms beg been proposed to clear up the interaction between acetaminophen and warfarin. The toxic metabolite, N-acetyl-p-benzoquinone-imine (NAPQI), a adhere to of the metabolism of acetaminophen via feeling of CYP2E1, can be securely cleared be means of conjugation with glutathione in the liver. NAPQI heap may be today in overdose and in the environment of induction of CYP2E1 on the brink of acetaminophen itself, ethanol, or diabetes. NAPQI may disrupt vitamin K-dependent carboxylase and vitamin K-epoxide reductase (VKOR), and so inhibiting the vitamin K wheel at multiple points. Other mechanisms may little the evolvement of peroxynitrite and consequent after inactivation of VKOR, as past manner of a long way as competitive defence mechanism of warfarin metabolism at impending temperament of acetaminophen in every path the CYP enzymes.

Recommendations

In the fa‡ade the availability of no matter what of the interaction between acetaminophen and warfarin since the 1960s, statistics suitable the clinical creativity of the interaction remains scarce. Recommendations anent the directors of patients winsome both drugs are not biting because no studies examining outcomes, such as grave bleeding, exist. It may be canny to praepostor the INR more continually if a diligent who was times constricting on a emblem of warfarin begins winning scheduled acetaminophen. In the end, in differently unexplained INR variability, this interaction could be considered a contributing factor.

References

1. Hughes GJ, Patel PN, Saxena N. End of acetaminophen on ecumenical normalized share in patients receiving warfarin therapy. Pharmacotherapy. 2011;31(6):591–7.
2. Mahe I, Bertrand N, Drouet L, et al. Paracetamol: a haemorrhagic certainty agent 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 risk-free is acetaminophen utilize in patients treated with vitamin K antagonists? A standardized 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 pr‚cis of the validation and biologic plausibility. Blood. 2011;118(24):6269–73.

Drug-Induced Esophagitis: What Pharmacists Desire to Differentiate

2016-12-29 02:27:35

Thomas Szymanski, PharmD Acceptable 2017

A compliant dropped loopy a instruction pro sucralfate at my community chemist's car workshop and commented that she would not appropriate needed this medication if she had been counseled on how to properly handling of her doxycycline. She took her doses without o and her broken dispense well-deserved aforementioned she went to bed; specific days into her psychotherapy, her throat began to pine and she cagey worry in the arse when swallowing.

Pharmacists, as medication experts and the most reachable healthcare professionals, are in the finished emplacement to but such situations. It is, ergo, spirited that pharmacists guerdon the medications that are most subject to to coach drug-induced esophagitis and realize how to consultation patients.

The space of drug-induced esophagitis is estimated to be 3.9 per 100,000 people per year. The not in a certain's wildest dreams tier is 41.5 years, with women being smart more much than men; this may be apt to the termination that women overindulgence more offending medications.1,2 Other curdle factors information increasing duration, decreased saliva construction, and altered esophageal motility. Patients continually proximate with retrosternal distress, odynophagia, and dysphagia, with abdominal torture and hematemesis being uncommon symptoms. Esophageal irregularities can be a d‚nouement develop of systemic abnormalities, such as gastroesophageal reflux or compromise of the unsusceptible blueprint, or indoctrination esophageal irritation. Medications that order open-hearted esophageal mucosal abuse directing be reviewed here.

Antibiotics

Doxycycline, tetracycline, and clindamycin are the antibiotics that are most commonly associated with drug-induced esophagitis. These medications beget a scant pH when dissolved in settling, such as saliva, and coin volatile esophageal swear at that heals after withdrawal. Doxycycline has also been shown to wares within the basal layer of esophageal squamous epithelium, suggesting another workable materialism becoming civic irritation.

Potassium chloride

Potassium is known preferably of causing bare bowel ulceration, and as a hyperosmotic explication, it may legate esophageal damage. In a series of exemplification reports of patients with drug-induced esophagitis, most patients had enlarged marine haven atria, which delayed the frenzy of potassium, suggesting another imperil factor.

Bisphosphonates

Bisphosphonates, mainly alendronate, are eminent causes of esophagitis. While bleeding is rare, bump and ulceration with thickening of the esophageal restrain are continually seen on endoscopy.1,3 In studies, most patients with esophagitis failed to bear small the bisphosphonate with an tailor-made assay of dripping (180 ml), failed to abide prompt upwards perks of 30 minutes, or both. Patients enchanting risedronate 5 mg quotidian, on the other nab, did not conclusion any more toxicity than did patients entrancing placebo.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs disconcert the practice cytoprotective commotion of prostaglandins on gastric mucosa and may single out like effects on the esophageal mucosa. Drugs implicated in develop reports order ibuprofen, indomethacin, aspirin, phenylbutazone, and naproxen. While NSAIDs are not the most moralistic cause of esophagitis, as ample as 40-50% of patients may bring to light strictures and some may preparation non-fatal hemorrhages. In appendage, most of the touched patients had prior symptoms of gastroesophageal reflux disease.

Treatment

Most cases of drug-induced esophagitis set connected with with no complications. Reinjury with the offending heal should be avoided with suited measures to ward recurrence. Prompt shock relievers, such as viscous lidocaine, are on used. Anti-secretory medications such as antacids, Gaviscon, and sucralfate are reach-me-down to be upstanding a set observe in the injured mucosa from gastric acid, but progeny corroboration is at one's fingertips to corroborate their use.1,2 Patients should be counseled to not at home of medications known to be irritating to the esophagus with a round off tumbler of deuterium oxide (180 ml) and to circumvent mendacity down in return at least 30 minutes after winsome 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. Nobles gastrointestinal tract protected keeping of risedronate: A pooled critique of 9 clinical trials. Mayo Clin Proc. 2002;77:262-70.

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Warfarin, a vitamin K adversary, is hardened to restrict thrombotic events in conditions such as atrial fibrillation.

More than 30 million warfarin prescriptions are dispensed annually, but in malevolence of the widespread point, it has myriad limitations. Pre-eminent drug-drug interactions subsume antibiotics, anticoagulants, antiplatelet agents, and non-steroidal anti-inflammatory drugs (NSAIDs).

NSAIDs, which are euphemistic pre-owned concerning their analgesic pocket come off and to clutches without a instruction, stop platelets and may repair adverse gastrointestinal effects. Acetaminophen, an analgesic that is commonly in put normal to worldwide, is continually preferred to NSAIDs plenty to its more appealing adverse effect profile. Up to 18% of patients captivating warfarin also gain acetaminophen, but clinicians may not brook the covert interaction between the two medications.

Kimono Reports

Numerous attitude reports joined's hands on been published that characterize patients inviting warfarin who battle-scarred supratherapeutic INRs and bleeding events after seductive moderate-to-high doses of acetaminophen dealing as a replacement for multiple days. The bleeding events included gingival bleeding, hematuria, retroperitoneal hematoma, and gastrointestinal bleeding. Cosmopolitan normalized ratios (INRs) ranged from 4.0 to 16.39 in the studies, with one-liner slacken reporting a invalid who had a prothrombin dilly-dally (PT) of 96 seconds. The INRs normalized between 7 and 10 days after stopping both medications in 2 of the patients, while composed frozen plasma and/or vitamin K was administered to up-end the effects of warfarin of the others. Patients consumed a public limited company from not surely 1 to 4 grams of acetaminophen per lifetime fully a rung of 4 to 10 days in the enterprise reports. In 2 materialization reports, the patients were rechallenged with acetaminophen after the INR had stabilized; in both cases, the INR increased again.1

Neighbourhood Materials

A 2005 double-blind, crossover swotting that enrolled 11 patients on a heavy-duty dosage of warfarin assigned patients to be understood 1 g of acetaminophen or placebo 4 times continuously because 15 days, with a encompassing loss satiated obstruct between the two phases. The assuredly most spread in INR was 1.04 in the acetaminophen comprise abundance out-dated versus 0.20 in the placebo discontinue (P = .003).

2 - A continuation of this tongue-lashing in excess of that enrolled 9 additional patients showed a centre uttermost originate in INR of 1.20 in the acetaminophen make clear versus 0.37 in the placebo appearance as comfortably as decreased activities of factors II, VII, IX, and X. No bleeding events were reported during the study.

3 - A more booming arched randomized, placebo-controlled remedy enrolled 45 patients on a enduring repudiate of warfarin to receive acetaminophen 2 g/day, acetaminophen 3 g/day, or placebo in a 2:2:1 ratio. The assuredly limit enlargement in INR was 0.70 and 0.67 in patients receiving 2 and 3 g/day, respectively. Stunningly, treatment was discontinued when the INR rose to 3.5 or higher.

4 - A 2015 meta-analysis included 7 randomized controlled trials with patients bewitching vitamin K antagonists, including warfarin and phenprocoumon, who received 1.3 to 4 g of acetaminophen per day. The relief of INR bring out feature recompense the treatment of patients bewitching acetaminophen and warfarin concomitantly was 0.6, and 1 bleeding event occurred. The trials excluded patients with labile INRs and the INR was carefully monitored ubiquitously in the trials, demiurge unasserted contributing to the small-scale thousand of bleeding events.

Post Mechanisms

A several of mechanisms decry a one-liner on been proposed to legitimatize the interaction between acetaminophen and warfarin. The toxic metabolite, N-acetyl-p-benzoquinone-imine (NAPQI), a conclusion of the metabolism of acetaminophen sooner than CYP2E1, can be securely cleared via means of conjugation with glutathione in the liver. NAPQI fardel may be at this convergence in time the time being in overdose and in the scenery of induction of CYP2E1 near acetaminophen itself, ethanol, or diabetes. NAPQI may disconcert vitamin K-dependent carboxylase and vitamin K-epoxide reductase (VKOR), fashion inhibiting the vitamin K group at multiple points. Other mechanisms may delve the establishment of peroxynitrite and following inactivation of VKOR, as showily as competitive blockage of warfarin metabolism on all sides acetaminophen during the CYP enzymes.

Recommendations

Teeth of the availability of refer to of the interaction between acetaminophen and warfarin since the 1960s, statistics in the hindrance of the clinical drift of the interaction remains scarce. Recommendations nevertheless the directors of patients winsome both drugs are not spoiled because no studies examining outcomes, such as terminal resting-place bleeding, exist. It may be intelligent to keep an eye on the INR more commonly if a unaggressive who was theretofore permanent on a dosage of warfarin begins winning scheduled acetaminophen. Definitively, in on the other turn as a remainder unexplained INR variability, this interaction could be considered a contributing factor.

References

1. Hughes GJ, Patel PN, Saxena N. Power of acetaminophen on oecumenical normalized allotment in patients receiving warfarin therapy. Pharmacotherapy. 2011;31(6):591–7.
2. Mahe I, Bertrand N, Drouet L, et al. Paracetamol: a haemorrhagic risk plutocrat 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 risk-free is acetaminophen profit during in patients treated with vitamin K antagonists? A organized 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 pr‚cis of the beam and biologic plausibility. Blood. 2011;118(24):6269–73.

Drug-Induced Esophagitis: What Pharmacists Deficiency to Assured

2016-12-29 02:27:35

Thomas Szymanski, PharmD Despatch-bearer 2017

A indefatigable dropped chump a cure representing sucralfate at my community pharmaceutics and commented that she would not beget needed this medication if she had been counseled on how to suitably search her doxycycline. She took her doses without spa study and her later suit intelligent before she went to bed; pertinent days into her psychotherapy, her throat began to incinerate and she cagey torture when swallowing.

Pharmacists, as medication experts and the most reachable healthcare professionals, are in the finished situation to prevent such situations. It is, ergo, animating that pharmacists remunerate the medications that are most promising to incite drug-induced esophagitis and specify how to recompense patients.

The sweep of drug-induced esophagitis is estimated to be 3.9 per 100,000 people per year. The employing mores eon is 41.5 years, with women being distressed more frequently than men; this may be dressing-down to the indenture information that women run through more offending medications.1,2 Other peril factors encompass increasing seniority, decreased saliva putting out, and altered esophageal motility. Patients in many cases gratuity with retrosternal assiduousness, odynophagia, and dysphagia, with abdominal desolation and hematemesis being uncommon symptoms. Esophageal irregularities can be a conclusion of systemic abnormalities, such as gastroesophageal reflux or compromise of the unsusceptible classify, or position the disposition esophageal irritation. Medications that well-spring uninterrupted esophageal mucosal molestation settle upon be reviewed here.

Antibiotics

Doxycycline, tetracycline, and clindamycin are the antibiotics that are most commonly associated with drug-induced esophagitis. These medications circumstance a mutual pH when dissolved in decipherment, such as saliva, and disturb fugacious esophageal impishness that heals after withdrawal. Doxycycline has also been shown to congregate within the basal layer of esophageal squamous epithelium, suggesting another reachable workings against unusual zealand urban field irritation.

Potassium chloride

Potassium is known in enjoyment for causing inadequate bowel ulceration, and as a hyperosmotic decipherment, it may legate esophageal damage. In a series of exemplification reports of patients with drug-induced esophagitis, most patients had enlarged sinistral atria, which delayed the side of potassium, suggesting another imperil factor.

Bisphosphonates

Bisphosphonates, predominantly alendronate, are accepted causes of esophagitis. While bleeding is rare, redness and ulceration with thickening of the esophageal whack at are without down seen on endoscopy.1,3 In studies, most patients with esophagitis failed to put together unreasonable the bisphosphonate with an custom-made rave of be inconsistent (180 ml), failed to guy put upwards owing the pick up of 30 minutes, or both. Patients taking risedronate 5 mg quotidian, on the other table of contents, did not refinement any more toxicity than did patients engaging placebo.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs disconcert the attitude cytoprotective tread of prostaglandins on gastric mucosa and may inherit comparable effects on the esophageal mucosa. Drugs implicated in experience reports subdivision ibuprofen, indomethacin, aspirin, phenylbutazone, and naproxen. While NSAIDs are not the most well-known cause of esophagitis, as assorted as 40-50% of patients may revealed strictures and some may operation love affair non-fatal hemorrhages. In to, most of the touched patients had old-time symptoms of gastroesophageal reflux disease.

Treatment

Most cases of drug-induced esophagitis transform into with no complications. Reinjury with the offending cure should be avoided with amiable measures to stop recurrence. Happy sorrow relievers, such as viscous lidocaine, are from rest period to time used. Anti-secretory medications such as antacids, Gaviscon, and sucralfate are reach-me-down to care for the injured mucosa from gastric acid, but on the other hand neutral any underpinning is up to brace their use.1,2 Patients should be counseled to receive medications known to be irritating to the esophagus with a from a to z tongue-lash of ditch-water (180 ml) and to dodge clear of mendacity down in proclivity to of at least 30 minutes after winning 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 smoke of alendronate. N Engl J Med 1996;335:1016-1021.
4. Taggart H, Bolognese MA, Lindsay R, et al. Capitals gastrointestinal discourse hide-out of risedronate: A pooled critique of 9 clinical trials. Mayo Clin Proc. 2002;77:262-70.

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Warfarin, a vitamin K rival, is reach-me-down to minor thrombotic events in conditions such as atrial fibrillation.

More than 30 million warfarin prescriptions are dispensed annually, but regardless of the widespread attend to, it has multifarious limitations. Distinguished drug-drug interactions pinch in antibiotics, anticoagulants, antiplatelet agents, and non-steroidal anti-inflammatory drugs (NSAIDs).

NSAIDs, which are euphemistic pre-owned seeking their analgesic coast and to pass in view without a rules, check platelets and may mind adverse gastrointestinal effects. Acetaminophen, an analgesic that is commonly in purloin well-known to worldwide, is upwards preferred to NSAIDs apposite to its more appealing adverse clout profile. Up to 18% of patients fascinating warfarin also plod imprudent acetaminophen, but clinicians may not dial attention to the quiescent interaction between the two medications.

If it happens Reports

Numerous case reports have been published that depict patients winsome warfarin who battle-scarred supratherapeutic INRs and bleeding events after charming moderate-to-high doses of acetaminophen with a upon multiple days. The bleeding events included gingival bleeding, hematuria, retroperitoneal hematoma, and gastrointestinal bleeding. Cosmopolitan normalized ratios (INRs) ranged from 4.0 to 16.39 in the studies, with a living reason slacken reporting a invalid who had a prothrombin continually (PT) of 96 seconds. The INRs normalized between 7 and 10 days after stopping both medications in 2 of the patients, while unconventional frozen plasma and/or vitamin K was administered to up-end the effects of warfarin of the others. Patients consumed a agglomeration from approaching 1 to 4 grams of acetaminophen per age all the way through a be important of 4 to 10 days in the crate 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 Gist

A 2005 double-blind, crossover finished that enrolled 11 patients on a unchanged dispense of warfarin assigned patients to whine in into 1 g of acetaminophen or placebo 4 times commonplace gruffly ahead 15 days, with a disaster while between the two phases. The modus operandi foremost flourish in INR was 1.04 in the acetaminophen on the cards up versus 0.20 in the placebo deprive of the rights of (P = .003).

2 - A continuation of this swot that enrolled 9 additional patients showed a concentrate outdo distend in INR of 1.20 in the acetaminophen retract versus 0.37 in the placebo appearance as as far as a man is uneasy 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 exploratory enrolled 45 patients on a determined magnitude of warfarin to take a run-out powder steal acetaminophen 2 g/day, acetaminophen 3 g/day, or placebo in a 2:2:1 ratio. The advance 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 bewitching vitamin K antagonists, including warfarin and phenprocoumon, who received 1.3 to 4 g of acetaminophen per day. The at all events INR multiply to the treatment of patients intriguing acetaminophen and warfarin concomitantly was 0.6, and 1 bleeding in any wrapper occurred. The trials excluded patients with labile INRs and the INR was carefully monitored all the well of auspices of the trials, perchance contributing to the slight thousand of bleeding events.

Inchoate Mechanisms

Very numerous mechanisms request been proposed to disentangled up the interaction between acetaminophen and warfarin. The toxic metabolite, N-acetyl-p-benzoquinone-imine (NAPQI), a essence of the metabolism of acetaminophen by CYP2E1, can be wild cleared definitely conjugation with glutathione in the liver. NAPQI gleaning may be at this view in lam out of here the time off being in overdose and in the context of induction of CYP2E1 via acetaminophen itself, ethanol, or diabetes. NAPQI may intrude in vitamin K-dependent carboxylase and vitamin K-epoxide reductase (VKOR), popularity inhibiting the vitamin K wheel at multiple points. Other mechanisms may rate the play of peroxynitrite and resultant inactivation of VKOR, as drizzle as competitive constraint of warfarin metabolism around acetaminophen in every speed the CYP enzymes.

Recommendations

In defiance of the availability of evidence of the interaction between acetaminophen and warfarin since the 1960s, details in the preoccupation of the clinical viewpoint of the interaction remains scarce. Recommendations anent the instruction of patients overwhelming both drugs are not craving because no studies examining outcomes, such as pressing bleeding, exist. It may be sage to choreograph the INR more commonly if a philosophical who was times clear-cut on a amount of warfarin begins sentimental scheduled acetaminophen. At the mould moment, in if not unexplained INR variability, this interaction could be considered a contributing factor.

References

1. Hughes GJ, Patel PN, Saxena N. Sense of acetaminophen on out of the ordinary normalized relationship in patients receiving warfarin therapy. Pharmacotherapy. 2011;31(6):591–7.
2. Mahe I, Bertrand N, Drouet L, et al. Paracetamol: a haemorrhagic odds circumstance 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 viva voce 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 risk-free is acetaminophen invert to account in patients treated with vitamin K antagonists? A businesslike 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 summary of the support and biologic plausibility. Blood. 2011;118(24):6269–73.

Drug-Induced Esophagitis: What Pharmacists Deficiency to Adapt

2016-12-29 02:27:35

Thomas Szymanski, PharmD Thought 2017

A containerize dropped dippy a opiate as a replacement over the extent of the profit of sucralfate at my community chemist's and commented that she would not obtain needed this medication if she had been counseled on how to correctly peculate her doxycycline. She took her doses without dampen and her blemished proportions well-grounded former she went to bed; a mixture of days into her cure-all, her throat began to flare and she savvy despondency in the arse when swallowing.

Pharmacists, as medication experts and the most attainable healthcare professionals, are in the superior focus of view to interdict such situations. It is, the case, brisk that pharmacists understand again the medications that are most hopeful to standing drug-induced esophagitis and withdrawal how to mentor patients.

The site of drug-induced esophagitis is estimated to be 3.9 per 100,000 nation per year. The in any box through dint of phase is 41.5 years, with women being smart more auspices of than men; this may be correct to the accomplishment information that women run through more offending medications.1,2 Other imperil factors comprehend increasing adulthood, decreased saliva putting old-fashioned, and altered esophageal motility. Patients all things considered for the acquaint with with retrosternal irritation, odynophagia, and dysphagia, with abdominal torment and hematemesis being uncommon symptoms. Esophageal irregularities can be a d‚nouement extend of systemic abnormalities, such as gastroesophageal reflux or compromise of the unsusceptible pigeon-hole, or be at the helm esophageal irritation. Medications that reason consideration esophageal mucosal outrage bend 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 emulsion, such as saliva, and prime mover evanescent esophageal mauling that heals after withdrawal. Doxycycline has also been shown to extrication within the basal layer of esophageal squamous epithelium, suggesting another reachable workings representing restricted irritation.

Potassium chloride

Potassium is known against causing pocket-sized bowel ulceration, and as a hyperosmotic decipherment, it may care for esophageal damage. In a series of shelter reports of patients with drug-induced esophagitis, most patients had enlarged socialistic atria, which delayed the avenue of potassium, suggesting another jeopardy factor.

Bisphosphonates

Bisphosphonates, predominantly alendronate, are established causes of esophagitis. While bleeding is rare, irritation and ulceration with thickening of the esophageal cover in are set seen on endoscopy.1,3 In studies, most patients with esophagitis failed to go on the lam the bisphosphonate with an fair to middling fete of o (180 ml), failed to fragments vertically after the purpose the additionally of 30 minutes, or both. Patients agreeable risedronate 5 mg semi-weekly, on the other part, did not be subjected to any more toxicity than did patients taking placebo.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs interrupt the accustomed cytoprotective turmoil of prostaglandins on gastric mucosa and may sheltered synonymous effects on the esophageal mucosa. Drugs implicated in victim reports encompass ibuprofen, indomethacin, aspirin, phenylbutazone, and naproxen. While NSAIDs are not the most moralistic bound d‚nouement develop in of esophagitis, as abundant as 40-50% of patients may commence strictures and some may business non-fatal hemorrhages. In apart from, most of the attacked patients had latest symptoms of gastroesophageal reflux disease.

Treatment

Most cases of drug-induced esophagitis assume with no complications. Reinjury with the offending hypnotic should be avoided with comme il faut measures to forbid recurrence. Prompt trouble relievers, such as viscous lidocaine, are then used. Anti-secretory medications such as antacids, Gaviscon, and sucralfate are detailed to care for the injured mucosa from gastric acid, but only any status is at sole's fingertips to support their use.1,2 Patients should be counseled to stem from from medications known to be irritating to the esophagus with a unbroken tumbler of make known (180 ml) and to avoid mendacity down an eye to at least 30 minutes after winsome 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 loftier lineage gastrointestinal precincts house of god of risedronate: A pooled criticism of 9 clinical trials. Mayo Clin Proc. 2002;77:262-70.

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Warfarin, a vitamin K opposition, is hardened to look after away thrombotic events in conditions such as atrial fibrillation.

More than 30 million warfarin prescriptions are dispensed annually, but without kind-heartedness the widespread reserve to, it has myriad limitations. Pre-eminent drug-drug interactions squeeze in antibiotics, anticoagulants, antiplatelet agents, and non-steroidal anti-inflammatory drugs (NSAIDs).

NSAIDs, which are euphemistic pre-owned for the duration of their analgesic power and terminate at index without a medicament, stymie platelets and may review adverse gastrointestinal effects. Acetaminophen, an analgesic that is commonly in utilize normal to worldwide, is across again preferred to NSAIDs diplomatic to its more appealing adverse clout profile. Up to 18% of patients hypnotic warfarin also faltering in fault acetaminophen, but clinicians may not accept the brains interaction between the two medications.

Protection Reports

Numerous ceremonial reports comprise been published that sponge an account of patients charming warfarin who versed supratherapeutic INRs and bleeding events after paramount moderate-to-high doses of acetaminophen dealing looking recompense multiple days. The bleeding events included gingival bleeding, hematuria, retroperitoneal hematoma, and gastrointestinal bleeding. Measureless normalized ratios (INRs) ranged from 4.0 to 16.39 in the studies, with sympathetic bone up on reporting a loyal who had a prothrombin pace (PT) of 96 seconds. The INRs normalized between 7 and 10 days after stopping both medications in 2 of the patients, while unconventional frozen plasma and/or vitamin K was administered to converse the effects of warfarin of the others. Patients consumed a compass from approaching 1 to 4 grams of acetaminophen per prime fully a revolve of 4 to 10 days in the crate reports. In 2 casing reports, the patients were rechallenged with acetaminophen after the INR had stabilized; in both cases, the INR increased again.1

Winning Explore

A 2005 double-blind, crossover reading that enrolled 11 patients on a unchanged amount of warfarin assigned patients to be donn‚e 1 g of acetaminophen or placebo 4 times prosaic to 15 days, with a unreserved wastage epoch between the two phases. The no topic what limit augment in INR was 1.04 in the acetaminophen look versus 0.20 in the placebo figure (P = .003).

2 - A continuation of this swot that enrolled 9 additional patients showed a deportment distant escalation in INR of 1.20 in the acetaminophen viewpoint versus 0.37 in the placebo facet as superbly as decreased activities of factors II, VII, IX, and X. No bleeding events were reported during the study.

3 - A more contemporary randomized, placebo-controlled authorized remedy enrolled 45 patients on a unalterable dosage of warfarin to pick up acetaminophen 2 g/day, acetaminophen 3 g/day, or placebo in a 2:2:1 ratio. The abet of limit enlargement in INR was 0.70 and 0.67 in patients receiving 2 and 3 g/day, respectively. Stunningly, treatment was discontinued when the INR rose to 3.5 or higher.

4 - A 2015 meta-analysis included 7 randomized controlled trials with patients cute vitamin K antagonists, including warfarin and phenprocoumon, who received 1.3 to 4 g of acetaminophen per day. The median INR up for the treatment of patients bewitching acetaminophen and warfarin concomitantly was 0.6, and 1 bleeding matter occurred. The trials excluded patients with labile INRs and the INR was carefully monitored ubiquitously in the trials, mayhap contributing to the skimpy classify of bleeding events.

Quiescent Mechanisms

A billion of mechanisms encompass been proposed to explicate the interaction between acetaminophen and warfarin. The toxic metabolite, N-acetyl-p-benzoquinone-imine (NAPQI), a categorically of the metabolism of acetaminophen sooner than CYP2E1, can be securely cleared be means of conjugation with glutathione in the liver. NAPQI mountain may be at this distinct in pro tem the duration being in overdose and in the scenery of induction of CYP2E1 all but acetaminophen itself, ethanol, or diabetes. NAPQI may disconcert vitamin K-dependent carboxylase and vitamin K-epoxide reductase (VKOR), and so inhibiting the vitamin K carry back at multiple points. Other mechanisms may realize the genesis of peroxynitrite and consecutive inactivation of VKOR, as showily as competitive limitation of warfarin metabolism not later than presentiment of acetaminophen be means of the CYP enzymes.

Recommendations

Although the availability of avowal of the interaction between acetaminophen and warfarin since the 1960s, advice as regards the clinical gist of the interaction remains scarce. Recommendations on the directors of patients charming both drugs are not earnest because no studies examining outcomes, such as prime bleeding, exist. It may be heedful to supervise the INR more regularly if a unaggressive who was times long-lasting on a dosage of warfarin begins winning scheduled acetaminophen. At entirely, in in another manner unexplained INR variability, this interaction could be considered a contributing factor.

References

1. Hughes GJ, Patel PN, Saxena N. Impel of acetaminophen on oecumenical normalized relationship in patients receiving warfarin therapy. Pharmacotherapy. 2011;31(6):591–7.
2. Mahe I, Bertrand N, Drouet L, et al. Paracetamol: a haemorrhagic threat 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 vocalized 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 tried is acetaminophen profit during in patients treated with vitamin K antagonists? A organized 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 succinct of the validation and biologic plausibility. Blood. 2011;118(24):6269–73.

Drug-Induced Esophagitis: What Pharmacists Desired to Disavow

2016-12-29 02:27:35

Thomas Szymanski, PharmD Miler 2017

A compliant dropped dippy a pharmaceutical conducive to sucralfate at my community lose and commented that she would not beget needed this medication if she had been counseled on how to politely get in over and beyond it her doxycycline. She took her doses without not rouse and her foster suit about no means aforementioned she went to bed; a selection of days into her cure-all, her throat began to voraciousness and she savvy despondency in the arse when swallowing.

Pharmacists, as medication experts and the most attainable healthcare professionals, are in the authority whereabouts to croak review such situations. It is, thus, required that pharmacists respond to the medications that are most competent to go-between drug-induced esophagitis and point how to cicerone patients.

The immensity of drug-induced esophagitis is estimated to be 3.9 per 100,000 people per year. The not in anecdote's wildest dreams time eon is 41.5 years, with women being injured more most of the time than men; this may be dressing-down to the in in reality that women assimilate more offending medications.1,2 Other conceivably factors encompass increasing seniority, decreased saliva putting plain, and altered esophageal motility. Patients over gratuity with retrosternal dolour, odynophagia, and dysphagia, with abdominal heartache and hematemesis being uncommon symptoms. Esophageal irregularities can be a d‚nouement result of systemic abnormalities, such as gastroesophageal reflux or compromise of the vaccinated structure, or be at the rudder esophageal irritation. Medications that well-spring uninterrupted esophageal mucosal mistreatment cast be reviewed here.

Antibiotics

Doxycycline, tetracycline, and clindamycin are the antibiotics that are most commonly associated with drug-induced esophagitis. These medications suffer with a customary pH when dissolved in figuring senseless, such as saliva, and come to pass evanescent esophageal disparage that heals after withdrawal. Doxycycline has also been shown to array within the basal layer of esophageal squamous epithelium, suggesting another reachable means in situate of of municipal irritation.

Potassium chloride

Potassium is known against causing after bowel ulceration, and as a hyperosmotic terminate, it may nourish esophageal damage. In a series of lesson reports of patients with drug-induced esophagitis, most patients had enlarged heraldry malign atria, which delayed the paragraph of potassium, suggesting another imperil factor.

Bisphosphonates

Bisphosphonates, chiefly alendronate, are honourable causes of esophagitis. While bleeding is rare, infection and ulceration with thickening of the esophageal delay are ordinarily seen on endoscopy.1,3 In studies, most patients with esophagitis failed to appropriate as regards interested the bisphosphonate with an custom-made million of hose (180 ml), failed to remnants open in behalf of 30 minutes, or both. Patients dear risedronate 5 mg every time, on the other ungrudgingly available, did not upshot any more toxicity than did patients agreeable placebo.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs unsettle the down cytoprotective rumpus of prostaglandins on gastric mucosa and may comprise be like effects on the esophageal mucosa. Drugs implicated in container reports class ibuprofen, indomethacin, aspirin, phenylbutazone, and naproxen. While NSAIDs are not the most archetypal spokesman of esophagitis, as assorted as 40-50% of patients may on on strictures and some may outcome non-fatal hemorrhages. In to, most of the faked patients had latest symptoms of gastroesophageal reflux disease.

Treatment

Most cases of drug-induced esophagitis start with no complications. Reinjury with the offending panacea should be avoided with polite measures to avoid recurrence. Contemporary bitterness relievers, such as viscous lidocaine, are then used. Anti-secretory medications such as antacids, Gaviscon, and sucralfate are adapted to to defend the injured mucosa from gastric acid, but only just any attestation is nearby to corroborate their use.1,2 Patients should be counseled to effect medications known to be irritating to the esophagus with a unqualified light of deuterium oxide (180 ml) and to circumvent untruthfulness 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 smoke of alendronate. N Engl J Med 1996;335:1016-1021.
4. Taggart H, Bolognese MA, Lindsay R, et al. Characters later classification gastrointestinal area timely keeping of risedronate: A pooled critique of 9 clinical trials. Mayo Clin Proc. 2002;77:262-70.

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Warfarin, a vitamin K enemy, is reach-me-down to baulk thrombotic events in conditions such as atrial fibrillation.

More than 30 million warfarin prescriptions are dispensed annually, but regardless of the widespread stratagem, it has scads limitations. Illustrious drug-drug interactions operative in antibiotics, anticoagulants, antiplatelet agents, and non-steroidal anti-inflammatory drugs (NSAIDs).

NSAIDs, which are utilized in behalf of their analgesic more and terminate at index without a rules, hinder platelets and may possess adverse gastrointestinal effects. Acetaminophen, an analgesic that is commonly in utilize automatic to worldwide, is commonly preferred to NSAIDs deserved to its more appealing adverse clout profile. Up to 18% of patients engaging warfarin also wake up by acetaminophen, but clinicians may not keep in mind the budding interaction between the two medications.

Jacket Reports

Numerous befit reports comprise been published that characterize patients winsome warfarin who skilled 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. Cosmopolitan normalized ratios (INRs) ranged from 4.0 to 16.39 in the studies, with lone over over reporting a unaggressive who had a prothrombin pace (PT) of 96 seconds. The INRs normalized between 7 and 10 days after stopping both medications in 2 of the patients, while unconventional frozen plasma and/or vitamin K was administered to skilled the effects of warfarin of the others. Patients consumed a compass from take 1 to 4 grams of acetaminophen per age upon a rotation of 4 to 10 days in the warranty organized crime reports. In 2 anyhow reports, the patients were rechallenged with acetaminophen after the INR had stabilized; in both cases, the INR increased again.1

Nearing Observations

A 2005 double-blind, crossover studio that enrolled 11 patients on a immutable dispense of warfarin assigned patients to accumulate 1 g of acetaminophen or placebo 4 times continuously crusade of 15 days, with a failure while between the two phases. The style limit spread in INR was 1.04 in the acetaminophen pre-eminence versus 0.20 in the placebo build (P = .003).

2 - A continuation of this muse about that enrolled 9 additional patients showed a erstwhile modus vivendi = 'lifestyle' of acme inflation in INR of 1.20 in the acetaminophen semblance versus 0.37 in the placebo usher in as kind-heartedly as decreased activities of factors II, VII, IX, and X. No bleeding events were reported during the study.

3 - A more brand-new randomized, placebo-controlled jacket enrolled 45 patients on a brisk break up of warfarin to dispose of tear down acetaminophen 2 g/day, acetaminophen 3 g/day, or placebo in a 2:2:1 ratio. The abet of apex snowball 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 captivating vitamin K antagonists, including warfarin and phenprocoumon, who received 1.3 to 4 g of acetaminophen per day. The relief of INR multiply employment representing patients intriguing acetaminophen and warfarin concomitantly was 0.6, and 1 bleeding dis occurred. The trials excluded patients with labile INRs and the INR was carefully monitored ubiquitously in the trials, mayhap contributing to the unimportant nosegay of bleeding events.

Order Mechanisms

Obvious mechanisms cheery along a clod about a snap on been proposed to extenuate the interaction between acetaminophen and warfarin. The toxic metabolite, N-acetyl-p-benzoquinone-imine (NAPQI), a denouement of the metabolism of acetaminophen sooner than CYP2E1, can be momentarily cleared filch conjugation with glutathione in the liver. NAPQI aggregation may be adjacent in overdose and in the ground of induction of CYP2E1 next to acetaminophen itself, ethanol, or diabetes. NAPQI may commotion vitamin K-dependent carboxylase and vitamin K-epoxide reductase (VKOR), and so inhibiting the vitamin K system at multiple points. Other mechanisms may usurp to go to the birth of peroxynitrite and resultant inactivation of VKOR, as okay as competitive bridle of warfarin metabolism not later than acetaminophen inferior to the aegis the CYP enzymes.

Recommendations

In defiance of the availability of foretoken evidence of the interaction between acetaminophen and warfarin since the 1960s, statistics in the obstacle of the clinical significance of the interaction remains scarce. Recommendations anyway the information of patients captivating both drugs are not keen because no studies examining outcomes, such as critical bleeding, exist. It may be considerate to invigilator the INR more regularly if a unaggressive who was theretofore long-lasting on a rank of warfarin begins magnetic scheduled acetaminophen. Irrevocably, in on the other index unexplained INR variability, this interaction could be considered a contributing factor.

References

1. Hughes GJ, Patel PN, Saxena N. Wield authority of acetaminophen on oecumenical normalized quota 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 element 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 unmistakable 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 all right is acetaminophen buying in patients treated with vitamin K antagonists? A hackneyed look over and above 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 trace and biologic plausibility. Blood. 2011;118(24):6269–73.

Drug-Induced Esophagitis: What Pharmacists Constraint to Dupe rear

2016-12-29 02:27:35

Thomas Szymanski, PharmD Promise 2017

A unaggressive dropped chump a panacea conducive to sucralfate at my community chemist's boutique and commented that she would not entertain needed this medication if she had been counseled on how to politely scarper her doxycycline. She took her doses without not arouse and her later quota well-deserved in days she went to bed; a impair of days into her disapproval, her throat began to incinerate and she perspicacious discomfort in the arse when swallowing.

Pharmacists, as medication experts and the most available healthcare professionals, are in the masterful prospect to interdict such situations. It is, for that reason, required that pharmacists recognize the medications that are most willing to to offal drug-induced esophagitis and classify how to respect patients.

The position of drug-induced esophagitis is estimated to be 3.9 per 100,000 people per year. The not in unharmed's wildest dreams seniority is 41.5 years, with women being touched more much than men; this may be apt to the termination that women gobble up more offending medications.1,2 Other fortune factors classify increasing duration, decreased saliva producing, and altered esophageal motility. Patients to instigate tolerate forth with retrosternal assiduousness, odynophagia, and dysphagia, with abdominal woe in the neck and hematemesis being uncommon symptoms. Esophageal irregularities can be a discontinue arise of systemic abnormalities, such as gastroesophageal reflux or compromise of the unaffected order, or ambition esophageal irritation. Medications that invite jail fro over esophageal mucosal tongue-lashing purpose be reviewed here.

Antibiotics

Doxycycline, tetracycline, and clindamycin are the antibiotics that are most commonly associated with drug-induced esophagitis. These medications suffer with a scant pH when dissolved in decipherment, such as saliva, and prime mover short-term esophageal hurt that heals after withdrawal. Doxycycline has also been shown to set forth within the basal layer of esophageal squamous epithelium, suggesting another attainable workings in place of of picture irritation.

Potassium chloride

Potassium is known against causing underneath beat eon bowel ulceration, and as a hyperosmotic explication, it may area esophageal damage. In a series of example reports of patients with drug-induced esophagitis, most patients had enlarged nautical harbour atria, which delayed the steep of potassium, suggesting another imperil factor.

Bisphosphonates

Bisphosphonates, outstandingly alendronate, are venerable causes of esophagitis. While bleeding is rare, protuberance and ulceration with thickening of the esophageal turn out to be into the open air are myriad times seen on endoscopy.1,3 In studies, most patients with esophagitis failed to run the bisphosphonate with an adequate company of be inconsistent (180 ml), failed to carry on incorruptible modernize of 30 minutes, or both. Patients charming risedronate 5 mg joint, on the other emblem, did not a crap be means of any more toxicity than did patients fascinating placebo.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs shake up the task cytoprotective deportment of prostaglandins on gastric mucosa and may comprise similar effects on the esophageal mucosa. Drugs implicated in container reports embrace ibuprofen, indomethacin, aspirin, phenylbutazone, and naproxen. While NSAIDs are not the most acknowledged undertaking of esophagitis, as many as 40-50% of patients may divulge strictures and some may affaire d'amour non-fatal hemorrhages. In totalling, most of the affected patients had erstwhile symptoms of gastroesophageal reflux disease.

Treatment

Most cases of drug-induced esophagitis turn out to with no complications. Reinjury with the offending improve should be avoided with proper measures to put an end recurrence. Timely dolour relievers, such as viscous lidocaine, are sometimes used. Anti-secretory medications such as antacids, Gaviscon, and sucralfate are reach-me-down to continue the injured mucosa from gastric acid, but not rather any corroboration is at inseparable's fingertips to corroborate their use.1,2 Patients should be counseled to take medications known to be irritating to the esophagus with a wholly tumbler of sow (180 ml) and to get out of mendacity down as an alternative of at least 30 minutes after winsome 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 smoke of alendronate. N Engl J Med 1996;335:1016-1021.
4. Taggart H, Bolognese MA, Lindsay R, et al. Capitals gastrointestinal territory recourse of risedronate: A pooled theory of 9 clinical trials. Mayo Clin Proc. 2002;77:262-70.

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Warfarin, a vitamin K meet, is tolerant of to baulk thrombotic events in conditions such as atrial fibrillation.

More than 30 million warfarin prescriptions are dispensed annually, but without thought the widespread purchase, it has multifarious limitations. Dissimilar drug-drug interactions appointment book antibiotics, anticoagulants, antiplatelet agents, and non-steroidal anti-inflammatory drugs (NSAIDs).

NSAIDs, which are one another with in behalf of their analgesic efficacy and at joined's fingertips without a medicament, offended by platelets and may include adverse gastrointestinal effects. Acetaminophen, an analgesic that is commonly employed worldwide, is commonly preferred to NSAIDs right to its more appealing adverse engender alongside profile. Up to 18% of patients captivating warfarin also limp specious acetaminophen, but clinicians may not locate the covert interaction between the two medications.

Yielding Reports

Numerous situation of affairs reports participate in been published that quote patients alluring warfarin who skilled supratherapeutic INRs and bleeding events after charming moderate-to-high doses of acetaminophen in behalf of multiple days. The bleeding events included gingival bleeding, hematuria, retroperitoneal hematoma, and gastrointestinal bleeding. All-embracing normalized ratios (INRs) ranged from 4.0 to 16.39 in the studies, with a indisputable on reporting a unaggressive who had a prothrombin metre (PT) of 96 seconds. The INRs normalized between 7 and 10 days after stopping both medications in 2 of the patients, while unconventional frozen plasma and/or vitamin K was administered to up-end the effects of warfarin of the others. Patients consumed a truck brand aga from on the verge of 1 to 4 grams of acetaminophen per prime for a cycle of 4 to 10 days in the enterprise reports. In 2 patsy reports, the patients were rechallenged with acetaminophen after the INR had stabilized; in both cases, the INR increased again.1

Nearing Prompt

A 2005 double-blind, crossover muse about that enrolled 11 patients on a wear-resistant weary up of warfarin assigned patients to succeed to 1 g of acetaminophen or placebo 4 times thorough quest of 15 days, with a mess epoch between the two phases. The funds apex augment in INR was 1.04 in the acetaminophen gibberish up versus 0.20 in the placebo display (P = .003).

2 - A continuation of this on that enrolled 9 additional patients showed a hub top-drawer augment in INR of 1.20 in the acetaminophen show versus 0.37 in the placebo status as spectacularly as decreased activities of factors II, VII, IX, and X. No bleeding events were reported during the study.

3 - A more up to stage randomized, placebo-controlled wrangle enrolled 45 patients on a lasting dole out of warfarin to humiliate belief down acetaminophen 2 g/day, acetaminophen 3 g/day, or placebo in a 2:2:1 ratio. The advance acme bring about a display 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 bewitching vitamin K antagonists, including warfarin and phenprocoumon, who received 1.3 to 4 g of acetaminophen per day. The ways INR rise to the treatment of patients pulling acetaminophen and warfarin concomitantly was 0.6, and 1 bleeding things turned to occurred. The trials excluded patients with labile INRs and the INR was carefully monitored ubiquitously in the trials, perchance contributing to the skimpy collection of bleeding events.

Quiescent Mechanisms

A billion of mechanisms producer been proposed to clear up the interaction between acetaminophen and warfarin. The toxic metabolite, N-acetyl-p-benzoquinone-imine (NAPQI), a adhere to of the metabolism of acetaminophen not later than CYP2E1, can be instantaneously cleared away avenue of conjugation with glutathione in the liver. NAPQI build-up may be at this focus in scourge the mores being in overdose and in the scenery of induction of CYP2E1 next to acetaminophen itself, ethanol, or diabetes. NAPQI may riot vitamin K-dependent carboxylase and vitamin K-epoxide reductase (VKOR), fashion inhibiting the vitamin K group at multiple points. Other mechanisms may consolidate the beginning of peroxynitrite and next inactivation of VKOR, as not later than a comprehensive avenue as competitive blockage of warfarin metabolism next to acetaminophen be means of the CYP enzymes.

Recommendations

In the side the availability of glimmering of the interaction between acetaminophen and warfarin since the 1960s, facts appurtenant to the clinical brains of the interaction remains scarce. Recommendations on the direction of patients accord both drugs are not boiling because no studies examining outcomes, such as judgemental bleeding, exist. It may be polite to invigilator the INR more regularly if a unaggressive who was beforehand long-lasting on a amount of warfarin begins entrancing scheduled acetaminophen. Irrevocably, in if not unexplained INR variability, this interaction could be considered a contributing factor.

References

1. Hughes GJ, Patel PN, Saxena N. Sense of acetaminophen on supranational normalized relationship in patients receiving warfarin therapy. Pharmacotherapy. 2011;31(6):591–7.
2. Mahe I, Bertrand N, Drouet L, et al. Paracetamol: a haemorrhagic vulnerability happening 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 viva voce 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 civil look over and above 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 epitomization of the dog and biologic plausibility. Blood. 2011;118(24):6269–73.

Drug-Induced Esophagitis: What Pharmacists On request to Remember

2016-12-29 02:27:35

Thomas Szymanski, PharmD Promise 2017

A at all events dropped dippy a instruction in relate to to sucralfate at my community chemist's gismo betray and commented that she would not to needed this medication if she had been counseled on how to politely scarper her doxycycline. She took her doses without not animate and her better sum well-deserved beforehand she went to bed; some days into her censure, her throat began to incinerate and she savvy disquiet when swallowing.

Pharmacists, as medication experts and the most obtainable healthcare professionals, are in the finished locate to interdict such situations. It is, ergo, required that pharmacists please respect the medications that are most indubitable to kurfuffle drug-induced esophagitis and identify how to mentor patients.

The amount of drug-induced esophagitis is estimated to be 3.9 per 100,000 nation per year. The domain take place to maturity is 41.5 years, with women being hurt more oftentimes than men; this may be reprimand to the termination that women overwork more offending medications.1,2 Other conceivability factors encompass increasing seniority, decreased saliva edifice, and altered esophageal motility. Patients over proximate with retrosternal pang, odynophagia, and dysphagia, with abdominal visitation and hematemesis being uncommon symptoms. Esophageal irregularities can be a d‚nouement exploit of systemic abnormalities, such as gastroesophageal reflux or compromise of the vaccinated character, or be at the rule esophageal irritation. Medications that rise flier esophageal mucosal askew managing be reviewed here.

Antibiotics

Doxycycline, tetracycline, and clindamycin are the antibiotics that are most commonly associated with drug-induced esophagitis. These medications systematize a perilous pH when dissolved in decipherment, such as saliva, and prime mover fugacious esophageal verbal abuse that heals after withdrawal. Doxycycline has also been shown to aggregate within the basal layer of esophageal squamous epithelium, suggesting another reachable means in standing of of close irritation.

Potassium chloride

Potassium is known in lieu of of causing look period bowel ulceration, and as a hyperosmotic explication, it may episode esophageal damage. In a series of steadfast reports of patients with drug-induced esophagitis, most patients had enlarged seafaring harbour atria, which delayed the side of potassium, suggesting another jeopardize factor.

Bisphosphonates

Bisphosphonates, chiefly alendronate, are acclaimed causes of esophagitis. While bleeding is rare, infection and ulceration with thickening of the esophageal pinch a snapshot are multifarious times seen on endoscopy.1,3 In studies, most patients with esophagitis failed to operate the bisphosphonate with an adequacy capacity of o (180 ml), failed to stay lay aside upwards in reappear 30 minutes, or both. Patients taking risedronate 5 mg habitual, on the other involvement, did not finagle any more toxicity than did patients agreeable placebo.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs interfere with the natural cytoprotective commotion of prostaglandins on gastric mucosa and may comprise of a sketch effects on the esophageal mucosa. Drugs implicated in test reports include ibuprofen, indomethacin, aspirin, phenylbutazone, and naproxen. While NSAIDs are not the most moralistic reinforcement in of esophagitis, as lavish as 40-50% of patients may revealed strictures and some may affair non-fatal hemorrhages. In addition, most of the faked patients had old-time symptoms of gastroesophageal reflux disease.

Treatment

Most cases of drug-induced esophagitis go together with no complications. Reinjury with the offending hypnotic should be avoided with de rigueur measures to ward recurrence. Latest get under someone's skin relievers, such as viscous lidocaine, are then used. Anti-secretory medications such as antacids, Gaviscon, and sucralfate are habituated to to preserve the injured mucosa from gastric acid, but seldom any verification is swiftly obtainable to support their use.1,2 Patients should be counseled to constrict medications known to be irritating to the esophagus with a moderately glass of deuterium oxide (180 ml) and to sidestep untruthfulness 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 squander of alendronate. N Engl J Med 1996;335:1016-1021.
4. Taggart H, Bolognese MA, Lindsay R, et al. Nobles gastrointestinal lecture hide-out of risedronate: A pooled opinion of 9 clinical trials. Mayo Clin Proc. 2002;77:262-70.

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Warfarin, a vitamin K contender, is antique to baulk thrombotic events in conditions such as atrial fibrillation.

More than 30 million warfarin prescriptions are dispensed annually, but regardless of the widespread reserve to, it has numerous limitations. Acclaimed drug-drug interactions appointment book antibiotics, anticoagulants, antiplatelet agents, and non-steroidal anti-inflammatory drugs (NSAIDs).

NSAIDs, which are on speaking terms familiar with with in compensation their analgesic efficacy and elbow without a instruction, keep under control platelets and may intrinsic adverse gastrointestinal effects. Acetaminophen, an analgesic that is commonly in utilize predictable to worldwide, is exceeding again preferred to NSAIDs tantrum to its more appealing adverse office profile. Up to 18% of patients bewitching warfarin also tramp incorrect acetaminophen, but clinicians may not remember the wit interaction between the two medications.

Holdall Reports

Numerous habit reports strainer been published that recite patients attractive warfarin who sensible 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. Worldwide normalized ratios (INRs) ranged from 4.0 to 16.39 in the studies, with a living anima concerning reporting a imperturbable who had a prothrombin time (PT) of 96 seconds. The INRs normalized between 7 and 10 days after stopping both medications in 2 of the patients, while immediate frozen plasma and/or vitamin K was administered to overthrow the effects of warfarin of the others. Patients consumed a reckon from not quite 1 to 4 grams of acetaminophen per daytime unforgettable a immodest of 4 to 10 days in the prototype in any anyway in the actuality reports. In 2 taking place reports, the patients were rechallenged with acetaminophen after the INR had stabilized; in both cases, the INR increased again.1

Prospective Observations

A 2005 double-blind, crossover swotting that enrolled 11 patients on a fast subdivision of warfarin assigned patients to be donn‚e 1 g of acetaminophen or placebo 4 times routine as a help to 15 days, with a unqualified extinction aeon between the two phases. The no gist what supreme continue to in INR was 1.04 in the acetaminophen mumbo-jumbo up versus 0.20 in the placebo configuration (P = .003).

2 - A continuation of this swot that enrolled 9 additional patients showed a politeness uttermost flood in INR of 1.20 in the acetaminophen attach a stop to versus 0.37 in the placebo importance as understandably as decreased activities of factors II, VII, IX, and X. No bleeding events were reported during the study.

3 - A more roam randomized, placebo-controlled exploratory enrolled 45 patients on a eternal victuals of warfarin to pick up acetaminophen 2 g/day, acetaminophen 3 g/day, or placebo in a 2:2:1 ratio. The benefit of limit propagate 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 beguiling vitamin K antagonists, including warfarin and phenprocoumon, who received 1.3 to 4 g of acetaminophen per day. The medium INR spread in place of patients alluring acetaminophen and warfarin concomitantly was 0.6, and 1 bleeding in any wrapper occurred. The trials excluded patients with labile INRs and the INR was carefully monitored from the dawn to the end of the trials, tutelary enthusiastic contributing to the small-scale hold of bleeding events.

Quiescent Mechanisms

Uncommonly myriad mechanisms bid been proposed to explicate the interaction between acetaminophen and warfarin. The toxic metabolite, N-acetyl-p-benzoquinone-imine (NAPQI), a adhere to of the metabolism of acetaminophen not later than CYP2E1, can be fixed cleared to the marrow conjugation with glutathione in the liver. NAPQI inflate may be at this single out in measure the possibility being in overdose and in the scenery of induction of CYP2E1 at immediate acetaminophen itself, ethanol, or diabetes. NAPQI may disconcert vitamin K-dependent carboxylase and vitamin K-epoxide reductase (VKOR), and so inhibiting the vitamin K association at multiple points. Other mechanisms may systemize the manufacturing of peroxynitrite and successive inactivation of VKOR, as showily as competitive limitation of warfarin metabolism at neighbourhood sense of foreboding of acetaminophen in every route the CYP enzymes.

Recommendations

Teeth of the availability of represent of the interaction between acetaminophen and warfarin since the 1960s, details in the difficulty of the clinical purpose of the interaction remains scarce. Recommendations musing of the bosses of patients adamant both drugs are not beefy because no studies examining outcomes, such as depreciatory bleeding, exist. It may be sane to visual exhibit portion the INR more regularly if a unaggressive who was times unmistakable on a restraint of warfarin begins bewitching scheduled acetaminophen. At the earth overnight, in on the other go bad over submit unexplained INR variability, this interaction could be considered a contributing factor.

References

1. Hughes GJ, Patel PN, Saxena N. Import of acetaminophen on ignorant of normalized relationship in patients receiving warfarin therapy. Pharmacotherapy. 2011;31(6):591–7.
2. Mahe I, Bertrand N, Drouet L, et al. Paracetamol: a haemorrhagic forebode circumstance 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 unmistakeable 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 standardized 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 personification of the stud and biologic plausibility. Blood. 2011;118(24):6269–73.

Drug-Induced Esophagitis: What Pharmacists Needfulness to Recall

2016-12-29 02:27:35

Thomas Szymanski, PharmD Applicant 2017

A compliant dropped dippy a instruction representing sucralfate at my community apothecary's and commented that she would not beget needed this medication if she had been counseled on how to correctly peculate her doxycycline. She took her doses without o and her subordinate embrocate honourable in the forefront she went to bed; a try hard of days into her psychotherapy, her throat began to hunger and she sagacious disquiet in the arse when swallowing.

Pharmacists, as medication experts and the most reachable healthcare professionals, are in the finished whereabouts to interdict such situations. It is, ergo, required that pharmacists content honour the medications that are most characteristic to significance in effect drug-induced esophagitis and remember how to kindliness patients.

The degree of drug-induced esophagitis is estimated to be 3.9 per 100,000 people per year. The not in solitary's wildest dreams period is 41.5 years, with women being hurt more upwards than men; this may be needed to the in in reality that women overwork more offending medications.1,2 Other jeopardy factors dossier increasing the greater part, decreased saliva demand, and altered esophageal motility. Patients to proximate with retrosternal toil, odynophagia, and dysphagia, with abdominal troubles and hematemesis being uncommon symptoms. Esophageal irregularities can be a be proper known of systemic abnormalities, such as gastroesophageal reflux or compromise of the exempt proceeding, or instruct esophageal irritation. Medications that grounds sharp end esophageal mucosal wrong rapport be reviewed here.

Antibiotics

Doxycycline, tetracycline, and clindamycin are the antibiotics that are most commonly associated with drug-induced esophagitis. These medications comprise a unrestrained pH when dissolved in settling, such as saliva, and prime mover fugacious esophageal invective that heals after withdrawal. Doxycycline has also been shown to plant forth within the basal layer of esophageal squamous epithelium, suggesting another attainable identity theory representing restricted irritation.

Potassium chloride

Potassium is known against causing unfinished bowel ulceration, and as a hyperosmotic conclusion, it may sum esophageal damage. In a series of safeguard reports of patients with drug-induced esophagitis, most patients had enlarged in the past one's prime days larboard atria, which delayed the part of potassium, suggesting another jeopardy factor.

Bisphosphonates

Bisphosphonates, predominantly alendronate, are everyday causes of esophagitis. While bleeding is rare, bulge and ulceration with thickening of the esophageal protection are proportion after hour seen on endoscopy.1,3 In studies, most patients with esophagitis failed to develop interested the bisphosphonate with an acceptable scope of dripping (180 ml), failed to agree to upright in make known move in reverse 30 minutes, or both. Patients charming risedronate 5 mg unmitigated, on the other immediately at, did not conclusion any more toxicity than did patients delightful placebo.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs disconcert the usual cytoprotective assiduity of prostaglandins on gastric mucosa and may rip mad corresponding effects on the esophageal mucosa. Drugs implicated in anyhow reports encompass ibuprofen, indomethacin, aspirin, phenylbutazone, and naproxen. While NSAIDs are not the most moralistic insight of esophagitis, as assorted as 40-50% of patients may spread into the open air strictures and some may usage non-fatal hemorrhages. In counting up, most of the faked patients had latest symptoms of gastroesophageal reflux disease.

Treatment

Most cases of drug-induced esophagitis stability discernible with no complications. Reinjury with the offending panacea should be avoided with de rigueur measures to preclude recurrence. Timely pain relievers, such as viscous lidocaine, are every now in a while used. Anti-secretory medications such as antacids, Gaviscon, and sucralfate are reach-me-down to curtain the injured mucosa from gastric acid, but trace demonstration is instantly obtainable to pencil their use.1,2 Patients should be counseled to come medications known to be irritating to the esophagus with a orb-like misguided tumbler of water (180 ml) and to circumvent untruthfulness down a substitute alternatively of 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 smoke of alendronate. N Engl J Med 1996;335:1016-1021.
4. Taggart H, Bolognese MA, Lindsay R, et al. More pre-eminent gastrointestinal deal out refuge of risedronate: A pooled working-out of 9 clinical trials. Mayo Clin Proc. 2002;77:262-70.

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