Page 7 - 53-Peptic ulcer diseases (Loét dạ dày)

CHAPTER 53 Peptic Ulcer Disease 811

PPIs, by raising the gastric pH, can affect the absorption of this population. Important drug interactions appear to be rare
a number of drugs. However, this pH effect rarely has clinically and can be avoided if sucralfate is administered at a time separate 53
important effects, except when the PPIs are given with keto- from other medications.
conazole or digoxin. 55-57 Ketoconazole requires gastric acid for Colloidal bismuth preparations, such as colloidal bismuth
absorption, and this antifungal drug may not be absorbed effec- subcitrate and bismuth subsalicylate (e.g., Pepto-Bismol), have
tively if PPIs have also been prescribed. If a patient requires both modest efficacy in healing peptic ulcers, but the mechanism is
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a PPI and antifungal therapy, it is recommended that an agent unclear. The bismuth salts form complexes with mucus that
other than ketoconazole be chosen. Conversely, an elevated appear to coat ulcer craters. Bismuth-induced increased muco-
gastric pH facilitates absorption of digoxin, resulting in higher sal prostaglandin synthesis and bicarbonate secretion have also
plasma digoxin levels. For patients treated concomitantly with been proposed. Bismuth salts have antimicrobial activity against
PPIs and digoxin, clinicians should consider monitoring plasma Hp, and bismuth has been approved in the USA by the FDA for
digoxin levels. use, in combination with other agents, for the treatment of Hp
Because PPIs are metabolized by the CYP system, they have infection (see Chapter 52). Bismuth is largely unabsorbed and
the potential to alter the metabolism of other drugs that are elim- excreted in the feces. Colonic bacteria convert bismuth salts to
inated by CYP enzymes. The potential interaction between PPIs bismuth sulfide, which turns the stools black. Trace amounts of
and clopidogrel has drawn widespread attention. Clopidogrel, a bismuth are absorbed in the UGI tract, with the bismuth then
nonaspirin antiplatelet prodrug, is activated by hepatic CYP2C19 slowly excreted in the urine for 3 months or longer. Short-term,
and other CYPs to its active metabolite. PPIs reduce the anti- standard-dose therapy with bismuth appears to carry little risk
platelet effect of clopidogrel through competitive inhibition of of toxicity; however, there is the potential for bismuth encepha-
CYP2C19. Meta-analysis of observational studies reported a sig- lopathy with neuropsychiatric symptoms if the agent is given
nificant increase in major adverse cardiovascular events includ- for extended periods in high dosage, especially in patients with
ing cardiovascular deaths among patients receiving concomitant chronic kidney disease.
PPIs and clopidogrel. 58,59 However, an association between PPI Misoprostol is a prostaglandin E 1 analog approved by the
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and clopidogrel use has not been confirmed by prospective stud- FDA for the prevention of NSAID-induced PUD. The drug
ies and a large-scale RCT. 60,61 Despite the inconsistent findings, not only enhances mucosal defense mechanisms but also inhibits
regulatory authorities in the USA and Europe have issued warn- gastric acid secretion through inhibition of histamine-stimulated
ings against the use of certain PPIs in patients receiving concomi- cyclic 3',5'-cyclic adenosine monophosphate (AMP) produc-
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tant clopidogrel. tion. Well absorbed after oral administration, the plasma miso-
There are other concerns about the safety of long-term use prostol concentration peaks after approximately 30 minutes, with
of PPIs. To date, PPI use has been implicated in many condi- a serum half-life of approximately 1.5 hours. The drug has no
tions, including osteoporosis, hypomagnesaemia, gastric cancer, effect on hepatic CYP450. Misoprostol metabolites are excreted
enteric infections, interstitial nephritis, pneumonia, dementia, in the urine, but dose reductions are unnecessary in patients
and NSAID-enteropathy. Currently, there is no definite evidence with chronic kidney disease. Dose-related diarrhea is the most
to suggest that these conditions are attributable to PPI use. It common adverse effect, occurring in up to 30% of patients and
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is possible that a new evidence will emerge to indicate a causal limiting the usefulness of misoprostol. Diarrhea is related to
relationship. In the meantime, long-term use of PPI without a prostaglandin-induced increases in intestinal electrolyte and
strong indication should be discouraged. water secretion and/or acceleration of intestinal transit time.
Administration of misoprostol with food may reduce diarrhea.
Potassium-Competitive Acid Blocker Misoprostol also stimulates uterine smooth muscle and is there-
Potassium-competitive acid blocker (P-CAB) therapy com- fore contraindicated in women who may be pregnant.
petes with potassium to inhibit H+, K+-ATPase in parietal
cells at the final stage of the acid secretory pathway (see Hp-associated Ulcers
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Chapter 51). Unlike PPIs, a P-CAB is acid stable and does
not require an acidic environment for activation (i.e., a pro- Treatment of Hp infection is discussed in detail in Chapter 51
drug is not required). To date, vonoprazan is the only P-CAB (Tables 51.2 and 51.3). It is well established that curing Hp infec-
commercially available in Japan and some other countries. tion not only heals peptic ulcers but also prevents ulcer relapses
Vonoprazan exerts a near-maximum inhibitory effect from the and complications. 72-75 Because Hp infection accounts for 80%
first dose and its effect lasts for 24 hours. In 2 phase 3 RCTs, to 90% of DU cases, testing for the infection in patients with
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vonoprazan (20 mg once daily) was not inferior to lansoprazole DU is mandatory. If the diagnosis of DU is made endoscopically,
(30 mg once daily) for the healing of GUs and DUs. RCTs. 64,65 gastric biopsy specimens should be taken to detect Hp infection.
Two other randomized trials showed that vonoprazan (10 and There is good evidence that a 10- to 14-day course of Hp eradi-
20 mg) was as effective as lansoprazole (15 mg) in preventing cation therapy is sufficient to heal DUs such that additional anti-
ulcer recurrence associated with long-term use of NSAIDs and secretory therapy is not usually required. Follow-up endoscopic
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low-dose aspirin. examination in order to document healing and perform testing
to document Hp eradication following antibiotic therapy is not
Mucosal Protective Agents recommended routinely in patients with uncomplicated DUs.
However, noninvasive tests such as the urea breath test can be
Sucralfate is a complex aluminum salt of sulfated sucrose. When used to confirm Hp eradication. Whether antisecretory therapy
exposed to gastric acid, the sulfate anions can bind electrostatically is required after a 7- to 14-day course of Hp eradication therapy
to positively charged proteins in damaged tissue. 67,68 Sucralfate in patients with GU is somewhat controversial. One week of
(1g 4 times daily) is equally effective to H2RAs in healing DUs antibacterial therapy without acid suppression effectively heals
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and is approved by the FDA in the USA for this indication. Very Hp-related GUs. In a meta-analysis of GU healing trials, treat-
little (<5%) of sucralfate is absorbed owing to its poor solubility, ment with Hp eradication therapy produced similar outcomes to
and the drug is excreted via the enteral route. Because of its lack treatment with an ulcer-healing drug; however, in patients with
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of systemic absorption, sucralfate appears to have no systemic large or complicated GUs, additional antisecretory therapy can
toxicity. The effect on the accumulation of aluminum in the body facilitate ulcer healing. Follow-up endoscopy is recommended
has not been adequately studied in patients with chronic kidney in patients with large or complicated GUs to document healing,
disease treated with sucralfate, and sucralfate is best avoided in exclude malignancy, and confirm successful Hp eradication.