anti secretory drugs

8/10/2019 Anti Secretory Drugs

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5TH YEAR CLINICAL PHARMACY STUDENTS

Gastric Acid Anti-Secretory

Therapeutic UpdatePractical Course Of Gastroenterology For ClinicalPharmacy Students

Clinical Pharmacy Department

2/17/2013

The fol lowing statements are intended to d escr ibe the required basics and the last up dates in therapeut ics

issues of ant-secretory dru gs and level of evidence being performed by associat ions assigned to these

updates. They are not intended to be an exhaust ive l is t of al l upd ates or cl in ical related issues. i t is intended to

descr ibe the general usage of these agents in gastr ic hypersecretory disorders and its consequences.


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Antacids

A.

Calcium-, aluminum-, and magnesium-based products are available OTC in

a wide variety of formulations (capsules, tablets, chewable tablets, and

suspensions).B.

Neutralizing acid and raising intragastric pH results in decreased activation

of pepsinogen and increased LES pressure; rapid onset of action but shortduration, necessitating frequent dosing

C.Some products (Gaviscon) contain the anti-refluxant alginic acid, whichforms a viscous layer on top of gastric contents to act as a barrier to reflux

(variable added efficacy).

D.Used as first-line therapy for intermittent (less than 2 times/week) symptomsor as breakthrough therapy for those on PPI/H2RA therapy; not appropriate

for healing established esophageal erosions

E.

Adverse reactions: Constipation (aluminum), diarrhea (magnesium),accumulation of aluminum/ magnesium in renal disease with repeateddosing

F.

Drug interactions: Chelation (fluoroquinolones, tetracyclines), reduced

absorption because of increases in pH (ketoconazole, itraconazole, iron,atazanavir, delavirdine, indinavir, nelfinavir) or increases in absorption

leading to potential toxicity (raltegravir, saquinavir)

Histamine-2-receptor antagonists

A.

Reversibly inhibit Histamine-2-receptors on the parietal cellB.

All agents available as prescription and OTC products; a variety of

formulations available;generics exist for all prescription productsC.

OTC H2RA products may be used for on-demand therapy for intermittent

mild-moderate GERD symptoms; preventive dosing before meals or

exercise is also possible for all agents. Higher prescription doses are often

required for more severe symptoms or for maintenance dosing. Prolongeduse may result in the development of tolerance and reduced efficacy

(tachyphylaxis).

D.

Therapy with H2RAs is less efficacious than therapy with PPIs in healingerosive esophagitis.


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E.

Adverse effects: Most are well tolerated. Central nervous system (CNS)

effects, such as headache, dizziness, fatigue, somnolence, and confusion, arethe most common. Elderly patients and those with reduced renal function are

more at risk. Prolonged cimetidine use is associated with rare developmentof gynecomastia.

F.

Drug interactions: May affect absorption of drugs dependent on lower

gastric pH, such as ketoconazole, itraconazole, iron, atazanavir, delavirdine,indinavir, and nelfinavir, or increases in absorption leading to potential

toxicity (raltegravir, saquinavir). Cimetidine also inhibits cytochrome P450(CYP) enzymes 1A2, 2C9, 2D6, and 3A4. Warfarin, theophylline, and other

agents metabolized by these enzymes may be affected. Cimetidinem mayalso compete with medications and creatinine for tubular secretion in the

kidney.


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Proton pump inhibitors

A.Irreversibly inhibit the final step in gastric acid secretion; greater degree of

acid suppression achieved and typically longer duration of action than

H2RAsB.

Most effective agents for short- and long-term management of GERD, as

well as for management of erosive disease (Aliment Pharmacol Ther 2003;18:55968)

C.

Most costly agents: Omeprazole and lansoprazole now available as a generic

prescription- strength product and OTC. The OTC products are considered

safe and effective for intermittent short-term (2 weeks) use in patients with

typical heartburn symptoms. Longterm use of OTC products should be

discussed with prescriber to prevent loss of followup or to assess for

potential undertreatment (Digestion 2009;80:22634).Pantoprazole and

esomeprazole are available in intravenous formulations.

D. Most effective when taken orally before meals; for divided dosing, give

evening dose before evening meal instead of at bedtime


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E.

Alternative administration

F.

Adverse reactions: Overall, well tolerated; possible adverse effects includeheadache, dizziness, nausea, diarrhea, and constipation. Long-term use is notassociated with significant increases in endocrine neoplasia or symptomatic

vitamin B12 deficiency.(( the most important part at all))

1.

A cohort study of 364,683 users of both PPIs and H2RAs found an

elevated risk of community-acquired pneumonia with these agents.The adjusted relative risk of pneumonia was 1.89 (95% confidence

interval [CI], 1.362.62) with PPI use and 1.63 (95% CI, 1.072.48)

for H2RA use. Patients at risk of community-acquired pneumoniainclude the immunocompromised, the elderly, children, and thosewith asthma or chronic obstructive pulmonary disease. Acid

suppression should be used for these patients only if necessary andonly at the lowest possible dose (CMAJ 2011; 183:310.)

2. A recent large prospective cohort study of hospitalized patients

revealed an increased risk of hospital-acquired pneumonia in


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nonventilated patients who were prescribed PPIs (OR = 1.3; 95% CI,

1.11.4) (JAMA 2009;301:21208).3.

Another recent study revealed a higher incidence of fracture in

patients receiving higher doses of PPIs for longer durations (OR =

1.44; 95% CI, 1.31.59) (Am J Gastroenterol 2012; 107:1361).This

may be attributable to reductions in the absorption of calcium inpatients receiving potent acid suppression or, possibly, interference

with osteoclast function.

4.New U.S. Food and Drug Administration (FDA) labeling for PPIs asof May 2010 stating that PPIs may increase the risk of hip and spine

fracture(www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInfor

mationforPatientsandProviders/ucm213206.htm#SafetyAnnouncement).The 2008 AGA guidelines cite insufficient evidence to recommend

bone density screening or calcium supplementation because of PPI

use. Screening for osteoporosis in populations at risk, such as theelderly, is recommended regardless of PPI use.

5. Recent FDA warning regarding development of C. difficile infection.http://www.fda.gov/Drugs/DrugSafety/DrugSafetyPodcasts/ucm2910

58.html-(Am J Gastroenterol 2012; 107:1011.)

I.

Magnitude of increase risk reported to be RR 1.4-2.75.

II. Recommendations include evaluating patients for C. difficleinfection if diarrhea does not improve in patients receiving

PPIs.

III.

Patients should be advised to seek immediate care from ahealthcare professional if they experience watery stool that doesnot go away, abdominal pain, and fever while taking PPIs.

IV. Patients should use the lowest dose and shortest duration of PPItherapy appropriate to the condition being treated.

V. Report adverse events involving PPIs to the FDA MedWatchprogram

6. FDA warning in 2011 regarding risk of hypomagnesemia is patientsreceiving PPIs (www.fda.gov/Drugs/DrugSafety/ucm245011.htm)

I. Most often associated with use greater than 1 year

II.

May lead to tetany, arrhythmias, or seizuresIII. May require discontinuation of PPIs and/or magnesium

supplementation.

IV. Consider checking a baseline serum magnesium concentration in

patients receiving diuretics or digoxin or requiring long-term PPI

use (Aliment Pharmacol Ther 2012; 36:405.).
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G.

Drug interactions: Drugs with pH-dependent absorption (ketoconazole,

itraconazole, protease inhibitors, etc.); omeprazole inhibits the metabolismof diazepam through CYP2C19. Recent data suggest a reduced effectiveness

of clopidogrel through CYP2C19- mediated inhibition of conversion to

active metabolite by omeprazole and esomeprazole.1.

Recommendations are to avoid omeprazole, esomeprazole, and

cimetidine (CYP effects, also) in patients receiving clopidogrel. SeeFDA letter at

www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm190848.htm.

2. Guidelines (JACC 2010;56:116) on PPI/clopidogrel interaction

conclude that the magnitude of interaction is generally less than ahazard ratio or odds ratio of 2. Findings from studies are inconsistent,

with most citing omeprazole as the most implicated. Although PPIs

should be used in patients at high risk of GI bleeding, H2RAs are lesseffective but could possibly be used in patients at low risk of bleedingor those whose symptoms are not severe enough to warrant PPI

therapy. Cimetidine should be avoided.

Sucralfate

A.Sucralfate(Carafate) is a sulfated polysaccharide, sucrose octasulfate,

complexed with aluminum hydroxide. It prevents acute chemically-induced

mucosal damage and heals chronic ulcers without altering gastric acid orpepsin secretion or significantly buffering acid . Similar to aluminum-

containing antacids, sucralfate stimulates angiogenesis and the formation of

granulation tissue, possibly due to growth factor binding . Sucralfate also

binds to the injured tissue, thereby delivering growth factors and reducingaccess to pepsin and acid.

B.Aluminum hydroxide mediates some of the actions ofsucralfate,but thesucrose octasulfate moiety may also have a role by contributing sulfhydryl

groups to reduce oxidant damage to epithelial cells. The binding of thisagent to the ulcer base is enhanced at a pH below 3.5, leading to the

recommendation that the drug be administered 30 to 60 minutes before

meals.C.Sucralfatehas been reported to suppress H. pylori and inhibit acid secretion

in infected patients with duodenal ulcers . No data are available to test the

relevance of this action by comparing ulcer healing in patients with H.pylori-positive versus -negative duodenal ulcer.
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D.

Adverse effectsSucralfatehas minimal adverse effects other than

possible aluminum toxicity . It can bind other drugs if taken simultaneously,although the clinical consequences are minor.

E. Aluminum toxicitySignificant absorption of aluminum occurs with

several antacid formulations andsucralfate. Daily consumption of 120mmol of aluminum-containing antacid tablets for four weeks increases

serum and urinary aluminum levels . A therapeutic dose of sucralfatecontains about 0.8 g of aluminum and the aluminum absorption iscomparable to that seen with antacids .

1. Aluminum is readily excreted by normal kidneys; urinary levels are

elevated for one to three weeks after discontinuing therapy. Bycomparison, significant aluminum retention occurs in patients with

renal failure, and may result in neurotoxicity and anemia following

treatment with either antacids orsucralfate. As a result, calciumcarbonate or acetate, rather than aluminum hydroxide is now theprimary agent used to bind dietary phosphate. Simultaneous

consumption of citrate enhances absorption of aluminum 50-fold inpatients with normal renal function, resulting in considerable

elevations in serum aluminum concentration . To avoid enhanced

aluminum absorption, especially in the setting of renal failure, it is

advisable to avoid combining antacids and probablysucralfatewithfoods or other agents that contain citrate. If necessary to correct

metabolic acidosis, alkali should be given as sodium bicarbonate, notsodium citrate.

2. The extent and consequences of aluminum deposition in tissues with

sustained use of either class of agents have not been defined; thepossibility of significant aluminum retention in the face of normal

renal function is remote. Aluminum deposits have been reported inbrain tissue in Alzheimer disease, but evidence points against

significant aluminum deposition in the brain or a role for this metal inthe pathogenesis of this disorder . Nevertheless, more rigorous

investigation of tissue aluminum is required in humans before firm

conclusions can be reached.

F. Aluminum hydroxide blocks intestinal absorption of phosphate; two weeks

of therapy with moderate doses can result in significant hypophosphatemia,especially if the patient is on a low phosphate diet or is phosphate-depleted

for other reasons .Sucralfatealso binds phosphate leading to similar
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theoretical consequences; combining sucralfate and antacids can potentiallyamplify these effects .

Bismuth

A.

Several forms of bismuth were used for ulcer treatment long before the role

of H. pylori was recognized. Currently, colloidal bismuth subcitrate (CBS),also known as tri-potassium di-citrato bismuthate (De-Nol), and bismuth

subsalicylate (BSS, Pepto-Bismol) are used in treatment of H. pylori

infection.

B.Bismuth subsalicylate is available in the United States either as Pepto-Bismol or Helidac, the latter in combination with tetracycline and

metronidazole. Helidac is approved in the United States for treatment of H.pylori-associated duodenal ulcer. However, to more effectively cure H.

pylori and to ensure ulcer healing, it should be combined with twice dailyproton pump inhibitor treatment. Furthermore, the metronidazole dose in

Helidac is only 1 gram daily, which is too low to be effective in the face ofmetronidazole resistance.

C.The most dramatic action of these bismuth salts is the suppression of H.pylori . Bismuth is not effective in H. pylori-negative ulcers, suggesting the

healing efficacy of bismuth primarily reflects suppression of the infection.However, there are numerous studies from the pre-H. pylori era suggesting

that bismuth also has other actions that may promote ulcer healing, includingthe following:

1.

Inhibition of peptic activity but not pepsin secretion

2. Bismuth from CBS may bind to ulcer craters3.

Macrophages, recruited to the edge of the ulcer crater in CBS-treated

rats, may promote healing4.

CBS may increase mucosal prostaglandin production, and mucus andbicarbonate secretion

D.Bismuth does not inhibit or neutralize gastric acid.

E.

The subsalicylate salt of bismuth has received too little study to determineits antiulcer properties . In the colon, bismuth salts react with hydrogen

sulfide to form bismuth sulfide, which blackens the stools .

F. Adverse effectsThe primary concern with bismuth compounds isbismuth intoxication; this was a problem primarily when bismuth subgallate

was used for prolonged periods at high doses. Bismuth absorption varieswith the specific form of bismuth; absorption is much greater with CBS than


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with BSS or bismuth subnitrate . Coadministration of H2 receptor

antagonists increases bismuth absorption from CBS, but not from BSS orbismuth subnitrate . Nevertheless, significant clinical toxicity has not been

reported in clinical trials with CBS or BSS . Bismuth should be avoided or

serum bismuth concentrations monitored in patients with renal failure [4].G.

The subsalicylate moiety in BSS is converted to salicylic acid and absorbed;

however, salicylate in the absence of the acetyl group does not inhibitplatelet function or appear to share the same high risk of aspirin for

gastrointestinal bleeding. However, the salicylate from bismuth subsalicylatewill contribute to serum salicylate levels and cause salicylate toxicity, and

combination with other salicylate products should therefore be avoided.

Prostaglandins

A.

Prostaglandins, particularly of the E and I group, inhibit acid secretion byselectively reducing the ability of the parietal cell to generate cyclic AMP in

response to histamine . Prostaglandins also enhance mucosal defensemechanisms.

B.While several prostanoids have been tested for peptic ulcer healing, onlymisoprostol (Cytotec) has been approved for use in the United States, and

not for ulcer healing but rather for prevention of NSAID-induced gastriculcer. Misoprostol is a 15-deoxy-15-hydroxy-16-methyl analogue of

prostaglandin E1. Topical action appears critical for prostaglandin action;oral administration of misoprostol gives greater antisecretory efficacy and

fewer side effects than systemic administration.C.

Adverse effectsThe most frequent side effects of the E type prostanoids

are dose-dependent crampy abdominal pain and diarrhea . These side effectsinterfere with compliance in many patients. The problem of misoprostol-induced diarrhea has been addressed in several ways:

1. Educate the patient to anticipate and manage mild, usually transientcramps and diarrhea, but to stop the drug for more persistent or

troublesome problems

2.

The patient should be instructed not to use concomitant catharticagents, to stop stool softeners unless absolutely necessary, and then toreevaluate the need for these agents after several weeks of therapy

3. The dose of misoprostol should begin at 100 micrograms three to fourtimes daily, then increased to a maximal daily dose of 800

micrograms as tolerated
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D.

Lower doses of misoprostol have been used with some success for ulcer

prevention with a lower incidence of side effects .E.

Prostaglandins of the E group are uterotropic. Misoprostol has been given

with mifepristone to induce abortion . As a result, it is contraindicated in

women of childbearing potential who are not on contraception. Allpatients should be informed of this risk to minimize the drug beinginadvertently given by the patient to a pregnant woman.

Promotility agents

A.Guidelines recommend against the use of metoclopramide as adjunctive

therapy or monotherapy in patients with both esophageal and

extraesophageal symptoms because the risk of adverse effects(extrapyramidal symptoms [EPS]) or tardive dyskinesia) outweighs the

benefit (grade D). Metoclopramide now has black box warning for TardiveDyskinesia.

B.Work through cholinergic mechanisms to facilitate increased gastricemptying.

C.

Metoclopramide: Dopamine antagonist; needs to be dosed several times a

day; associated with many adverse effects such as dizziness, fatigue,somnolence, drowsiness, EPS, and hyperprolactinemia. New 5- and 10-mg

ODT formulations (metoclopramide [Metozolv ODT]) are now available.

Indications for GERD and diabetic gastroparesisD.

Bethanechol: Cholinergic agonist; poorly tolerated because of adverse

effects such as diarrhea, blurred vision, and abdominal cramping; may alsoincrease gastric acid production

E.

Cisapride: Available only on a restricted basis for patients whose other

therapies have failed; cisapride was withdrawn from the market initiallybecause of cardiac arrhythmia (torsades de pointes) when used in

combination with drugs inhibiting CYP3A4.

anti secretory drugs

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