PPI Rational Use Jan 18

8/8/2019 PPI Rational Use Jan 18

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Rational use ofRational use of

protonproton--pump inhibitorspump inhibitors

Philip AbrahamPhilip Abraham

P D Hinduja National Hospital and

K E M Hospital, Mumbai

Why this discussionWhy this discussion

Healing of acid-related disorders directly related to degree and

duration of acid suppression and length of treatment

Introduction in 1989 of proton pump inhibitors, covalent

inhibitors of gastric H+,K+-ATPase, resulted in significant

improvement in management of acid-related disorders

PPI produce significantly more effective and prolonged acid

suppression than H2-receptor antagonists without evidence of

tolerance

Why this discussionWhy this discussion

Spurt of new releases (second-generation) with big claims.

More PPI released in last 7 years than in previous 15 years

Most commonly co-prescribed medication

PPI prescriptions for questionable indications in 40%-70% of

hospitalized patients (Aliment Pharmacol Therdoi: 10.1111/j.1365-

2036.2008.03924)

ProtonProton--pump inhibitorspump inhibitors

Omeprazole

Lansoprazole First generation

Pantoprazole

Esomeprazole

Rabeprazole

Second generation

General informationGeneral information

Substituted benzimidazoles

Weak bases; require acid environment for conversion to active

moiety

5% pumps active on fasting, 60%-70% after meal

Best administration, therefore, immediately before meals;

esomeprazole administration 1 h before, because food

decreases absorption 33%-50%


Enteric-coated acid-labile pro-drugs, so peak levels after 2-5 h

Well absorbed after oral dosing

Plasma half-life 24 h; 1 week therapy

inhibits acid >98%


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No interference with concomitant antacids

Food may delay absorption of lansoprazole, pantoprazole and

rabeprazole, but this does not alter area under plasma

concentrationtime curve

Generally no dose adjustment for renal or hepatic failure, or in

elderly

Eradicating H. pylorirenders PPI less effective in elevating

gastric pH in patients with duodenal ulcer


Significant genetic polymorphisms for one of the CYP

isoenzymes involved in PPI metabolism, CYP2C19

~3% of white persons and 15% of Asians deficient in CYP2C19

This substantially raises plasma levels of omeprazole,

lansoprazoleand pantoprazole, but not of rabeprazole and

esomeprazole

Rational use of PPIRational use of PPI

Choosing an acid inhibitorChoosing an acid inhibitor

PPI

generally more effective than H2RA, but difference not

significant in non-ulcer dyspepsia and peptic ulcers

preferred for GERD, with night-time H2RA if required

reduce risk of NSAID-associated endoscopic ulcer disease but

there is less evidence for reduction in bleeding events (Cochrane

Database Syst Rev2002:CD002296)

Choosing an acid inhibitorChoosing an acid inhibitor

PPI

preferred for primary and secondary prevention, and for

treatment, of non-variceal upper GI bleed (Aliment Pharmacol

Ther2008;28:629-7;Health Technol Assess2007;11:1-164)

preferred in treatment for H. pylori

IssuesIssues

Speed and efficacy

Dosing

IV formulations

Safety issues


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IssuesIssues

Speed and efficacy

Dosing

IV formulations

Safety issues

In vitroIn vitro activation time at acidic pH (1.2)activation time at acidic pH (1.2)

0

50

100

150

200

250

300

Rabe

praz

ole

Lans

oprazole

Omep

razole

Pantop

razole

-- Pharmacology 1998;56:57-70

seconds

Activation time comparisonActivation time comparison

At acidic pH (as obtained in parietal cells), activation half-life for PPI

ranges from 1-5 min

Serum half-life about 1 h for all

Hence, no functional significance in differences in activation time

Recently available fastpreparations (coupled with alkalis) useful

only on day 1 as antacid

comparisoncomparison

Omeprazole, pantoprazole and lansoprazole have equivalent

potency for normalizing intra-oesophageal acid exposure after 3

days of treatment in non-erosive reflux disease patients; the former

two act earlier (Aliment Pharmacol Ther2008;28:250-5)

All current PPI equally recommended for H. pylorieradication

regimens. In a recent study, omeprazole-based triple therapy gave

higher eradication rate in non-ulcer dyspepsia (Korean J

Gastroenterol 2008;52:80-5)

IssuesIssues

Speed and efficacy

Dosing

IV formulations

Safety issues

Standard daily dose (mg; once daily)Standard daily dose (mg; once daily)

Omeprazole 20/40

Lansoprazole 30

Pantoprazole 40

Esomeprazole 40

Rabeprazole 20


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Dosing comparisonDosing comparison

Although recommended doses of PPI vary, data suggest

30-40 mg as optimal daily dose of each

Different dose recommendations based on different

strategies to balance optimal dosage with safety

No real difference in milligram-related efficiencies

Median 24Median 24--hourhour intragastricintragastric pHpHafter single doseafter single dose

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

Baselin

e

Ome10

Ome20

Rabe

10

Rab

e20

Esom

20

Esom

40

Baselin

e

Ome20

Pant

o40

Lans

o30

Rabe20

West India

-- Gastroenterology2000;118:A5895 -- Ashar, Abraham. 2003

Median % time pH >4 in 24 h afterMedian % time pH >4 in 24 h aftersingle dose (Indian)single dose (Indian)

0

10

20

30

40

50

60

70

80

Baselin

e

Ran30

0

Ome10

Ome20

Rabe

10

Rabe20

Esom

20

Esom

40

%

-- Ashar, Abraham. 2003

DosingDosing

Few studies indicate that low doses of PPI are as effective as

standard doses in management of acid-related diseases

Low doses are inferior to standard doses in healing esophagitis

and GERD symptom relief

Low doses may be therapeutically similar to standard doses in

maintenance therapy of GERD and peptic ulcer disease

IssuesIssues

Speed and efficacy

Dosing

IV formulations

Safety issues

Intravenous formulationIntravenous formulation

Intravenous formulations of all PPI currently available

IV PPI act even without meal stimulation

IV PPI is currently mainstay in management of upper GI

bleeding in peptic ulcer patients who have undergone

endoscopic hemostasis (Ann Intern Med2003;139:843-57)

Use of similar regimen prior to endoscopy may reduce high-risk

stigmata at endoscopy (N Engl J Med2007;356:1631-40)


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Intravenous formulationIntravenous formulation

Unfortunately, IV PPI commonly used where not indicated, and

even where recommended, are used in higher doses and for

longer durations than recommended (Can J Gastroenterol

2004;18:567-71)

Once-daily IV PPI may give same benefit as continuous infusion

(Am J G astroenterol 2008;103:3011-8 a nd 3019-21)

Conceivably, oral PPI may offer same benefit (Aliment Pharmacol

Ther2008;28:326-33;BMJ2005;330:568)

IssuesIssues

Speed and efficacy

Dosing

IV formulations

Safety issues

Chronic therapyChronic therapy

Tolerance not seen during short-term treatment

Rebound acid hypersecretion by 14 days after cessation of

therapy. Found in H. pylori-negative, but not -positive, subjects;

can persist for >2 months after prolonged therapy

H. pylorishift from antrum to body / fundus acid cell atrophy

Enteric infections

May decrease mineral and cobalaminabsorption







Enteric infections

May decrease mineral and cobalamin absorption


Significant increase in Clostridium difficileinfection in antibiotic

recipients who receive PPI, but absolute risk increase is modest

(Aliment Pharmacol Therdoi: 10.1111/j.1365-2036.2008.03924)

PPI may increase risk of nosocomial pneumonia in ICU

populations, but evidence is controversial (J Crit Care

2008;23:513-8)

Gastric and jejunal bacterial overgrowth follows PPI use in

compromised environs (Indian J Gastroenterol 1995;14:134-6)


In settings with low rates of such infection, benefit of PPI

therapy outweighs risk of developing it

Still, inappropriate use of PPI in hospitalized patients must

be decreased


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Enteric infections

May decrease mineral and cobalaminabsorption

Absorption of nutrientsAbsorption of nutrients

PPI use decreases absorption of protein-bound vitamin

B12 in short-term studies ( Aliment Pharmacol Ther

1996;10:541-5)

Screening for vitamin B12 deficiency recommended on

long-term PPI treatment (Basic Clin Pharmacol Toxicol

2006;98:4-19)

Absorption of nutrientsAbsorption of nutrients

Results of long-term studies are, however, inconsistent

(Ann Pharmacother2002;36:812-6)

Some report decline in serum vitamin B12 (Ann

Pharmacother2002;36:812-6)

Not clear whether decline is clinically significant (Clin

Gastroenterol 2000;30:29-33)

Recent studies suggest screening may not be required

( Aliment Pharmacol Ther2008;27:491-7)

CarcinoidCarcinoid tumors and carcinogenesistumors and carcinogenesis

Hypergastrinemia ECL cell hyperplasia hyperplastic polyps

Gastric carcinoid tumors reported in rats on prolonged PPI

therapy

No evidence of carcinoid tumors or carcinogenesis in humans

Elevated gastrin returns to normal within 4 weeks after

discontinuing PPI therapy

Colorectal cancerColorectal cancer

PPI use associated with increased serum gastrin levels

and bacterial overgrowth, resulting in more toxic bile salt

formation, which may increase risk of colorectal neoplasia

No association between use of PPI and risk of colorectal

cancer (Am J Gastroenterol 2008;103:966-73)

Drug interactionsDrug interactions

Elevated gastric pH

may inhibit ketoconazole absorption

facilitates digoxin absorption, resulting in higher plasma levels

Potential to alter metabolism of drugs eliminated by CYP

enzymes

Omeprazole delays clearance of warfarin, diazepam and

phenytoin; clinically important drug interactions uncommon

Lansoprazole, pantoprazole and rabeprazole do not interact

significantly


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Use in pregnancyUse in pregnancy

Omeprazole in FDA category C (contraindicated)

Other PPI in FDA category B (use with caution)

PPI excreted in breast milk; discontinue use if not essential

Recent data suggest that PPI do not represent major teratogenic

risk in humans, including when used in first trimester (Aliment

Pharmacol Ther2005;21:269-75)

ConclusionsConclusions

PPI have advantages over H2RA in many situations

All PPI equipotent for standard treatment of acid-peptic disorders

and for H. pylorieradication regimens

Second-generation PPI have advantages of consistency in

response and lower drug interactions, but at higher cost

Low-dose PPI may suffice in many situations in Indians with lower

parietal cell mass and possibly CYP2C19 deficiency

ConclusionsConclusions

IV PPI have well-defined roles, but should not be overused

Safety issues (including potential for drug interactions, nosocomial

infections, and micronutrient deficiency) preclude injudicious use

of PPI

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PPI Rational Use Jan 18