PROTON PUMP INHIBITORS

รองศาสตราจารย ดร มยุรี ตันติสิระ

ภาควิชาเภสัชวิทยา คณะเภสัชศาสตรจุฬาลงกรณมหาวิทยาลัย

Omeprazole

Pantoprazole

Lansoprazole

Rabeprazole

Esomeprazole

Tenatoprazole

Proton Pump Inhibitors Available in Thailand

Omeprazole Lansoprazole Pantoprazole Rabeprazole Esomeprazol

Oral

preparation

Trade name

Generic product

Injection

- MUP tab

- Capsule

20 mg

-

Losec

> 20

40 mg

- Capsule

- FDT

15 mg

30 mg

Prevacid

-

-

- Gastro-

resistant tab

20 mg

40 mg

Controloc

-

40 mg

- Film coated

tab

10 mg

20 mg

Pariet

-

-

- MUP tab

20 mg

40 mg

Nexium

-

40 mg

Physiology of acid secretion

Physiology of Gastric secretion

Antrum(gastrin)

Partietal cells(HCl)

Chief cells(pepsinogen)

Normal Gastric Protective Mechanisms

Acid and pepsin StomachlumenpH 2

pH 7

HCO3-

?HCO3

-

?HCO3

-

?HCO3

-

?

Mucouslayer

Gastricepithelium

Gastric pH

HCl HClProtective factor

Mucous layerthickness(PG dependent)

Cell membranehydrophobicity

Bicarbonatesecretion(PG dependent)

Submucosalblood flow(PG dependent)

Mechanism of NSAID-Induced Ulcer

Normal Mucosa Ulcer

Aggressive Defensive

Acid-peptic activity ? Bicarbonate production

? Gastric blood volume

? Mucus secretion

Suppress endogenousprostaglandins

NSAIDs

Intestinal epithelial cells are continually renewed

Regulation of acid secretion

- Neurocrine

- Endocrine

- Paracrine

parlietal

cell

Vagus

M3

H2

SSR

CCK-B

ECLcell

Dcell

CCK-B

M

H

-

Gcell

Gastrinendocrine

Ach (neurocrine)

FUNDUS

ANTRUMDcellHCl

HCl

ccirculation

Aminoaciddistention

somatostatin-SSR

CCK-B

Basolateral membrane

Apical membrane

GastrinHistamineAch

cAMP ?Calcium ?

Secretingproton pump

LUMENCYTOPLASM

Basolateral membrane

Apical membrane

GastrinHistamineAch

cAMP ?Calcium ?

Secretingproton pump

SSR

Pharmacodynamics ofProton Pump Inhibitors

Pharmacological properties of the different proton pump inhibitors

Generic name Half-life Peak effect Duration of pKa Bioavailability Protein Metabolism Excretion References

(h) (h) effect (h) (%) binding (%) (%)

Omeprazole

Pantoprazole

Lansoprazole

Rabeprazole

Esomeprazole

F = faeces; pKa = dissociation constant; U = urine

0.7

1

2

1

1.3

2

2.5

1.7

2-5

1.5

24-72

24-72

>24

24

24-72

3.97

3.96

4.01

4.9

3.97

30-40

77

80

52

64

95

98

97

95

97

Extensively

hepatic

Extensively

hepatic

Extensively

hepatic

Extensively

hepatic

Extensively

hepatic

U = 77;

F=23

U = 71;

F=18

U = 35;

F=65

U = 90;

F=10

U = 80;

F=20

6

7

8

9

10

The recommended dosing schedule for delayed-release PPIs is 30 minutes before breakfast

- food stimualted parietal cell acid secretion

- PPIs bind to actively secreting proton pumps

In a survey of 1046 PCPs across the US

- 36 % did not give advice on the time of PPI dosing or advised patients to take a PPI before food

In a survey of 152 omeprazole prescribed in King Chulalongkorn Memorial Hospital (1999)

- 25.17 % were prescribed before meal.

Rational Use of Omeprazole in Gastric Acid-Related diseases in King Chylalongkorn Memorial Hospital,1999.

Chey et al, Am J Gastroenterol 2005; In press

Pezanoski et al, Gastroenterology 2003; 124:A228

Sachs, G.Pharmacotherapy 2003;23(10 Pt 2):68S-73S

Binding of PPIs to Proton Pump

cysteineDrug 321 813 822 892

Omeprazole - / - /

Lansoprazole / / - /

Pantoprazole - / / -

Rabeprazole / / - /

Recovery of acid secretion in human

- Omeprazole 27 h.

- Lansoprazole 13 h.

- Pantoprazole 46 h.

Half life of proton pump = 48 h.

Reversal of omeprazole-and pantoprazole-induced pump inhibition withglutathione in vitro. Inhibited ATPase was isolated from treated rat andthe recovery of ATPase activity measured as a function of time ofincubation with 10 mM glutathione.

Pharmacokinetics of Proton Pump Inhibitors

All PPIs are prodrugs, acid labile and availableas enteric coated delayed-release pellets/tablets.

At duodenum the enteric coated dissolves andunprotonated prodrug is absorbed.

They are highly protein bound, extensivelymetabolized by cytochrome P 450 and excretedmainly by kidney.

Pharmacological properties of the different proton pump inhibitors

Generic name Half-life Peak effect Duration of pKa Bioavailability Protein Cmax AUC 0-24 Metabolism

(h) (h) effect (h) (%) binding (%) (?M/L) (?M*h/l)

Omeprazole

(20 mg)

Pantoprazole

(40 mg)

Lansoprazole

(30 mg)

Rabeprazole

(20 mg)

Esomeprazole

(40 mg)

F = faeces; pKa = dissociation constant; U = urine

0.7

1

2

1

1.3

2

2.5

1.7

2-5

1.5

24-72

24-72

>24

24

24-72

-3.97

-3.96

-4.01

-4.9

-3.97

30-40

(65)

77

80

(85)

52

64

(89)

95

98

97

95

97

0.7

5.73

2.25

0.48

2.4

1.11

(2.23)

9.93

5.01

2.2

4.32

(11.21)

Extensively

hepatic

Extensively

hepatic

Extensively

hepatic

Extensively

hepatic

Extensively

hepatic

0.00 0.25 0.50 0.75 1.00 1.25

Pantoprazole day 7

Omeprazole day 7

Pantoprazole day 1

Omeprazole day 1

Range in CV values

0.37

0.35

0.83

0.50

Median and range for CV values for omeprazole andpantoprazole AUC data on day 1 and day 7 of dosing.

Yacyshyn and ThomsonDigestion 2002 :66:67-78.

0.0

5.0

10.0

15.0

20.0

25.0

1 2 3

20.5%

10.4%6.9%

Dou

ble

d ose

d (%

)

Omeprazole Lansoprazole Pantoprazole 20 mg 30 mg 40 mg

Percentage of claims that are for double doses of the3 PPIs available in Canada in 2000. Canadian claimsfor these agents were compiled over and 18-monthperiod up to , and including, July 2000.

Yacyshyn and ThomsonDigestion 2002 :66:67-78.

5-O-Desmethylomeprazole 3-Hydroxyomeprazole

Omeprazole sulfide

Omeprazole/Esomeprazole

CYP2C19 CYP3A4 CYP3A4

3-Hydroxyomeprazole Omeprazole sulfone

CYP2C19

(CYP3A4) CYP3A4

Omeprazole hydroxysulfone

CYP3A4 CYP2C19

Demethylated rabeprazole Rabeprazole thioether

CYP2C19 Nonenzymatic

Rabeprazole sulfone

CYP3A4

Lansoprazole sulfide

3-Hydroxyomeprazole Lansoprazole sulfone

CYP2C19

(CYP3A4)

CYP3A4

CYP3A4

Pantoprazole sulfide

Demethylated pantoprazole Pantoprazole sulfone

CYP2C19 CYP3A4

Pantoprazole sulfate

Sulfotransferase

Robinson M and Horn J..Drugs 2003; 63(24); 2739-3754.

Rabeprazole

Lansoprazole

Pantoprazole

Based on ability to metabolise CYP2C19substrates, individuals can be classified as extensivemetabolisers (EMs) or poor metabolisers (PMs).

Distribution of EM and PM genotypes andphenotypes shows wide interethnic differences.

PM

- Caucasians and African American 3-5 %

- Asians 12-25 %

CYP3A4 is more important in PMs.

?, no datoa available; ↓, decreases; ↑, increases

None?????

None?

Absorption ↑??????

None?

NoneNoneNone

NoneNoneNoneNoneNoneNoneNoneNoneNoneNoneNoneNoneNoneNoneNoneNoneNoneNoneNoneNone

NoneClearance ↓

Conflicting resultsClearance ↓

?Conflicting results

Clearance ↓None

Absorption ↑None

?NoneNone

Absorption ↑Clearance ↓Clearance ↓Clearance ↓

None?

NoneClearance ↓

Conflictingresults

Clearance ↑None

?Conflicting

results?

None??

None?????

None?

Clearance ↓Clearance ↑

None

??????

Clearance ↓????????

Clearance ↓???

None

AutacidAntipyrineCaffeineCarbamazepineContraceptives(oral)CyclosporineDiazepamDiclofenacDigoxinEthanolGlibenclamideMetoprololNaproxenNifedipinePhenprocoumonPhenytoinPiroxicamTacrolimusTheophyllineWarfarin

RabeprazolePantoprazole

OmeprazoleLansoprazoleEsomeprazoleConcomitantdrug

Metabolic drug interactions: effect of proton pump ingibitors (PPIs) on concomitant drugs

Drug Interactions

Adverse effects & precaution.

PPIs are generally well tolerated

Side effect < 5 %

Diarrhea, headache are common.

Used with caution in severe hepatic disease

Not recommended in breast-feeding mothers

Clinical Application of PPIs

Acid – related disorders

Gastro Esophageal Reflux Disease (GERD)- non-erosive reflux diesease (NERD)

- Erosive esophagitis

- Barrett’s esophagus

Peptic Ulcer disease (PUD)

- gastric ulcer

- duodenal ulcer

NSAID-associated ulcer

Fennerty et al.New Advances in Immediate Release PPI Therapy, Chicago ; May 17, 2005

DU - >3 for 18 h/days 4 weeks

GU - >3 for 18 h/days 8 weeks

GERD - >4 for 18 h/days 4-8 weeks

Pathophysiological and pharmacological targets in thetreatment of gastro-oesophageal reflux disease.

Pathophysiological target Pharmacologica target Therapeutic agents

Secretion

Motility

CCK = cholecystokinin ; LOS = lower oesophageal sphincter.

Gastric acid secretion

Oesophageal clearance of refluxed

contents

LOS dysfunction

decreased LOS tone

enhanced transient LOS relaxations

Proton pump inhibitors,histamine H2-receptor antagonists

Prokinetics: serotonin 5-HT4-receptoragonists

Motilides, CCK1-receptor antagonists

GABA-B-receptor agonists,? -opioid-receptor agonists,muscarinic-receptor antagonists,CCK1-receptor antagonists, nitric oxidesynthase inhibitors, cannabinoidreceptor-1 agonists.

Tonini M Giorgio R.D.and Ponti F.D.Drugs 2004:64(4): 347-361.

Fennerty et al.New Advances in Immediate Release PPI Therapy, Chicago ; May 17, 2005

Fennerty et al.New Advances in Immediate Release PPI Therapy, Chicago ; May 17, 2005

Castell et al. Lansoprazole 30 mg/d15 mg/d

Mulder et al. Lansoprazole 30 mg/d

Mee & Rowley Lansoprazole 30 mg/d

Mossner et al. Pantoprazole 40 mg/d

Corinaldesi et al. Pantoprazole 40 mg/d

Delchier et al. Rabeprazole 20 mg/d

Dekkers et al. Rabeprazole 20 mg/d

++

+

+

+

+

+

+

0.0 1.0 2.0Odds ratio + 95% confidence interval

Different proton pump inhibitors compared withomeprazole 20mg daily (odds ratio =1)

Katz O.P.New Advances in Immediate Release PPI Therapy, Chicago ; May 17, 2005

PPI dosing regimens for FDA-approved indications

Indication Esomeprazole Lansoprazole Omeprazole Pantoprazole Pabeprazole

Healing 20-40 mg 30mg QD 20 mg QD 40 mg QD 20 mg QDerosive QD up to 8 x 4-8 weeks up to 8 x 4-8esophagitis x 4-8 weeks weeks weeks weeks

Maintenance 20 mg QD 15 mg QD 20 mg QD 40 mg QD 20 mg QD

of erosiveesophagitis

Symptomatic 20 mg QD 15 mg QD 20 mg QD

GERD x 4 weeks up to 8 x 4 weeks weeks

Peptic ulcer disease

Helicobacter pylori

NSAIDs-induced ulcers

Acid Hypersecretion

Differences Between NSAID-InducedUlcers and Classic Peptic Ulcer Disease

NSAID-induced Ulcers Classic PepticUlcer Disease

Etiology

Site of Damage

Pathogenesis

Symptomatology

NSAID use altering gastricmucosa

Gastric more often than duodenal

Primarily decreased mucosadefenses (inhibit PG synthesis)

Rather asymptomatic

Mostly Helicobacterpylori

Primarily Duodenal

Imbalance of aggressiveand defensive factors

Usually pain/dyspepsia

Eradication therapy (Triple Therapy)Antisecretary 1 ชนิด รวมกับยาตานจลุชีพ 2

ชนดิ เปนเวลา 7 วันantisecretary คือomeprazole 20 mg bid ac หรือlansoprazole 30 mg bid ac หรือRBC 400 mg bid pc

Antimicrobials คือAmoxycillin 1,000 mg bid pc หรือClarithromycin 500 mg bid pc หรือMetronidazole 400 mg bid pc หรือTetracycline 500 mg qid pc

No major differences in which PPIwas used

Triadafilopoulos C..New Advances in Immediate Release PPI Therapy, Chicago ; May 17, 2005

Mechanism of NSAID-Induced Ulcer

Normal Mucosa Ulcer

Aggressive Defensive

Acid-peptic activity ? Bicarbonate production

? Gastric blood volume

? Mucus secretion

Suppress endogenousprostaglandins

NSAIDs

NSAID Use and Increased Risk forPeptic Ulcer Disease in the Elderly

Total

Drug Standard Dose Patients(n) Relative Risk

(mg) (95% Cl)

Ibuprofen

Indomethacin

Sulindac

Naproxen

Fenoprofen

Piroxicam

Tolmetin

Meclofenamate

1200

50

300

500

900

20

600

200

83

30

37

121

34

109

21

21

2.3(1.8-3.0)

3.8(2.4-6.0)

4.2(2.8-6.3)

4.3(3.4-5.4)

4.3(2.8-6.6)

6.4(4.8-8.4)

8.5(4.5-16.1)

8.7(4.6-16.4)Griffin et al 1991

Ann intern Med 1991; 114:257-263.

Triadafilopoulos, G.New Advances in Immediate Release PPI Therapy, Chicago ; May 17, 2005

Triadafilopoulos, G.New Advances in Immediate Release PPI Therapy, Chicago ; May 17, 2005

Preventive medication in high risk patients

- PPIs

- Misoprostol

Risk factors- Elderly

- history of PUD

- steroid co-medication

- multiple NSAIDs

Clinical application of PPIs

- GERD

- Eradication of HP

- Preventive medication

- Hypersecretion e.g. Zollinger Ellison symdrome

- Stress ulcer prophylaxis

Criteria for improving the current delayed-release PPIs

Reduction in individual variability in pharmacokinetics and pharmacodynamics

More rapid onset of action

Sustained control of intragastric acidity

Improved nocturnal acid control

Dosing independent of meals

Maintained tolerability and safety of current PPIs

New PPIs

Tenatoprazole/Benatoprazole (TU 199)

- Imidazopyridine derivative

- developed by Mitsubishi Chemical /Phase 3 trial

- Prolonged plasma half life (7 h.)

- 2-4 fold more potent than omeprazole in animal modelGalmiche et al

Aliment Pharmacol Ther 19, 655-662.(2004)

New Pharmaceutical Preparation

Uncoated omeprazole powder 20 mg or 40 mg

NaHCO3 1680 mg (20 mEq) (to protect the acid labile omeprazole-no enteric coating necessary)

Reconstituted in 15-30 mL water

Peach-mint flavor

Immediate-release omeprazole (IR-OME)prowder for oral suspension

New Pharmaceutical PreparationImmediate-release omeprazole in a capsuleformulation (Santarus, NDA Filed)

Howden C.W.New Advances in Immediate Release PPI Therapy, Chicago ; May 17, 2005

Howden C.W.New Advances in Immediate Release PPI Therapy, Chicago ; May 17, 2005

New Pharmaceutical PreparationImmediate-release omeprazole in a capsuleformulation (Santarus, NDA Filed)

DR-OME 40 mg IR-OME 40 mgReduction of gastric acid in

30 min post-dose

Cmax (ng/ml)

Tmax (min)

AUC (ng.h/ml)

No change

544

127

11700

-78%

1019

25

1120

Potential advantages of uncoated PPI-antacid combination(IR-OME)

Antacid protects the PPI from acid degradation in stomach

- there is no need for an enteric coating

+ absorption more rapid and predictable

Immediate therapeutic effect due to acid buffering

Rapid rise in pH may stimulate gastrin release

- temporary stimulation of proton pumps

+ improves uptake of PPI by parietal cells independent of food intake

+ more rapid control of acid secretion

Summary

Delayed-release PPIs

- acid-labile

- enteric-coated to protect from acid degradation

- absorption delayed

- optimally taken 30 mins before food

IR-OME

- peak plasma concentrations within 30 minutes

- rapid onset of antisecretory action

- achieves intragastric pH>4 for 18.6 hours

0

2

4

6

8

10

1 0

1

2

3

4

1

0

1

2

3

4

1 0

1

2

3

1

Tim

e pH

>4 (h

)

Med

ian

gast

ric p

H

Med

ian

gast

ric p

H

Med

ian

gast

ric p

H

24 hours

Night-timeDaytime

Rabeprazole 20mg

Lansoprazole 30 mg

Pantoprazole 40mg

Omeprazole MUPS 20mg

Omeprazole 20 mgPlacebo

24-Hour antisecretory activity of different proton pump inhibitors in healthy volunteers.

******# +

*****+

*****+

******# +

*****# +

*****# +

*****# +

+

+

+

+ +

+

+

+

+

+

Robinson M and Horn J..Drugs 2003; 63(24); 2739-3754.

Fennerty et al.New Advances in Immediate Release PPI Therapy, Chicago ; May 17, 2005

Katz P.O.New Advances in Immediate Release PPI Therapy, Chicago ; May 17, 2005

Katz P.O.New Advances in Immediate Release PPI Therapy, Chicago ; May 17, 2005

Additional risk factors

Closed head injury

Mutiple trauma

Major surgery

Burns > 30%

Acute renal failure

Acidosis

Coagulopathy

Thrombocytopenia

Coma

Hypotension / shock

SepsisConrad et al, Crit Care Med 2005; 33: 760

Metz D.C.New Advances in Immediate Release PPI Therapy, Chicago ; May 17, 2005

Metz D.C.New Advances in Immediate Release PPI Therapy, Chicago ; May 17, 2005

Conclusions IV cimetidine is approved for the prevention of bleeding

from stress ulcers

IV PPIs are not approved, although widely used

Compared with IV cimetidine, IR-OME by gastric tube

- is at least as effective

- provides more effective pH control

+ rapid

+ sustained

- has no increase in nosocomial pneumonia

IR-OME is the only PPI that is USFDA-approved for the reduction of risk of UGI bleeding