U inkovine za zdravljenje ulkusa

• Antagonisti H2 receptorjev (npr. cimetidin, ranitidin,

famotidin)
• Zaviralci protonske rpalke (omeprazol, esomeprazol,
lansoprazol, pantoprazol,
rabeprazol)
• Antagonisti muskarinskih receptorjev (npr. pirenzepin)
• Prostaglandini (npr. misoprostol)
• Zaviralci gastrina (proglumid)
• Antacidi
• Sukralfat

Mehamizem izlo anja klorovodikove kisline

misoprostol

parietalna
celica

1
 Proglumid

H3C

N O
H3C

HO
NH

O
O

- zaviralec gastrina
- zaviralec holecistokinina

Mehamizem izlo anja klorovodikove kisline

misoprostol

parietalna
celica

2
 Pirenzepin

O
H
N

N N

O
N

N
CH3
Selektivni antagonist muskarinskih M1 receptorjev

Mehamizem izlo anja klorovodikove kisline

misoprostol

parietalna
celica

3
 Misoprostol

O
O
CH3
O
H3C OH
CH3

HO

misoprostol
za profilakso ulkusa pri terapiji z NSAID

Sukralfat

4
Mehamizem izlo anja klorovodikove kisline

misoprostol

parietalna
celica

H+/K+ - ATPaza

proti
gradientu

A general model of cation motive ATPases illustrating the cytoplasmic, membrane and extramembranal sectors. The dominant
region is the cytoplasmic domain, but transport occurs across the membrane domain as illustrated schematically.

5
 H+/K+ - ATPaza

A possible arrangement of the membrane segments

of a P2-type ATPase with the ion (blue sphere)
transport pathway largely enclosed by TM4, 5, 6
and 8.

Inhibitorji protonske rpalke

OMe
H3C CH3
O N OMe
N S
omeprazol
N
OCH2CF3 H
CH3
O N
N S lansoprazol
N
H
OMe
OMe
O N OCF2H
N S pantoprazol
N
H
O(CH2)3OMe
CH3
O N
N S rabeprazol
N
H

6
 Omeprazol kot predzdravilo

uveden v terapijo 1988

Omeprazol kot predzdravilo

7
 Razvoj omeprazola in esomeprazola
patentni
problemi!
toksi nost,
vgradnja v obro

metabolit,
ni patentno atrofija ne zavira
zaš iten š itnice absorpcije joda

višji pKa

Esomeprazole magnesium
Launched 2000

Esomeprazole magnesium (formerly known as perprazole), the (S)-enantiomer of the marketed

proton pump inhibitor omeprazole (Losec), has been developed by AstraZeneca as an improved
second-generation successor to Losec with several advantages over the first-generation
compound. Omeprazole has one significant known drawback: polymorphic metabolism.
Approximately 3% of all Caucasian patients and some 15-20% of Oriental patients metabolize
omeprazole more slowly than the general population. In slow metabolizers, plasma concentrations
of the drug are higher than the average. Since the inhibition of gastric acid secretion is correlated
to the plasma concentration AUC, these slow metabolizers experience a more pronounced effect
from the drug. As such, the search was initiated for an improved version of omeprazole with less
interindividual variation and that would produce higher plasma levels. The result of this search
was the discovery of esomeprazole, which proved throughout an extensive clinical testing
program to possess unique pharmacokinetic properties of esomeprazole that contribute to rapid
symptom resolution and high and predictable healing rates. AstraZeneca recently filed for
marketing approval of esomeprazole sodium (Nexium) in the U.S. and Europe. The drug is
targeted for the treatment of GERD, including reflux esophagitis, and for the healing and
prevention of relapse of Helicobacter pylori-associated duodenal ulcers.

8
9
Sinteza
omeprazola
(I)

Sinteza
omeprazola
(II)

Polonovski-jeva
premestitev

10
Sinteza
omeprazola
(V)

Sinteza
omeprazola
(VI)

11
 Ti(OPr)4, H2O2, (-)-dietil D-tartrat
Penicillium frequetans

Rhodobacter capsulatus

12
 Sinteza lansoprazola

Sinteza pantoprazola

13
Sinteza pantoprazola

14
Sinteza rabeprazola

15