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1-Chemistry
Omeprazole - C17H19 N3O3S
2-Pharmacology
The actions of Lorsec® are mediated by inhibition of the H+-
K+ ATPase in gastric parietal cells. Lorsec® is a weak base
and a prodrug which is converted at low pH to a reactive
sulfenamide intermediate which binds to SH groups in the
extracellular sequence of the catalytic ??subunit. Covalent
binding to systemic residues inactivates the H+-K+ ATPase,
leading to prolonged inhibition of acid secretion. Lorsec® is
a highly specific drug whose site of action is essentially
limited to the parietal cell. In vivo, Lorsec® is an extremely
effective antisecretory agent which is able to completely
absolish acid secretion. The drug has been demonstrated to
cause prolonged inhibition of basal and stimulated acid output
in a variety of animal models.
3-Toxicology
In long - term toxicity studies, Lorsec® was well tolerated in
rodents dosed at up to 414 mg.kg-1 per day, equivalent to
some 1400 times the human therapeutic dose. Oral
administration of Lorsec® for 2 years in the daily dose range
14-140 mg.kg-1 induced enterochromaffin-like (ECL)cell
hyperplasia in the rat oxyntic mucosa. Chronic administration
of Lorsec® to rats reduces the number of chief cells in the
mucosa and increases the number of immature pepsinogenproducing
cells containing
class III mucin.
4- Clinical pharmacology
Dose- related inhibition of basal and stimulated acid secretion
occurs over the dose range 10-80mg. At a dose of 80mg,
Lorsec® completely inhibited pentagastrin-stimulated acid
output for at least 4h. The duration of action of Lorsec® is
also dose related with significant inhibition of acid output
detectable 72 h after a single 40 mg dose. Secretion returns
to pretreatment levels 3-5days after a single dose. Consistent
inhibition of acid output occurs at doses of 20-30 mg. There
is evidence that the efficacy of Lorsec® is greater when the
drug is administered in the morning compared with evening
dosing.
Peak antisecretory effects are not generally achieved until
after 2 or 3 days treatment. Plasma gastrin levels rise in human
subjects and ulcer patients, returning to pretreatment levels
within 7-14 days of stopping treatment.
5-Pharmacokinetics
There are considerable interindividual differences in the
kinetics of Lorsec®, partly because of the fact that it is a
substrate for CYP2C19 which is subject to an important
polymorphism.
A study using C-omeprazole showed a plasma half-life of
0.7 h in young normal subjects and a plasma clearance of
594 ml. min-1. Such a high clearance suggests appreciable
presystemic metabolism will take place. Antisecretory effect
is proportional to dose but there is no direct correlation
between pharmacodynamic response and plasma concentration.
There is a progressive increase in plasma C max and AUC
on repeated dosing over 5-7 days, which could reflect increased
bioavailability as a result of progressive inhibition of acid
secretion. Food may delay absorption of Lorsec® , but overall
systemic bioavailability is unaffected by ingestion of either
a meal or antacids.
Oral absorption 65%
Presystemic metabolism 20%
Plasma half - life 60 min
mean
range
Volume of distribution 0.4. l.kg-1
Plasma protein binding 95%
Lorsec® is distributed to various organs including stomach,
Omeprazole
LORSEC
N
S
N
CH2
CH3
OCH3
H3C
O
N
OCH3
H
9
R
liver, kidney and gall bladder.
6- Metabolism
About 20% of the administered dose is excreted in the feces
and the remaining 80% is excreted in the urine as metabolites.
Lorsec® is rapidly and completely matabolized. The three
major metabolites identifiable in plasma are hydroxyomeprazole,
a sulfide derivative, and a sulfone.
7- Therapeutic use
Mode of use
Lorsec® is available in 20 mg capsules containing entericcoated
granules. They may be taken in the morning or evening.
The dose may have to be adjusted , particularly for gastroesophageal
reflux disease where more severe cases may
relapse on 20 mg and require 40 or even 60 mg daily for
effective control. Adequate control of gastric acidity is achieved
by 20 mg administered once daily in the majority of patients.
The prolonged action of the drug means that there is a
pharmacological effect in excess of 24h, which is an aid with
compliance. No rebound phenomenon had been reported.
Indications
1- Duodenal ulcer
The proportion of duodenal ulcers healing at 2 weeks on
Lorsec® 20 mg daily is 24 to 86% and at 4 weeks it is 63 to
100%. The recurrence rate after 12 months of treatment with
Lorsec® 20mg daily was 13%.
2-Gastric ulcer
Lorsec® 40 mg daily healed 80% of gastric ulcers at 4 weeks.
Maintenance treatment in gastric ulcer has shown a much
reduced relapse rate of 2% over 1 year with Lorsec® 20 mg
daily compared 19% on 20 mg every other day.
3- Reflux esophagitis and esophageal ulceration
Reflux esophagitis relapses swiftly (84% to 92%) on cessation
of therapy. Long - term treatment is often needed to prevent
relapse, with an appreciable therapeutic gain for Lorsec®, 20
mg being more effective than 10 mg . Even so, 20 to 40% of
patients will relapse on Lorsec® 20mg daily, but these patients
seem to respond to an increase in dose to 40 mg.
4- Zollinger - Ellison - Syndrome
The dose required to control acid secretion varies from 20 to
160 mg daily but usually in the range 60 to 70 mg daily.
5- Resistant ulcers
Ulcers which have not healed with conventional doses of
histamine H2 receptor antagonists over a variably defined
period have then been given Lorsec® , with good healing rates
being achieved: 88% to 100% over 8 weeks.
6- Eradication of Helicobater Pylori in Combination with
antibiotics
Lorsec® suppresses H. Pylori but does not eradicate the
organism without additional antibiotics. A combination of
Lorsec® 40 mg daily with amoxicillin 500 mg three or four
times a day for 2 weeks eradicates H. Pylori in 50 % to 80%
of patients. More recently, Lorsec® has been used in 7-day
triple therapy regimens. Lorsec® 20 or 40 mg daily has been
given with amoxicillin 500 mg and metronidazole 400 mg
(both 3 times daily), clarithromycin 250 mg and metronidazole
400 mg (both twice daily)or amoxicillin 1 g and clarithromycin
500 mg (both twice daily) . Eradication rates of between 85%
and 96 % have obtained in clinical studies in which these
regimens were used.
7- Lesions associated with non- steroidal anti-inflammatory
drugs (NSAIDs)
Lorsec® 40 mg daily was superior to ranitidine and sucralfate,
allowing healing to take place despite the use of an NSAID.
Lorsec® is used for the prophylaxis of NSAID associated
gastic ulcers, gastroduodenal erosions,and dyspeptic symptoms
in patients with a previous history of gastroduodenal lesions
who require continued NSAID treatment.
Contraindications
None is known.
8- Adverse reactions
Potentially life-threatening effects
None has been reported to date. In humans, there is a rise in
the serum gastrin the first 3 months of treatment, which
thereafter remains constant.
Symptomatic adverse effects
Diarrhea (4%) and headache (2% to 3%) are the only adverse
reactions reported consistently with Lorsec®.
Interference with clinical pathology tests
None is known.
9- High risk groups
Neonates
There are no data to support the use of Lorsec® in neonates.
Breast milk. There are no data on the secretion of Lorsec® in
breast milk.
Children
Lorsec® had been found to be effective in congenital hiatus
hernia with reflux esophagitis in children and infants. The
dose range is 0.7 to 1.4 mg.kg-1 daily, to a maximum of 40
mg daily, for 4 to 12 weeks.
Pregnant women
Lorsec® has been shown to cross the placenta in mice and
sheep.
The elderly
No problems have been encountered in clinical use.
Concurrent disease
Bioavailability is increased in liver cirrhosis, but there are no
reports of increased toxicity.
10- Drug interactions
Potentially hazardous interactions
Lorsec® competes with other drugs for the subfamily 2 C of
the cytochrome P450 system. This reduces the rate of
metabolism of diazepam, warfarin, carbamazepine and
phenytoin.
Potentially useful interactions
Lorsec® is used in combination with antibiotics to treat patients
where ulcers are associated with Helicobacter pylori infection.
Storage
Store below 30º C. Protect from light and moisture.
Packaging
Plastic container of 14 Capsules
LORSEC
Omeprazole Cap.
20 mg
R
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