Drugs used in Peptic ulcer pdf - د. نجلاء

Drugs used in Peptic ulcer

Regulation of gastric acid secretion



Gastric acid secretion is under the control of

Gastric acid secretion is under the control of 33

principal agonists: histamine, acetylcholine and

gastrine

gastrine.. The final common pathway is through

The final common pathway is through

the proton pump, H

/ K

ATPase

ATPase..



Inhibitiors

Inhibitiors of the activities of the first

of the activities of the first 22

secretagogues

secretagogues and of the proton pump have

and of the proton pump have

been developed

Regulation of gastric acid secretion



Gastric acid secretion is under the control of

Gastric acid secretion is under the control of 33

principal agonists: histamine, acetylcholine and

gastrine

gastrine.. The final common pathway is through

The final common pathway is through

the proton pump, H

/ K

ATPase

ATPase..



Inhibitiors

Inhibitiors of the activities of the first

of the activities of the first 22

secretagogues

secretagogues and of the proton pump have

and of the proton pump have

been developed

Effects of acetylcholine, histamine, prostaglandin E

Effects of acetylcholine, histamine, prostaglandin E22,,

and gastrin on gastric acid secretion by the parietal cells

of stomach.

of stomach. Gs

Gs and

and Gi

Gi are membrane proteins that

are membrane proteins that

mediate the stimulatory or inhibitory effect of receptor

coupling to adenylyl

coupling to adenylyl cyclase

cyclase

Histamine

HH--22 Blocker

Blocker

ATP

cAMP

Vagus

Nerve

From Circulation

Ca++

Energy

H+/K+

ATPase

Pump

H+

K+

Pathogenesis of peptic ulcer disease



Nonsteroidal

Nonsteroidal anti

anti--inflammatory drug

inflammatory drug

(NSAID) use.



Infection with gram

Infection with gram--negative Helicobacter

negative Helicobacter

pylori



Increased hydrochloric acid secretion



Inadequate mucosal defense against

gastric acid.

Pathogenesis of peptic ulcer disease



Nonsteroidal

Nonsteroidal anti

anti--inflammatory drug

inflammatory drug

(NSAID) use.



Infection with gram

Infection with gram--negative Helicobacter

negative Helicobacter

pylori



Increased hydrochloric acid secretion



Inadequate mucosal defense against

gastric acid.

Treatment approaches

1. Eradicating the H. pylori infection

Eradicating the H. pylori infection

2. Reducing secretion of gastric acid with the use

Reducing secretion of gastric acid with the use

of H

--receptor antagonists or PPIs, and/or

receptor antagonists or PPIs, and/or

3. protect the gastric mucosa from damage, such

protect the gastric mucosa from damage, such

as misoprostol

misoprostol and

and sucralfate

sucralfate..

4. Neutralizing gastric acid with

Neutralizing gastric acid with nonabsorbable

nonabsorbable

antacids

5. Surgical treatment in( acute complications )

Surgical treatment in( acute complications )

Treatment approaches

1. Eradicating the H. pylori infection

Eradicating the H. pylori infection

2. Reducing secretion of gastric acid with the use

Reducing secretion of gastric acid with the use

of H

--receptor antagonists or PPIs, and/or

receptor antagonists or PPIs, and/or

3. protect the gastric mucosa from damage, such

protect the gastric mucosa from damage, such

as misoprostol

misoprostol and

and sucralfate

sucralfate..

4. Neutralizing gastric acid with

Neutralizing gastric acid with nonabsorbable

nonabsorbable

antacids

5. Surgical treatment in( acute complications )

Surgical treatment in( acute complications )

Antimicrobial agents



Combinations of antimicrobial

Combinations of antimicrobial drugs.Give

drugs.Give 90

90 % or

% or

greater eradication rate.



Triple therapy

Triple therapy consisting of a PPI with either

consisting of a PPI with either

metronidazole or amoxicillin plus

metronidazole or amoxicillin plus clarithromycin

clarithromycin



Quadruple therapy

Quadruple therapy of bismuth subsalicylate and

of bismuth subsalicylate and

metronidazole plus tetracycline plus a PPI



Are administered for a

Are administered for a 22--week course.

week course.

Note:

Bismuth salts inhibit pepsin and increase the

secretion of mucus& form a barrier against the

diffusion of acid in the ulcer.

Antimicrobial agents



Combinations of antimicrobial

Combinations of antimicrobial drugs.Give

drugs.Give 90

90 % or

% or

greater eradication rate.



Triple therapy

Triple therapy consisting of a PPI with either

consisting of a PPI with either

metronidazole or amoxicillin plus

metronidazole or amoxicillin plus clarithromycin

clarithromycin



Quadruple therapy

Quadruple therapy of bismuth subsalicylate and

of bismuth subsalicylate and

metronidazole plus tetracycline plus a PPI



Are administered for a

Are administered for a 22--week course.

week course.

Note:

Bismuth salts inhibit pepsin and increase the

secretion of mucus& form a barrier against the

diffusion of acid in the ulcer.

Important

Important HH22--Antagonists

Antagonists

Cimetidine

Ranitidine

Famotidine

Nizatidine

Roxitidine



HH22 Antagonists bind to H

Antagonists bind to H22 receptor, preventing

receptor, preventing

histamine from binding to these receptors.



Block

Block the action of histamine on stomach cell

the action of histamine on stomach cell

thus reducing stomach acid

Important

Important HH22--Antagonists

Antagonists

Cimetidine

Ranitidine

Famotidine

Nizatidine

Roxitidine



HH22 Antagonists bind to H

Antagonists bind to H22 receptor, preventing

receptor, preventing

histamine from binding to these receptors.



Block

Block the action of histamine on stomach cell

the action of histamine on stomach cell

thus reducing stomach acid

Indication of use of H

Indication of use of H22--Antagonists :

Antagonists :

1. Peptic

Peptic ulcer

ulcer..

2. Gastro esophageal reflux disease(GERD)

Gastro esophageal reflux disease(GERD)

3. Erosive

Erosive esophagitis.

esophagitis.

4. Zollinger

Zollinger--Ellison

Ellison syndrome.

syndrome.

5. Before

Before anesthesia

anesthesia



Cimetidine

Cimetidine: cause

: cause gynecomastia

gynecomastia,, galactorrhea

galactorrhea,,

and reduced sperm count& inhibits metabolism

of warfarin

warfarin,, phenytoin

phenytoin..



Ranitidine:

Ranitidine: Compared to

Compared to cimetidine

cimetidine, ranitidine is

, ranitidine is

longer acting, and is

longer acting, and is 55--10

10 fold more potent.

fold more potent.



Famotidine

Famotidine isis 33--20

20 times more potent than

times more potent than

ranitidine.



Are metabolized by liver but

Are metabolized by liver but nizatidine

nizatidine isis

eliminated principally by kidney



Cimetidine

Cimetidine: cause

: cause gynecomastia

gynecomastia,, galactorrhea

galactorrhea,,

and reduced sperm count& inhibits metabolism

of warfarin

warfarin,, phenytoin

phenytoin..



Ranitidine:

Ranitidine: Compared to

Compared to cimetidine

cimetidine, ranitidine is

, ranitidine is

longer acting, and is

longer acting, and is 55--10

10 fold more potent.

fold more potent.



Famotidine

Famotidine isis 33--20

20 times more potent than

times more potent than

ranitidine.



Are metabolized by liver but

Are metabolized by liver but nizatidine

nizatidine isis

eliminated principally by kidney

Pharmacokinetic of H

Pharmacokinetic of H22--Antagonists :

Antagonists :



Well absorbed from the gut.



Undergo varying degrees of hepatic inactivation

before being excreted in the urine.



Half

Half--life is

life is 22--33 hours.

hours.



Duration of action is longer.



Administered once or twice daily

Pharmacokinetic of H

Pharmacokinetic of H22--Antagonists :

Antagonists :



Well absorbed from the gut.



Undergo varying degrees of hepatic inactivation

before being excreted in the urine.



Half

Half--life is

life is 22--33 hours.

hours.



Duration of action is longer.



Administered once or twice daily

Adverse effects

1. Central nervous system.

Central nervous system.

2. Cardiovascular

Cardiovascular reaction.

reaction.

3. Hepatic

Hepatic reaction.

reaction.

4. Hematological

Hematological reaction.

reaction.

5. Endocrine.

Endocrine.

6. Risk to the fetus

Risk to the fetus

Adverse effects

1. Central nervous system.

Central nervous system.

2. Cardiovascular

Cardiovascular reaction.

reaction.

3. Hepatic

Hepatic reaction.

reaction.

4. Hematological

Hematological reaction.

reaction.

5. Endocrine.

Endocrine.

6. Risk to the fetus

Risk to the fetus

Cimetidine inhibits CYP

Cimetidine inhibits CYP450

450,,

slow metabolism &,

potentiate the action of

warfarin, diazepam,

phenytoin

Drug interactions with cimetidine

Inhibitors of the H+/K+

Inhibitors of the H+/K+--ATPase

ATPase proton

proton

pump (PPIs

))

Omeprazole

Lansoprazole

Rabeprazole

Pantoprazole

Esomeprazole



The proton pump inhibitors produce quicker

healing and provide greater symptomatic

relief than H

-- antagonists in patients with

antagonists in patients with

peptic ulcer disease and GERD

Inhibitors of the H+/K+

Inhibitors of the H+/K+--ATPase

ATPase proton

proton

pump (PPIs

))

Omeprazole

Lansoprazole

Rabeprazole

Pantoprazole

Esomeprazole



The proton pump inhibitors produce quicker

healing and provide greater symptomatic

relief than H

-- antagonists in patients with

antagonists in patients with

peptic ulcer disease and GERD



Omeprazole

Omeprazole is the first drug of this class ,it

is the first drug of this class ,it

bind to the H

--ATPase

ATPase enzyme system

enzyme system

(proton pump) of the parietal cell, thereby

suppressing secretion of hydrogen ions into the

gastric lumen.



The proton pump is the final step in the

secretion of gastric acid



Omeprazole

Omeprazole is the first drug of this class ,it

is the first drug of this class ,it

bind to the H

--ATPase

ATPase enzyme system

enzyme system

(proton pump) of the parietal cell, thereby

suppressing secretion of hydrogen ions into the

gastric lumen.



The proton pump is the final step in the

secretion of gastric acid

Actions of PPIs



These agents are

These agents are prodrugs

prodrugs with an acid

with an acid--

resistant enteric coating to protect them

from premature degradation by gastric

acid.



The coating is removed in the alkaline

duodenum, and the

duodenum, and the prodrug

prodrug, a weak

, a weak

base, is absorbed and transported to the

parietal cell

parietal cell canaliculus

canaliculus

Actions of PPIs



These agents are

These agents are prodrugs

prodrugs with an acid

with an acid--

resistant enteric coating to protect them

from premature degradation by gastric

acid.



The coating is removed in the alkaline

duodenum, and the

duodenum, and the prodrug

prodrug, a weak

, a weak

base, is absorbed and transported to the

parietal cell

parietal cell canaliculus

canaliculus

Omeprazole



Omeprazole

Omeprazole in itself is not the active

in itself is not the active

inhibitor of the H

/ K

-- ATPase

ATPase. It needs

. It needs

transformation in acid media to an

intermediate compound, a

intermediate compound, a sulphenamide

sulphenamide,,

that effectively inhibits the H

/ K

-- ATPase

ATPase



The

The sulphenamide

sulphenamide interacts covalently with

interacts covalently with

the

the sulphydryl

sulphydryl groups of

groups of cysteine

cysteine residues in

residues in

the extracellular domain of the H

/ K

ATPase

ATPase, thereby inhibiting its activity

, thereby inhibiting its activity

Omeprazole



Omeprazole

Omeprazole in itself is not the active

in itself is not the active

inhibitor of the H

/ K

-- ATPase

ATPase. It needs

. It needs

transformation in acid media to an

intermediate compound, a

intermediate compound, a sulphenamide

sulphenamide,,

that effectively inhibits the H

/ K

-- ATPase

ATPase



The

The sulphenamide

sulphenamide interacts covalently with

interacts covalently with

the

the sulphydryl

sulphydryl groups of

groups of cysteine

cysteine residues in

residues in

the extracellular domain of the H

/ K

ATPase

ATPase, thereby inhibiting its activity

, thereby inhibiting its activity

Indications of PPIs

1. Peptic ulcer (Duodenal and Gastric ulcers

Peptic ulcer (Duodenal and Gastric ulcers

2. Eradication of Helicobacter pylori in the gut

Eradication of Helicobacter pylori in the gut

that causes ulcers in combination with

antibiotics

3. NSAID

NSAID -- induced gastric ulcers

induced gastric ulcers

4. Gastroesophageal

Gastroesophageal reflux disease ulcers

reflux disease ulcers

5. Zollinger

Zollinger -- Ellison syndrome: proton pump

Ellison syndrome: proton pump

inhibitors are the treatment of choice for

zollinger

zollinger -- Ellison syndrome

Ellison syndrome

Indications of PPIs

1. Peptic ulcer (Duodenal and Gastric ulcers

Peptic ulcer (Duodenal and Gastric ulcers

2. Eradication of Helicobacter pylori in the gut

Eradication of Helicobacter pylori in the gut

that causes ulcers in combination with

antibiotics

3. NSAID

NSAID -- induced gastric ulcers

induced gastric ulcers

4. Gastroesophageal

Gastroesophageal reflux disease ulcers

reflux disease ulcers

5. Zollinger

Zollinger -- Ellison syndrome: proton pump

Ellison syndrome: proton pump

inhibitors are the treatment of choice for

zollinger

zollinger -- Ellison syndrome

Ellison syndrome

Pharmacokinetics of PPIs



All these agents are delayed

All these agents are delayed--release

release

formulations and are effective orally.



Some are also available for intravenous

injection.



Metabolites of these agents are excreted

in urine and feces.

Pharmacokinetics of PPIs



All these agents are delayed

All these agents are delayed--release

release

formulations and are effective orally.



Some are also available for intravenous

injection.



Metabolites of these agents are excreted

in urine and feces.

Adverse effects of PPIs

1. GIT: flatulence, diarrhea (by Clostridium

GIT: flatulence, diarrhea (by Clostridium

difficile

difficile colitis )or constipation, nausea,

colitis )or constipation, nausea,

vomiting or abdominal pain.

2. CNS:

CNS: paraesthesia

paraesthesia, dizziness, somnolence

, dizziness, somnolence

and headache.

3. Skin: rashes, itching

Skin: rashes, itching

4. Muscle: pain (

Muscle: pain (myalgia

myalgia).).

5. Kidney: Interstitial nephritis

Kidney: Interstitial nephritis

Adverse effects of PPIs

1. GIT: flatulence, diarrhea (by Clostridium

GIT: flatulence, diarrhea (by Clostridium

difficile

difficile colitis )or constipation, nausea,

colitis )or constipation, nausea,

vomiting or abdominal pain.

2. CNS:

CNS: paraesthesia

paraesthesia, dizziness, somnolence

, dizziness, somnolence

and headache.

3. Skin: rashes, itching

Skin: rashes, itching

4. Muscle: pain (

Muscle: pain (myalgia

myalgia).).

5. Kidney: Interstitial nephritis

Kidney: Interstitial nephritis

Prostaglandins

Misoprostol



Prostaglandin E

, produced by the gastric mucosa, inhibits

secretion of

secretion of HCl

HCl and stimulates secretion of mucus and

and stimulates secretion of mucus and

bicarbonate (

bicarbonate (cytoprotective

cytoprotective effect).

effect).



Misoprostol

Misoprostol an analog of prostaglandin E

an analog of prostaglandin E

, as well as

some PPIs, are used for prevention of gastric ulcers

induced by NSAIDs (in the elderly )& also used in patients

with ulcer complications



It is less effective than H

antagonists and the PPIs

Side effects of

Side effects of Misoprostol

Misoprostol

1. Produces uterine contractions

Produces uterine contractions

2. Diarrhea and nausea

Diarrhea and nausea

Prostaglandins

Misoprostol



Prostaglandin E

, produced by the gastric mucosa, inhibits

secretion of

secretion of HCl

HCl and stimulates secretion of mucus and

and stimulates secretion of mucus and

bicarbonate (

bicarbonate (cytoprotective

cytoprotective effect).

effect).



Misoprostol

Misoprostol an analog of prostaglandin E

an analog of prostaglandin E

, as well as

some PPIs, are used for prevention of gastric ulcers

induced by NSAIDs (in the elderly )& also used in patients

with ulcer complications



It is less effective than H

antagonists and the PPIs

Side effects of

Side effects of Misoprostol

Misoprostol

1. Produces uterine contractions

Produces uterine contractions

2. Diarrhea and nausea

Diarrhea and nausea

Antimuscarinic

Antimuscarinic agents (

agents (anticholinergic

anticholinergic agents)

agents)



Muscarinic

Muscarinic receptor stimulation increases

receptor stimulation increases

gastrointestinal motility and

gastrointestinal motility and secretory

secretory activity.

activity.



A cholinergic antagonist, such as

A cholinergic antagonist, such as dicyclomine

dicyclomine can

can

be used as an adjunct in the management of

peptic ulcer disease and

peptic ulcer disease and Zollinger

Zollinger--Ellison

Ellison

syndrome, particularly in patients who are

refractory to standard therapies.



Its many side effects (for example, cardiac

arrhythmias, dry mouth, constipation, and urinary

retention) limit its use.

Antimuscarinic

Antimuscarinic agents (

agents (anticholinergic

anticholinergic agents)

agents)



Muscarinic

Muscarinic receptor stimulation increases

receptor stimulation increases

gastrointestinal motility and

gastrointestinal motility and secretory

secretory activity.

activity.



A cholinergic antagonist, such as

A cholinergic antagonist, such as dicyclomine

dicyclomine can

can

be used as an adjunct in the management of

peptic ulcer disease and

peptic ulcer disease and Zollinger

Zollinger--Ellison

Ellison

syndrome, particularly in patients who are

refractory to standard therapies.



Its many side effects (for example, cardiac

arrhythmias, dry mouth, constipation, and urinary

retention) limit its use.

Antacids

Aluminum hydroxide

Magnesium hydroxide

Calcium carbonate

Sodium bicarbonate.



Are weak bases that react with gastric acid to

form water and a salt, thereby diminishing

gastric acidity. Because pepsin is inactive at a pH

greater than

greater than 44, antacids also reduce pepsin

, antacids also reduce pepsin

activity.



Used for symptomatic relief of peptic ulcer

disease and GERD; they may promote healing of

duodenal ulcers

Antacids

Aluminum hydroxide

Magnesium hydroxide

Calcium carbonate

Sodium bicarbonate.



Are weak bases that react with gastric acid to

form water and a salt, thereby diminishing

gastric acidity. Because pepsin is inactive at a pH

greater than

greater than 44, antacids also reduce pepsin

, antacids also reduce pepsin

activity.



Used for symptomatic relief of peptic ulcer

disease and GERD; they may promote healing of

duodenal ulcers

Adverse effects

1. Constipating (aluminum hydroxide)

Constipating (aluminum hydroxide)

2. Diarrhea (magnesium hydroxide)

Diarrhea (magnesium hydroxide)

3. Preparations that combine these agents aid

Preparations that combine these agents aid

in normalizing bowel function.

4. Important consideration in patients with

Important consideration in patients with

hypertension or congestive heart failure

(sodium content of antacids)

Adverse effects

1. Constipating (aluminum hydroxide)

Constipating (aluminum hydroxide)

2. Diarrhea (magnesium hydroxide)

Diarrhea (magnesium hydroxide)

3. Preparations that combine these agents aid

Preparations that combine these agents aid

in normalizing bowel function.

4. Important consideration in patients with

Important consideration in patients with

hypertension or congestive heart failure

(sodium content of antacids)

Mucosal protective agents (

Mucosal protective agents (cytoprotective

cytoprotective

compounds)

Sucralfate



It is complex of aluminum hydroxide and sulfated

sucrose



It Binds to positively charged groups in proteins of

both normal and necrotic mucosa



Forming complex gels with epithelial cells, &creates

a physical barrier that impairs diffusion of

a physical barrier that impairs diffusion of HCl

HCl and

and

prevents degradation of mucus by pepsin and acid.



It also stimulates prostaglandin release as well as

mucus and bicarbonate output, and it inhibits

peptic digestion



It is effectively heals duodenal ulcers

Mucosal protective agents (

Mucosal protective agents (cytoprotective

cytoprotective

compounds)

Sucralfate



It is complex of aluminum hydroxide and sulfated

sucrose



It Binds to positively charged groups in proteins of

both normal and necrotic mucosa



Forming complex gels with epithelial cells, &creates

a physical barrier that impairs diffusion of

a physical barrier that impairs diffusion of HCl

HCl and

and

prevents degradation of mucus by pepsin and acid.



It also stimulates prostaglandin release as well as

mucus and bicarbonate output, and it inhibits

peptic digestion



It is effectively heals duodenal ulcers

Bismuth subsalicylate



This compound effectively heal peptic ulcers.



Have antimicrobial actions



Inhibit the activity of pepsin



Increase secretion of mucus, and interact with

glycoproteins in necrotic mucosal tissue to

coat and protect the ulcer crater.

Bismuth subsalicylate



This compound effectively heal peptic ulcers.



Have antimicrobial actions



Inhibit the activity of pepsin



Increase secretion of mucus, and interact with

glycoproteins in necrotic mucosal tissue to

coat and protect the ulcer crater.