Drugs for Peptic Ulcer

Gastrointestinal DrugsDrugs for Peptic Ulcer

Vinay GuptaLecturer

Department of PharmacologyUP Rural Institute of Medical Sciences &

Research

Saifai, Etawah, India

What is Peptic Ulcer Disease

• Definition of Peptic Ulcer:

–A benign lesion of gastric or duodenal mucosa occurring at a site where the mucosal epithelium is exposed to acid and pepsin.

– It results due to an imbalance b/w the aggressive (acid, pepsin, bile & H. pylori) & the defensive (gastric mucus & bicarbonate secretion, PG etc.)

1) Excess acid production

2) Intrinsic defect in the mucosal defense barrier

A Gastric Peptic Ulcer

Who Gets Peptic Ulcers

• Peptic Ulcer Disease Affects All Age Groups

–Can occur in children, although rare

–Duodenal ulcers tends to occur first at around the age 25 and continue until the age of 75

–Gastric ulcers peak in people between the ages of 55 and 65

• Men Have Twice The Risk as Women Do

• Genetic Factors

–High levels of acid production, weakness in mucosal layer, abnormal nonprotective mucus production

• Increase Acid Production and/or Decrease in Bicarbonate and PG Production

–Caffeine, Cigarettes, Alcohol, Fruit Juices, Stress

What Causes Peptic Ulcer Disease

•NSAIDs

Long term use of nonsteroidal anti-inflammatory drugs. NSAIDs block COX enzymes and decrease prostaglandins (PGs).

•Gastrinoma (Zollinger-Ellison Syndrome)

Tumors of the duodenum or pancreas secretes abnormally high amounts of gastrin which stimulates gastric acid.

•Stress ulcers

Result of physical trauma (i.e., burn patients).

Pathophysiological Processes Involved in Duodenal and Gastric Ulcers

HP

NSAID

Cancer (ZE)

Other

Duodenal Ulcer Gastric Ulcer

Regulation of gastric acid secretion-

• In gastric ulcer generally acid secretion is normal or low and in duodenal ulcer acid secretion is usually high.

• Proton Pump (H+K+ATPase) secretes H+ ions which can be activated by-

1. Histamine Paracrine

2. Ach Neural

3. Gastrin Hormonal

• They act via their own receptors located on the basolateral membrane.

• Out of the three, histamine acts through H2

receptors & plays dominant role while gastrin & Ach acts partly by releasing histamines.

H+, K+-ATPase (the proton pump) is the final transport pathway for parietal cell

hydrogen ion secretion

• H+, K+-ATPase is located in the apical membrane of the oxyntic cell along the secretory canaliculi;

• The pump requires large amounts of energy that is supplied by intracellular ATP;

• Inhibition of H+, K+-ATPase blocks both basal and stimulated acid secretion.

Each Secretagogue Binds to its Own Receptor and Interacts with the Others

Gastrin

Histamine

Acetylcholine

H+

CCK2

H2

M3

cAMP dep. pathwayPP

Gastric

Lumen

Strategies for Protecting the Gastric Mucosa from Acid Exposure

Inhibit

secretion

Prevent

contact

Neutralize

acid

Mechanisms Example

Cimetidine

Omeprazole

Prostaglandins

Muscarinic antagonists

Sucralfate

Antacids

H+

H+

H+

What is GERD?

•Gastroesophageal Reflux Disease (GERD):

GERD is when acid and pepsin from the stomach flows backward up into the esophagus often called heartburn;

What Causes GERD?

1) Overproduction of acid/pepsin

2) Over relaxation of the Lower Esophageal Sphincter (LES);

Complications;

if not treated - severe chest pains, bleeding or a pre-malignant change in the lining of the esophagus called Barrett’s esophagus – can result in adenocarcinoma.

Treatment of Peptic Ulcer

1) Reduction of gastric acid secretion

A) H2 antihistamines- (R2FC) Ranitidine, Roxatidine, Famotidine, Cimetidine.

B) Proton Pump Inhibitors (PPI)- (PRO-LE) Pantoprazole, Rabeprazole, Omeprazole, Lansoprazole, Esomeprazole.

C) Anticholinergics -(PPO) Pirenzepine, Propantheline, Oxyphenonium.

D) Prostaglandin Analogue- Misoprostol

Treatment of Peptic Ulcer Cont…

2) Neutralization of Gastric acid (Antacids)-

a) Systemic- Sod. bi carbonate, Sod. Citrate.

b) Nonsystemic- Mag Hydroxide, Mag tricilicate, Al hydroxide gel, Calcium carbonate, Magaldrate.

3) Ulcer Protectives- Sucralfate, Collidal bismuth subcitrate.

4) Anti Helicobacter pylori Drugs- Amoxicillin, Clarithromycin, Metronidazole, Tinidazole, Tetracycline.

Histamine Receptors

•H1 receptors

– Smooth muscle

– Nerves

•H2 receptors

– Parietal cells

Histamine H2 Antagonists Decrease Acid Output

Histamine

ProteinKinase

ATP

cAMP

K+

H+

Histamine

Antagonist

PP

1. Reduction of gastric acid secretion

Histamine H2 Antagonists

4 drugs are available- Ranitidine, Roxatidine, Famotidine& Cimetidine. & have competitive interaction with H2

receptors.

Cimetidine was the 1st H2blocker to be introduced & Prototype..

All H2 antagonist block histamine induced gastric secretion.

The ulcer healing dose produces 60-70% inhibition of 24 hr acid output.

Cimetidine is absorbed orally (bioavailability is 60-80% d/t 1st pass hepatic metabolism).

Mild adverse effects in 5% is common- headache, dizziness, bowel upset, CNS effects- restlessness, convulsions

Drugs for Acid-Peptic Disorders - Cimetidine

Additional Side effects:

• In some patients, cimetidine acts as a nonsteroidalantiandrogen (i.e., interferes with estrogen metabolism).

decrease in male sexual function

gynecomastia (swelling of the breasts and soreness of the nipples in males)

• Can produce confusion and disorientation in elderly patients;

• Diarrhea, rash and miscellaneous other effects in a small number of patients.

Interactions-Antacids reduces absorption of all H2 blockers. A gap of

2 hr is recommended for concurrent use with antacids.

Cimetidine dose – 400mg BD or 800mg HS. Orally

for stress ulcer – 50mg/hr IV

Ranitidine

5 times more potent than cimetidine with a lower incidence of side effects.

Dose – 150 mg BD or 300mg HS

or 50mg IM / slow IV in 6-8 hr.

Roxatidine-

Pk, Pd & side effect profile is similar to Ranitidine bt its twice as potent & longer acting.

Dose – 75 mg BD or 150 mg HS

Famotidine-

It is 5-8 times more potent than ranitidine

Dose- 20 mg BD or 40 mg HS or 20mg I.V. / 12 hr.

Proton Pump Inhibitors (PRO-LE)

Omeprazole-

Inhibits final common step in gastric acid secretion & have overtaken H2 blockers for acid –peptic disorders.

Bioavailability of all PPIs is reduced by food, hence they should be taken as empty stomach.

Uses- Duodenal Ulcers, Gastric Ulcers, Stress Ulcers, GERD (gastroesophageal reflux disesse)

Dose- 40mg/Day

Interaction-

Omeprazole inhibits oxidation of certain drugs like Diagepam, Phenytoin and warfarin levels may be increased.

Clarithromycin inhibits omeprazole metabolism & increases its plasma concentration.

Esomeprazole-

It is S-enantiomer of omeprazole, have higher bioavailability & to produce better control of intragastricpH than omeprazole in GERD.

Dose- 20-40 mg OD

Lansoprazole

More potent than omeprazole.

Higher bioavailability. Dose should be reduced in liver diseases.

Side effects are similar bt drug interactions are less significant.

Dose- 15-30 mg OD.

Pantoprazole

It is more acid stable & has higher bioavilability.

It is also available for I.V. Administration.

Dose- 20mg OD.

Strategies for Inhibiting Parietal Cell Acid Secretion

Gastrin

Histamine

Acetylcholine Ca2+

ProteinKinase

ATP

cAMP

Prostaglandin

Agonists (-)

K+

H+

PP

H2

M3

CC

K2

EP

3

Ca2+

Drugs for Acid-Peptic Disorders -Prostaglandins

Misoprostol (Cytotec):

• Synthetic Analog of Prostaglandin E1

• Anti-acid secretory

• 0.1 to 0.2 mg results in 85% to 95% acid reduction

• Prevention of NSAID gastric ulcers

Side Effects

• Diarrhea

• Abortion

• Exacerbate IBD and should not be given

Neutralization of gastric acidDrugs for Acid-Peptic Disorders - Antacids• Antacids are weak bases that neutralize HCl in the

stomach;

• They do not decrease the secretion of acid, and in some cases increase secretion;

• They do not suppress nocturnal acid secretion

1. Neutralize acid

2. Decrease acid load to duodenum

3. Diminish pepsin activity

Drugs for Acid-Peptic Disorders -Antacids

• Magnesium hydroxide

• Magnesium trisilicate

• Magnesium-aluminum mixtures

• Calcium carbonate

• Sodium bicarbonate

Characteristics of Common Antacids

Feature Sodium

Bicarbonate

Calcium Magnesium

Hydroxide

Aluminum

Onset of

action rapid intermediate rapid slow

Duration of

action short moderate moderate moderate

Systemic

alkalosis yes ? no no

Effect on

stool --- constipating laxative constipating

Ulcer ProtectivesDrugs for Acid-Peptic Disorders – Sucralfate

• Sucralfate is a basic aluminum salt of sucrose octasulfate;

• In the presence of acid (pH < 3-4) some of the aluminum ions dissociate and the resulting negatively charged molecule polymerizes to form a viscous paste-like substance;

• This substance adheres strongly to gastric and duodenum mucosa and adheres even more strongly to partially denatured proteins such as those found at the base of the ulcer.

Drugs for Acid-Peptic Disorders - Sucralfate (Carafate)

•This compound does not decrease the concentration or total amount of acid in the stomach;

•Sucralfate protects the gastric and duodenal mucosa from acid/pepsin attack.

Side effects:

• The compound is not really absorbed and, therefore, side-effects are minimal:

– constipation

– diarrhea

– nausea

Anti H. pylori drugs

• Helicobacter Pylori (H. pylori)

–Most ulcers are the result of infection with H. pylori

–Not all of those infected with H. pylori develop ulcers

– H. pylori MAY result in a weakening of the mucosal defense systems, allowing for development of ulcer subsequent to acid/pepsin aggression; by producing ammonia which maintains a neutral micro environment around the bacteria & promotes back diffusion of H+ions.

Helicobacter pylori

Spiral shaped, flagellated, Gram negative bacterium

Helicobacter pylori on gastric mucus-secreting epithelial cells

Role of H. pylori in Peptic Ulcer Disease

•The host reaction to H. pylori determines the outcome of the infection:

– Gastritis

– GERD

– Gastric & Duodenal Ulcers

– Gastric Cancer (?)

Role of H. pylori in Peptic Ulcer Disease

•Treatment

–If H. pylori detected, eradication of the bacteria, along with inhibition of acid.

–Eradication of H. pylori is a cure as reinfection rates in Western countries is less than 1%.

Role of H. pylori in Peptic Ulcer Disease

•Combination therapy with Omeprazole and Amoxycillin

H. pylori Eradication Rates with Either Dual, Triple or Quad Therapy (1999)

Treatment Pooled Eradication

Rate

Dual Therapy 72%

Triple Therapy 85%

Quad Therapy 90%

H. pylori Eradication Rates with Either Dual, Triple or Quad Therapy (1999)

GENERIC NAME DOSING DURATION CURE RATE (%)

Dual therapies

omeprazole 500 mg TID 14 days 70-80

amoxycillin 1,000 mg TID 14 days

ranitidine 400 mg BID 28 days 73-84

clarithromycin 500 mg TID 14 days

lansoprazole 30 mg TID 14 days 66-77

amoxycillin 1,000 mg TID 14 days

H. pylori Eradication Rates with Either Dual, Triple or Quad Therapy (1999) Cont.

GENERIC NAME DOSING DURATION CURE RATE (%)

Triple therapies

lansoprazole 30 mg BID 14 days 86-92

amoxycillin 1,000 mg BID 14 day

clarithromycin 500 mg BID 14 days

H. pylori Eradication Rates with Either Dual, Triple or Quad Therapy (1999) Cont.

GENERIC NAME DOSING DURATION CURE RATE (%)

Quad therapies

bismuth subsalicylate Two tablets 7 days 85-95

525 mg QID

metronidazole 250 mg QID 7 days

tetracycline 500 mg QID 7 daysomeprazole 20 mg BID 7 days

or

lansoprazole 30 mg BID 7 days

New Strains of H. pylori

• Recently a more virulent genetic strain of H. Pylori known as cytotoxin-associated gene A (cagA) has been found in some people with peptic ulcers

Functional Disorders of the GI

• Primary

– infection, inflammation, congenital defects (disorders of the neuronal/muscular activity);

• Secondary

–metabolic disorders (hypo- or hyper-parathyroidism, hypercalcemia), neurologic (diabetes mellitus -damage to vagal and sympathetic extrinsic nerves, intrinsic nerves; MS, heavy metal toxicity, carcinoma);

• Examples of colonic dysfunction:

– IBS; chronic constipation; Hirschsprung’s disease (agangliosis of myenteric plexus); sphincter dysfunction, etc.