acid peptic disease (vk)

Drugs used for acid peptic Drugs used for acid peptic diseasedisease

Drugs used for acid peptic Drugs used for acid peptic diseasedisease

Introduction Introduction

Acid peptic disorders include a number of Acid peptic disorders include a number of conditions whose pathophysiology is believed to conditions whose pathophysiology is believed to be the result of damage from acid and peptic be the result of damage from acid and peptic activity in gastric secretions. activity in gastric secretions.

It include gastroesophageal reflux, peptic ulcer It include gastroesophageal reflux, peptic ulcer (gastric and duodenal), and stress-related (gastric and duodenal), and stress-related mucosal injury. mucosal injury.

In all these conditions, mucosal erosions or In all these conditions, mucosal erosions or ulceration arise when the caustic effects of ulceration arise when the caustic effects of aggressive factors overwhelm the defensive aggressive factors overwhelm the defensive factors of the gastrointestinal mucosafactors of the gastrointestinal mucosa

Pathogenesis

Aggressive Factors

Acid, pepsin

Bile salts

Drugs (NSAIDs)

H. pylori

Defensive Factors

Mucus, bicarbonate layer

Blood flow, cell renewal

Prostaglandins

Phospholipid

Therapy is directed at enhancing host defense or eliminating aggressive factors; i.e., H. pylori.

Imbalance of FactorsImbalance of Factors

Aggressive Factors

Defensive Factors

Gastric Acid SecretionGastric Acid Secretion Acid secretion can be viewed as under basal and

stimulated conditions

Basal acid production occurs in a circardian pattern with highest levels occurring during night

Cholinergic and histaminergic inputs are main contributors to basal acid secretion

Gastrin (after the meals) is the main stimulant for increased acid secretion

Gastric Acid Secretion (Basal)Gastric Acid Secretion (Basal) Proton pumps are located

within canaliculus and in cytoplasmic tubulovesicles

The distribution of proton pumps between canaliculus and vesicles varies according to cell activity

Under resting conditions only 5% pumps are within canaliculus

Canaliculus

Resting

H+, K+-ATPase

Tubulovesicles

Gastric Acid Secretion Gastric Acid Secretion (Stimulated)(Stimulated)

On stimulation of parietal cell (after a meal) 60-70% pumps are transferred to canaliculus membrane.

Once cell activation stops, pumps are recycled back to cytoplasmic vesicles

The tubulovesicular pumps are inactive

HCl

KCl

Ca cAMP

Gastrin

ACh HistamineActive Pumps

Canaliculus

H+, K+-ATPase

H3O+

Stimulated

KCl

Regulation of gastric acid secretion at Regulation of gastric acid secretion at the cellular levelthe cellular level

ACh Histamine PGE2

+

Gastrin

M3H2

Adenylatecyclase

-

H+

PUMP

K-

K-

H+

H+

+ +

+

+

Pirenzepine H2Blocker Misoprostol Octretide

PPI -

- - -

Drugs TherapyDrugs Therapy

1.Drugs which reduce gastric acid secretion

H2-Receptors antagonists

Proton pump inhibitors

Anticholinergics

Prostaglandin agonists

Drugs TherapyDrugs Therapy

2.Mucosal protective agents

3.Drugs which neutralise gastric

acid(Antacids)

4. Ulcer healing drugs

5.Antibiotics for H. pylori eradication

H2-Receptor AntagonistsH2-Receptor Antagonists

Exhibit competitive inhibition at the parietal cell

H2 receptor, and suppress basal and meal-

stimulated acid secretion in a linear, dose-

dependent manner.

The volume of gastric secretion and concentration

of pepsinare also reduced.

Reduce acid secretion stimulated by histamine as

well as by gastrin and cholinomimetic agents.

H2-Receptors AntagonistsH2-Receptors Antagonists

Inhibit 60–70% of total 24-hour acid secretion in

usual prescription doses.

They block more than 90% of nocturnal acid but only

60–80% of daytime acid secretion.

Nocturnal and fasting intragastric pH is raised to 4–5

but the impact upon the daytime, meal-stimulated

pH profile is less.

Clinical Comparisons of H2 Receptor BlockersClinical Comparisons of H2 Receptor Blockers..Drug Relative

PotencyDose to Achieve >50% Acid Inhibition for 10 hrs

Dose for Acute Duodenal or Gastric Ulcer

Dose for Gastro eosophageal Reflux Disease

Dose for Prevention of

Stress-Related

Bleeding

Cimetidine 1 400–800 mg

800 mg HS or 400mg bid

800 mg bid 50 mg/h

Continuous inf

Ranitidine 4-10 150 mg 300 mg HS or 150 mg bid

150 mg bid 6.25 mg/h

Continuous inf or 50mg IV every 6–8 h

Nizatidine 4-10 150mg 300 mg HS or 150mgbid

150 mg bid Not available

Famotidine 20-50 20mg 40 mg HS or

20 mg bid

20 mg bid 20 mg IV every 12hr

H2-Receptors AntagonistsH2-Receptors AntagonistsPharmacokineticsPharmacokinetics

Rapidly absorbed 1-3 hrs to peak

Ranitidine & Cimetidine hepatically

metabolized whereas Famotidine &

Nizatidine are renally excreted

Dose adjustment is needed in some renal &

hepatic failure patients

H2-Receptors AntagonistsH2-Receptors AntagonistsSide EffectsSide Effects

Usually minor; include headache, dizziness, diarrhea, & muscular pain

Hallucinations & confusion in elderly patients;

Cimetidine elevates serum prolactin & alters estrogen metabolism in men

Gynecomastia or impotence in men and Galactorrhea in women.

H2-Receptors AntagonistsH2-Receptors Antagonists

Although there are no known harmful effects on the fetus, these agents cross the placenta.

Therefore, they should not be administered to pregnant women unless absolutely necessary.

Secreted into breast milk and may therefore affect nursing infants..

PROTON PUMP PROTON PUMP INHIBITORSINHIBITORS

Most potent suppressors of gastric acid secretion which act by inhibiting gastric H+,K+-ATPase (proton pump)

In typical doses, these drugs diminish the daily production of acid (basal and stimulated) by 80% to 95%.

Five proton pump inhibitors are available for clinical use: omeprazole and its S-isomer esomeprazole , lansoprazole, rabeprazole, and pantoprazole.

PROTON PUMP PROTON PUMP INHIBITORSINHIBITORS PPI are Pro-drugs - require acidic environment

for activation. Activated in acidic canaliculi to sulfenamide,

trapping the drug so that it cannot diffuse back across the canalicular membrane.

The activated form then binds covalently with sulfhydryl groups of cysteines in the H+,K+-ATPase, irreversibly inactivating the pump molecule.

Acid secretion resumes only after new pump molecules are synthesized and inserted into the luminal membrane.


Provides a prolonged (up to 24 - 48hrs) suppression of acid secretion, despite the much shorter plasma half-lives (0.5 - 2 hrs) of the parent compounds.

Inhibit both fasting and meal-stimulated secretion because they block the final common pathway of acid secretion.

In standard doses, PPIs inhibit 90–98% of 24-hour acid secretion


Pharmacokinetics. Pharmacokinetics. Ideally should be given about 30 min before

meals so that the peak serum conc coincides with the maximal activity of proton pump secretion.

Rapidly absorbed in the small bowel Highly protein bound, and extensively

metabolized by hepatic CYP450, particularly CYP2C19 and CYP3A4.

Clinical Comparisons of PPIsClinical Comparisons of PPIs

Agent Usual Dosage for Peptic Ulcer or GERD

Maintenance Therapy

Esomeprazole 20–40 mg qd 20 mg qd

Lansoprazole 30 mg qd 15 mg qd

Omeprazole 20 mg qd 20 mg qd

Pantoprazole 40 mg qd 40 mg qd

Rabeprazole 20 mg qd 20 mg qd


Comparative Anti-secretory Efficacy of the Comparative Anti-secretory Efficacy of the Different PPIsDifferent PPIs

Among different PPIs administered at standard doses, esomeprazole 40 mg/day has a greater anti-secretory potency

Rabeprazole 20 mg/day & lansoprazole 30 mg/day show a faster action, & slightly greater acid inhibition capacity than omeprazole 20 mg/day & pantoprazole 40 mg/day

Adverse EffectsAdverse Effects

Nausea, abdominal pain, constipation,

flatulence

Subacute myopathy, arthralgias, headaches,

and skin rashes.

In some patients continuously taking PPIs, a

mild vitamin B12 deficiency has been seen as the

result of decreased vitamin absorption due to

impaired release of the vitamin from food.

ANTICHOLINERGIC DRUGSANTICHOLINERGIC DRUGS

Non selective- Propantheline,Oxyphenonium.

Selective M1– Pirenzepine,Telenzepine

Block muscarinic M1 receptors in stomach

inhibiting acid secretion. Minimal atropine like side effects on

CVS,GIT or urinary bladder. Effectively heal as well as prevent the

recurrence of peptic ulcer.

Prostaglandin AgonistsProstaglandin Agonists MisoprostolMisoprostol (PGE1) (PGE1)

It is a methyl analog of PGE1 Stimulate secretion of mucus & bicarbonate Binds to a prostaglandin receptor on

parietal cells, reducing histamine-stimulated cAMP production and cause modest acid inhibition

Stimulates intestinal electrolyte and fluid secretion, intestinal motility and uterine contractions.

MisoprostolMisoprostolAdministrationAdministrationShould be given 4 time/ day

Side effectsSide effectsUp to 20% develop diarrhea & cramps

Should not be used during pregnancy.

MisoprostolMisoprostol

Misoprostol reduces the incidence of

NSAID-induced ulcers to less than 3% and

the incidence of ulcer complications by 50%.

It is approved for prevention of NSAID-

induced ulcers in high-risk patients.

Mucosal Protective AgentsMucosal Protective Agents

These potentiate the mucosal defensive mechanisms for the prevention and treatment of acid-peptic disorders..

SucralfateSucralfate = =salt of sucrose complexed to sulfated aluminium hydroxide

Forms a viscous, tenacious paste in water or acidic solutions that binds to ulcers or erosions for up to 6 hours.

SucralfateSucralfate

Mechanism of action:Mechanism of action: Breaks down into sucrose sulfate (strongly

negatively charged) and an aluminium salt. The negatively charged sucrose sulfate binds to

positively charged proteins in the base of ulcers or erosion, forming a physical barrier that restricts further caustic damage.

Stimulates mucosal prostaglandin and bicarbonate secretion.

It also bind to epithelial growth factor and fibroblast growth factor, enhancing mucosal repair.

SucralfateSucralfate

AdministrationAdministration Should not be given with food, give 1hr before or

3hr after meal

Dose:Dose: 1gm/ 4times daily or 2 gm/ 2times daily

Side EffectsSide Effects Constipation; black stool & dry mouth It is very safe in pregnancy

Colloidal Bismuth CompoundsColloidal Bismuth Compounds

Bismuth subsalicylate

Bismuth subcitrate

Bismuth dinitrate

Colloidal bismuth sulfate:

– Water soluble, precipitate at pH less than 5

– PG ↑ mucus secretion & bicarbonate

– Forms glycoprotein complex coats ulcer

– Detaches H.pylori from mucosa, kills directly

– Dose = 120 mg QID

Adverse EffectsAdverse Effects

Bismuth causes blackening of the stool

Prolonged usage may rarely lead to bismuth

toxicity resulting in encephalopathy (ataxia,

headaches, confusion, seizures).

High dosages of bismuth subsalicylate may

lead to salicylate toxicity..

ULCER HEALING DRUGSULCER HEALING DRUGS

Carbenoxolone sodium: – Steroid like derivative of glycyretenic acid found

in liquorice root

– Augments viscid mucus production

– Prolongs life span of gastric epithelial cells, prevents bile reflux

– Major problem = mineralocorticoid action so not used now a days

AntacidsAntacids

Weak bases that react with gastric acid to form water & salt (Neutralize acid)

Also promote mucosal defense mechanisms through stimulation of mucosal PG production.

A single dose of 156 meq antacid given 1 hr after meal effectively neutralize gastric acid for 2 hr.

AntacidsAntacids Sodium bicarbonateSodium bicarbonate reacts rapidly with

HCl to produce carbondioxide and NaCl. Formation of CO2 results in gastric distention

and belching. Unreacted alkali is readily absorbed,

potentially causing metabolic alkalosis when given in high doses or to patients with renal insufficiency.

NaCl absorption may exacerbate fluid retention in heart failure, hypertension, and renal insufficiency.

AntacidsAntacids

Calcium carbonate is less soluble and reacts more slowly than sodium bicarbonate with HCl to form carbon dioxide and CaCl2

Excessive doses of either sodium bicarbonate or calcium carbonate with calcium-containing dairy products can lead to hypercalcemia, renal insufficiency, and metabolic alkalosis(milk-alkali syndrome).

AntacidsAntacids Magnesium hydroxideMagnesium hydroxide or or AAluminum luminum

hydroxidehydroxide react slowly with HCl to form magnesium chloride or aluminium chloride and water.

No gas is generated, belching does not occur.

Unabsorbed magnesium salts may cause an osmotic diarrhea and aluminium salts may cause constipation, these agents are commonly administered together..

Antibiotics for Antibiotics for H. pylori H. pylori eradicationeradication

Many regimens for H. pylori eradication have

been proposed.

Ideal regimen in this setting should achieve a

cure rate of at least 80%.

Five important considerations influence the

selection of an eradication regimen

Helicobacter pyloriHelicobacter pylori


1.Combination therapy with two or three antibiotics (plus acid-suppressive therapy) is associated with the highest rate of H. pylori eradication.

2. A PPI or H2-receptor antagonist significantly enhances the effectiveness of H. pylori antibiotic regimens containing amoxicillin or clarithromycin.

3. A regimen of 10 to 14 days of treatment appears to be better than shorter treatment regimens


4. Packaging that combines the daily doses

into one convenient unit is available and

may improve patient compliance .

5. The emergence of resistance to

clarithromycin and metronidazole

increasingly is recognized as an important

factor in the failure to eradicate H. pylori.

Therapy of Therapy of Helicobacter pyloriHelicobacter pylori

Dual therapy (7-10 days): Omeprazole 40mg OD + Clarithromycin 500

mg TDS or Ranitidine bismuth citrate 400mg BD

+Clarithromycin 500mg TDS or Omeprazole 40 mg OD +Amoxycillin 1g BD.

Therapy of Therapy of Helicobacter pyloriHelicobacter pylori

Triple therapy × 14 days: [PPI +

clarithromycin 500 mg + (metronidazole 500

mg or amoxicillin 1 g)] twice a day.

(Tetracycline 500 mg can be substituted for

amoxicillin or metronidazole.)

Therapy of Therapy of Helicobacter pyloriHelicobacter pylori Quadruple therapy × 14 days: PPI twice a

day + metronidazole 500 mg three times daily + (bismuth subsalicylate 525 mg + tetracycline 500 mg four times daily)

Or

H2-receptor antagonist twice a day + (bismuth subsalicylate 525 mg + metronidazole 250 mg + tetracycline 500 mg) four times daily

Adverse Effects Adverse Effects

The most commonly reported adverse events were

nausea, vomiting, & diarrhea

A bitter or metallic taste in the mouth is associated

with eradication regimens containing clarithromycin

Bismuth subsalicylate may cause a temporary

grayish-black discoloration of the stool

acid peptic disease (vk)

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