H2 blockers and proton pump inhibitorsH2 blockers and proton pump inhibitors

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Prof. Hanan HagarProf. Hanan Hagar

Peptic ulcer disease (PUD):Peptic ulcer disease (PUD): a localized lesion of the mucous membrane of a localized lesion of the mucous membrane of the stomach the stomach (gastric ulcer)(gastric ulcer) or duodenum or duodenum (duodenal ulcer),(duodenal ulcer), typically extending through the typically extending through the muscularis mucosa.muscularis mucosa.

Peptic ulcer disease is most frequently Peptic ulcer disease is most frequently secondary to either Helicobacter pylori infection secondary to either Helicobacter pylori infection or use of NSAIDs.or use of NSAIDs.

Helicobacter pylori Helicobacter pylori is the major etiological factor is the major etiological factor in PUD and requires treatment within PUD and requires treatment withantimicrobial agents.antimicrobial agents.

All individuals with a diagnosis of PUD All individuals with a diagnosis of PUD must bemust be evaluated for H. pylori.evaluated for H. pylori.

Patients with H. pyloriPatients with H. pylori should be treated with an should be treated with anappropriate antimicrobial regimen, which may be appropriate antimicrobial regimen, which may be combined with a proton pump inhibitor (PPI).combined with a proton pump inhibitor (PPI).

Gastric secretionsGastric secretions1.1. HCl and intrinsic factor (Parietal cells).HCl and intrinsic factor (Parietal cells).

2.2. Pepsinogens (Chief cells).Pepsinogens (Chief cells).

3.3. Mucus, bicarbonate (mucus-secreting cells).Mucus, bicarbonate (mucus-secreting cells).

Regulation of Gastric secretionsRegulation of Gastric secretionsParietal cells secrete acid in response to:Parietal cells secrete acid in response to:

1.1. Histamine (local hormone): HHistamine (local hormone): H22 receptors receptors

2.2. Gastrin (hormone).Gastrin (hormone).

3.3. Ach (neurotransmitter): MAch (neurotransmitter): M3 3 receptorsreceptors

4.4. Proton pump (H+/ K+ ATPase) Proton pump (H+/ K+ ATPase)

Gastric hyposecretory drugsGastric hyposecretory drugs

Include: Include: 1.1. HH22 receptor blockers receptor blockers

2.2. proton pump inhibitorsproton pump inhibitors3.3. Antimuscarinic drugsAntimuscarinic drugs

Hyposecretory drugs decrease gastric acid Hyposecretory drugs decrease gastric acid secretion secretion Promote healing & relieve pain.Promote healing & relieve pain.

Proton Pump InhibitorsProton Pump Inhibitors (PPIs) (PPIs)

OmeOmeprazole – prazole – LansoLansoprazole - prazole - PantoPantoprazoleprazole

RaRaprazoleprazole

Mechanism of actionMechanism of action

irreversibleirreversible inhibition of proton pump (H+/ K+ inhibition of proton pump (H+/ K+

ATPase) that is responsible for final step in ATPase) that is responsible for final step in

gastric acid secretion from the parietal cell.gastric acid secretion from the parietal cell.

Gastric secretion by parietal cells

PharmacodynamicsPharmacodynamics

Produce marked inhibition of basal and Produce marked inhibition of basal and

stimulated-acid secretion.stimulated-acid secretion.

TheyThey are the most potent inhibitors of acidare the most potent inhibitors of acid

secretion available today. secretion available today.

PharmacokineticsPharmacokinetics Given orally as enteric coated capsules Given orally as enteric coated capsules

(unstable in acidic medium).(unstable in acidic medium). Pantoprazole is also available in IV Pantoprazole is also available in IV

formulation. formulation. Are prodrugsAre prodrugs rapidly absorbed from the intestine. rapidly absorbed from the intestine. Activated in the acidic medium of parietal Activated in the acidic medium of parietal

cell canaliculi.cell canaliculi. Inactivated if at neutral pH Inactivated if at neutral pH ( # combined ( # combined

with H2 blockers or antiacids).with H2 blockers or antiacids).

Have long duration of action (> 12 h-24 h).Have long duration of action (> 12 h-24 h). Once daily dose is sufficient Once daily dose is sufficient Given 1 h before meal.Given 1 h before meal. Bioavailability is reduced by food.Bioavailability is reduced by food. metabolized in the liver by Cyt-P450.metabolized in the liver by Cyt-P450. Dose reduction is required in severe liver Dose reduction is required in severe liver

failure.failure.

USESUSES

1.1. Eradication of H. pylori Eradication of H. pylori (combined with(combined with

antimicrobial drugs).antimicrobial drugs).

1.1. Hypersecretory conditions as Zollinger Hypersecretory conditions as Zollinger Ellison syndrome and gastrinoma(First choice).Ellison syndrome and gastrinoma(First choice).

2.2. Resistant severe peptic ulcer ( 4-8 weeks).Resistant severe peptic ulcer ( 4-8 weeks).

used for acute therapy only if H2RAs fail or

cannot be used

3.3. Reflux esophagitis.Reflux esophagitis.

Zollinger Ellison syndrome Zollinger Ellison syndrome

Gastrin-secreting tumor of the pancreas.Gastrin-secreting tumor of the pancreas.

Gastrin produce: Gastrin produce: Parietal cell hyperplasia (trophic factor).Parietal cell hyperplasia (trophic factor). Excessive gastric acid production.Excessive gastric acid production.

Adverse effectsAdverse effects Headache, diarrhea & abdominal pain.Headache, diarrhea & abdominal pain.

Achlorhydria Achlorhydria Hypergastrinaemia.Hypergastrinaemia.

Gastric mucosal hyperplasia. Gastric mucosal hyperplasia. -Increased bacterial flora Increased bacterial flora -increased risk of community-acquired increased risk of community-acquired pneumoniapneumonia

Long term use:Long term use: - - Vitamin B12 deficiencyVitamin B12 deficiency - increased risk of fractures- increased risk of fractures

H2 receptor blockersH2 receptor blockers

- Cime- Cimetidine tidine - Rani- Ranitidinetidine- Famo- Famotidine tidine - Niza- Nizatidinetidine

Mechanism of actionMechanism of action They competitively and reversibly block They competitively and reversibly block

HH22 receptors on the parietal cells. receptors on the parietal cells.

PharmacokineticsPharmacokinetics Good oral absorptionGood oral absorption Given before meals.Given before meals. Famotidine is the most potent drug.Famotidine is the most potent drug. Exposed to first pass metabolism (Exposed to first pass metabolism (except except

nizatidine that has 100 % bioavailability).nizatidine that has 100 % bioavailability). Duration of action (4-12 h).Duration of action (4-12 h). Metabolized by liver.Metabolized by liver. Excreted mainly in urine.Excreted mainly in urine. Cross placenta & excreted in milk (should not Cross placenta & excreted in milk (should not

be given in pregnancy unless it is necessary). be given in pregnancy unless it is necessary).

Pharmacological actions:Pharmacological actions: reduce basal and food stimulated-acid reduce basal and food stimulated-acid

secretion.secretion. Block 90% of nocturnal acid secretion Block 90% of nocturnal acid secretion

(which depend largely on histamine) & 60-(which depend largely on histamine) & 60-70% of total 24 hr acid secretion. 70% of total 24 hr acid secretion. Therefore, it is better to be given before Therefore, it is better to be given before night sleep.night sleep.

Reduce pepsin activity.Reduce pepsin activity. Promote mucosal healing & decrease painPromote mucosal healing & decrease pain

Uses:Uses:• Gastroesophageal reflux disease (GERD).

• Acute ulcer healing • Duodenal Ulcer (6-8 weeks).

• Benign gastric ulcer (8-12 weeks).• Post–ulcer healing maintenance therapy.

• Pre-anesthetic medication (to prevent aspiration pneumonitis).

• Zollinger Ellison Syndrome (large doses).

Adverse effects of HAdverse effects of H22 blockers blockers

1.1. GIT disturbances (Nausea & Vomiting).GIT disturbances (Nausea & Vomiting).

2.2. CNS effects: CNS effects:

Headache - confusion (elderly –hepatic Headache - confusion (elderly –hepatic /renal dysfunction)./renal dysfunction).

3.3. Bradycardia and hypotension (rapid I.V.)Bradycardia and hypotension (rapid I.V.)

4.4. CYT-P450 inhibition CYT-P450 inhibition (Only Cimetidine)(Only Cimetidine) decrease decrease metabolism of warfarin, phenytoin, metabolism of warfarin, phenytoin, benzodiazepines. benzodiazepines.

3.3. Endocrine effects Endocrine effects (Only Cimetidine)(Only Cimetidine) Galactorrhea (Hyperprolactinemia )Galactorrhea (Hyperprolactinemia ) Antiandrogenic actions (gynecomasteia –Antiandrogenic actions (gynecomasteia –

impotence) due to inhibition of impotence) due to inhibition of dihydrotestosterone binding to androgen dihydrotestosterone binding to androgen receptors.receptors.

PrecautionsPrecautionsDose reduction of H2 RAs in severe renal or Dose reduction of H2 RAs in severe renal or hepatic failure and elderly.hepatic failure and elderly.

Maintenance therapy for PUD

maintenance therapy includes the following: Cimetidine 400 mg at bedtime is the least

expensive and should be used as the medication of first choice.

PPIs should be used as a maintenance medication only if H2 blockers fail or cannot be used.

The patient should be evaluated after six months Maintenance anti-ulcer therapy will only be

approved after consultation and approval by a gastroenterologist

Summary Test for H. pylori prior to beginning therapy. Acid-reducing medications for PUD include the

following: H2RAs

PPI’s should be used for acute therapy only if H2RAs fail or cannot be used, or as part of treatment for H. pylori.

Complete H. pylori eradication is required to prevent relapse.

Maintenance therapy can be given until successful H. pylori eradication.