HH22 blockers and proton pump blockers and proton pump inhibitorsinhibitors

ByByProf. Hanan HagarProf. Hanan Hagar

Objectives:

Understand the key points of pathophysiology of the peptic ulcer disease

Enumerate various classes of dugs used in peptic ulcer disease

Correlate actions of anti-ulcer drugs with pathphysiology of the disease. Understand the mechanisms of action, routes of administration and adverse of drugs used in peptic ulcer disease.

Understand the rationale of combination triple & quadruple therapy for H. pylori infected ulcers

Identify potential adverse drug interactions of anti-ulcer drugs.

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

Pathophysiology:Pathophysiology: is imbalance between aggressive factors is imbalance between aggressive factors (acid &(acid &

pepsinpepsin) ) and defensive factors and defensive factors (e.g. prostaglandins,(e.g. prostaglandins,

mucus & bicarbonate layermucus & bicarbonate layer). ). However, nowadays, itHowever, nowadays, it

seems that H. pylori theory is very importantseems that H. pylori theory is very important..

Helicobacter pylori Helicobacter pylori is the major etiological factor is the major etiological factor in peptic ulcer disease (95% in duodenal and 80% in in peptic ulcer disease (95% in duodenal and 80% in gastric ulcer).gastric ulcer).

Pathophysiology:Pathophysiology:

1.1. Hydrochloric acid and pepsin Hydrochloric acid and pepsin destroy gastric and destroy gastric and duodenal mucosa.duodenal mucosa.

2.2. Mucus and bicarbonate Mucus and bicarbonate ion secretions protect ion secretions protect mucosamucosa

3.3. ProstaglandinsProstaglandins (PGE (PGE22 & PGI & PGI22) protect mucosa by ) protect mucosa by

inhibiting acid secretion, increasing mucus and inhibiting acid secretion, increasing mucus and bicarbonate production and by enhancing mucosal bicarbonate production and by enhancing mucosal blood flow.blood flow.

Etiology:Etiology: H. pylori infectionH. pylori infectionAlcoholAlcoholSmokingSmokingCaffeineCaffeineGenetic factorsGenetic factorsDietDietHypersecretory states Hypersecretory states (Zollinger Ellison syndrome)(Zollinger Ellison syndrome)

Drugs (e.g.) NSAIDsDrugs (e.g.) NSAIDs

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 secretions

Parietal 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): CCKGastrin (hormone): CCK22 receptors receptors

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

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

N.B. CCKN.B. CCK22= cholecystokinin receptors= cholecystokinin receptors

Treatment of peptic ulcerTreatment of peptic ulcer Eradication of H. pylori infections Hyposecretory drugs.

Proton pump inhibitors H2 receptor blockers Antimuscarinic drugs

Mucosal cytoprotective agents. Prostaglandin analogues

Neutralizing agents (antacids).

Gastric hyposecretory drugsGastric hyposecretory drugs

Include: Include: HH22 receptor blockers receptor blockers proton pump inhibitorsproton pump inhibitors Antimuscarinic drugsAntimuscarinic drugs

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

Proton Pump InhibitorsProton Pump Inhibitors (PPIs) (PPIs)

OmeOmeprazoleprazole – Lanso – Lansoprazole prazole

PantoPantoprazoleprazole –Ra –Raprazole-prazole-esomeesomeprazoleprazole

Acts by Acts by irreversibleirreversible inhibition of proton pump inhibition of proton pump

(H+/ K+ ATPase) (H+/ K+ ATPase) that is responsible for final step that is responsible for final step

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

Gastric secretion by parietal cells

PharmacodynamicsPharmacodynamics

TheyThey are the most potent inhibitors of acid are the most potent inhibitors of acid secretion available today. secretion available today.

Produce marked inhibition of basal & meal Produce marked inhibition of basal & meal stimulated-acid secretionstimulated-acid secretion (90-98%).(90-98%).

Reduce pepsin activity.Reduce pepsin activity. Promote mucosal healing & decrease pain.Promote mucosal healing & decrease pain. Proton pump inhibitors heal Proton pump inhibitors heal fasterfaster the ulcers the ulcers

than Hthan H22 blockers, and blockers, and have H. pylori inhibitory have H. pylori inhibitory

properties. properties.

PharmacokineticsPharmacokinetics Given orallyGiven orally Are pro-drugsAre pro-drugs 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. Should not combined with HShould not combined with H22 blockers or blockers or

antacids. antacids.

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

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

antimicrobial drugs).antimicrobial drugs).

Peptic ulcer ( 4-8 weeks) resistant to HPeptic ulcer ( 4-8 weeks) resistant to H22

antagonists.antagonists. Reflux esophagitis.Reflux esophagitis.

Hypersecretory conditions as Zollinger Ellison Hypersecretory conditions as Zollinger Ellison syndrome syndrome (drug of choice).(drug of choice).

Zollinger Ellison syndrome Zollinger Ellison syndrome

Is characterized by Is characterized by excessive production of gastrin excessive production of gastrin by gastrinoma of the pancreas or duodenum that by gastrinoma of the pancreas or duodenum that stimulates parietal cells of the stomach to release stimulates parietal cells of the stomach to release excessive amounts of gastric acid.excessive amounts of gastric acid.

Gastrin produces: Gastrin produces: Parietal cell hyperplasia Parietal cell hyperplasia (trophic factor).(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 respiratory increased risk of community-acquired respiratory infections & pneumoniainfections & pneumonia

Long term use:Long term use: Vitamin BVitamin B1212 deficiency deficiency

increased risk of hip fracturesincreased risk of hip fractures

HH22 receptor blockers receptor blockers

- Cime- Cimetidinetidine - Rani- Ranitidinetidine- Famo- Famotidinetidine - 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 Cross placenta & excreted in milk (should(should

not be given in pregnancy unless it is necessary).not be given in pregnancy unless it is necessary).

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

secretionsecretion Block 90% of nocturnal acid secretion (which Block 90% of nocturnal acid secretion (which

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

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

Uses:Uses: GERD (heartburn/ dyspepsia).

Acute ulcer healing in moderate cases Duodenal Ulcer (6-8 weeks).

Benign gastric ulcer (8-12 weeks). Zollinger Ellison Syndrome Pre-anesthetic medication (to prevent

aspiration pneumonitis). Prevention of bleeding from stress-related

gastritis. Post–ulcer healing maintenance therapy.

Adverse effects of HAdverse effects of H22 blockers blockers

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

CNS effects: Headache - confusion CNS effects: Headache - confusion

(elderly, hepatic dysfunction, renal dysfunction).(elderly, hepatic dysfunction, renal dysfunction).

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

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

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

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

PrecautionsPrecautionsDose reduction of HDose reduction of H22 RAs in severe renal or RAs in severe renal or

hepatic failure and elderly.hepatic failure and elderly.

Antacids These drugs are mainly inorganic salts e.g.: NaHCO3; Ca CO3; Al (OH)3; Mg (OH)2

acts by direct chemical neutralization of HCL and as a result may decrease pepsin activity.

used to relief pain of peptic ulcer & for dyspepsia. All antacids absorption of some drugs as

tetracycline, fluoroquinolones, iron.NaHCO3: Systemic alkalosis; Ca CO3 : milk alkali

syndrome (hypercalcemia, renal failure)

Al (OH)3 : constipation; Mg (OH)2 : Diarrhea

Misoprostol Prostaglandin analogues (PGE1 )

HCL secretion. protective measures ( mucous/bicarbonate & gastric mucosal blood flow).Orally, must be taken 3-4 times/day.Used for NSAIDS-induced peptic ulcer. Adverse effects:

Abdominal cramps; diarrhea Uterine contraction (dysmenorrhea or abortion);Vaginal bleeding.

Eradication of Helicobacter pylori Eradication of Helicobacter pylori All PUD patients must be evaluated for H. pylori.Patients with H. pylori should be treated.Eradication is important to prevent recurrence of ulcer.A combination of antibiotics and acid-reducing medicines is the most effective treatment.

PPIs or H2 receptor blockers Antibiotics

Clarithromycin Tetracycline or amoxicillin Metronidazole if patient allergic to penicillin.

Bismuth subsalicylate.

Triple therapy (First-line therapy):1. Proton pump inhibitors (PPIs) 2. Clarithromycin3. Amoxicillin (metronidazole is substituted for

amoxicillin in patients allergic to penicillin).

Quadruple therapy (bismuth-based regimen)1. Proton pump inhibitors (PPIs) 2. Bismuth subsalicylate 3. Metronidazole4. Tetracycline

Summary Test for H. pylori prior to beginning therapy. Complete H. pylori eradication is required to prevent relapse. Acid-reducing medications are prescribed in case of PUD

without H pylori infections. Acid-reducing medications for PUD include:

• 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.

PUD with H pylori infections can be treated with Triple therapy

PPI’s + clarithromycin + amoxicillin Quadruple therapy

PPI’s + Bismuth + Metronidazole + tetracycline