Drugs in peptic ulcerDrugs in peptic ulcer(H(H22 blockers and proton pump inhibitors) blockers and proton pump inhibitors)

ByBy

Profs Alhaider & Hanan HagarProfs Alhaider & Hanan Hagar

Objectives:

Understand the key points of pathophysiology of the peptic ulcerDisease

Enumerate various classes of dugs used in peptic ulcer disease

Correlate actions of anti-ulcer drugs with pathophysiology of the Disease .

Understand the mechanisms of action, routes of adminisntration and adverse of drugs used in peptic ulcer disease.

Understand the Rationale of combination triple therapy for h. pylori

infected ulcers

Identify potential adveverse drug interactions of anti-ulcer drugs.

Peptic ulcerPeptic ulcer

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

Pathophysiology:Pathophysiology:

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

pepsinpepsin) ) and and

defensive factorsdefensive factors(e.g. prostaglandins,(e.g. prostaglandins,

mucus & bicarbonate layermucus & bicarbonate layer). ).

Helicobacter pylori Helicobacter pylori is the major etiological factor in peptic is the major etiological factor in peptic ulcer disease (PUD) (95% in duodenal and 70% in gastric ulcer disease (PUD) (95% in duodenal and 70% in gastric ulcer).ulcer).

Drugs induced such as NSAIDs (e.g aspirin, Drugs induced such as NSAIDs (e.g aspirin, diclofenac, naproxen etc on long term use)diclofenac, naproxen etc on long term use)

Pathophysiology:Pathophysiology:1. Hydrochloric acid and pepsin destroy

gastric and duodenal mucosa.2. Mucus and bicarbonate ion secretions

protect mucosa3. Prostaglandins protect mucosa by

enhancing mucus and bicarbonate production and by enhancing mucosal 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)

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

H2 receptor blockers Antimuscarinic drugs Proton pump inhibitors

Mucosal cytoprotective agents. Prostaglandin analogues Sucralfate (CarafateR)

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 -Raprazoleprazole

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 painPromote mucosal healing & decrease pain Proton pump inhibitors heal faster the ulcers Proton pump inhibitors heal faster the ulcers

than H-2 blockers, and have H.pylori inhibitory than H-2 blockers, and have H.pylori inhibitory properties How?. properties How?.

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

(unstable in acidic medium in stomach).(unstable in acidic medium in stomach). 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. Therefore,Therefore, Should not be combined with HShould not be combined with H22 blockers or blockers or

antacids. antacids. Inactivated if at neutral pH.Inactivated if at neutral pH.

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

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

Zollinger Ellison syndrome Zollinger Ellison syndrome

Gastrin -secreting tumor of the non-beta islet Gastrin -secreting tumor of the non-beta islet cell of pancreas.cell of pancreas.

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 increased risk of community-acquired

respiratory infections & nosocomial pneumoniarespiratory infections & nosocomial pneumonia Long term use:Long term use:

Vitamin BVitamin B1212 deficiency deficiency increased risk of hip fracturesincreased risk of hip fractures

H2 receptor blockersH2 receptor blockers

- Cime- Cimetidinetidine - Rani- Ranitidinetidine- Famo- Famotidinetidine - Niza- Nizatidinetidine

Mechanism of actionMechanism of action They competitively and They competitively and reversiblyreversibly block 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). Pre-anesthetic medication (to prevent

aspiration pneumonitis). Prevention of bleeding from stress-related

gastritis. Post–ulcer healing maintenance therapy. Together with NSAIDs to prevent ulcers

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

Therefore, combination of Mg (OH)2 plus Al (OH)3 commonly used.

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 but H2 blockers

or proton pump inhibition are better.Adverse effects:

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

If H. pylori infection is diagnosed in the presence of peptic ulcer disease

Eradication with most commonly "triple therapy" with a PPI, clarithromycin, and  amoxicillin +/- metronidazole for 7-14 days (Cure rates of 70% to 90% ).

Pentaprazole 40 mg BID Amoxicillin 1000 mg BID Clarithromycin 500 mg BID

Notes: Test for H. pylori prior to beginning therapy. Complete H. pylori eradication is required to

prevent relapse ( by Repeating the course and metronidazole should be added.

Treatment of Gastric Esophageal refluxAviod a big and fat meals and sleeping after meals.Use of many pilows (45 degree) Aviod coffee PPIs or H2 antagonists + metoclopromide or

Domperidone

What is Sucralfate?Is a sucrose sulfate-aliminium complex works as

an oral cytoprotective agent via binding to the duedenal mucosa and thus creating physical barrier. Also, may stimulate bicarbonate secretion

USESMainly as an addition for resistance gastritis or

GERD