Peptic ulcer treatment

Pharmacotherapy of Peptic ulcer

Objectives Regulation of Gastric acid secretion Classification of drugs used in peptic

ulcer Mechanism of action, Uses & Adverse

effects, drug interactions of H2 Blockers Proton pump inhibitors Antacids Ulcer protectives

Drugs for eradication of H.pylori

Why Peptic ulcer occurs Imbalance primarily between Aggressive

factors and Defensive factors

Aggressive

factors, e,g,

acid, pepsin,

bile , H.pylori.

Defensive

factors, e.g.

mucus,

HCO3, PG,

NO

Formation of HCL

Regulation of gastric acid secretion

Classification of drugs used in peptic ulcer 1. Drugs that inhibit gastric

acid secretion 2. Drugs that neutralize

gastric acid (Antacids)3. Ulcer protectives 4. Anti H. pylori drugs

Classification (Contd.)

Drugs that inhibit gastric acid secretion H2 receptor blockers: Cimetidine,

Ranitidine, Famotidine Proton pump inhibitors: Omeprazole,

Pantoprazole, esomeprazole Anticholinergics : Pirenzepine Prostaglandin analogues: Misoprostol

Classification (Contd..) Drugs that neutralize gastric acid

(Antacids) Systemic:

• Sodium bicarbonate, sodium citrate Non systemic:

• Magnesium hydroxide, Mag. Trisilicate, Aluminium hydroxide gel, Magaldrate

Classification (Contd..) Ulcer protectives

Sucralfate Colloidal Bismuth Sulfate (CBS)

Anti H. pylori drugs Amoxicillin, Clarithromycin,

Metronidazole, Tinidazole, Tetracycline

H2 ANTAGONISTS

Mechanism of action Competitively block H2 receptors on

parietal cell & inhibit gastric acid production

Supress secretion of acid in all phases but mainly nocturnal acid secretion

Also reduce acid secretion stimulated by Ach, gastrin, food, etc.

Pharmacokinetics Absorption is not interfered by food Can cross placental barrier and reaches milk,

Poor CNS penetration The serum half-lives range from 1.1 to 4

hours; Cleared by a combination of hepatic

metabolism, glomerular filtration, and renal tubular secretion.

Dose reduction needed in moderate to severe renal insufficiency

Bioavailability 80 50 40 >90

Relative Potency 1 5 -10 32 5 -10

Half life (hrs) 1.5 - 2.3 1.6 - 2.4 2.5 - 4 1.1 -1.6

DOA (hrs) 6 8 12 8

Inhibition of 1 0.1 0 0

CYP 450

Dose mg (bd) 400 150 20 150

Cimetidine Ranitidine Famotidine Nizatidine

Comparison of H2 antagonists

H2 antagonists - UsesPromote the healing of gastric and duodenal ulcers Duodenal ulcer – 70 to 90% at 8 weeks Gastric Ulcer – 50 to 75% NSAID ulcers induced ulcers Stress ulcer and gastritis GERD Zollinger-Ellison syndrome Prophylaxis of aspiration pneumonia

Adverse effects Headache, dizziness, bowel upset, dry

mouth CNS: Confusion, restlessness Bolus IV – release histamine –

bradycardia, arrhythmia, cardiac arrest Cimetidine has antiandrogenic actions

Drug interactions Cimetidine inhibits several CYP-450

isoenzymes and reduces hepatic blood flow, so inhibits metabolism of many drugs like theophylline, metronidazole, phenytoin, imipramine etc.

Antacids reduce the absorption of all H2 blockers

Proton Pump Inhibitors Most effective drugs in antiulcer therapy Prodrugs requiring activation in acid

environment Activated forms binds irreversibly to

H+K+ATPase and inhibit it

Omeprazole Pantoprazole Lansoprazole Esomeprazole

Mechanism of Action Prodrugs inactive at neutral pH

At pH < 5 rearranges to two charged cationic

forms (sulfenamide + sulphenic acid) that bind

covalently with SH groups of H K ATPase and ⁺ ⁺inactivate it irreversibly

Also inhibits gastric mucosal carbonic anhydrase

Pharmacokinetics - PPI Available as enteric coated tablets They should be given 30 minutes to 1 hour

before food intake half life is very short and only 1-2 Hrs Still the action persists for 24 Hrs to 48 hrs after a

single dose Action lasts for 3-4days even after stoppage of

the drug

PPI – contd. Therapeutic uses:

1. Gastroesophageal reflux disease (GERD)2. Peptic Ulcer - Gastric and duodenal ulcers3. Bleeding peptic Ulcer 4. Zollinger Ellison Syndrome5. Prevention of recurrence of nonsteroidal

antiinflammatory drug (NSAID) - associated gastric ulcers in patients who continue NSAID use.

6. Reducing the risk of duodenal ulcer recurrence associated with H. pylori infections

7. Aspiration Pneumonia

Comparative success of therapy with PPI and H2 antagonist

Adverse Effects Nausea, loose stools, headache

abdominal pain, constipation, Muscle & joint pain, dizziness, rashes Rare

Gynaecomastia, erectile dysfunction Leucopenia and hepatic dysfunction Osteoporosis in elderly on prolonged use Hypergastrinemia

Drug interactions Omeprazole inhibits the metabolism

of warfarin, phenytoin, diazepam, and cyclosporine.

However, drug interactions are not a problem with the other PPIs.

PPI – Dosage schedule Omeprazole 20 mg o.d. Lansoprazole 30 mg o.d. Pantoprazole 40 mg o.d. Rabeprazole 20 mg o.d. Esomeprazole 20-40 mg o.d

Proton Pump Inhibitors Lansoprazole :

Partly reversible, more potent, slightly more against H pylori, Higher BA, rapid onset.

Pantoprazole: More acid stable, I.V, CYP450 less affinity

Rabeprazole: claimed to most rapid Es-omeprazole

Better intragastric pH , higher healing rates.

Muscarinic antagonists

Block the M1 class receptors Reduce acid production, Abolish gastrointestinal

spasmPirenzepine and Telenzepine Reduce meal stimulated HCl secretion by reversible

blockade of muscarinic (M1) receptors on the cell bodies of the intramural cholinergic ganglia

Unpopular as a first choice because of high incidence of anticholinergic side effects (dry mouth and blurred vision)

Prostaglandin analogues- Misoprostol Inhibit gastric acid secretion Enhance local production of mucus or

bicarbonate Help to maintain mucosal bloodTherapeutic use:

Prevention of NSAID-induced mucosal injury (rarely used because it needs frequent administration – 4 times daily)

Misoprostol Doses: 200 mcg 4 times a day ADRs:

Diarrhoea and abdominal cramps Uterine bleeding Abortion Exacerbation of inflammatory bowel disease and

should be avoided in patients with this disorderContraindications:1. Inflammatory bowel disease2. Pregnancy (may cause abortion)

Antacids Weak bases that neutralize acid Also inhibit formation of pepsin (As pepsinogen converted to pepsin at

acidic pH) Acid Neutralizing Capacity:

Potency of Antacids Expressed in terms of Number of mEq of 1N

HCl that are brought down to pH 3.5 in 15 minutes by unit dose of a preparation (1 gm)

Systemic antacids Sodium Bicarbonate:

Potent neutralizing capacity and acts instantly ANC: 1 gm = 12 mEq

DEMERITS: Systemic alkalosis Distension, discomfort and belching – CO2

Rebound acidity Sodium overload

Non systemic antacids Insoluble and poorly absorbed basic

compounds React in stomach to form

corresponding chloride salt The chloride salt again reacts with

the intestinal HCO3- so that HCO3- is not spared for absorption

Non systemic Antacids Magnesium hydroxide (ANC 30 mEq)

Aqueos suspension is called Milk of magnesia

Magnesium trisilicate (ANC 10 mEq) Aluminium Hydroxide (ANC 1-2.5mEq/g)(Magaldrate – hydrated hydroxy magnesium

aluminate)

Non systemic antacids Duration of action : 30 min when taken in empty

stomach and 2 hrs when taken after a meal Adverse effects:

Aluminium antacids – constipation (As they relax gastric smooth muscle & delay gastric emptying) – also hypophosphatemia and osteomalcia

Mg2+ antacids – Osmotic diarrhoea In renal failure Al3+ antacid – Aluminium toxicity

& Encephalopathy

Miscellaneous drugs Simethicone: Decrease surface

tension thereby reduce bubble formation - added to prevent reflux

Alginates: Form a layer of foam on top of gastric contents & reduce reflux

Oxethazaine: Surface anaesthetic

Chemical reactions of antacids with HCl in the stomach

Drug interactions By raising gastric pH & forming insoluble

complexes ↓ absorption of many drugs Tetracyclines, iron salts, H2 Blockers,

diazepam, phenytoin, isoniazid, ethambutol

Sucralfate – ulcer protective Aluminium salt of sulfated sucrose MOA:

In acidic environment ( pH <4) it polymerises by cross linking molecules to form sticky viscous gel that adheres to ulcer crater - more on duodenal ulcer

Astringent action and acts as physical barrier Dietary proteins get deposited on this layer

forming another coat

Sucralfate – contd. Concurrent antacids avoided, (as it needs acid for

activation) Uses:

Prophylaxis of Stress ulcers Bile reflux gastritis Topically – burn, bedsore ulcers, excoriated skins

Dose: 1 gm 1 Hr before 3 major meals and at bed time for 4-8 weeks

ADRs: Constipation, hypophosphatemia Drug interactions : adsorbs many drugs and

interferes with their absorption

Colloidal Bismuth Subcitrate (CBS) Mechanism of action

CBS and mucous form glycoprotein bi complex which coats ulcer crater

↑ secretion of mucous and bicarbonate, through stimulation of mucosal PGE production

Detaches H.pylori from surface of mucosa and directly kills them

Colloidal Bismuth subcitrate Dose: 120 mg 4 times a day Adverse effects

blackening of tongue, stools, dentures Prolonged use may cause

osteodystrophy and encephalopathy Diarrhoea, headache, dizziness

Eradication of H.pylori

No acidNo ulcerOLD TESTAMENT

No HP No ulcer

NEW TESTAMENT

H. pylori Gram (-) rod Associated with gastritis,

gastric & duodenal ulcers, gastric adenocarcinoma

Transmission route fecal-oral Secretes urease → convert

urea to ammonia Produces alkaline

environment enabling survival in stomach

Higher prevalence in Low SES

Who are they ?

Barry J Marshall J. Robin Warren

Nobel Laureates of Medicine – 2005

Discovery of H. pylori & its role in peptic

ulcer

Triple TherapyThe BEST among all the Triple therapy regimen is:

Omeprazole / Lansoprazole - 20 / 30 mg bd

Clarithromycin - 500 mg bd

Amoxycillin / Metronidazole - 1gm / 500 mg bd

Given for 14 days followed by P.P.I for 4 – 6 weeks

Short regimens for 7 – 10 days not very effective

Other 2 weeks regimen(mg) Amoxicillin 750/ + Tinidazole 500

+omeprazole 20 mg/ lansoprazole 30 mg BD

clarithromycin 250 + Tinidazole 500/amoxicillin 1000 + lansoprazole 30 mg BD

Thank You