peptic ulcer drugs

Pharmacotherapy of Peptic Ulcer : 

Pharmacotherapy of Peptic Ulcer Department of Pharmacology NEIGRIHMS, SHILLONG MEGHALAYA

Contents : 

Contents Physiology of Gastric acid secretion An introduction to Peptic Ulcer Disease An outline on the Drugs used in such disorders Pharmacokinetics and Pharmacodynamics of important groups of Drugs Clinical pharmacology of Peptic Ulcer Disease

Physiology of Gastric Secretion : 

Physiology of Gastric Secretion Vagus Food GC CNS H2 – cAMP M3 & CCK2 – IP3-DAG

Phases of gastric secretion : 

Phases of gastric secretion

What is Peptic Ulcer ? : 

What is Peptic Ulcer ? A peptic ulcer disease or PUD is an ulcer (defined as mucosal erosions equal to or greater than 0.5 cm) of an area of the gastrointestinal tract exposed to the acid and pepsin secretion Gastritis is the precursor to PUD and it is clinically difficult to differentiate the two Stomach (called gastric ulcer) Duodenum (called duodenal ulcer) Esophagus (called Esophageal ulcer) Meckel's Diverticulum (called Meckel's Diverticulum ulcer)

Duodenal Vs Gastric Ulcers : 

Duodenal Vs Gastric Ulcers Duodenal Age: 25-75 years Gnawing or burning upper abdomen pain relieved by food but reappears 1-3 hrs after meals Worse pain when stomach empty Bleeding occurs with deep erosion Hematemesis Melena Gastric Age: 55-65 years Relieved by food but pain may persist even after eating Anorexia, wt loss, vomiting Infrequent or absent remissions Small % become cancerous Severe ulcers may erode through stomach wall

Gastroesophageal Reflux Disease (GERD) : 

Gastroesophageal Reflux Disease (GERD) Common and GI motility disorder Acidity of Gastric contents – most common factor Acid contents reflux back into esophagus Intense burning, sometimes belching Can lead to esophagitis, esophageal ulcers, and strictures Barrett’s esophagus Commonly associated with obesity Improves with lifestyle management

Why Ulceration Occurs? : 

Why Ulceration Occurs? High [H+] in the gastric lumen Require defense mechanisms to protect oesophagus and stomach Oesophagus – LES Stomach: a number of mechanisms Mucus secretion: slows ion diffusion Prostaglandins: I2 and E2 (alcohol, aspirin, and other drugs) Bicabonate ions High Blood Flow (nitric oxide)

Because of Imbalance : 

Because of Imbalance Imbalance primarily between Aggressive factors and Defensive factors: Aggressive factors, e,g, acid, pepsin, bile etc. Defensive factors, e.g. mucus, HCO3, PG

What may contribute imbalance ? : 

What may contribute imbalance ? Helicobacter pylori NSAIDs Ethanol Tobacco Severe physiologic stress (Burns, CNS trauma, Surgery, Severe medical illness) Steroids

H. pylori : 

H. pylori Gram (-) rod with flagella H pylori is most common cause of PUD Transmission route fecal-oral Secretes urease → convert urea to ammonia Produces alkaline environment enabling survival in stomach Almost all duodenal and 2/3 gastric ulcer pt’s infected with HP Considered class 1 carcinogen → gastric cancer Higher prevalence in Low SES

Who are they ? : 

Who are they ? Barry J Marshall J. Robin Warren Nobel Laureates of Medicine – 2005 Discovery of H. pylori & its role in peptic ulcer

NSAIDS : 

NSAIDS Damage to the cytoprotective role of PGs – PGE2 and PGI2

Differentiating between H. pylori and NSAID-induced ulcer : 

Differentiating between H. pylori and NSAID-induced ulcer Ulcers associated with H. pylori More often in duodenum Often superficial Less severe GI bleeding Ulcers associated with NSAIDs More often in stomach Often deep More severe GI bleeding Sometimes asymptomatic

Slide 15: 

Drugs of Ulcer treatment

Slide 16: 

Proglumide ACh PGE2 Histamine Gastrin Adenyl cyclase ATP cAMP Protein Kinase (Activated) Ca++ Ca++ Proton pump K K+ H+ Gastric acid Parietal cell Lumen of stomach H2 M3 PGE receptor Gastrin receptor

Peptic Ulcers : 

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

Classification : 

Classification Acid Neutralizing agents: (ANTACIDS) Systemic: Sodium Bicarbonate and Sod. Citrate Nonsystemic: Magnesium hydroxide, Mag. Treisilicate, Aluminium hydroxide gel, Magaldrate and calcium carbonate Reduction in Gastric acid secretion: H2 antihistamines: Cimetidine, Ranitidine, Famotidine, Nizatidine and Roxatidine Proton pump inhibitors: Omeprazole, Lansoprazole Pantoprazole, Rabeprazole and Esomeprazole Anticholinergics: Pirenzepine, Propantheline and Oxyphenonium Prostaglandin analogue: Misoprostol

Classification – contd. : 

Classification – contd. Ulcer protectives: Sucralfate, Colloidal Bismuth sudcitrate Anti-H. pylori Drugs: Amoxicillin, Clarithromycin, metronidazole, tinidazole and tetracycline

Antacids : 

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)

Antacids - The Oldest Remedy : 

Antacids - The Oldest Remedy Sodium Bicarbonate: Potent neutralizing capacity and acts instantly ANC: 1 gm = 12 mEq NOT USED ANYMORE FOR ITS DEMERITS: Systemic alkalosis Distension, discomfort and belching – CO2 Rebound acidity Sodium overload

Antacids : 

Antacids Present day antacids : Aluminium Hydroxide (ANC 1-2.5mEq/g) Magnesium Hydroxide (ANC 30 mEq) – milk of magnesia Magnesium trisilicate (ANC 1mEq/g) Duration of action : 30 min when taken in empty stomach and 2 hrs when taken after a meal Side 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 (Magaldrate – hydrated hydroxy magnesium aluminate)

Antacids – contd. : 

Antacids – contd. 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

Therapeutic Questions : 

Therapeutic Questions Is it rational to combine Aluminium hydroxide and magnesium hydroxide in antacid preparations ? How to avoid formation of insoluble complexes of drugs by antacids, that are not absorbed ?

Answers (!) : 

Answers (!) Interactions can be avoided by taking antacids 2 hrs before or after ingestion of other drugs Combination provides a relatively fast and sustained neutralizing capacity (Magnesium Hydroxide – Rapidly acting Aluminium Hydroxide - Slowly acting ) Combination preserves normal bowel function (Aluminium Hydroxide – constipation Magnesium hydroxide – diarrhoea )

The Reality : 

The Reality Not part of Physician prescribed regimen – frequency of dosing and rebound acidity Over the counter (OTC) drug for symptomatic relief of dyspepsia May only be prescribed for very short term: Non-ulcer dyspepsia and minor episodes of heart burn As adjuvant in GERD – quick relieve

Sucralfate – ulcer protective : 

Sucralfate – ulcer protective Salt of sucrose complexed to sulfated aluminium hydroxide (basic aluminium salt) MOA: In acidic pH polymerises to viscous gel that adheres to ulcer crater - more on duodenal ulcer Precipitates protein on surface proteins and acts as physical barrier Dietary proteins get deposited on this layer forming another coat Delays gastric emptying and causes gastric PG synthesis – protective action

Sucralfate – contd. : 

Sucralfate – contd. Taken on empty stomach 1 hr. before meals Concurrent antacids, H2 antagonist avoided (as it needs acid for activation) Uses: NSAID induced ulcers Patients with continued smoking ICU Topically – burn, bedsore ulcers, excoriated skins Dose: 1 gm 1 Hr before meals ADRs: Constipation, hypophosphatemia

Chemical reactions of antacids with HCl in the stomach : 

Chemical reactions of antacids with HCl in the stomach

Antacids : 

Antacids Capsules & Tablets: Powders Chewable tablets Suspensions Effervescent granules and tablets

H2 Antagonists : 

H2 Antagonists Cimetidine, Ranitidine, Famotidine, Roxatidine, Nizatidine and MOA: Reversible competitive inhibitors of H2 receptor Highly selective, no action on H1 or H3 receptors All phases of gastric acid secretion Very effective in inhibiting nocturnal acid secretion (as it depends largely on Histamine ) Modest impact on meal stimulated acid secretion (as it depends on gastrin, acetylcholine and histamine) Volume of pepsin content and IF are also reduced Volume reduced by 60 – 70% - anti ulcerogenic effect No effect on motility

H2 antagonists : 

H2 antagonists Kinetics: All drugs are absorbed orally adequately Bioavailability upto 80 % Absorption is not interfered by presence of food Can cross placental barrier and reaches milk Poor CNS penetration 2/3rd of the drugs are excreted unchanged in bile and urine Preparations: available as tablets, injections

H2 antagonists - ADRs : 

H2 antagonists - ADRs Extremely safe drugs and well tolerated Main ADRs are related to Cimetidine: Antiandrogenic effects Increases prolactin secretion and inhibits degradation of estradiol by liver Cytochrome P450 inhibition – theophylline, metronidazole, phenytoin, imipramine etc. Antacids Others: Headache, dizziness, bowel upset, dry mouth Bolus IV – release histamine – bradycardia, arrhythmia, cardiac arrest Elderly - precaution

Slide 34: 

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 Duration of 6 8 12 8 action (hrs) Inhibition of 1 0.1 0 0 CYP 450 Dose mg (bd) 400 150 20 150 Cimetidine Ranitidine Famotidine Nizatidine Comparison of H2 antagonists Antiandrogenic effect, prolactin secretion and gynocomastia

H2 antagonists - Uses : 

H2 antagonists - Uses Promote the healing of gastric and duodenal ulcers Duodenal ulcer – 70 to 90% Gastric Ulcer – 50 to 75% (NSAID ulcers)) Stress ulcer and gastritis GERD Zollinger-Ellison syndrome Prophylaxis of aspiration pneumonia Urticaria Doses: 300 mg/40 mg/150 mg at bed time of R, F, Rox respectively for healing Maintenance: 150/20/150 mg BD of R, F, Rox

H2 blockers Tablets in Peptic ulcer : 

H2 blockers Tablets in Peptic ulcer

Question : 

Question Your friend wants to take a H2 antagonist before he takes alcohol to avoid gastric irritation .He consults you .Which H2 antagonist will you ask him to take ? Ranitidine/Famotidine/Roxatidine/Tiznidine ?

H2 antagonists – contd. : 

H2 antagonists – contd. Answer : Famotidine Explanation : All H2 antagonist except famotidine inhibit gastric first pass metabolism of ethanol and increase its bioavailability

Proton Pump Inhibitors : 

Proton Pump Inhibitors Most effective drugs in antiulcer therapy Prodrugs requiring activation in acid environment Block enzymes responsible for secreting HCl - binds irreversibly to H+K+ATPase Prototype: Omeprazole (Prilosec) Examples: Lansoprazole Pantoprazole Rabeprazole Esomeprazole Omeprazole

Omeprazole - MOA : 

Omeprazole - MOA Substituted Benzimidazole derivative Its a Prodrug Diffuses into G. canaliculi = accumulation pH < 5 (proton catalyzed )= tetracyclic sulfenamide + sulphenic acid Covalent binding with sulfhydryl cysteines of H⁺K⁺ ATPase Irreversible inactivation of the pump molecule (The charged forms cannot diffuse back across the canaliculi) Acid suppressants regardless of stimulating factors Also inhibits gastric mucosal carbonic anhydrase

Pharmacokinetics - PPI : 

Pharmacokinetics - PPI Oral forms are prepared as acid resistant formulations that release the drug in the intestine (because they are degraded in acid media) After absorption, they are distributed by blood to parietal cell canaliculi They irreversibly inactivate the proton pump molecule – but half life is very short and only 1-2 Hrs Still action persists for 24 Hrs to 48 hrs after a single dose – irreversible inhibition of PPI and new PP synthesis takes time (24 to 48 hour suppression of acid secretion, despite the much shorter plasma half-lives of the parent compounds) Platue state is attained after 4-5 days of dosing Action lasts for 4-5 days even after stoppage of the drug

Question : 

Question Half life of proton pump inhibitors is 1.5 hours only and these drugs are generally given once daily. How this can be justified ? Answer : P.P.I - Irreversible inhibitors of H+K+ATPase (Hit and run drugs)

Pharmacokinetics - PPI : 

Pharmacokinetics - PPI Given on an empty stomach because food affects absorption They should be given 30 minutes to 1 hour before food intake because an acidic pH in the parietal cell acid canaliculi is required for drug activation, and food stimulates acid production Concomitant use of other antisecretory drugs - H2 receptor antagonists – reduces action Highly protein bound and rapidly Metabolized by the liver by CYP2C19 and CYP3A4 – dose reduction necessary in severe hepatic failure Excreted in Kidneys minimally (no dose reduction needed in renal failure and elderly)

Adverse Effects : 

Adverse Effects The most common are GIT troubles in the form of nausea, abdominal pain, constipation, flatulence, and diarrhea Subacute myopathy, arthralgias, headaches, and skin rashes Prolonged use: Gynaecomastia, erectile dysfunction Leucopenia and hepatic dysfunction Vitamin B12 deficiency Hypergastrinemia which may predispose to rebound hypersecretion of gastric acid upon discontinuation of therapy and may promote the growth of gastrointestinal tumors (carcinoid tumors )

PPI – contd. : 

PPI – contd. Drug Interaction: Inhibits metabolism of Warfarin, Diazepam Therapeutic uses: Gastroesophageal reflux disease (GERD) Peptic Ulcer - Gastric and duodenal ulcers Bleeding peptic Ulcer Zollinger ellison Syndrome Prevention of recurrence of nonsteroidal antiinflammatory drug (NSAID) - associated gastric ulcers in patients who continue NSAID use. Reducing the risk of duodenal ulcer recurrence associated with H. pylori infections Aspiration Pneumonia

PPI – Dosage schedule : 

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.

Muscarinic antagonists : 

Muscarinic antagonists Atropine: Block the M1 class receptors Reduce acid production Abolish gastrointestinal spasm Pirenzepine and Telenzepine Mechanism of action: Reduce meal stimulated HCl secretion by reversible blockade of muscarinic (M1) receptors on the cell bodies of the intramural cholinergic ganglia (receptors on parietal cells are M3). Unpopular as a first choice because of high incidence of anticholinergic side effects (dry mouth and blurred vision)

Prostaglandin analogues : 

Prostaglandin analogues Inhibit gastric acid secretion Exhibit ‘cytoprotective’ activity Enhance local production of mucus or bicarbonate Promote local cell regeneration Help to maintain mucosal blood

Prostaglandin analogues - Misoprostol : 

Prostaglandin analogues - Misoprostol Actions: Inhibit histamine-stimulated gastric acid secretion Stimulation of mucin and bicarbonate secretion Increase mucosal blood flow (Reinforcing of mucous layer buffered by HCO3 secretion from epithelial cells) Therapeutic uses: Prevent ion of NSAID-induced mucosal injury (rarely used because it needs frequent administration – 4 times daily)

Misoprostol : 

Misoprostol Doses: 200 mcg 4 times a day (Misoprost) ADRs: Diarrhoea and abdominal cramps Uterine bleeding Abortion Exacerbations of inflammatory bowel disease and should be avoided in patients with this disorder Contraindications: Inflammatory bowel disease Pregnancy (may cause abortion)

Question : 

Question A patient comes to your clinic at midnight complaining of heart burn. You want to relieve his pain immediately. What drug will you choose?

Answer is : 

Answer is Antacids Explanation : Antacids neutralize the already secreted acid in the stomach. All other drugs act by stopping acid secretion and so may not relieve symptoms atleast for 45 min

Slide 53: 

Eradication of H.pylori Omeprazole Amoxicillin Clarithromycin Metronidazole

Slide 54: 

Triple Therapy The 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

Slide 55: 

Triple Therapy – cont … Bismuth subsalicylate – 2 tab qid Metronidazole - 250 mg qid Tetracycline - 500 mg qid Some other Triple Therapy Regimens are Ranitidine Bismuth citrate - 400 mg bd Tetracycline - 500 mg bd Clarithromycin / Metronidazole - 500 mg bd

Bismuth subsalicylate : 

Bismuth subsalicylate Pharmacological actions: Undergoes rapid dissolution in the stomach into bismuth and salicylates Salicylates are absorbed Bismuth coats ulcers and erosions protecting them from acid and pepsin and increases prostaglandin and bicarbonate production Uses: Treatment of dyspepsia and acute diarrhoea

Slide 57: 

Question A pregnant lady (first trimester) comes to you with peptic ulcer disease. Which drug will you prescribe for her ?

Slide 58: 

Answer : Antacids or Sucralfate Explanation ; H2 antagonists cross placenta and are also secreted in breast milk. Safety of Proton pump inhibitors not established in pregnancy. Misoprostol causes abortion

Additional : 

Additional Drugs causing peptic ulcer: Non Steroidal Anti Inflammatory Drugs (NSAIDs) Glucocorticoids Cytotoxic agents Stress induced ulceration after head trauma -Cushing’s ulcer Stress induced ulceration after severe burns - Curling’s ulcer

H2 Receptor Antagonists : 

H2 Receptor Antagonists in stomach at all stages decreases formation of HCl by selective blocking of H2 receptors therapeutic effect after 4 weeks - 60 -80% efficiency, after 8 weeks even 90%, 10-15% resistance Ranitidine, Famotidine /more effective/, Nizatidine: /1- 2x daily/ - good pharmacokinetic /p.o. absorbtion, metabolism in liver/ and safety profile, good tollerance - long-term maintenance therapy after uncomplicated peptic ulcer healing and treatment of some forms of gastric dyspepsias Khublei Shibun /Mitela/ Thank you