KARAGANDA STATE MEDICAL UNIVERSITY

REPORT

PEPTIC ULCER

SUBJECT- PHARMACOLOGY

SUBMITTED TO-

SUBMITTED BY-

GROUP-

KGMU,2016

CONTENTS;-

Physiology of Gastric acid secretion

An introduction to Peptic Ulcer Disease

Drugs used in PUD

PHYSIOLOGY OF GASTRIC ACID SECRETION

• Food is broken into macroparticles

• Acid causes hydrolysis, sterilizes the meal content

& activates pepsinogen to pepsin

• Acid secretion:

• Basal

• Stimulated

DIAGRAM SHOWING OXYNTIC GASTRIC GLAND

GASTRIC PARIETAL CELL UNDERGOING TRANSFORMATION AFTER SECRETAGOGUE MEDIATED STIMULATION

PHASES OF GASTRIC ACID SECRETION AND THEIR REGULATION

PATHOPHYSIOLOGY

PHYSIOLOGICAL REGULATION OF GASTRIC ACID SECRETION

PEPTIC ULCER DISEASE;-

• PEPTIC ULCER is defined as disruption of the mucosal integrity of the stomach and/or duodenum leading to a local defect or excavation due to active inflammation.

Epidemiology

• Middle-age to older age .

• peptic ulcers - first portion of the duodenum or in the stomach, in a ratio of about 4:1.

HCLGASTRINHISTAMINEECL

• Male/female ratio is 3:1

CLINICAL PRESENTATION

PEPTIC ULCER DISEASE

IMBALANCE

FACTORS THAT PROTEC

T AGAINS

T ACIDITY

FACTORS THAT INCREASE ACID SECRETI

ON

AcidPepsin Bile acidsNSAIDsH. pylori AlcoholPancrea

tic enzyme

s

Mucusbicarbonate layerBlood flowcell renewalProstaglandinsTight junction b/w epithelium

• Epigastric pain

• Burning, aching, gnawing, hunger pain

aggravated by food in Gastric ulcer ,

relieved by food in Duodenal ulcer

• Bloating and nausea

• Loss of appetite and weight loss in Gastric ulcer

• In Severe Cases

- Vomiting blood or coffee ground like material

- Black tarry stools

CLASSIFICATION OF ANTI-ULCER DRUGS;-

1.Drugs for reduction of acid secretion:

Proton Pump Inhibitors :- Omeprazole , Lansoprozole, Dexlansoprazole ,Pantoprozole ,Rabeprozole, Esomeprozole

H 2 receptor antagonists:- Ranitidine, Famotidine, Cimetidine ,Roxatidine

Anticholinergics : - Pirenzepine, Propantheline ,Oxyphenonium

Prostaglandin analogues : - Misoprostol

2.Drugs to neutralize gastric acid (antacids):

Nonsystemic :- Aluminium hydroxide , Mag. hydroxide

Magaldrate , Mag. trisilicate ,Calcium carbonate .

Systemic :- Sodium bicarbonate , Sodium citrate

MISCELLANEOUS ADJUVANTS -

Simethicone

Sodium alginate

3.Ulcer Protectives:

• Sucralfate, • Colloidal Bismuth Subcitrate and Bismuth

Subsalicylate• Ranitidine bismuth citrate• Newer cytoprotectives- Rebamipide,Ecabet

4.Antimicrobial drugs for H. pylori eradication: • Amoxycillin • Clarithromycin • Metronidazole • Tinidazole • Tetracycline

PHYSIOLOGICAL AND PHARMACOLOGICAL REGULATION OF GASTRIC ACID SECRETION

PROTON PUMP INHIBITORS;-

• Diminish daily acid production (basal and stimulated) by 80-95%• Absorbed from small intestine at a pH of 6• PPIs are prodrugs - acidic environment needed for activation.

MECHANISM OF ACTION • After absorption prodrug gets activated to a tetracyclic sulfenamide

cation .• Activated form then binds covalently with sulfhydryl groups of cysteines in

the H+, K+-ATPase, irreversibly inactivating the pump molecule.

• Maximum acid inhibitory effect between 2 and 6 hours after administration and duration of inhibition lasting up to 72–96 hours.

• Because the pumps need to be activated for these agents to be effective, their efficacy is maximized if they are administered before meal.

DOSAGE OF PPIs :-• Omeprazole 20 mg OD• Esomeprazole 20 - 40 mg OD• Rabeprazole 20 mg OD• Lansoprazole 30 mg OD• Pantoprazole 40 mg OD

PPIs: ADRs• Nausea, Diarrhea, Abdominal pain, Flatulence.• Nosocomial pneumonia• Clostridium difficle diarrhoea • Hypergastrinemia, REBOUND hypersecretion of acid• Arthralgia, headache, skin rashes.

Drug interactions : Decreased acidity may decrease the absorption of Ketoconazole,

Ampicillin esters, Iron salts, Digoxin CYP2C19 and CYP3A4 enz inhibition ®

¯ metabolism of benzodiazepines, warfarin, phenytoin, diazepam, theophylline etc

H 2 RECEPTOR ANTAGONISTS ;-

• Inhibit acid production by reversibly competing with histamine for binding to H2 receptors on the basolateral membrane of parietal cells.

• Suppress acid production by 70%

• Inhibit basal and stimulated acid secretion, which accounts for their efficacy in suppressing nocturnal acid secretion.

• Ranitidine, Famotidine, Roxatidine, Nizatidine.Adverse Drug Reactions of H2 antagonists;-• Diarrhea, headache, drowsiness, fatigue, muscular pain, and constipation. • Confusion, delirium, hallucinations, slurred speech• REBOUND hyperacidity • Pancytopenia, neutropenia, anemia, and thrombocytopenia

Dose of H 2 antagonists;- Ranitidine 300 mg hs Famotidine 40 mg hs Nizatidine 300 mg hs

PROSTGLANDIN ANALOGUES;-

MISOPROSTOL- PGE1 ANALOGUE• MOA- Binds to EP3 receptor on parietal cells and stimulate

Gi pathway- thereby decreasing intracellular cAMP & gastric acid secretion.• Cytoprotective effects

Daily dose –• The usual recommended dose for ulcer prophylaxis is

200 micrograms four times a day.

Pharmacokinetics • Inhibit acid sec.in 30 min.,peaks at 60-90 min.,lasts for 3 hrs.

Adverse effects• Diarrhea• Exacerbations of IBD• C/I in pregnancy as increases uterine motility

ANTICHOLINERGICS (rarely used now) SELECTIVE M1 BLOCKERS-PIRENZEPINE,TELENZEPINE The ACh receptor on the parietal cell is of the M3 subtype. Suppress neural stimulation of acid production via actions on M1

receptors of intramural ganglia. Poor efficacy, significant and undesirable anticholinergic side effects, and

risk of blood disorders (pirenzepine)

ANTACIDS• ALUMINIUM HYDROXIDE, MAGNESIUM HYDROXIDE,

MAGNESIUM TRISILICATE, CALIUM CARBONATE, MAGALDRATE

MOA-neutralises HCL and form AlCl3 and MgCl2 & Carbonates • Fixed combinations of magnesium and aluminum

(Al3+ can relax gastric smooth muscle, producing delayed gastric emptying and constipation; Mg2+ causes loose stools).

• The magnesium-containing preparations : contraindicated in chronic renal failure patients because of possible hypermagnesemia.• Aluminum causes chronic neurotoxicity.

( Calcium Carbonate and Sodium Bicarbonate rarely used now a days.)

DRUG INTERACTIONS• Aluminium and Magnesium ions form inert complexes-

Tetracyclines, Fluoroquinlones, Itraconazole, Digoxin or Iron salts• Aluminium group of antacids decrease the bioavailability of

Phosphates, Iron salts and Digoxin • By raising gastric pH and ionization, antacids decrease the

absorption of acidic drugs- Barbiturates, Phenytoin, NSAIDS .

SIMETHICONE• Silicon polymer, reduces flatulence and hiccups• Surfactant,antifoaming agent, cause proper dispersal of antacid

over gastric surface , coats ulcer base. SODIUM ALGINATE-• Hydrophilic colloidal carbohydrate derived from seaweeds• Used with antacid & H2 antagonist-heart burn & GERD

ULCER PROTECTIVES• SUCRALFATE-• Complex sucrose salt - the hydroxyl groups substituted by

aluminum hydroxide and sulfate.• MOA:

Enhances prostaglandin synthesis, Stimulates mucus and bicarbonate secretion, and Enhances mucosal defense and repair.

Dose:• 1 g four times daily (for active duodenal ulcer) • 1 g twice daily (for maintenance therapy)

SIDE EFFECTS• Constipation• Avoided in pts. with chronic renal insufficiency to prevent

aluminum-induced neurotoxicity • The "sticky" nature of the viscous gel - bezoars in some patients

with underlying gastroparesis.

COLLOIDAL BISMUTH SUBCITRATE & BISMUTH SUBSALICYLATE• In acidic media CBS- forms acid resistant protective coating over

ulcer base• Also stimulates mucosal PGE2 synthesis & HCO3- secretion• Dislodges H.PYLORI from gastric mucosa –antimicrobial activity.• Dose: 120 mg qid • Heals ulcer in 4 – 8 wks• ADRs- blackening of stool,darkening of tongue• Prolonged use –Neuropathy,osteodystrophy, encephalopathy.

Anti H.pylori drugs;-• Helicobacter pylori: gram negative bacillus• Attaches to gastric epithelium:gastritis, dyspepsia, peptic ulcer, gastric

lymphoma, gastric carcinoma.• No single agent is effective in eradicating the organism.• Combination therapy for 14 days provides the greatest efficacy• The agents used with the greatest frequency include amoxicillin,

metronidazole, tetracycline, clarithromycin, and bismuth compounds.

• Choice of a particular regimen will be influenced by - Efficacy, Patient tolerance, Existing antibiotic resistance, Cost of the drugs

• Two anti-H. pylori regimens available in prepackaged formulation: Prevpac (lansoprazole, clarithromycin, and amoxicillin)

The contents taken twice per day for 14 days Helidac (BSS, tetracycline, and metronidazole).

Helidac constituents taken four times per day with an antisecretory agent (PPI or H2 blocker), also for at least 14 days.

TRIPLE THERAPY;- The BEST among all the Triple therapy regimens is

Omeprazole / Lansoprazole - 20 / 30 mg BDClarithromycin - 500 mg BDAmoxycillin - 1gm BD Given for 14 days followed by P.P.I for 4 – 6 weeks

QUADRUPLE THERAPY;-GIVEN WHEN TRIPLE THERAPY FAILS Omeprazole/lansoprazole - 20 / 30 mg OD Bismuth subsalycilate - 525 mg Metronidazole - 250 mg QID Tetracycline - 500 mg QID

SEQUENTIAL THERAPY (10 DAYS);-

For 1-5 days• Omeprazole /lansoprazole -20 mg/30mg BD• Amoxicillin -1 g BD

Followed by 6-10 days• Omeprazole/lansoprazole -20mg/30mg BD• Clarithromycin -500 mg BD• Tinidazole -500 mg BD

Major SIDE EFFECTS of drugs ;- • Bismuth : black stools, constipation, or darkening of the tongue.

• Amoxicillin : nausea, vomiting, skin rash, allergic reaction , pseudomembranous colitis , antibiotic-associated diarrhea.

• Tetracycline : rashes and, very rarely, hepatotoxicity and anaphylaxis.

Treatment of patients infected with resistant strains of H.pylori

• Regimens considered for second-line therapy include:• Combi. of Pantoprazole, Amoxicillin, and Rifabutin for 10 days (86% cure

rate)• Levofloxacin-based triple therapy

(Levofloxacin, Amoxicillin, PPI) for 10 days .• furazolidone-based triple therapy

(Furazolidone, Amoxicillin, PPI) for 14 days.

THANK YOU