Pharmacotherapy

of
Peptic ulcer

Dr. Sanjay Kumar

Assistant Professor
Dept. Of Pharmacology
LCMC&H
Anatomy of gastric glands
Gastric
acid
synthesis
 Gastric acid secretion

Cephalic phase Vagus nerve Acetylcholine Binds to M3 receptors

(sight, smell, taste, released on parietal cells
anticipation of
food)
Gastric acid
GRP released
released

Others
(Local distension of Antral Histamine Histamine
stomach, change in G-cells Stimulate released diffuse to Binds to H2
constituents of secreate ECL cells (paracrine parietal cells receptor
gastric juice) gastrin mediator) (H+K+ATPase)
Gastric acid secretion inhibition
Increased gastric Presence of chyme in duodenum / Others
acid Distension of small bowel
• Vasoactive
intestinal
peptide
Lower pH within Entero-endocrine • Gastric
Enterogastricreflex
stomach reflex inhibitory
peptide

Stimulates D cells Inhibits enteric Inhibitory signal to Release Secretin &

nervous system medulla cholecystokinin

Somatostatin Delays gastric ↓vagal stimulation

released emptying of stomach

Inhibition of stomach acid

secretion
Function of gastric acid

– Activation of pepsinogen to pepsin → protein digestion.

– Kills ingested micro organisms & prevents intestinal infections.

– Intrinsic factor (which is essential for absorption of vitamin B12 in the ileum) is secreted by the parietal cells

along with the secretion of hydrochloric acid.

Etiology of peptic ulcer

1. Hereditary- Increased parietal cell number

2. H. Pylori infection
3. Use of NSAIDs
4. Smoking , alcohol consumption
5. Stress related mucosal damage (SRMD) – due to severe stress like burns, sepsis, trauma, surgery, shock,
respiratory, renal or liver failure.
6. Rare - Gastrinoma (Zollinger-Ellison syndrome) etc..
Pathogenesis of peptic ulcer

Gastric acid hypersecretion

↓
Pepsin-mediated hydrolysis of mucosal proteins
↓
Loss of mucosal defence barrier
↓
Mucosal erosion and ulcerations
Symptoms of peptic ulcer
Diagnosis

1. Clinically by symptoms
2. Upper endoscopy.
3. Upper GI barium radiography.
Treatment

Objectives: – Avoid food containing high citric content like oranges

– Pain relief & tomatoes

– Healing of ulcer – Reduce intake of caffeine, tea and coffee

– Prevention of complications – Avoid carbonated beverages

– Prevention of recurrences – Avoidance of smoking & alcohol

– Consume milk

Conservative management: – Drink plenty of water

– Light early dinner – Discontinue use of NSAIDs

– Avoid pickle, vinegar, red pepper, junk food – Reduce stress

– Practice yoga and meditation
Pharmacotherapy of
peptic ulcer
 Drugs for peptic ulcer

Gastric acid Gastric acid Ulcer Anti H. Pylori

secretion neutralizers protectives drugs
inhibitors (Antacids)
Sucralfate Amoxicillin
Colloidal bismuth Clarithromycin
Proton pump Prostaglandin subcitrate Metronidazole
H2 blockers Anticholinergics Tinidazole
inhibitors analogues
Tetracycline
CBS
Cimetidine Omeprazole Pirenzepine Misoprostol
Famotidine Esomeprazole Telenzepine
Ranitidine Pantoprazole
Lansoprazole Systemic Non systemic
Roxatidine
Lafutidine Rabeprazole
Dexrabeprazole Sodium Magnesium hydroxide
Ilaprazole bicarbonate Magnesium trisilicate
Sodium citrate Aluminium hydroxide
Magaldrate
Calcium carbonate
H2 receptor antagonists

G-protein coupled receptor

Location:
– Gastric glands – acid secretion
– Blood vessels – relaxation
– Heart- positive ionotropic & chronotropic
– Uterus – relaxation
Prototype drug: cimetidine
Mechanism of action:
– reversibly compete with histamine to bind to H2
receptors on parietal cells.
– Less potent (24 hrs gastric acid suppression by 70% )
– All phases (basal, cephalic, gastric) of secretion are suppressed dose-dependently. Secretory response to all
stimuli (histamine, ACh, gastrin, insulin, alcohol, food) is attenuated.

Pharmacokinetics:
Rapid absorption
Minimal plasma protein binding
Minimal hepatic metabolism
Excretion by filtration & tubular secretion in kidneys → dose reduction in renal disease
Drug interactions:
– Cimetidine → CYP450 inhibition → inhibits the metabolism of many drugs so that they can accumulate to
toxic levels e.g. theophylline, phenytoin, carbamazepine, phenobarbitone, sulfonylureas, metronidazole,
warfarin, imipramine, lidocaine, quinidine.
– Antacids reduce absorption of H2 blockers.
– Loss of gastric acidity → ↓Absorption of iron salts, ketoconazole etc.

Adverse Effects:
Well tolerated.
Nausea, diarrhoea, fatigue.
Secondary hypergastrinemia → rebound hypersecretion of acid on discontinuation.
Cimetidine has anti-androgenic action → displaces dihydrotestosterone from its cytoplasmic receptor, increases
plasma prolactin & inhibits degradation of estradiol by liver → gynaecomastia, loss of libido, impotence and
short-lasting decrease in sperm count.
On IV administration: Thrombocytopenia, hallucinations, mental confusion.
Individual agents: 2. Famotidine
1. Ranitidine – Similar to ranitidine
– 5 times more potent – Covalent binding to H2 receptor → longer duration of
– Longer duration of action (t1/2 = 2-3 hrs) action (t1/2= 2.5-3.5 hrs)

– No anti-androgenic action – Dose: 20mg BD

– Lesser permeability into the brain

↓ 3. Roxatidine

Lower propensity to cause CNS effects. – More potent and longer acting than ranitidine
– Dose: 75mg BD

– Less marked inhibition of hepatic metabolism of

other drugs 4. Lafutidine
↓ – enhance nitric oxide production
No significant drug interactions – improve gastric mucosal blood flow
– Dose: 150mg BD – exert gastro-protective effect by increasing mucus
production and somatostatin release
– Dose: 10mg BD
Therapeutic uses:
1. Peptic ulcer
2. Non ulcer dyspepsia
- mostly functional
- characterized by abdominal fullness, gas, bloating, pain, nausea and early satiety
3. GERD
4. Stress ulcer
5. Prophylaxis of aspiration pneumonia- H2 blockers given preoperatively reduce the risk of aspiration of acidic
gastric contents during anaesthesia and surgery.

Current status:

Second line drug for

peptic ulcer, dyspepsia,
GERD, stress ulcer and
prophylaxis of aspiration
pneumonia
Proton Pump Inhibitors
Mechanism of action:
Prodrugs (activation in acidic environment)
↓
Trapping of drug in acidic secretory canaliculi of parietal cell
↓
Irreversible covalent binding with H+K+ATPase pump
↓
24-48 hr suppression of acid secretion (most potent)

– Blocks final step of acid secretion → both basal and stimulated acid secretion inhibited
Phamacokinetics:
Dosage forms to increase bioavailabilty:
-Enteric coated tablets
-Admixture with sodium bicarbonate → neutralize stomach acid
– Dose: 20mg BD 30 mins before meal
– Acid suppression is maximum at 2 hr, is still half maximal at 24 hr and lasts for 2- 3 days
– Parenteral for critically ill
– Rapid absorption
– High plasma protein binding
– Extensively metabolised by CYP2C19 (Asian metabolise PPIs slowly)

Drug Interactions: seen with omeprazole

– Loss of gastric acidity → ↓Absorption of iron salts, ketoconazole etc
– CYP2C19 inhibitor → Accumulation of warfarin, diazepam, phenytoin etc
Adverse effects:
– Excellent safety profile
– Mild A/E: nausea, diarrhea, flatulence etc
– Achlorhydria
– Reduced calcium absorption in the absence of gastric acid
↓
Increased risk of osteoporosis & bone fractures in elderly
– Hypergastrinemia --> Rebound hypersecretion of gastric acid on discontinuation
– Prolonged loss of acid barrier to colonisation by ingested bacteria → increased risk of respiratory and enteric
infections.
Individual agents: Thus minimal drug interactions
1. Esomeprazole: Dose: 40mg OD
– Higher oral bioavailability
– slower elimination → longer t½ 4. Rabeprazole
– Dose: 20mg OD Faster onset
No drug interactions
2. Lansoprazole Dose: 20mg OD
– Higher oral bioavailability
– More potent 5. Dexrabeprazole
– Faster onset More potent than rabeprazole
– Longer t1/2 Dose: 10mg OD
– Dose: 15mg OD
6. Ilaprazole
3. Pantoprazole Similar to omeprazole but more potent
– Higher oral bioavailability Dose: 10mg OD
– Affinity for cytochrome P450 is lower
Therapeutic uses:
– Gastric & duodenal ulcers
– Bleeding peptic ulcer
Gastric Acid → clot dissolution → ulcer bleed.
Suppression of gastric acid → clot formation → reducing blood loss
– GERD
– Helicobacter pylori infection
– NSAIDs associated gastric ulcers- The NSAID should be
discontinued. lf not possible switch over to a COX-2 selective NSAID
– Stress ulcers Current status:
– Zollinger Ellison syndrome First line drug for peptic ulcer,
– Prophylaxis of aspiration pneumonia GERD, stress ulcer, NSAIDs
associated gastric ulcer, zollinger
Ellison syndrome, stress ulcer &
prophylaxis of aspiration
pneumonia.
Zollinger Ellison syndrome- Gastrinoma (a rare tumour secreting gastrin) → gastric hypersecretory state→
Difficult to heal gastric/duodenal ulcer.
Treatment:
High dose oral PPI (60-120 mg/day in 2 doses) is the drug of choice for controlling symptom.
Definitive treatment is resection of the tumour, if possible.
Anticholinergic agents

Mechanism of action:
– Reduce the volume of gastric juice.
– Stimulated gastric secretion is less completely inhibited.

Pirenzepine :
– Selective M1 anticholinergic
– Dose- 100 – 150 mg OD
– Adverse effects: Blood dyscrasias
Telenzepine:
an analogue of pirenzepine, has higher potency and similar selectivity for M1 receptors.
Dose: 3-5mg OD

Current status:

Replaced by more
effective H2 blockers and
PPls.
Misoprostol
– synthetic analogue of PGE1

Mechanism of action:
1. Binds EP3 receptor on parietal cells → ↓cAMP → ↓Gastric acid secretion
2. Cytoprotective : ↑ bicarbonate & mucin secretion
Pharmacokinetics:
Rapid oral absorption
Extensive de-esterification to form active metabolite
A single dose inhibits acid production within 30 min & lasts for up to 3 h.
80% inhibition of basal and food stimulated acid secretion
Excretion in urine
Current status

Adverse effects: Second line drug for

Diarrhea NSAIDs associated ulcer
Abdominal pain
Exacerbate inflammatory bowel disease
↑ Uterine contractions → Uterine bleeding , Abortion → Contraindicated in pregnancy

Therapeutic uses:
FDA approved to prevent NSAID-induced mucosal injury (200 mcg QID)
Sucralfate
– Sucralfate
consists of the
octasulfate of
sucrose to
which Al(OH)3
has been
added.
Mechanism of action:
1. Acid environment (pH < 4)
↓
Sucralfate undergoes extensive cross-linking to produce a viscous, sticky polymer
↓
Polymer adheres to epithelial cells and ulcer craters for up to 6 h after a single dose.
↓
Surface proteins at the ulcer base are precipitated, together with which it acts as a physical barrier preventing
acid, pepsin and bile from coming in contact with the ulcer base
2. Stimulation of local production of PGs and epidermal growth factor
3. Delays gastric emptying → so that its own stay in stomach is prolonged.
4. Binds bile salts
Pharmacokinetics:
Activated by acid → hence taken on an empty stomach
→ Avoid use of antacids within 30 min of a dose of sucralfate

Drug interactions:
1. Aluminum-containing antacids with sucralfate can precipitate aluminium toxicity.
2. Sucralfate layer in the stomach → may inhibit absorption of other drugs (eg- phenytoin, digoxin, cimetidine,
ketoconazole and fluoroquinolone antibiotics) → Hence sucralfate taken 2 h after the administration of other
drugs.

Adverse effect:
Constipation
Hypophosphatemia (by binding phosphate ions in the intestine)
Sticky nature of the viscous gel produced by sucralfate in the stomach → development of bezoars
Therapeutic uses:
1. Peptic ulcer (1g taken in empty stomach 1 hour before the 3 major meals and at bed time for 4-8 weeks)
2. Stress ulcer prophylaxis (No risk of nosocomial pneumonia in critically ill)
3. Oral mucositis (radiation and aphthous ulcers)
4. Mucosal inflammation/ulceration
5. Radiation proctitis and solitary rectal ulcers (Sucralfate rectal enema)
6. Bile reflux gastropathy
7. A topical fomulation of sucralfate is available as a protective for application on burns, bedsores,
diabetic/radiation ulcers and excoriated skin
Current status

• First line agents for treatment

of peptic ulcer and GERD in
pregnant females
• Second line drug for peptic
ulcer and stress ulcer
prophylaxis
Colloidal bismuth subcitrate

– It is a colloidal bismuth compound; water soluble but precipitates at pH < 5.

– Heals 60% ulcers at 4 weeks and 80-90% at 8 weeks.

Mechanism of action: Probablities

• May increase gastric mucosal PGE, mucus and HCO3- production.
• May precipitate mucus glycoproteins and coat the ulcer base.
• May detach and inhibit H. pylori directly.
Pharmacokinetics:
– Most of the ingested CBS passes in the faeces. Small amounts absorbed are excreted in urine.
– Antacids should not be taken concomitantly.

Adverse effect:
Diarrhoea
Headache and dizziness
Blackening or tongue, dentures and stools

Therapeutic use:
H. Pylori infection: component of triple
Current status
drug anti H.pylori regimen (120 mg QID for 4-8 weeks)
Component of triple drug
anti H.pylori regimen.
Antacids

– Basic substances which neutralize gastric acid → raise pH of gastric contents.

Mechanism of action:
Pepsin is secreted as a complex that dissociates at
pH<5 (pH for optimum peptic activity is pH 2 to 4)
↓
Antacids raise the antral pH to > 4
↓
Peptic activity is indirectly reduced at pH > 4
↓
Symptomatic relief
Acid neutralizing capacity:
– denotes potency of an antacid
– number of mEq of 1N HCI that are brought to pH 3.5 in 15 min (or 60 min in some tests) by a unit dose of the
antacid preparation

Classification:

Systemic Non-systemic

• Sodium bicarbonate • Magnesium hydroxide

• Sodium citrate • Magnesium trisilicate
• Aluminium hydroxide gel
• Magaldrate
• Calcium carbonate
A. Systemic antacids:
1. Sodium bicarbonate 2. Sodium citrate
Water soluble → instantaneous action Properties similar to sodium bicarbonate
Short duration of action CO2 is not evolved.
Potent neutralizer → pH may rise >7
Demerits:
– Absorbed systemically → induce alkalosis
– Produces CO2 in stomach → distention,
discomfort, belching, risk of ulcer perforation
– Acid rebound
– Increases Na+ load → worsen edema and CHF
Uses:
– Heartburn- quick symptomatic relief
– Alkalinize urine
– Treat acidosis.
B. Nonsystemic Antacids:
Insoluble and poorly absorbed basic compounds
React in stomach to form the corresponding chloride salt which again reacts with the intestinal bicarbonate so
that HCO3- is not spared for absorption- no acid base disturbance occurs.

1. Magnesium hydroxide (Milk of magnesia)

Has low concentration of OH- ions and thus low alkalinity.
Reacts with HCI promptly → efficacious antacid ( I g • 30 mEq HCI).

2. Magnesium trisilicate
Has low reactivity

Demerit: All Mg salts generate osmotically active MgCI2 in the stomach → laxative action.
3. Aluminium hydroxide gel
– Bland, weak and slowly reacting antacid
– On keeping it slowly polymerizes into less reactive forms → ANC gradually declines on storage
– Al+3 ions relax smooth muscle → delays gastric emptying → causes constipation due to its smooth muscle
relaxant and mucosal astringent action.
– Small amount of Al+3 that is absorbed is excreted by kidney. Thus in renal failure → aluminium toxicity
(encephalopathy, osteoporosis)

4. Magaldrate - Hydrated complex of hydroxymagnesium aluminate

4. Calcium carbonate
Potent and rapidly acting acid neutralizer.
Liberates CO2 in the stomach → cause distention and discomfort.
Ca+3 ions diffuse into the gastric mucosa → ↑HCI production (directly by parietal cells & by releasing gastrin) →
Acid rebound
In past: Large quantity of milk + CaCO3 (or NaHCO3) → Milk alkali syndrome → hypercalcaemia and alkalosis →
Headache, anorexia, weakness, abdominal discomfort, abnormal Ca+2 deposits and renal stones

Drug interactions:
1. Antacids → ↑ gastric pH & forms complexes → ↓ the absorption of other drugs (tetracyclines, iron salts,
fluoroquinolones, ketoconazole, H2 blockers, diazepam, phenothiazines, indomethacin, phenytoin, isoniazid,
ethambutol and nitrofurantoin).
2. Antacids → Alkalinization of urine → Efficacy of nitrofurantoin reduced
Demerits:
Large and frequent doses → inconvenient → poor patient acceptability.
Acid rebound
Bowel upset
Little nocturnal protection

Uses:
Only for intercurrent pain relief, dyspepsia and acidity, nonulcer dyspepsia, acid eructation and minor episodes of
acid reflux (heartburn).
Current status:
Gastroesophageal reflux- faster symptom relief but not sustained.
-Acute treatment of acid
reflux, dyspepsia and
GERD
-First line agents for
treatment of peptic ulcer
and GERD in pregnant
females
Other agents

Rebamipide:
– used for ulcer therapy in parts of India and Asia.
– cytoprotective effects are exerted by increasing PG generation in gastric mucosa and by scavenging reactive
oxygen species.

Ecabet
used for ulcer therapy, mostly in Japan.
Increase the formation of PGE2 and PGI2.
Other agents

Carbenoxolone:
– Used with modest success for ulcer therapy in Europe
– Derivative of glycyrrhizic acid found in licorice root.
– Increases the secretion of gastric mucus.
– Adverse effect: It inhibits the type I isozyme of 11β-hydroxysteroid dehydrogenase (which protects the
mineralocorticoid receptor from activation by cortisol in the distal nephron) → excessive mineralocorticoid
receptor activation→ Hypokalemia and hypertension.
Helicobacter pylori
Helicobacter pylori

– H. pylori is a gram negative bacillus (a commensal in 20-70% normal individuals)

Pathophysiology:
It attaches to the surface epithelium beneath the mucus
↓
Produces ammonia (high urease activity) which maintains a neutral microenvironment around the bacteria
↓
Promotes back diffusion of H+ ions
↓
Asymptomatic neutrophilic gastritis lasting 7- 10 days
↓
Chronic gastritis, dyspepsia, peptic ulcer
↓
Gastric lymphoma and gastric carcinoma
Detection of H.pylori
Endoscopy
Detection of antibodies in serum
Rapid urease test of antral biopsy
The fecal antigen test- sensitive, specific and inexpensive
Urea breath test- used to confirm eradication of H. pylori

Who should receive anti H.pylori therapy:

– All H. pylori positive ulcer patients
– In the absence of H. pylori testing, all cases with failed conventional ulcer therapy and relapse cases
Treatment of H.pylori infection:
1. Triple drug regimen
2. Quadruple drug regimen
– Recommended for eradication failure cases.
Sr No. Quadruple drug regimen
1 CBS 120 mg QID + tetracycline 500 mg QID + metronidazole 400 mg TDS + omeprazole 20 mg BD

2 PPI + amoxicillin + clarithromycin + metronidazole all BD for 2 weeks

Benefits of anti H.pylori therapy:

– Lowers ulcer disease prevalence.
– Prevents gastric carcinoma/lymphoma.

Demerits of anti H.pylori therapy:

Complex and expensive regimens.
Frequent side effects.
Poor compliance.
Gastroesophageal reflux
disease
Gastroesophageal reflux disease

Characterized by heartburn, acid eructation, sensation of stomach contents coming back in the food pipe,
especially after a large meal, aggravated by stooping or lying flat.

Etiology:
1. Anatomical: Hiatus hernia.
2. Functional: due to reduced Lower esophageal spincter tone
– Pregnancy
– Consumption of fats, alcohol, coffee, chocolates
– Anticholinergics, tricyclic antidepressants, Ca+2 channel blockers, nitrates
– Smoking
Stages of GERD
Stage 1: Occasional heartburn (<3 episodes per week)
-Due to precipitating factors
-Mild symptoms
-No esophageal lesions

Stage 2: >= 3 episodes/week

-moderate to severe symptoms
-nocturnal awakening due to regurgitation
-esophagitis present or absent

Stage 3: -Daily/chronic symptoms

-Disturbed sleep, esophagitis/erosions/
stricture/extraesophageal symptoms like laryngitis,
hoarseness, dry cough, asthma.
-Symptoms recur soon after treatment is stopped
Complications of GERD:
Esophagitis, cough, erosions, ulcers, pain on swallowing, dysphagia, strictures, laryngitis, pulmonary complication,
increased risk of esophageal carcinoma.
Treatment:
A) Conservative management
B) Pharmacological therapy
1. Proton pump inhibitors
2. H2 blockers
3. Prokinetic drugs
Eg- Metoclopromide , domperidone, mosapride etc
Mechanism of action:
– Increasing LES tone
– Facilitate gastric emptying
4. Antacids
5. Sodium alginate
Increases viscosity of gastric contents
↓
Forms a thick frothy layer which floats on the gastric contents like a rail
↓
Prevent contact of acid with esophageal mucosa.
Peptic ulcer disease in pregnant female

Mild cases- Conservative management

Pharmacotherapy:
First line agents: Antacids , sucralfate
Second line agents: H2 blockers (Preferred drug- Ranitidine)
Intractable symptoms/ complicated reflux disease: Proton pump inhibitors ( safest choice- Omeprazole,
lansoprazole & pantoprazole)
Complicated peptic ulcers
Perforated peptic ulcer
– Gastroenterostomy
– Vagotomy
– Gastroduodenal resections:
– Anterectomy/ subtotal gastrectomy
– Distal gastrectomy
– Partial duodenectomy
– Billroth I & II operation
Bleeding peptic ulcer:
Endoscopic hemostasis using
– Injection (epinephrine and thrombin/fibrin glue)
– Electrocoagulation
– Heater probe
– Sclerosants (eg- absolute alcohol)
– Application of clips
– Transcatheter arterial embolization (polyvinyl alcohol,
gelatine sponge, N-butyl cyanoacrylate and coils)
Algorithm for
treatment of
peptic ulcer
Thank You