PEPTIC ULCER

Dr. AFROZ ABIDI

Professor, Pharmacology
ELMC, Lucknow.
 Peptic Ulcer
• An Ulcer is …

 Erosion in the lining of the stomach or the

duodenum.

Ulcers damage the mucosa of the alimentary tract,

which extends through the sub mucosa and
muscularis mucosa or deeper.
Ulcers that form in the stomach are called gastric ulcers; in
the duodenum, they are called duodenal ulcers. Both types
are referred to as peptic ulcers.
 Why Peptic ulcer occurs

• Imbalance primarily between Aggressive factors

and Defensive factors

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 Pathogenesis of peptic ulcer disease

AGGRESSIVE FACTORS DEFENSIVE FACTORS

• Acid • Prostaglandins
• Pepsin • Mucosal blood flow
• Helicobacter pylori • Mucous gel layer
• NSAIDS • HCO3
• Stress • Regeneration of the
epithelial layer
• Epidermal growth factor

Gastric ulcer – acid secretion is normal to low, more role of

deficient mucosal barrier & defense mechanism
Duodenal ulcer – acid secretion is usually increased.
 Helicobacter pylori
• 1981 - Robin Warren, M.D.,
an Australian pathologist,
discovered numerous
bacteria living in tissue
taken during a stomach
biopsy.

– Spiral urease-producing,
Gram-negative bacteria
always accompanied by
changes in the stomach
lining
– Breakdown urea to ammonia
 Phases of acid secretion
• Cephalic phase: Sight, smell, taste of food. 30%
secretion
• Gastric phase: Food stimulates stretching of
stomach. 60% secretion
• Intestinal phase: Food reaches duodenum which
regulates acid sec. 10% secretion
• Basal (Interdigestive phase): Occurs in between
meals. Regulated by body wt, number of parietal
cells & time of day.
Acid secretion is lowest in morning before
awakening & highest at night.
 Physiology of gastric acid secretion
• Gastric acid secretion is a complex, continuous
process in which multiple central and peripheral
factors contribute to a common endpoint →
secretion of H⁺ by parietal cells.
• Neuronal(Ach),paracrine(histamine), and endocrine
(gastrin) factors all regulate acid secretion.
• Their specific receptors (M ,H2,and CCK2 receptors,
3

respectively) are on the basolateral membrane of

parietal cells in the body and fundus of the
stomach.
• The H2 receptor is a GPCR that activates the
Gs- adenyl cyclase –cyclic AMP-PKA pathway.
• Ach (M3) and gastrin (CCK2) signal through
GPCRs that couple to the Gq-PLC-IP3-Ca2+
pathway in parietal cells .
• In parietal cells , the cyclic AMP and the Ca2+
dependant pathways activate H+,K+-ATPase
(the proton pump), which exchanges hydrogen
and potassium ions across the parietal cell
membrane
• PGE2 (EP3 receptor) produced by gastric
mucosa inh acid secretion – Gi rec (inh cAMP)
PARIETAL CELL
• Most imp secretagouge is Histamine thru H2
receptor, bcz Ach & gastrin act partly directly &
also indirectly by releasing histamine from
paracrine enterochromaffin cells called
histaminocytes.
• PG have cytoprotective role by ↑ mucus &
bicarbonate secretion from epithelial cell &
decrease acid secretion from parietal cell.
 Symptoms of Peptic Ulcer
• Abdominal pain – Epigastric burning or gnawing
discomfort, ill defined aching sensation
• DU- Pain Starts 2/3 hours after meals, or in the
middle of the night & awakes the pt- (specific for
DU)- Relieved by antacids or food.
• GU- Discomfort ppt by food, more nausea & wt loss
• Feeling of Fullness
• Indigestion/dyspepsia- Nausea & vomiting
• Bleeding/perforated PU- Haematemesis, Melena
• Anorexia, Unexplained weight loss
 Diagnosis
• Endoscopy:
Flexible tube fitted with
camera is threaded down
the esophagus in to
stomach to see the ulcer by
physician
• Barium meal:
Barium liquid is drunk
making ulcer visible on X-
ray
 Test for diagnosing H.pylori

 Breath test :by measuring the amount of CO2

in exhaled breath.
 Blood test: by identifying H.pylori antibodies
by ELISA test.
 Stool test :stool sample tested with H.pylori
antigen.
 Classification of drugs
1. Drugs that inhibit gastric acid
secretion
2. Drugs that neutralize gastric acid
(Antacids)
3. Ulcer protectives
4. Anti H. pylori drugs
 Classification
• Drugs that inhibit gastric acid secretion
– Proton pump inhibitors: Omeprazole, Pantoprazole,
Rabeprazole, esomeprazole
– H2 receptor blockers: Cimetidine, Ranitidine,
Famotidine
– Anticholinergics : Pirenzepine
– Prostaglandin analogues: Misoprostol
• Drugs that neutralize gastric acid (Antacids)
– Systemic: Sodium bicarbonate, sodium citrate
– Non systemic : Magnesium hydroxide, Mag.
Trisilicate, Aluminium hydroxide gel, Magaldrate
 Classification
• Ulcer protectives
– Sucralfate
– Colloidal Bismuth Subcitrate (CBS)
• Anti H. pylori drugs
– Amoxicillin, Clarithromycin, Metronidazole,
Tinidazole, Tetracycline
 Proton Pump Inhibitors
Most effective drugs in antiulcer therapy
• Omeprazole Lansoprazole
• Esomeprazole Pantoprazole

• Significant action of PPI is dose dependent supression of

gastric acid secretion without cholinergic or H2 blockade.
• It is a powerful inhibitor of gastric acid: can totally abolish
HCL secretion both resting as well as stimulated by food
• No action on pepsin, intrinsic factor, juice volume or
gastric motility
 MOA- Omeprazole
• Prodrugs inactive at neutral pH - requiring activation in
acid environment
• 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
• After diffusing in parietal cell, conc in canaliculi which is
acidic as the charged forms are unable to diffuse back.
• It is tightly bound to enzyme & inhibits it irreversibly,
hence acid secretion will resume only when new
enzyme is synthesized.
• Also inhibits gastric mucosal carbonic anhydrase
 Pharmacokinetics - PPI
• They should be given 30 minutes to 1 hour before food intake.
• BA decreased by food
• Only active secreting pumps are inhibited so to activate pumps
food taken after 1 hr, PPI reaches peak and activated pumps are
more inhibited.
• Half life is very short and only 1-2 Hrs
• Still the action persists for 24 Hrs to 48 hrs after a single dose as
it is tightly bound to enzyme
• Action lasts for 3-4 days even after stoppage of the drug
• Only active secreting pumps are inhibited, & only few pumps are
active during PPI intake , hence antisecretory action ↑ on daily
dosing & plateaus after 4 days.
 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: Fastest acid suppression
• Es-omeprazole
– High BA, Better intragastric pH , higher healing
rates.
 Uses of PPI
• Gastroesophageal reflux disease (GERD)
• Peptic Ulcer - Gastric and duodenal ulcers
• Bleeding peptic Ulcer
• Zollinger Ellison Syndrome: gastric hypersecretion d/t
gastrin secreting tumor
• 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: preoperatively night before ↓
aspiration of acidic contents during surgery & anesthesia
 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
 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
– Long term use- Achlorhydria , compensatory
hypergasternemia.
 Drug interactions
• Omeprazole inhibits the metabolism of
warfarin, phenytoin, diazepam, and
cyclosporine.
• However, drug interactions are not a problem
with the other PPIs.
H2 ANTAGONISTS
 Mechanism of action
• Competitively block H2 receptors on parietal cell
& inhibit gastric acid production
• Suppress secretion of acid in all phases but
mainly basal nocturnal acid secretion is
suppressed.
• Most imp secretagouge is Histamine thru H2
receptor, bcz Ach & gastrin act partly directly &
also indirectly by releasing histamine from
paracrine ECL cells.
• Also reduce acid secretion stimulated by Ach,
gastrin, food, etc.
• Upto 70% inh of 24 hr acid output at the ulcer
healing dose.
• Gastric ulcers d/t stress, drugs prevented.
• Ranitidine- Ulcer healing- 300 mg hs or 150mg
BD, Maintenance- 150 mg hs
• Famotidine- Ulcer healing- 40 mg hs or 20 mg
BD, Maintenance-20 mg hs.
• Roxatidine- Ulcer healing- 150 mg hs or 75 mg
BD, Maintenance- 75 mg hs
 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
 Comparison of H2 antagonists

Cimetidine Ranitidine Famotidine Nizatidine

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
 H2 antagonists - Uses
Promote the healing of gastric and duodenal ulcers
• Duodenal ulcer – 70 to 90% heal in 8 weeks
• Gastric Ulcer – 50 to 75% heal in 8 wks
• NSAID induced ulcers
• Stress ulcer and gastritis
• GERD
• Zollinger-Ellison syndrome: gastric hypersecretion d/t gastrin
secreting tumor
• Prophylaxis of aspiration pneumonia: preoperatively night
before ↓ aspiration of acidic contents during surgery &
anesthesia
 Adverse effects
• Well tolerated, safe
• Headache, dizziness, bowel upset, dry mouth,
rashes.
• CNS: Confusion, restlessness, convulsions, coma
• Cimetidine has antiandrogenic actions, ↑
prolactin & ↓ estrogen degradation by liver.
Gynecomastia, impotency, ↓ sperm count.
• Elevation of liver enzymes.
 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. Given in 2 hrs gap.
• Ketoconazole absorption is decreased d/t
reduced acidity
Muscarinic antagonists- Anticholinergics

• Block the M1 class receptors

• Reduce acid production, abolish gastrointestinal spasm

Pirenzepine and Telenzepine

• Reduce meal stimulated HCl secretion by reversible blockade
of muscarinic (M1) receptors on the cell bodies of the
intramural cholinergic ganglia
• This further reduces cholinergic innervation to ECL cells
releasing Histamine.
• Unpopular as a first choice because of high incidence of
anticholinergic side effects (dry mouth and blurred vision)
 Prostaglandin analogues- Misoprostol
• PGE1 Ester
• Inhibit gastric acid secretion (Gi rec on parietal cells)
• Enhance local production of mucus or bicarbonate
• Cytoprotective action: Secretion of mucous & HCO3-,
gastric mucus forms an adherent gel like film over
mucosa which traps HCO3 – ions. Also protects
mucosa from pepsin attack
• Help to maintain mucosal blood flow
• Short acting, T1/2 = 3hrs
• Ulcer healing in 4-8 wks, but does not relieve ulcer
pain.
 Misoprostol
• Therapeutic use:
– Prevention of NSAID-induced mucosal injury (rarely used
because it needs frequent administration – 4 times daily)
– 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 disorder

• Contraindications:
– Inflammatory bowel disease
– Pregnancy (may cause abortion)
 Antacids
• Weak bases that neutralize acid, ↑ pH
• Also inhibit formation of pepsin
(As pepsinogen converted to pepsin at acidic pH)

• Acid Neutralizing Capacity: (ANC)

– Potency of Antacids
– Expressed in terms of Number of mEq of 1N HCl
that are brought to pH 3.5 in 15 minutes by unit
dose of a preparation (1 gm)
• Single dose in empty stomach acts for 30-
60 min
• With meals acts for 2-3 hrs
• Antacids evoke reflex gastrin release,
more acid secreted, esp in pts with
hyperacidity & duodenal ulcer leading to
acid rebound & ↑ gastric motility.
 Systemic antacids
• Sodium Bicarbonate:
– Water soluble, short duration of action
– Potent neutralizing capacity and acts instantly
– ANC: 1 gm = 12 mEq HCl, pH > 7.
• Demerits:
– Systemic alkalosis
– Distension, discomfort and belching – CO2
– Rebound acidity
– Sodium overload- worsen edema & CHF
• Uses:
– Heartburn
– Alkalinize urine & t/t of acidosis
 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 absorbed-
no acid base disturbance
 Non systemic Antacids
• Magnesium hydroxide (ANC 30 mEq) :Aqueous
suspension is called Milk of magnesia
• Magnesium trisilicate (ANC 10 mEq)
Mg salts cause diarrhea
• Aluminium Hydroxide (ANC 1-2.5mEq/g)
Causes constipation, hypophosphatemia and
osteomalacia
• Magaldrate – hydrated hydroxy magnesium
aluminate (ANC 28mEq/g)
• Calcium Carbonate (ANC 20mEq/g)
Causes acid rebound & milk alkali syndrome.
Chemical reactions of antacids with HCl in
the stomach
 Non systemic antacids
• Duration of action : 30 min when taken in empty
stomach and 2 hrs when taken after a meal
• Adverse effects:
– Mg2+ antacids – Osmotic diarrhoea
– Aluminium antacids – constipation (As they relax
gastric smooth muscle & delay gastric emptying) –
also hypophosphatemia and osteomalcia
– In renal failure Al3+ antacid – Aluminium toxicity
& Encephalopathy
 Uses & Drug interactions
• Uses
 Nonulcer dyspepsia, episodes of heartburn
 GERD
• Drug Interactions
 By raising gastric pH & forming insoluble complexes ↓
absorption of many drugs
– Tetracyclines, iron salts, H2 Blockers, diazepam, phenytoin,
isoniazid, ethambutol
 Adm delayed by 2 hrs
 Sucralfate – ulcer protective
• Basic 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
preventing acid, pepsin & bile from coming in contact
with ulcer
• Dietary proteins get deposited on this layer forming
another coat
• No acid neutralization, delays gastric emptying, own
stay prolonged
• Not absorbed, local action- healing of peptic ulcers
 Sucralfate
• 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 – TC, FQ, Cimetidine, phenytoin,
digoxin.
Colloidal Bismuth Subcitrate (CBS)
Mechanism of action
• CBS and mucous form glycoprotein Bi complex
which coats ulcer crater & acts as diffusion
barrier
• ↑ 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, ½ hr before meals
& at bed time for 4-8 wks
• Adverse effects
– blackening of tongue, stools, dentures
– Prolonged use may cause osteodystrophy and
encephalopathy
– Diarrhoea, headache, dizziness
 H.pylori
• Gram (-) rod
• Associated with chronic
gastritis, gastric & duodenal
ulcers, gastric lymphoma &
adenocarcinoma
• Transmission route fecal-oral
• Secretes urease → convert
urea to ammonia which
maintains alkaline
environment enabling survival
in stomach
• Higher prevalence in Low SES
 Eradication of H.pylori: Triple
Therapy
Triple therapy: 3 drugs (PPI + 2 groups of antibiotics)

BEST among all the Triple therapy regimen is:

Lansoprazole - 30 mg bd
Clarithromycin - 500 mg bd
Amoxycillin / Metronidazole - 1gm / 500 mg bd

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

Short regimens for 7 – 10 days not very effective
 Other regimens
• Amoxicillin 750 mg + Tinidazole 500 mg
+omeprazole 20 mg/ lansoprazole 30 mg BD
• Clarithromycin 250 mg + Tinidazole
500/amoxicillin 1000 mg + lansoprazole 30 mg
BD
• Quadruple therapy x 14 days: 4 drugs (PPI + 2
groups of antibiotics + ulcer protective)
Proton pump inhibitor BD + metronidazole
500 mg TDS + tetracycline 500 mg QID +
bismuth subsalicylate 525 mg
 GERD
• Symptoms- heart burn, acid eructation,
regurgitation, aggravated by lying flat
• Relaxation of LES- reflux of acidic contents in
esophagus causing esophagitis, erosions,
ulcers, pain on swallowing, dsyphagia,
strictures,↑ risk of esophageal carcinoma.
• Causes-
– Pregnancy
– DIET rich in fats, alcohol, chocolates, coffee
– DRUGS- anticholinergics, TCA, CCB, Nitrates
 GERD Grading
• Stage 1: Ocassional ( 3 episodes/wk), mild
symptoms, ppt factors present, no esophageal
lesions
• Stage 2:  3 episodes/wk, moderate
symptoms, nocturnal awakening d/t
regurgitation, esophagitis present or absent
• Stage 3: Daily chronic symptoms, disturbed
sleep, esophagitis, erosions, strictures
present. Extraesophageal symptoms-
laryngitis, hoarseness, dry cough.
 T/t of GERD
• Dietary/Lifestyle modifications: Light early
dinner, wt reduction, avoid ppt factors, raise
head end of bed.
• PPI & H2 blockers: Symptomatic relief &
healing of lesion
• Antacids: occasional relief of heartburn
• Prokinetics: Metoclopramide, cisapride etc
relieve regurgitation & heartburn by ↑ LES
tone, improve esophageal clearence &
facilitate gastric emptying. Combined with PPI.