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PHARMACOTHERAPY OF PEPTIC ULCER DISEASE

Dr Harsha R Assistant Professor Department of Pharmacology

PHARMACOTHERAPY OF ACID PEPTIC DISEASE

Dr Harsha R Assistant Professor Department of Pharmacology

Peptic ulcer disease

Peptic ulcer disease is one of the common GI disorder in clinical practice

Peptic ulcer is defined as breach in mucosa that occurs in part of GIT which is exposed to gastric acid and pepsin i.e.

Stomach and Duodenum

Peptic ulcer Disease

  • 1. Gastric ulcer

  • 2. Duodenum ulcer

  • 3. Stress ulcers

  • 4. NSAIDs induced ulcer

Peptic ulcer disease

In all these condition at the end MUCOSAL EROSION OR ULCERATION

develops

The exact etiology for development of these ulceration is unknown.

It results probably due to imbalance between the aggressive factors and the defensive factors

Peptic ulcer disease

Gastric ulcer vs. Duodenal ulcer

 

Gastric ulcer

Duodenal ulcer

1.

Acid secretion is Normal

Acid secretion is higher

2.

Deficient mucosal defense plays a key role in gastric ulcer

3.

H Pylori has a role NSAIDs has a role

H Pylori has a role

4.

Gastric ulcer tend to occur later in life With peak incidence reported in 6 th decade

 
 
 
 
 

Peptic ulcer disease

1 st approach in treating any case of ACID PEPTIC DISEASE ( GERD, GASTRIC ULCER, DUODENAL ULCER, NSAIDs Induced ulcer, Stress ulcer, non ulcer dyspepsia) is reduction of gastric acid secretion

Classification of drugs used in APD

Drugs used to reduce gastric acid secretion

1. Drugs reducing gastric acid secretion secretory)

( Anti

  • a) Proton Pump Inhibitors( PPIs)

  • b) H 2 antihistamines

  • c) Anti-cholinergic drugs

Proton Pump Inhibitors

Most widely prescribed acid suppressing drugs world wide due to their

outstanding efficacy and safety.

PPIs have assumed a major role for the treatment of acid peptic disorders

PPIs available for clinical use

Omeprazole ( Prototype) Esomeprazole Patoprazole Rabeprazole Dexrabeprazole Lansoprazole Dexlansoprazole

Omeprazole(Prototype drug)

Mechanism of Action Uses Adverse effects

Gastric gland

Gastric gland

Gastric Parietal cell

Gastric Parietal cell

Mechanism of action

PPIs are administered as Inactive Prodrug. Inactive Prodrug is acid labile

To protect this acid labile inactive prodrug from rapid destruction- PPIs are

Enteric coated tablets Delayed release tablets

Mechanism of action

PPIs- Enteric

Mechanism of action

This active drug molecule inside the parietal cell will form a covalent

disulfide bond with H + /K + - ATPase irreversibly inactivating the enzyme.

Mechanism of action

Mechanism of action

Pharmacokinetics

All PPIs are administered orally in enteric coated form or in delayed release formulation. Bioavailability: Of all PPIs is reduced by Food

All PPIs should be taken in Empty stomach, followed one hour later by a meal to activate the H + /K + - ATPase.

PPB: highly bound to Plasma Proteins

Uses

  • 1. Gastro esophageal reflux disease

  • 2. Peptic ulcer disease

    • A. H pylori associated ulcer

      • B. NSAID- associated ulcer

      • C. Prevention of re-bleeding from peptic ulcer

        • 3. Non ulcer dyspepsia

        • 4. Prevention of stress releated mucosal bleeding

1. Gastro-esophageal reflux disease(GERD)

Gastro-esophageal reflux disease(GERD)

2. Peptic ulcer disease

A. Peptic ulcer disease- H pylori associated ulcer

OCA- Regimen

OCM- Regimen

OCT- Regimen

B. PUD-NSAIDs induced ulcer

NSAIDs are weak organic acids

NSAIDs induced ulcer

Aspirin and other NSAIDs inhibit

NSAIDs induced ulcer

NSAIDs induced ulcer

C. Prevention of rebleeding from peptic ulcers

3. Non ulcer dyspepsia

PPIs have modest efficacy for treatment of non ulcer dyspepsia

It benefits only 10-20% of patients having non ulcer dyspepsia

4. Prevention of stress related Mucosal bleeding

Adverse effects

PPIs are extremely safe PPIs produce minimal adverse effects

PPIs are not teratogenic in animal models

However safety during pregnancy has not been established

Adverse effects

Adverse effects

Q1-Explain why proton pump inhibitors should be administered on empty stomach?

PPIs to be taken 30 Minutes before breakfast

PPIs to be taken in empty stomach then one hour later patient is advised to take food

Q2-Explain why PPIs are administered once daily even though they have short half life ?

 

Drug

Half life

Administration

  • 1 Omeprazole

1hr

OD

  • 2 Esomeprazole

1.5hr

OD

  • 3 Lansoprazole

1-2hr

OD

  • 4 Dexlansoprazole

1-2hr

OD

  • 5 Pantoprazole

1-2hr

OD

  • 6 Rabeprazole

1-2hr

OD

 

Paracetamol

6-8hr

3-4times a day

Rationale

Though PPIs have a short serum half life of about 1-2hrs, acid inhibition is present

for up to 24hrs. This is due to Irreversible inactivation of the proton pump (H + /K + - ATPase)

The synthesis of new proton pump (H + /K + - ATPase) will take around 18- 24hrs. Till then action of PPIs will last

Q3-Explain why PPIs are called “hit and run” drugs?

After few hours of administration of PPIs , they are removed from the body but their effect( Acid supressing effect) continues

Esomeprazole

It is the S-enantiomer of omeprazole Claimed to have higher oral bioavailability Claimed to have better acid supression effect

Pantoprazole

It is similar in potency and clinical efficacy to omeprazole

More acid stable Higher bioavailability It is also available for IV administration

Rabeprazole

This newer PPI is claimed to cause fastest acid suppression

Potency and efficacy similar to omeprazole

H2 blockers

Write a note on H 2 – Receptor Antagonist Explain disadvantage of cimetidine Rantidine is preferred over cimetidine in peptic ulcer. Rantidine is preferred over cimetidine in clinical practice . Give reasons. How does cimetidine differ from ranitidine?

H 2 – Receptor Antagonist

H 2 – Receptor Antagonist commonly referred as H 2 blockers

Before the advent of PPIs H 2 blockers were the first line of drugs in treating APD

Four H 2 blockers are in clinical use Cimetidine ( Prototype) Ranitidine Famotidine Nizatidine : Roxatidine

Cimetidine( Prototype drug)

MOA Cimetidine vs Rantidine Uses Adverse effects

MOA

Because of structural similarity to histamine , these drugs act selectively by competitive blockade of parietal cell H 2 Receptor.

Tolerance : due to down regulation of H 2 receptor

Rebound phenomenon: May occur

MOA

MOA

MOA

When given in usual prescription dose all

H 2

– Receptor Antagonist inhibit 60-70% of total 24hr acid secretion H 2 – Receptor Antagonist are specially effective at inhibiting Nocturnal acid secretion ( which depends largely on histamine) Modest impact on meal- stimulated acid secretion ( which depends on Ach, Gastrin, and histamine)

Q1-Rantidine vs Cimetidine

Rantidine is 5 times more potent than Cimetidine

Rantidine has longer duration of action with greater 24hrs acid supression

No Anti- androgenic effect. Cimetidine has Anti- androgenic effect it causes gyanecomastia and reduced sperm count and impotence

Less Central nervous system effects:

Rantidine does not cross BBB , hence incidence of CNS effects very less

Leeser drug interaction with Rantidine when compared with cimetidine

Q2-Explain why cimetidine but not rantidine prolong half life of concurrently administered drugs ?

Cimetidine inhibits several Cytochrome P-450 isoenzymes- Drug metabolising enzymes like CYP1A2, CYP2C9, CYP2D6.

Thus it can inhibit the metabolism of various other drugs whose metabolism is depended on these enzymes and increase their concentration leading to toxicity.

Q2-Explain why cimetidine but not rantidine prolong half life of concurrently administered drugs

Drug interaction seen with cimetidine Phenytoin Phenobarbitone Sulfonylureas Carbamazepine Metronidazole

Uses

GERD

Peptic ulcer disease ( gastric ulcer, duodenal ulcer, NSAIDs induced ulcer, H- plylori associated ulcer)

Non ulcer dyspepsia

Prevention of bleeding from stress related gastritis

Antacids

Write a note on non systemic antacids? As antacids magnesium trisilicate and aluminium hydroxide are used in combination. Give reason Rationale for combination of antacids in peptic ulcer therapy

Why are antacids not given along with sucralfate in peptic ulcer?

Antacids

Antacids are weak bases that react with gastric HCL to form salt and water

Or

Antacids are defined as basic substances which neutralizes gastric acid and rises gastric Ph

Antacid

Raising gastric Ph although is possible with antacids , it is difficult to maintain it continuously, because antacids acts for only 30-60min

In spite of their limitation ( Short duration of action), antacids are valuable as they produce considerable, immediate symptomatic relief in patients with APD

Antacid- classification

Non systemic antacid

  • 1. Aluminium hydroxide

  • 2. Magnesium hydroxide

  • 3. Magnesium trisilicate

  • 4. Calcium carbonate

. Systemic antacid

Non systemic antacids

Non systemic antacids
Non systemic antacids

Non systemic antacids

Non systemic antacids

Non systemic antacids

Non systemic antacids

Q1-Rationale for using combination of two or more antacid

 

Magnesium

Aluminum

Combination

hydroxide

hydroxide

( magnesium hydroxide + aluminum hydroxide )

Onset of

Fast

Slow

Sustained

action

Effect on

Laxative

constipating

Will nullify each others

intestine

action: Bowl movement least affected

Gastric

Hasten

Delay

Will nullify each others

emptying

action: gastric emptying least affected

Dose

Can be

Reduced

Adverse effect minimal

reduced

 

Q2-Rationale for withholding drugs for two hours after administration of antacids

Non systemic antacids forms complexes( weak bases+ acid= non absorbablecomplex)

These complexes may decrease the absorption of many drugs to varying extent

Tetracyclins Diazepam Phenytoin Isoniazide Ethambutol Iron salts

Sucralfate

Write a note on sucralfate

Rationale for using sucralfate in peptic ulcer disease

Explain the interaction between sucralfate and antacids

Ulcer protective agents – Sucralfate

Is an octasulfate

Sucrose + Aluminium hydroxide ( Sucr+ alfate)

In acidic environment ,the drug undergoes extensive cross- linking to produce a viscous, sticky, polymer that adheres to epithelial cell

It thus creates a physical barrier on the ulcer base and prevent the ulcer from the damaging effects of the acid .

Sucralfate

Sucralfate action is entirely local Sucralfate has no acid neutralising effect Surcalfate is minimal absorbed after oral administration

Ulcer healing dose of sucralfate is 1g to be taken in empty stomach one hour before three major meal and at bed time for 4-8 weeks

Q1-Explain the interaction between sucralfate and antacids

PROSTAGLANDIN ANALOGUE

Misoprostol

Rationale for using prostaglandin analogue in peptic ulcer

Uses of misoprostol

PROSTAGLANDIN

ANALOGUE

Misoprostol (PGE1) Enprostil (PGE2) Rioprostil (PGE2)

Rationale for using prostaglandin analogue in peptic ulcer

Misoprostol