Drugs used for Acid Associated Diseases

Question 1

What are the factors that may lead to the development of peptic ulcer disease

Answer 1

An ulcer is basically lesions of the gastric and duodenal mucosa:

1. Gastric Acid
2. H. pylori
3. NSAIDS, Smoking as well as excessive alcohol intake, GI Ischeamia

Question 2

MECHANISM OF GASTRIC

ACID SECRETION

Answer 2

By a proton pump( H+K+ ATPase)

Acid stimuli:
- Acetycholine via M1 and M3 receptors
- Gastrin via Gastrin G-receptors
- Histamine via H2- receptors.
By a proton pu

Question 3

Drugs which are used in the treatment of Peptic Ulcers disease/Reduce gastric acidity) and describe the mechanism of action of each pump.

Answer 3

1. Antacids
2. Acid anti-secretory agents:

• H2-antagonists
• Proton pump inhibitors

3. Mucosal protective agents
   - Prostaglandin-analogues
   - Sucralfate
   - Bismuth
   - Carbenoxolone
4. Antimuscarinic agents
5. Antibiotics

Question 4

Antacids

Answer 4

They chemically neutralize stomach acid by increasing the GI pH sufficiently to relieve the pain of dyspepsia and acid indigestion enabling peptic ulcers to heal

• Sodium bicarbonate
• Calcium carbonate
• Magnesium hydroxide or oxide
• Aluminium hydroxide

Question 5

Sodium Bicarbonate

Answer 5

Sodium bicarbonate + H+ => CO2 + H2O
- Belching and abdominal distension (CO2).
- Systemic alkalosis [HCO3]
- Na is absorbed => c/i HT, renal failure and
cardiac failure [Na+].

Question 6

Calcium Bicarbonate

Answer 6

Calcium carbonate + 2H+ => CO2 + H2O
• Belching and abdominal distension (CO2).
• Hypercalcemia or milk alkaline synd.
• Rebound acid hypersecretion (Ca2+)

Question 7

Magnesium Hydroxide/Oxide

Aluminium Hydroxide

Answer 7

Magnesium hydroxide => Diarrhea.
Aluminium hydroxide => Constipation.
Is c/i in renal failure (neurotoxic).
Combination of Al and Mg (OH) reduces
diarrhea and constipation

Question 8

Anti-secretory agents

Answer 8

1. H2 -receptor antagonists

2. Proton pump inhibitors

Question 9

List the H2-antagonists/Histamine H2-receptor antagonists

Answer 9

Cimetidine

Ranitidine,

Famotidine

Nizatidine

Question 10

MOA of H2-Antagonists

Answer 10

Similar structure to that of histamine thus the drug competes for binding on the H2 receptor on gastric parietal cells.

Potent inhibitors of Meal stimulated secretion and nasal secretion of gastric acid,They reduce the volume and conc. og gastric acid and they produce a proportionate reduction in the production of pepsin because gastric acid catalyzes the conversion of inactive pepsinogen>pepsin.

Also reduce the secretion of Intrinsic Factor but not enough to significatly reduce Vit. B12 absorption.

No effect on gastric emptying time, esophageal sphincter pressure or pancreatic enzyme secretion

Question 11

H2-Antagonists Uses

Answer 11

• Duodenal and gastric ulcers
• Hypersecretory states, ZES
• Reflux eosophagitis
• Prevention of recurrence
• Prevention of aspiration syndrome

Question 12

Cimetidine:

MOA

Answer 12

• Competitive inhibitor of histamine action
  on H2-receptors on the parietal cells.
• CNS; dizziness and mental confusion esp. in elderly.
• GIT; Diarrhea/constipation.
• Endocrine: gyneacomastia, impotence & decreased libido
• Hyperprolactinemia
• Androgenic receptor antagonist.
• Inhibits metabolism of estradiol (CYP450).
• Dose = 400 mg tds plus a bed time dose, (or 800 mg bd)
  x 4-8 weeks.
  21
  Ranitidine
• Safer than cimetidine
• Little crosses BBB
• No endocrine effects
• No significant inhibition of CYP450
  Kinetics
• Similar to cimetidine but F < 50%.
• Dose = 15 mg BD x 4-6 weeks, or
  single bedtime 30 mg/day.

Question 13

Cimetidine:

Kinectics

Answer 13

• Well absorbed from GIT => F = 70-80%
• Half-life = 2 hrs. 15-20% Prot. bound.
• Excreted renally by filtration and
  secretion (same mechanism as creatinine).
• Crosses placenta & BBB
• CNS effects esp. elderly and sev. ill.

Question 14

Cimetidine:

Drug Interactions

Answer 14

Inhibits cytochrome P450 isoenzymes,These isoenzymes are involved in the metabolism of numerous drugs including; Alprazolam,Carbamazepine warfarin, theophyline, Cisapride, DDisopyramide, Felodipine, Lovastatin, Saquinavir, Triazolame.

The dosagaes of these drugs need to be reduced in patients who are taking Cimetidine.

Reduces absorption of ketoconazole (high pH)

Inhibits renal excretion of metformin and procainamide.

Other H2 blockers do not inh Cytochrome P450 enzymes significantly and are prepared for patients receiving concomitant drug theraphy

Question 15

Cimetidine:

Adverse Effects/Side Effects

Answer 15

• CNS; dizziness and mental confusion esp. in elderly.
• GIT; Diarrhea/constipation.
• Endocrine: gyneacomastia, impotence & decreased
  libido
• Hyperprolactinemia
• Androgenic receptor antagonist.
• Inhibits metabolism of estradiol (CYP450).
• Dose = 400 mg tds plus a bed time dose, (or 800 mg bd) x 4-8 weeks.

Question 16

Alternative drug to Cimetidine

Answer 16

Ranitidine:

• Safer than cimetidine
• Little crosses BBB
• No endocrine effects
• No significant inhibition of CYP450

Kinetics

• Similar to cimetidine but F < 50%.
• Dose = 15 mg BD x 4-6 weeks, or
  single bedtime 30 mg/day.

Question 17

Proton Pump Inhibitos(PPI)

Answer 17

Omeprazole

Lansoprazole

Esomeprazole

Pantoprazole

Question 18

PPI MOA

Answer 18

Form a -Disulfide link with a cysteinyl residue in the proton pump(H+K+-ATPase) found in the luminal membrane of gastric parietal cells.

Irreversibly inhibit the proton pump and prevent the secretion of gastric acid for an extended period.

Activated by acid to active sulfenamic
acid.

The drugs can produce a dose-dependent inhibition of up tp 95% of gastric acid secretion and a single dose for 1-2 days

Question 19

Proton Pump Inhibitors Indications/Uses

Answer 19

Treatment of peptic ulcer disease-Duodenal and Gastric mucosa

Reflex and Erosion Esophagitis

Zollinger-Ellison Syndrome-Conditon characterised by severe ulcers resulting from gastrin-secreting tumours(Gastrinoma’s)

GERD

Tx of Heartburn and Dyspepsia

Prevention of peptic ulcers and bleeding in person recieving high-dose or long term theraphy with NSAIDs such as Diclofenac

Question 20

Proton Pump Inhibitors

Kinetics

Answer 20

• Well absorbed from GIT.
• Half-life 0.5-1.5 hrs. 95% protein bound.
• Metabolized rapidly by liver
• 20% excreted in feces.

Question 21

Proton Pump Inhibitors

Drug Interations

Answer 21

• Inhibits metabolism of warfarin, diazepam
  & theophylline (CYP450).
  -Dose = 20 mg/d, ± antibiotics
• NB: do not use with antacids.

Omeprazole and Esomeprazole prevent the activation of Clopidegrel by inhibiting CYP2C19, Leading to low clopidogrel levels.

Not to be used with antiplatelet drugs-Pantoprazole does not appear to cause this interaction and can be used concurrently with clopidogrel

Question 22

Proton Pump Inhibitors

Adverse Effects

Answer 22

Minor GI and CNS side effects have occured in some pts and skin rash.

Elevated Hepatic enzymes

Hypomagnesemia-In pts taking the drug for >1 year

CKD-Long term use of high dose

Increased risk of osteoporosis-small potential of malabsorption of Vit B12

Increased risk of community acquired pneumonia and certain GI infections including Clostridium difficile infection

Can elevated serum levels of Methotrexate in pts with high doses of Methotrexate.

Question 23

Mucosal protective agents/Cytoprotective Agents

Answer 23

• Sucralfate
• Prostaglandin analogues
• Bismuth colloids (dicitrate).
• Carbenoxolone

Question 24

Sucralfate

MOA

Sucralfate ctned
• Uses: Duodenal & gastric ulcers, &
reflux esophagitis
• Kinetics
- Poorly absorbed from GIT & is
excreted in feces
• Adverse effects: Constipation.
• Interaction: Binds & reduces abs. of
theophylline & phenytoin.
• Dose; 1 g qid x 4 wks

Answer 24

Viscous polymer of sucrose octasulfate and aluminium hydroxide.

Sulfated polysaccharide adheres to ulcer craters and epithelial cells and inhibit pepsin-catalysed hydrolysis of mucosal proteins.

Stimilates PGE synthesis in mucosal cells

These actions form a protective barrier to acid and pepsin facilitating the healing of ulcers

Adsorbs bile acids in the duodenum.

Question 25

Sucralfate Kinetics

Answer 25

Oral administration-Tablet/Suspension Drug not absorbed significantly from the gut and is primarily excreted in the feces Pts absorb a small amount of aluminium from the the drug, so sucralfate should be used cautiously in pts with renal impairements

Question 26

Sucralfate Uses

Answer 26

The management of Peptic Ulcer diseases-treat active or supress the recurence of ulcers Less effective than drugs that inh gastric acid secretion and is primarily used in pts who cannot tolerate H2 blockers or PPI's

Question 27

Sucralfate Adverse Effects/Side Effects

Answer 27

Few systemic adverse effects,constipation and other GI disturbances Larygospasm Impair absorption of other drugs-Digoxin, Fluroquinolones, Ketoconazole and Phention-This can be avoided by ingesting sucralfate 2 hrs before or after these other drugs

Question 28

Misoprostol MOA

Answer 28

Misoprostol = Analogue of PgE1 - Increases both mucus & bicarbonate production - Increases mucosal blood flow. - Inhibits gastric acid secretion (the proton pump) via a cAMP signal.

Question 29

Misoprostol Uses

Answer 29

- Prophylaxis: duodenal/gastric ulcers. | - Prevention of NSAID induced ulcers.

Question 30

Misoprostol Adverse Effects

Answer 30

N, V, D and abd. pain/Intestinal cramping (dose dependent) Skin rashes Can stimulate terine contraction which results in abortion and abnormal vaginal bleeding. - c/i: pregnancy; Dose = 200 mg qid

Question 31

Misoprostol Kinetics

Answer 31

Extensively Metabolised

Question 32

Bismuth colloids (dicitrate) MOA

Answer 32

- Precipitates in acid & coats ulcer base. - Increase mucus secretion. - Antibacterial effect (toxic to H.pylori). - NB: Do not use with antacids.

Question 33

Bismuth colloids (dicitrate) Adverse Effects

Answer 33

- Confusion. - Black discolouration of tongue, stools - c/i renal failure (neurotoxic)

Question 34

Carbenoxolone MOA

Answer 34

Mechanism of action: unknown. - Increases mucosal secretion only. - No effect on acid secretion or gastric motility.

Question 35

Carbenoxolone Adverse Effects

Answer 35

s assoc. with many s/e. - Headache, Na+ and fluid retention due to aldosterone action. - Edema and hypokalemia. c/i HT, CCF and epilepsy. - Others: peripheral neuropathy, myasthenia, and myoglobinuria

Question 36

Anti-muscarinic agents 1

Answer 36

* Propantheline * Dicyclomine * Glycopyrrolate * Pirenzepine * Atropine

Question 37

Anti-muscarinic agents 2 | Mechanism of action

Answer 37

- They inhibit acid secretion (M1) and gastric motility(M2). - M1 and M3 receptors mediate glandular secretion. - M2 receptors mediate GIT motor functions. - Pirenzepine is selective for M1.

Question 38

Anti-muscarinic agents 3 | • Adverse effects

Answer 38

Due to non-selective action - Dry mouth, constipation, tachycardia, - Urinary retention, blurring of vision, - Loss of accommodation and impotence.

Question 39

Anti-Muscarinic Agents Uses

Answer 39

- Non-ulcer dyspepsia. - Irritable bowel syndrome. - Diverticular disease. - Less frequently used for peptic ulcers.

Question 40

Anti-Bacterials

Answer 40

Amoxycillin; => diarrhea Metronidazole; => mild GIT upset Tetracycline; => mild GIT upset Clarithromycin:=> taste disturbance Bismuthsalicylate;=> melena & tinnitis NB: combined with antisecretory agent.

Question 41

Examples of triple therapy regimens

Answer 41

• First choice: – Omeprazole + Clarithromycin + amoxycillin => 90% efficacy – Substitution with amoxycillin for metronidazole or doxycycline => efficacy of 80%. Others: • Bismuthsalicylate + tetracycline + metronidazole => 90% efficacy rate. • Ranitidine + metronidazole + amoxycillin = 90% efficacy.