Drugs used for Acid Associated Diseases Flashcards
What are the factors that may lead to the development of peptic ulcer disease
An ulcer is basically lesions of the gastric and duodenal mucosa:
- Gastric Acid
- H. pylori
- NSAIDS, Smoking as well as excessive alcohol intake, GI Ischeamia
MECHANISM OF GASTRIC
ACID SECRETION
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
Drugs which are used in the treatment of Peptic Ulcers disease/Reduce gastric acidity) and describe the mechanism of action of each pump.
- Antacids
- Acid anti-secretory agents:
- H2-antagonists
- Proton pump inhibitors
- Mucosal protective agents
- Prostaglandin-analogues
- Sucralfate
- Bismuth
- Carbenoxolone - Antimuscarinic agents
- Antibiotics
Antacids
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
Sodium Bicarbonate
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+].
Calcium Bicarbonate
Calcium carbonate + 2H+ => CO2 + H2O
• Belching and abdominal distension (CO2).
• Hypercalcemia or milk alkaline synd.
• Rebound acid hypersecretion (Ca2+)
Magnesium Hydroxide/Oxide
Aluminium Hydroxide
Magnesium hydroxide => Diarrhea. Aluminium hydroxide => Constipation. Is c/i in renal failure (neurotoxic). Combination of Al and Mg (OH) reduces diarrhea and constipation
Anti-secretory agents
- H2 -receptor antagonists
2. Proton pump inhibitors
List the H2-antagonists/Histamine H2-receptor antagonists
Cimetidine
Ranitidine,
Famotidine
Nizatidine
MOA of H2-Antagonists
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
H2-Antagonists Uses
- Duodenal and gastric ulcers
- Hypersecretory states, ZES
- Reflux eosophagitis
- Prevention of recurrence
- Prevention of aspiration syndrome
Cimetidine:
MOA
- 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.
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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.
Cimetidine:
Kinectics
- 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.
Cimetidine:
Drug Interactions
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
Cimetidine:
Adverse Effects/Side Effects
- 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.
Alternative drug to Cimetidine
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.
Proton Pump Inhibitos(PPI)
Omeprazole
Lansoprazole
Esomeprazole
Pantoprazole
PPI MOA
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
Proton Pump Inhibitors Indications/Uses
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
Proton Pump Inhibitors
Kinetics
- Well absorbed from GIT.
- Half-life 0.5-1.5 hrs. 95% protein bound.
- Metabolized rapidly by liver
- 20% excreted in feces.
Proton Pump Inhibitors
Drug Interations
- 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
Proton Pump Inhibitors
Adverse Effects
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.
Mucosal protective agents/Cytoprotective Agents
- Sucralfate
- Prostaglandin analogues
- Bismuth colloids (dicitrate).
- Carbenoxolone
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
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.
Sucralfate
Kinetics
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
Sucralfate
Uses
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
Sucralfate
Adverse Effects/Side Effects
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
Misoprostol
MOA
Misoprostol = Analogue of PgE1
- Increases both mucus & bicarbonate production
- Increases mucosal blood flow.
- Inhibits gastric acid secretion (the proton pump) via a cAMP signal.
Misoprostol
Uses
- Prophylaxis: duodenal/gastric ulcers.
- Prevention of NSAID induced ulcers.
Misoprostol
Adverse Effects
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
Misoprostol
Kinetics
Extensively Metabolised
Bismuth colloids (dicitrate)
MOA
- Precipitates in acid & coats ulcer base.
- Increase mucus secretion.
- Antibacterial effect (toxic to H.pylori).
- NB: Do not use with antacids.
Bismuth colloids (dicitrate)
Adverse Effects
- Confusion.
- Black discolouration of tongue, stools
- c/i renal failure (neurotoxic)
Carbenoxolone
MOA
Mechanism of action: unknown.
- Increases mucosal secretion only.
- No effect on acid secretion or gastric motility.
Carbenoxolone
Adverse Effects
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
Anti-muscarinic agents 1
- Propantheline
- Dicyclomine
- Glycopyrrolate
- Pirenzepine
- Atropine
Anti-muscarinic agents 2
Mechanism of action
- 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.
Anti-muscarinic agents 3
• Adverse effects
Due to non-selective action
- Dry mouth, constipation, tachycardia,
- Urinary retention, blurring of vision,
- Loss of accommodation and impotence.
Anti-Muscarinic Agents
Uses
- Non-ulcer dyspepsia.
- Irritable bowel syndrome.
- Diverticular disease.
- Less frequently used for peptic ulcers.
Anti-Bacterials
Amoxycillin; => diarrhea
Metronidazole; => mild GIT upset
Tetracycline; => mild GIT upset
Clarithromycin:=> taste disturbance
Bismuthsalicylate;=> melena & tinnitis
NB: combined with antisecretory agent.
Examples of triple therapy regimens
• 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.
