Pharmacology of GI drugs

Antacids MOA

• chemical reaction (neutralisation) to reduce acidity → weak base react with strong gastric HCL to form salt and water

• quick onset of action, quick duration (1-2 hours)

Antacids eg and adverse effects

• Sodium bicarbonate, Calcium carbonate

  • PK: ideally not absorbed, but may be absorbed. excreted by kidneys

  • formation of CO2 may cause belching (burping)

  • may potentially cause metabolic alkalosis when given in high doses or to patients with renal insufficiency (when absorbed in SI and unable to excrete excess alkaline fast enough)

• Magnesium hydroxide/ Aluminium hydroxide

  • PK: absorbed and renally excreted, should not use for long-term in patients with renal insufficiency

  • Belching does not occur, but causes diarrhea (MgOH2) and constipation (AlOH3)

    • usually combined in formulation to cancel out the effects

Potential DDI of antacids

increase pH of stomach, may interact with absorption of drugs etc

• eg destroy coat of enteric coated drugs, drug is degraded before absorption, result in lowered dose

H2-Antagonists MOA

• reversible, competitive inhibition at parietal cell H2-receptor

  • reversed when [histamine] >> [drug]

• highly selective, does not affect H1 and H3

• reduces volume of gastric secretion and concentration of pepsin

• good for nocturnal acid secretion (largely histamine regulated)

• suppresses basal and meal-stimulated acid secretion in linear and dose-dependent way (ie double dose means double effect until point of saturation where all receptors are occupied)

H2- antagonists eg and adverse effects

1. Cimetidine — inhibits binding of dihydrotestosterone to androgen receptors,……, cause gynecomastia (enlargement of breast) or impotence in men and galactorrhea (leaking milk when not breastfeeding)

2. Ranitidine

3. Famotidine

4. Nizatidine

= common side effect: headache, diarrhea, constipation

= rare: agitation/ hallucinations

H2- antag PK

A — rapid absorption (30-70% F)

D — ~1L/kg adult , 20-30% protein binding

M — partially metabolised (by liver)

• cimetidine is a potent inhibitor of many CYP enzymes (DDI)

E — 35-60% excreted unchanged

Dose reduction needed for pts with moderate to severe renal insufficiency

Potential DDI of H2 receptors

• Cimetidine is a potent inhibitor of CYP enzymes, will inhibit metabolising activity of other drugs

(weak base)

• increase pH of stomach, may interact with absorption of drugs etc

• eg destroy coat of enteric coated drugs, drug is degraded before absorption, result in lowered dose

Proton Pump Inhibitors (PPI)

• all substituted benzimiadoles

• all are acid-labile (reactive with acid), inactive prodrugs

• works systematically

PPI MOA

• inactive prodrug gets absorbed in the small intestine

• enters systemic circulation

• reaches the stomach, diffuse readily across lipid mbns into parietal cells

• PPI rapidly protonated in the acidic canaliculus, gets trapped due to charge

• establishing conc m, gets concentrated, rapidly undergoes molecular conversion to active drug

  • reactive thiophilic sulfenamide cation forms covalent disulfide bond with active proton pump (H+/K+-ATPase) , irreversibly inactivating the enzyme

    

    • taken before 30-60 mins before meal — time for PPI to be absorbed and start working when pt eating breakfast where concentration of active pumps are highest