Gastrointestinal Acid Secretion & Ulcer Treatment: Key Concepts and Drugs

carbonic anhydrase

produces acid in parietal cells

H/K ATPase

secretes acid by parietal cells

mucosal layer

uses HCO3- to protect stomache

physical barriers of GI

LES and pyloric sphincter

prostoglandins

stimulate mucus, HCO3-

GERD causes

decrease in LES tone causing spontaneous LES relaxation

delayed gastric emptying

increased gastric pressure

Hiatal hernia

impaired peristalsis

impaired mucosal defense

GERD complication

Esophagitis

erosive esophagitis

esophageal strictures

barrets's esophagus

erosive esophagitis

inflammation that erodes mucus

esophageal strictures

narrowing of the esophagus forming scar tissue/inflammation

Barrets esophagus

columnar cell lining instead of squamous epithelial

inc in strictures and cancer chances

PPI

acid activated drug

Covalent inhibition of parietal cell H/k ATPase mediated secretion of acid

PPI prodrug activation

activated to bind sulfenic acid or sulfenamide intermediates to make irreversible disulfide bonds with cysteine

phase 1 metabolism

OH,NH,SH,CO2H

CYP450

phase 2 metabolism

sulfate, glucuronide, glutathione, or acetyl

PPI absorption

prodrugs activate at low pH

enterically coated to prevent stomach activation

IV available for esomeprazole and pantoprazole

PPI metabolism

CYP3A4 substrate (all)

CYP2C19 substrate (demethylation or hydroxylation)

CYP2C19 inhibitor (esomeprazole, omeprazole)

PPI DDI

inc gastric pH, so drugs that req acidic pH (phenytoin, mesalamine, fluoroquinolones)

Clopidogrel is activated by CYP2C19 substrates

heterocycle in H2RA

mimics imidazole

Thioether in H2RA

improves potency

Guanidine in H2RA

contains electron-withdrawing group hydrogen bonds with H2-receptor

Cimetidine

Very strong CYP inhibitor for many substrates

through imidazole nitrogen binding with heme Fe center

H2RA

reversible inhibition of H2 receptor by mimicing histamine

interacts vis hydrogen and ionic bonds

H2RA absorption

oral bioavailability 40-60% (cimetidine and famotidine)

90% (nizatidine)

H2RA metabolism

Cimetidine is a weak substrate, but strong inhibitor (3A4,2C9, 2D6)

H2RA excretion

Adjust dose if renal impairment

OCT2, Oat1/3 substrate (cimetidine)

OCT2 (famotidine

H2RA DDI

inc gastric pH impacting high acid pH req drugs (ketoconazle, iron, salts)

Antacids

weak base that neutralizes stomache acid

Al(OH)3

Mg(OH)2

CaCO3

NaHCO3

Antacid DDI

inc gastric pH bad for acid pH req drugs

Antacid side effects

matabolic alkalosis (CaCO3, NaHCO3)

Belching (CaCO3, NAHCO3)

Hypercalcemia (CaCO3)

bad for renal insufficiency (AL(OH)3, MG(OH)2, CaCO3)

PUD underlying causes

H.pylori

NSAIDS

stress damage/ critical illness

Complications (like bleeding or cancer)

H.pylori

urease converts urea to CO2 and NH3 to neutralize acid environment

Catalase converts H2O2 to H2O and O2 evading ROS in phagocytes

Sucralfate

binds protein in ulcer protecting against acid and pepsin

Bismuth subaslicylate

binds ulcers and erosions providing physical protection and can reduce inflammation

Misoprostol

prodrug hydrolyzed be esterases

synthetic prostaglandin E1 analogue that replenishes prostaglandin stores

Tetracycline

drug class: Tetracycline

MOA:inhibits protein synthesis (30s)

Levofloxacin

drug class: fluoquinolone

MOA: inhibits nucleic acid synthesis

Clarithromycin

Drug class: macrolide

MOA: inhibits protein synthesis (50S)

Amoxicillin

Drug class: penicillin

MOA: inhibits cell wall synthesis

Metronidazole

drug class: nitroimidazole

MOA: inhibits nucleic acid synthesis

NSAIDS

inhibit prostaglandin synthesis, decrease mucous and HCO3- production