GI Pharmacology
Acid suppression, mucosal armor, and the drugs that move or calm the gut
Acid secretion and its suppression
Parietal cell control. Histamine from enterochromaffin-like (ECL) cells acts on H2 receptors and raises cAMP; acetylcholine (M3) and gastrin (CCK-B) raise intracellular calcium, and gastrin also releases histamine from ECL cells. Every pathway ends at the H+/K+ ATPase, which pumps H+ into the lumen in exchange for K+.
- Histamine, ACh, gastrinBind H2, M3 and CCK-B receptors
- Parietal cell activatedcAMP and calcium rise
- H+/K+ ATPaseThe proton pump, the final common step
- HCl secretedPPIs block the pump; H2 blockers remove only the histamine input
Proton pump inhibitors. Omeprazole and the other -prazoles are prodrugs activated in the acidic secretory canaliculus that bind the H+/K+ ATPase covalently and irreversibly. Blocking the final step makes them the strongest acid suppressants; secretion recovers only as new pumps are made, and they work best taken before a meal. Uses: GERD, peptic ulcer disease, Zollinger-Ellison syndrome, NSAID-ulcer prevention and H. pylori regimens.
Long-term PPI risks. Hypomagnesemia from impaired intestinal absorption (cramps, tetany, and secondary hypocalcemia because low magnesium blunts PTH); vitamin B12 deficiency, since acid frees B12 from food protein; fractures from reduced calcium absorption; C. difficile infection and pneumonia from loss of the acid barrier; and acute interstitial nephritis. Omeprazole also inhibits CYP2C19, which activates clopidogrel.
H2 blockers. Cimetidine, famotidine and nizatidine (-tidine; ranitidine was withdrawn in 2020) reversibly block the parietal cell H2 receptor. Acetylcholine and gastrin still drive the pump, so suppression is weaker than with PPIs, but onset is quick; they suit mild or nocturnal reflux.
Cimetidine, the troublemaker. It is an antiandrogen (gynecomastia, impotence), a potent cytochrome P450 inhibitor that raises warfarin, phenytoin and theophylline levels, and it reduces renal tubular secretion of creatinine, raising serum creatinine without a true fall in GFR. It also crosses the blood-brain barrier (confusion in the elderly). A man on cimetidine with breast tenderness and a toxic warfarin level shows both classic problems; famotidine avoids them.
| Feature | PPIs (-prazole) | H2 blockers (-tidine) |
|---|---|---|
| Target | H+/K+ ATPase (final step) | H2 receptor (histamine input only) |
| Binding | Irreversible | Reversible |
| Strength | Strongest suppression | Weaker; quick onset |
| Typical uses | GERD, PUD, Zollinger-Ellison, H. pylori | Mild or nocturnal reflux |
| Signature toxicity | Low Mg and B12, fractures, C. difficile, interstitial nephritis | Cimetidine: P450 inhibition, antiandrogen, ↑creatinine |
Antacids, mucosal protectants and H. pylori
Antacids. These weak bases neutralize acid already secreted; they do not reduce secretion.
- Aluminum hydroxide: constipation and hypophosphatemia (it binds dietary phosphate); accumulation in renal failure causes osteodystrophy and muscle weakness.
- Magnesium hydroxide: diarrhea; hypermagnesemia in renal failure (hyporeflexia, hypotension).
- Calcium carbonate: rebound acid secretion and milk-alkali syndrome (hypercalcemia, metabolic alkalosis, kidney injury).
All antacids chelate other drugs, lowering absorption of tetracyclines, fluoroquinolones, iron and levothyroxine, so doses are separated.
AluMINIMUM amount of feces: aluminum constipates. Mg = Must Go to the bathroom: magnesium loosens.
Sucralfate. This aluminum–sucrose sulfate complex polymerizes in acid into a sticky layer that binds the ulcer base. It requires an acidic pH, so it is not given alongside PPIs, H2 blockers or antacids.
Misoprostol. A PGE1 analog that raises mucus and bicarbonate secretion and lowers acid output, replacing the protective prostaglandins that NSAIDs deplete. It prevents NSAID ulcers but contracts the uterus: it is an abortifacient and contraindicated in pregnancy, a property used deliberately for cervical ripening and medical abortion. Diarrhea is the common side effect.
Bismuth. Bismuth salts coat ulcers, have direct antimicrobial activity against H. pylori and treat traveler's diarrhea; they harmlessly blacken the stool and tongue.
H. pylori regimens. Both are usually given for 14 days.
- Bismuth quadruple therapy (preferred): PPI + bismuth + metronidazole + tetracycline; first-line when clarithromycin susceptibility is unknown, since clarithromycin resistance is common.
- Clarithromycin triple therapy: PPI + clarithromycin + amoxicillin (metronidazole if penicillin-allergic); only for strains known to be susceptible.
Eradication heals ulcers and lowers the risk of gastric adenocarcinoma and MALT lymphoma; early gastric MALT lymphoma can regress with eradication alone.
Antiemetics and prokinetics
Ondansetron. Ondansetron and the other -setrons block 5-HT3 receptors in the chemoreceptor trigger zone and on vagal afferents, which chemotherapy activates by releasing gut serotonin. They are powerful agents for chemotherapy-induced and postoperative nausea. Adverse effects: QT prolongation, headache, constipation, and serotonin syndrome with other serotonergic drugs.
Metoclopramide. A D2 antagonist and 5-HT4 agonist that increases acetylcholine release in the myenteric plexus, speeding gastric emptying and raising lower esophageal sphincter tone; it is used for diabetic gastroparesis and as an antiemetic. Central D2 blockade causes extrapyramidal symptoms: acute dystonia, akathisia, drug-induced parkinsonism (resting tremor, cogwheel rigidity) and tardive dyskinesia, whose risk grows with duration. It also raises prolactin.
Avoid metoclopramide in bowel obstruction (it drives peristalsis against the blockage) and in Parkinson disease (D2 blockade worsens it).
| Receptor blocked | Drugs | Best use | Key adverse effects |
|---|---|---|---|
| 5-HT3 | Ondansetron, granisetron | Chemotherapy, postoperative nausea | QT prolongation, headache, constipation |
| D2 | Metoclopramide, prochlorperazine | Gastroparesis (metoclopramide), general nausea | Extrapyramidal symptoms, hyperprolactinemia |
| NK1 (substance P) | Aprepitant | Chemotherapy, especially delayed vomiting | CYP3A4 interactions |
| H1 | Meclizine, promethazine | Motion sickness, vertigo | Sedation, anticholinergic effects |
| Muscarinic | Scopolamine patch | Motion sickness | Dry mouth, blurred vision, confusion |
Laxatives and antidiarrheals
| Class | Examples | Mechanism | Notes |
|---|---|---|---|
| Bulk-forming | Psyllium, methylcellulose | Fiber holds water, adds stool mass | Needs adequate fluid; bloating |
| Osmotic | Polyethylene glycol, magnesium citrate, lactulose | Poorly absorbed solutes pull water into the lumen | PEG for bowel prep; lactulose for hepatic encephalopathy |
| Stimulant | Senna, bisacodyl | Stimulate enteric nerves to drive motility | Cramping; chronic senna causes melanosis coli |
| Stool softener | Docusate | Surfactant lets water into stool | Weak on its own |
Lactulose in hepatic encephalopathy. Colonic bacteria ferment lactulose into acids that convert ammonia (NH3) into nonabsorbable ammonium (NH4+), trapping it for excretion; rifaximin is the usual add-on.
Loperamide. A μ-opioid agonist that slows gut motility but is kept out of the CNS by P-glycoprotein efflux, so it lacks analgesia and abuse potential at usual doses; massive doses prolong the QT interval. Diphenoxylate can reach the CNS at high doses, so it is combined with a small dose of atropine: overuse brings unpleasant anticholinergic effects that deter abuse.
Antimotility agents are avoided in bloody, febrile dysentery and in C. difficile colitis, where slowing transit prolongs toxin exposure and risks toxic megacolon.
Other antidiarrheals. Bismuth subsalicylate helps traveler's diarrhea; octreotide treats secretory diarrhea, including carcinoid diarrhea.
IBD agents and hepatobiliary drugs
5-Aminosalicylates. 5-ASA acts topically as an anti-inflammatory on inflamed colonic mucosa and is a mainstay for mild-to-moderate ulcerative colitis. Sulfasalazine links 5-ASA to sulfapyridine by an azo bond that colonic bacteria cleave. The absorbed sulfa moiety causes rash, hemolysis (especially with G6PD deficiency) and reversible oligospermia. Mesalamine delivers 5-ASA without the sulfa carrier.
Steroids and thiopurines. Glucocorticoids induce remission but are not maintenance drugs; budesonide's high first-pass metabolism limits systemic effects. Azathioprine and 6-mercaptopurine are steroid-sparing; check TPMT activity first.
Biologics. For moderate-to-severe disease:
- Infliximab, adalimumab: anti-TNF-α antibodies; screen for latent TB and hepatitis B first because both can reactivate.
- Natalizumab: anti-α4 integrin; risks progressive multifocal leukoencephalopathy (PML) from JC virus.
- Vedolizumab: targets the gut-selective α4β7 integrin, limiting systemic immunosuppression.
- Ustekinumab: blocks IL-12 and IL-23 via their shared p40 subunit.
Place a PPD or IGRA before anti-TNF therapy: TNF maintains granulomas, so blocking it lets latent TB reactivate, often as extrapulmonary or disseminated disease.
Ursodiol. Ursodeoxycholic acid lowers cholesterol secretion into bile and slowly dissolves cholesterol gallstones in patients who cannot have surgery; it is first-line therapy for primary biliary cholangitis.
Octreotide. This somatostatin analog reduces splanchnic blood flow to control variceal and other GI bleeding and suppresses hormone excess in acromegaly, carcinoid syndrome and VIPomas, controlling their secretory diarrhea. Adverse effects include nausea, steatorrhea and gallstones, because it inhibits gallbladder contraction.