PUD/GERD Pharmacology

What receptors promote acid secretion? What stimulates them?

• Muscarinic receptor - ACh

• Histamine-2 receptor - Histamine

• Gastrin receptor - Gastrin

All promote the proton pump - to secrete hydrogen into the stomach lumen

What receptors inhibit acid secretion? What stimulates them?

• Prostaglandin Receptor - prostaglandins

What cell houses the proton pump, and is responsible for maintaining stomach acidity?

Parietal cell

What is the role of the superficial epithelial cell?

• releases mucous and bicarbonate keeping pH superficially at ~7.4

• some muscarinic and prostaglandin signaling

PPIs

• omeprazole

• esomeprazole (S isomer of omeprazole)

• pantoprazole

PPI - MOA

• structurally-related to H2 receptor antagonists

  • NO affinity for H2 histamine receptor

• specific and selective effects on gastric proton pump

  • selective for gastric over other’s in the body

• most are prodrugs

  • avoid breakdown prior to being absorbed

  • able to reach site of action

• could also be enteric-coated, instead of prodrugs

• once exposed to acidic environment in stomach lumen, activates and then binds covalently to alpha subunit of proton pump

PPI - PKs

• may inhibit absorption for drugs/vitamins & minerals that need acidic condition for absorption

  • vitamin B12

  • iron, calcium, magnesium

  • ketoconazole

  • digoxin

• almost no renal clearance

• extensively metabolized including first pass by CYP2C19 and CYP3A4

• short plasma half-life but long duration of effect

Why can a PPI have a short half-life but long duration of effect?

• due to irreversible inhibition of the proton pump

• able to have duration of effect of 12-24h

PPI - Clopidogrel interaction

• clopidogrel is prodrug activated by CYP2C19

• PPIs are CYP2C19 inhibitors and reduce efficacy of clopidogrel - less conversion to active metabolite

• theoretical interaction - not proven if converts to clinical negative cardiovascular outcomes

PPI - toxicity

• common: diarrhea and headache

• association studies: kidney dysfunction, fractures and infection

  • fractures due to inhibition of calcium absorption

  • infections due to changes in gut flora

H2 Receptor Antagonists (H2RA)

• Cimetidine

  • less selective so more off target effect and more drug interactions

• Ranitidine

• Nizatidine

• Famotidine

were first line until PPIs came on the market

H2RA - MOA

• competitive H2 receptor antagonist

  • blockade of H2 receptors on parietal cells

• very selective - few off target effects

• no efficacy for H1 receptors (allergies)

• highest efficacy again nocturnal acid secretion

H2RA - toxicity

• common: diarrhea or constipation, headache, muscle pain

  • cimetidine also includes:

    • androgen receptor antagonism

    • increased prolactin levels

    • inhibition of estradiol metabolism

    • drug interactions through CYP inhibition

Antacids

• common use for self-limited and/or intermittent GERD

• sodium bicarbonate

• calcium carbonate

• magnesium/aluminum hydroxide

Antacid - MOA

• bases ingested

  • has direct interaction with H+ to form salt and water (with or without CO2 production)

• may also stimulate prostaglandin production

  • promote more bicarbonate and mucous secretion

How to identify how much antacid is needed after a meal?

• one meal results ~45mEq of HCl secretion

• most antacid doses contain 3-4x mEq of base salts

Antacid - sodium bicarbonate

• one of first antacids

• CO2 is produced as by-products

  • causes bloating, distension and belching

• can be absorbed systemically and cause metabolic alkalosis

  • particularly with reduced renal function

  • contraindicated in pregnancy

Antacid - calcium carbonate

• CO2 is produced as by-product, but at slower rate compared to sodium bicarbonate

  • since produced over time, less likely to cause the adverse effects

Antacids - magnesium/aluminum hydroxide

• no CO2 production

• very low risk of metabolic alkalosis

• usually in combo because magnesium causes osmotic diarrhea and aluminum causes constipation (adverse effects oppose each other)

Misoprostol

• methyl-PGE1 analogue

• activates the PGE2 receptor

  • decreases acid secretion

  • promotes bicarbonate and mucous secretion

• very short serum half-life

• may stimulate uterine contractions

  • contraindicated in pregnancy

  • caution in women of childbearing age

Bismuth compounds

• MOAs:

  • coats erosions and ulcers

  • stimulates prostaglandin production

    • leads to increased mucous and bicarbonate secretion

  • decreases GI secretions to treat diarrhea

  • direct antimicrobial effects (including against H. pylori)

• ADRs:

  • blackening of the stool

  • darkening of the tongue

Sucralfate

• sucrose complexed with aluminum hydroxide

• forms a viscous solution when mixed with water

• MOA:

  • thought to bind and coat areas of GI tract with greatest negative charge (possibly areas around ulcers)

Promotility Agents - Dopamine Receptor Antagonists - MOA

• dopamine inhibits cholinergic smooth muscle stimulation

  • blocking D2 receptors is prokinetic (inhibiting an inhibitor = promotion)

• increased peristalsis in esophagus promoting gastric emptying

• relatively smaller effect on small intestine

• also antiemetic (treat NV) due to central blockade of D2 receptors in CTZ

Promotility Agents - Dopamine Receptor Antagonists - Toxicity

• mainly CNS:

  • restlessness, drowsiness, insomnia, anxiety, agitation - more pronounced in elderly

  • extrapyramidal symptoms at high doses - tardive dyskinesia (movement disorder - parkinsons like) so no long-term use - more pronounced in elderly

  • elevated prolactin levels - galactorrhea (milk production unrelated to pregnancy/lactation), gynecomastia (enlargement of breast tissue), impotence and menstrual disorders

• domperidone less ADRs because does not extensively cross BBB

Promotility Agents - Cisapride and prucalopride

• 5-HT4 receptor agonists

• cisapride removed due to rare but fatal cardiac arrhythmia

Promotility Agents - Alosetron

• 5-HT3 receptor antagonists

• used primarily for antiemetic properties, but provide some prokinetic activity

Promotility Agents - Erythromycin

• mimics actions of motilin

  • small peptide (22 residues) secreted by GI tract to increase motility

• may work “too well” moving undigested food into small intestine

• ability to develop a tolerance