Histamine and Antihistamines

HISTAMINE

•Histamine is an autacoid present at high levels in the lungs, skin, and the gastrointestinal tract and is released from mast cells and basophils bytype I hypersensitivity reactions, drugs, venoms, and trauma.

•Histamine receptors are ofthe serpentine family, with seven transmem­ brane-spanning domains with G-protein-coupled second messenger effectors.

-H1 activation

0 i capillary dilation (via NO) -7J, BP

0 i capillary permeability -7i edema

0 i bronchiolar smooth muscle contraction (via IP3 and DAG release)

0 i activation ofperipheral nociceptive receptors -7i pain and pruritus

0J, AV nodal conduction

-H2 activation

0i gastric acid secretion -7i gastrointestinal ulcers

0i SA nodal rate, positive inotropism, and automaticity

H1 ANTAGONISTS

•Mechanism of action:

-H1 antagonists act as competitive antagonists ofhistamine and there­ fore may be ineffective at high levels ofhistamine.

-Vary in terms ofboth pharmacologic and kinetic properties, but all require hepatic metabolism and most cross the placental barrier.

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Section VI • Drugs for Inflammatory and Related Disorders

•Uses:

-PUD (overall less effective than proton pump inhibitors)

-Gastroesophageal reflux disease (GERD)

-Zollinger-Ellison syndrome

•Side effects:

-Cimetidine is a major inhibitor of P450 isoforms drug interaction via i effects

-Cimetidine J, androgens gynecomastia and J, libido

Proton Pump Inhibitors

• Mechanism ofaction:

- Omeprazole and related"-prazoles" are irreversible, direct inhibitors ofthe proton pump (K+/H+ antiport) in the gastric parietal cell

•Uses:

-More effective than H2 blockers in peptic ulcer disease (PUD)

-Also effective in GERD and Zollinger-Ellison syndrome

-Eradication regimen for H. pylori

Misoprostol

•Mechanism ofaction: PGE1 analog, which is cytoprotective i mucus and bicarbonate secretion and J, HCl secretion

•Uses: Selective use in NSAID-induced gastrointestinal ulcers

Sucralfate

•Mechanism of action: polymerizes on gastrointestinal luminal surface to form a protective gel-like coating ofulcer beds. Requires acid pH (antacids may interfere)

•Uses: i healing and J, ulcer recurrence

Bismuth Subsalicylate

•Mechanism ofaction: like sucralfate, binds selectively to ulcer, coating it, and protecting it from acid and pepsin

•Combined with metronidazole and tetracycline to eradicate H. pylori (BMT regimen)

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