H2 Receptor Antagonists for PUD Lecture 1 Flashcards
(17 cards)
Biosynthesis of Histamine
Decarboxylation of histidine (amino acid)
Location:
- Mast cells
- Basophils and eosinophils
- Enterochromaffin-like cells (stomach)
- Histaminergic neurons in CNS
H1 Receptors
Location and Function
CNS
- promotes wakefulness, decreased appetite (anorexic), motion sickness, emesis
Periphery (vascular, bronchial smooth muscle, endothelium, primary sensory afferents (skin)) - bronchoconstriction, vasodilation, increased vascular permeability, edema, increased nociception, itch, urticaria
H2 Receptors
Parietal cells (stomach)
- stimulation of gastric acid secretion
Vascular smooth muscle
- Vasodilation (minor)
General Classes of Drug Affecting the Actions of Histamine
Mast Cell Stabilization
- Beta-adrenergic agonists
- Chromones (e.g. cromolyn sodium)
H1 receptor antagonist for hypersensitivity/allergic reactions and various other “off-target” uses
H2 receptor antagonists for inhibition of gastric acid secretion
H2 Histamine Receptor Properties
G-protein coupled receptor
Stimulates adenylyl cyclase (AC), activating cAMP/PKA signaling
Major presence in gastric parietal cells where it stimulates acid secretion
Minor presence in bronchial and vascular smooth muscle where it causes relaxation (broncho- and vaso- dilation)
Therapeutic Uses of H2 Receptor Antagonists
Peptic ulcer disease
Gastroesophageal reflux disease (GERD)
Dyspepsia
Prophylaxis of stress ulcer
Muscarinic Receptor Antagonists
Targets the M3
H2 Blockers
Targets the H2 receptor
PPIs
Target the H+ / K+ ATPase (Proton Pump)
Antibiotics
Targets H. Pylori
Prostaglandins (PGE2 & PGI2)
Target EP3
Determinants of Peptic Ulcer Disease (PUD)
H. Pylori infection
- 70% of patients with gastric ulcers
- > 95% of patients with duodenal ulcers
NSAID use associated with ~30% of gastric ulcers
Excess acid production
General Classes of Drugs Used for Treatment of PUD
Proton Pump (H+ / K+ -ATPase) Inhibitors (PPIs)
H2 Histamine Receptor Antagonists (H2RAs)
Antibiotics for the elimination of H. Pylori
Muscarinic Receptor Antagonists
Prostaglandins
Mucosal Protective Agents
Antacids
H2 Histamine Receptor Antagonists (H2RAs)
Highly selective to H2 receptor
Reversible, competitive inhibition
Suppress acid secretion by ~70%
Rapidly absorbed after oral administration
Mostly renal elimination
Terminal half-life = 1 to 3 hours
Relatively few adverse effects, except for cimetidine
Cimetidine = inhibits a number of CYPs and has the potential for DDI (drug-drug interactions) and has some anti-androgenic activity that can cause gynecomastia
H2RA Drugs
Cimetidine
Famotidine
Nizatidine
Proton Pump (H+ / K+ - ATPase) Inhibitors (PPIs)
Highly selective for the gastric H+ / K+ - ATPase
Irreversible, noncompetitive inhibition via covalent binding
All prodrugs requiring activation in an acidic environment; must reach the parietal cell by the way of blood
Enteric-coated to prevent degradation in the stomach and to promote absorption in the small intestine
Short half life = 60-90 mins
Long half life = 24-48 hours
Extensively metabolized by CYP3A4 and CYP2C19; potential drug-drug interactions
Suppress acid secretion by 80-95%
Relatively few adverse effects, most common being nausea, abdominal pain, constipation, flatulence and diarrhea
Some concern that chronic use may increase risk of bone fractures and increased susceptibility to infections, esp. C. difficile
Hypergastrinemia may cause rebound hypersecretion of acid upon discontinuation of therapy
Uses are similar to H2 receptor antagonists, but also include prophylaxis of NSAID-induced GI toxicity and Zollinger-Ellison syndrome (gastrin-secreting tumor)
PPI Drugs
Omeprazole (Prilosec)
Lansoprazole (Prevacid)
Pantoprazole (Protonix)
Rabeprazole (AcipHex)
