Histamine Pharmacology and GI Disease Flashcards
How is histamine made and what cofactor is required?
Made via decarboxylation of L-histidine via histidine decarboxylase
Requires pyridoxal phosphate (Vitamin B6) as cofactor
Why is histamine referred to as an “autacoid” and what are its major effects?
It is a local hormone -> must be degraded quickly
Effects: Vasodilation, increased vascular permeability, gastric secretion, and smooth muscle contraction.
It is also chemoattractant for inflammatory cells, and causes platelet aggregation / complement activation
Where is histamine primarily found in the blood and in the tissues?
In the blood - basophils
In the tissues - mast cells
Where is histamine stored? What is it stored with?
Stored in metachromatic secretory granules, complexed as an inactive componud with heparin and chondroitin sulfate
Where is turnover of histamine very rapid?
In non-mast cells:
Enterochromaffin-like cells, brain, etc
What is the function of enterochromaffin-like cells and what inhibits it?
They release histamine to stimulate gastric acid secretion
Inhibited by D cells in the antrum which release somatostatin in response to low pH
Stimulated by gastrin-production from G cells, which are also inhibited by somatostatin
How is histamine degraded and what its major breakdown product?
Degraded by liver by an N-metyhltransferase enzyme + monoamine oxidase
Forms methylimidazole acetic acid (MIAA) -> can be seen in urine
What is the immunologic cause of histamine secretion?
Hypersensitivity reaction -> B cells put IgE on mast cells and basophils, which degranulate in response to antigen
What are the mechanical and chemical causes of histamine release?
Mechanical - scratches or exposure to sunlight (skin turns red)
Chemical - Increased intracellular calcium causes exocytosis
What drug blocks the release of histamine from mast cells directly?
Cromolyn sodium (sodium cromoglycate), bocks influx of divalent cations including Ca+2
What do Compound 48/80 and polymyxin B do?
They act as ionophores, resulting in influx of Ca+2 and resultant histamine release
How do many therapeutic compounds stimulate histamine release?
Cause the dissociation of histamine from heparin-bound complex inside the granules (includes tubocurarine and radiocontrast dies)
What type of receptors are the histamine receptors? How many forms are there?
GPCR
There are H1-H4
H3 is presynaptic in brain
What is the mechanism of the H1 receptor and where are they found?
Found on smooth muscle of gut and bronchi, on endothelium, and in brain.
Gq -> cause contraction and bronchoconstriction (test for asthma) via Ca+2
Remember histamine causes contraction of GI smooth muscle
Where are H2 receptors found? What’s their mechanism?
Gastric mucosa (parietal cells), cardiac muscle cells, “mast cells”
Gs -> increase cAMP
What does cardiovascular histamine release cause?
Increased heart rate (H2) and decreased blood pressure (H1) -> reason why you feel flushed, get a headache, and feel warm
What causes hives?
Histamine-induced edema
Why does histamine cause itching?
H1-receptor mediated stimulation of sensory nerve endings (insect stings / venoms)
The “allergy pills” and “sleep aids” we know of -> what is their mechanism of action?
H1 receptor inverse agonist (reduce the histamine receptor functioning even below baseline)
What are the first generation antihistamines for rhinitis? What is their drawback?
Diphenyhydramine and chlorpheniramine
They put people to sleep as well as treat allergies
What is allegra and why is it used over terfenadine? How is it metabolized?
Second generation antihistamine called fexofenadine
Used over terfenadine because it does not cause Torsades de pointes (Ventricular arrhythmia)
Metabolized via CYP3A4
What are the motion sickness first generation antihistamines? How do they work?
Meclizine (antivert), Dimenhydrinate (dramamine)
Work via blocking H1 receptor in CNS (between inner ear and brainstem)
What is the third generation antihistamine?
Levocetirizine (zyrtec purified)
What is Claritin?
Loratidine
What are the H2 blockers of choice and what are they used for?
Cimetidine and ranitidine
Used for treatment of duodenal ulcer, gastritis, and reflux esophagitis
What causes pathologic hypersecretion of gastrin?
Zollinger-Ellison Syndrome - gastrin-secreting tumor, often found in pancreas
What two things cause the vast majority of peptic ulcers?
- Helicobacter pylori
2. NSAIDs
What three things are needed to treat ulcerative / inflammatory GI disease?
- Neutralize acid
- Reduce acid secretion
- Enhance mucosal defenses through cytoprotective or antimicrobial mechanisms
What antacid contains sodium? What is its side effect of concern?
Sodium bicarbonate -> systemic alkalosis
What is the side effect of concern with calcium carbonate?
Hypercalcemia, kidney stones
What are the side effects of concern with aluminum or magnesium hydroxide antacids?
Aluminum -> constipation
Magnesium -> diarrhea
Why do we think antacids are cytoprotective? How does this work?
They are effective at much lower doses than we would expect -> not based on acid neutralization
They probably bind irritating compounds
What three agonists control secretion of gastric acid?
Gastrin - CCK2 reecptor
Acetylcholine - M3 receptor
Histamine - H2 receptor (cAMP)
How do the H2 antagonists reduce gastric acid secretion?
Because the effects of the three agents are synergistic, a single dose of the H2 antagonist like Cimetidine and Ranitidine can prevent 90% of acid secretion
When are proton pump inhibitors used? How do they work?
In very severe situations - Zollinger-Ellison, gastric / duodenal ulcers, or severe gastroesophageal disease
They irreversibly bind the proton pump and don’t allow secretion
List 4 important PPIs:
Esomeprazole
Omeprazole
Lansoprazole
Pantoprazole
What is the drug interaction and side effect of concern with PPIs?
Interferes with antiplatelet drug clopidogrel / plavix, and long-term use is associated with increased risk of heart attack!! (cardiovascular problems)
How does octreotide work to reduce acid? What is its downside?
Somatostatin analog -> inhibits gastrin secretion
Downside is it is only available IV
Who is at risk for not responding to H2 blockers or antacids? What should you do?
Smokers and elderly people
-> consider treatment for H. pylori or switch drugs
Why do NSAIDs cause stomach ulcers?
Interfere with prostaglandin synthesis, which prevent gastric acid secretion by blocking histamine-stimulated cAMP production
Also disrupt protective barrier of stomach
What prostaglandin drug is the drug of choice when NSAIDs are the cause of the gastric ulcer?
Misoprostol - a prostaglandin analog
What are two drugs which are good at “coating” the gastric ulcer a protective barrier?
- Bismuth subsalicylate
2. Sucralfate - aluminum salt of a sulfated dissacharide (coats stomach and protects it)
What is the ideal regimen for H. pylori infection?
2 antibiotics + a PPI
Clarithromycin
Amoxicillin
Omeprazole
What is the cheaper regimen for H. pylori infection?
2 inferior antibiotics + bismuth + H2 blocker
Tetracycline
Metronidazole
Bismuth
Cimetidine
