Histamine Pharmacology and GI Disease Flashcards Preview

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Flashcards in Histamine Pharmacology and GI Disease Deck (44):
1

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

2

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

3

Where is histamine primarily found in the blood and in the tissues?

In the blood - basophils
In the tissues - mast cells

4

Where is histamine stored? What is it stored with?

Stored in metachromatic secretory granules, complexed as an inactive componud with heparin and chondroitin sulfate

5

Where is turnover of histamine very rapid?

In non-mast cells:

Enterochromaffin-like cells, brain, etc

6

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

7

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

8

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

9

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

10

What drug blocks the release of histamine from mast cells directly?

Cromolyn sodium (sodium cromoglycate), bocks influx of divalent cations including Ca+2

11

What do Compound 48/80 and polymyxin B do?

They act as ionophores, resulting in influx of Ca+2 and resultant histamine release

12

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)

13

What type of receptors are the histamine receptors? How many forms are there?

GPCR

There are H1-H4

H3 is presynaptic in brain

14

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

15

Where are H2 receptors found? What's their mechanism?

Gastric mucosa (parietal cells), cardiac muscle cells, "mast cells"

Gs -> increase cAMP

16

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

17

What causes hives?

Histamine-induced edema

18

Why does histamine cause itching?

H1-receptor mediated stimulation of sensory nerve endings (insect stings / venoms)

19

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)

20

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

21

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

22

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)

23

What is the third generation antihistamine?

Levocetirizine (zyrtec purified)

24

What is Claritin?

Loratidine

25

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

26

What causes pathologic hypersecretion of gastrin?

Zollinger-Ellison Syndrome - gastrin-secreting tumor, often found in pancreas

27

What two things cause the vast majority of peptic ulcers?

1. Helicobacter pylori
2. NSAIDs

28

What three things are needed to treat ulcerative / inflammatory GI disease?

1. Neutralize acid
2. Reduce acid secretion
3. Enhance mucosal defenses through cytoprotective or antimicrobial mechanisms

29

What antacid contains sodium? What is its side effect of concern?

Sodium bicarbonate -> systemic alkalosis

30

What is the side effect of concern with calcium carbonate?

Hypercalcemia, kidney stones

31

What are the side effects of concern with aluminum or magnesium hydroxide antacids?

Aluminum -> constipation
Magnesium -> diarrhea

32

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

33

What three agonists control secretion of gastric acid?

Gastrin - CCK2 reecptor
Acetylcholine - M3 receptor
Histamine - H2 receptor (cAMP)

34

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

35

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

36

List 4 important PPIs:

Esomeprazole
Omeprazole
Lansoprazole
Pantoprazole

37

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)

38

How does octreotide work to reduce acid? What is its downside?

Somatostatin analog -> inhibits gastrin secretion

Downside is it is only available IV

39

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

40

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

41

What prostaglandin drug is the drug of choice when NSAIDs are the cause of the gastric ulcer?

Misoprostol - a prostaglandin analog

42

What are two drugs which are good at "coating" the gastric ulcer a protective barrier?

1. Bismuth subsalicylate
2. Sucralfate - aluminum salt of a sulfated dissacharide (coats stomach and protects it)

43

What is the ideal regimen for H. pylori infection?

2 antibiotics + a PPI

Clarithromycin
Amoxicillin
Omeprazole

44

What is the cheaper regimen for H. pylori infection?

2 inferior antibiotics + bismuth + H2 blocker

Tetracycline
Metronidazole
Bismuth
Cimetidine