Fondell - Antihistamines Flashcards
How is histamine synthesized?
From Histidine it will be decarboxylated by the enzyme L-Histidine decarboxylase to become histamine.
How long is the half life of Histamine? What happens to it?
Only like 30-60 seconds. It has 2 fates:
1) broken down into methyl ImAA (more common)
2) or it gets broken down into ImAA ribosome
Which cells have histamine
Basophils
Mast cells
Enterochromaffin-like cells
Histaminergic neurons
Storage of Histamine in mast cells and basophils? ECLs and histaminergic neurons?
Mast cells and Basophils - they are sequestered and bound in cytoplasmic granules along with GAGs like heparin, serotonin, proteases, and cytokines
ECL and neurons - stored in vesicles that pinch of
Mechanisms of histamine release
1) immunological release
2) Mast cell injury/damage
3) . Endocrine or neuronal stimulation
4) chemical displacement - drugs can cause histamine release from mast cells.
Mechanism of mast cell degranulation
the allergen causes the Cross-linking as we discussed. This Causes LYN and SYK, which are associated with the intracellular portion o the FCeRI receptor to act on LAT. Through downstream mechanisms , Inositol Triphopshate and DAG are activated, which cause the release of calcium and protein kinase C, which cause the release of histamine, cytokines, and proteases.
- However, it isn’t just about de granulation. As we see, the MAPK pathway is also activate, which causes the activation of Phospholipase A (PLA), and thus release of prostaglandins and leukotrienes as well as the upregulation of transcription factors for cytokines.
What type of receptor class is used for histamine?
G protein
H1
Alpha subunit: q
Effects - up regulation of IP3 and DAG, which will cause histamine degranulation I
Where? - smooth muscle, endothelium, peripheral neurons, brain
What? - itching, pain, secretion from mucosa, vasodilation via NO, edema, bronchoconstriction, contraction of the gut
H2
Alpha subunit: s
Effects: increase in cAMP, which will cause degranulation
Where? - gastric mucosa, cardiac muscle, vascular smooth muscle, mast cells, basophils, brain
What? - increase gastric acid secretion, vasodilation via cAMP, and increased heart rate
H3
Alpha subunit: i
Effects - decrease in cAMP
Where? - Presynaptic histaminergic neurons in the brain, myenteric plexus
What? - decrease in histamine release
H4
Alpha subunit - i
Effects - decrease in cAMP
Where? - cells of hematopoietic origin including: eosinophils, neutrophils, dendritic cells, basophils, monocytes, T cells.
What? - differentiation of myeloma sets and promyelocytes, chemotaxis, secretion of cytokines, up regulation of adhesion factors.
Why do first generation antihistamines make you tired?
Because it would act on the H1 and H3 receptors in the CNS.
What is the benefit of capillary permeability due to histamine release?
- allows immune cells access to the injury
- histamine and the other released cytokines have chemotactic properties that facilitate immune cell recruitment
- allows for local afferents axons to sense the foreign object.
Anti-histamines - how do they work?
The histamine receptors have two states, the active state and the inactive state. In response to histamine, the active form is favored and we have reaction. Anti-histamines bind to the inactive form and make it more stable. Therefore, no response is seen.
Differences between first. And second. Generation anti–histamines
1st generation is neutral at physiological pH so they readily cross the blood-brain barrier and enter the CNS.
- therefore they are highly sedative
- they are anti-emetic (used for nausea)
- used to treat insomnia, motion sickness, and anti-itch
- they are not as specific
- short acting
2nd generation is ionized at physiological pH so it can’t get into the CNS.
- no sedative effect
- not anti-emetic
- highly selective
- longer-acting
First Generation H1 antihistamines
- used for hives, itching, allergy symptoms. May cause drowsiness/dizziness.
- interacts with the CYP450 enzymes in the liver so there is possibility for overdose
Diphenylhydramine Tripelennamine Chlorpheniramine Promethazine Hydroxyzine Cyclizine Cyproheptadine
Second generation H1 antihistamines
Non-drowsy, for people who want it to work all day.
- cetirizine
- laratadine - metabolized by CYP450 enzymes into an active metabolite that exerts the effects. So drugs that inhibit these enzymes can minimize the effectiveness of the drug.
- fexofenadine
3rd generation H1 antihistamines
Levocetirizine - It is the purified R enantiomer of cetirizine, which means it will have a greater effect with less of a dose
Desloratidine - is the metabolite from loratidine that was metabolized by the P450 enzymes and exerts the effects.
Regulation of gastric acid secretion via H2 receptors
Within the fund us of the stomach we know that Ach or Gastrin can act on receptors in the parietal cells to release calcium, which causes upregulation of the H+/K+ receptors. Histamine, coming from the ECL cells and acting on the H2 receptors in the parietal cells will increase cAMP and have the same affect.
- H2 Anti-histamines will block this pathway and make less acid secretion.
H2 antihistamines
Will lower acid secretion at night (but can’t lower secretion in response to food)
- cimetidine - inhibits P450 so you gotta watch out for drug-drug interactions
- ranitidine
- famotidine
- Nizatidine
Drugs to know
Final slide of lecture
Histamine structure
Imidazole ring with ethylamine
Cromolyn and nedocromil
Inhibitors of mass cell degranulation
Way to remember H2 antihistamines
Climb Ranier For Nike - they also all end in DINE
- Cimetidine
- Raitidine
- Famotidine
- Nizatidine
Way to remember 3rd generation antihistamines
Letz Dance (then dine)
- Levocetrizine
- Desloratadine
Way to remember Second generation H1 antihistamines
Cat Licks Fox
- Cetrizine
- Loratidine
- Fexofenadine
Ways to remember First generation antihistamine
Anything that ends in amine.
- it is the only one that has one that starts with T,H,M,P — THMP
