Ph- Antihistamines Flashcards
What are the H1 histamine receptor antagonists?
- Diphenhydramine
2. loratadine
What are the inhibitors of mast cell degranulation?
cromolyn sodium
What are the H2 histamine receptor antagonists?
ranitidine
What are the 3 main endogenous functions of histamine?
- immediate allergic response
- gastric acid secretion (GERD, peptic ulcers)
- neurotransmitter in CNS (Alzheimer’s, ADHD)
Describe the synthesis of histamine.
It is synthesized from L-histidine by histidine decarboxylase.
What tissues have the highest concentration of histamine?
Lungs, skin and intestinal mucousa
What are the major storage sites of histamine? Is the turn over rate rapid or slow in each site?
- Mast cells (in tissue) and basophils (circulating)- these are turned over slowly bc they are only used in response to specific and relatively rare stimuli
- GI mucousa- rapidly turned over
- Nerve endings in the brain- rapidly turned over
- cells of rapidly growing tissue - rapidly turned over
How is histamine released and degraded?
How long does it take to disappear from serum?
It is released by calcium-induced exocytosis of storage vesicles
Degradation:
Methylation of histamine —> inactive N-methylimidazole acetid acid–> urine
It disappears from serum in minutes and appears as breakdown products in the tissues
The effects of histamine are __________ and generally limited to _________ where it is ______.
(essentially, is histamine local or systemic)
short term and limited to the area where they are released.
Local rather than systemic effects
There are 4 main types of histamine receptors.
What type of G receptor is each?
What do they do the Ca levels and cAMP levels
H1- Gq receptor that increases Ca (smooth muscle contraction and endothelial increased permeability)
H2- Gs receptor that increases cAMP
H3- Gi,o receptor that decreases Ca and cAMP reducing responses of synapses
H4- Gi,o receptor that INCREASES Ca via bg pathways and decreases cAMP
What is the effect of histamine on capillaries?
What are the receptors and locations?
H1- endothelial cells (increase Ca) release of factors that relax-
H2- smooth muscle cells (increase cAMP)
This causes dilation and hypotension
What is the effect of histamine on larger vessels?
contraction– this is overshadowed by the effects on capillaries which dilate and cause hypotension
What is the effect of histamine on extravascular smooth muscle?
H1- contract
H2 -relax
Which one “wins” depends on teh site
What is the effect of histamine on bronchi?
Constriction/bronchospasm– H1 dominates
What is the effect of histamine on endothelial cells?
H1–> contraction–> separation and increased permeability to plasma–> edema
What is the effect of histamine on gastric mucousa?
H2- acid secretion
What is the effect of histamine on nerve endings/CNS?
H1– increased Ca–> itch/pain
What are the effects of histamine on presynaptic modulation?
H3- inhibits by decreasing cAMP and Ca. –> modulated cognition, awakeness, homeostatic function
What is the effect of histamine on the immune system?
H4–> enhanced activation of mast cells, autocrine enhancement of mast cells, recruitment of immune cells to site of inflammation
What is the prominent location of H3 receptors?
What is their major function?
What 4 diseases are H3 antagonists being looked at to treat?
They are found predominantly in the CNS and act by feedback mechanism to block the release of presynaptic histamine
- narcolepsy
- parkinsons
- alzheimer’s
- ADHD
Where is the prominent location of H4 receptors?
What is their major function?
What 3 things are antagonists being looked at to treat?
In the immune system to regulate chemotaxis and attraction of mast cells and eosinophils to the site of inflammation to augment Ca driven activation
Antagonists are being studied for:
- allergic rhinitis
- atopic dermatitis
- inflammatory and autoimmune disorders
What are H1 agonists used for?
- Bronchial reactivity testing
- Nerve integrity testing
- positive control for skin tests of allergies
What are H2 agonists used for?
- test gastric secretory function
How do first and second generation H1 receptor antagonists differ in effectiveness and deliver?
First line (diphenhydramine) - competitive antagonists that penetrate CNS and are safe and OTC Second line (loratadine) - does NOT penetrate CNS so has better specificity and few side effects
What are the side effects of first line H1 antagonists like diphenhydramine?
- sedation (first line only)
- GI disturbances - vomiting, loss of appetite
- antimuscarinic activity (dry mouth, urinary retention)
What are the major uses of H1 antagonists?
- immediate hypersensitivity reactions (although INEFFECTIVE in bronchial asthma and anaphylaxis)
- motion sickness - due to anticholinergic properties
- Urticaria (drowsiness might even be beneficial)
- nausea
What are the 3 ways histamine released during an immediate hypersensitivity reaction?
- Antigen mediated degranulation :
- antigen interacts with IgE on cell surface
- phosphatidylinositol turnover
- increased intracellular Ca
- extrusion of secretory granule content by exocytosis - Other releasing agents: cytotoxic, polysaccharides, lectins, anaphylatoxins, venom (polybasic compounds), weakly basic compounds (drugs)
- cell injury (mechanical, thermal, radiation
What preformed substances are released from stored granules in a hypersensitivity reaction?
Histamine heparin proteoglycan neutral proteases acid hydrolases SO2 dismutase eosinophil chemotatic factor neutrophil chemotactic factor
What chemical mediators are generated upon cellular activation in hypersensitivity reactions?
- PGD2
- 5-HETE
- LTC4, D4 (slow reacting substance of anaphylaxis)
- PAF
Why do histamines only partially block reactions involving hypersensitivity?
There are plenty of other reactants that are released in addition to histamine that facilitate the hypersensitivity reaction, especially the systemic effects.
Histamine is mainly local effects like uticaria, swelling, redness and local pain/itch.
What does cromolyn sodium do?
Who uses it?
What are drawbacks?
It blocks the release of inflammatory agents from pulmonary mast cells.
It is used for prophylactically to treat allergic bronchial asthma and exercise-induced asthma.
It takes weeks to develop an effect, is ineffective in many individuals and is not useful for treating acute attacks.
What is the major H2 receptor antagonist?
What are the therapeutic uses?
Ranitidine is used as an H2 antagonist to modulate gastric acid secretion from parietal cells (which is usually released in response to neural stimulation and gastrin release upon feeding)
- duodenal and gastric ulcers
- prevent ulceration with maintenance doses
- GERD
- Zollinger Ellison syndrome
- High doses of aspirin
What is Zollinger-Ellison syndrome?
It is elevated gastrin due to non-beta cell tumor in the pancreas
What is the effect of prostaglandins on stomach acid release?
Decreased prostaglandins increase acid secretion because prostaglandins inhibit the H2 channels from increasing cAMP
What drug interactions do ranitidine cause?
Decreased stomach acid changes the bioavailability and rate of absorption of many drugs
