Ph- Antihistamines

Question 1

What are the H1 histamine receptor antagonists?

Answer 1

1. Diphenhydramine

2. loratadine

Question 2

What are the inhibitors of mast cell degranulation?

Answer 2

cromolyn sodium

Question 3

What are the H2 histamine receptor antagonists?

Answer 3

ranitidine

Question 4

What are the 3 main endogenous functions of histamine?

Answer 4

1. immediate allergic response
2. gastric acid secretion (GERD, peptic ulcers)
3. neurotransmitter in CNS (Alzheimer’s, ADHD)

Question 5

Describe the synthesis of histamine.

Answer 5

It is synthesized from L-histidine by histidine decarboxylase.

Question 6

What tissues have the highest concentration of histamine?

Answer 6

Lungs, skin and intestinal mucousa

Question 7

What are the major storage sites of histamine? Is the turn over rate rapid or slow in each site?

Answer 7

1. 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
2. GI mucousa- rapidly turned over
3. Nerve endings in the brain- rapidly turned over
4. cells of rapidly growing tissue - rapidly turned over

Question 8

How is histamine released and degraded?

How long does it take to disappear from serum?

Answer 8

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

Question 9

The effects of histamine are __________ and generally limited to _________ where it is ______.

(essentially, is histamine local or systemic)

Answer 9

short term and limited to the area where they are released.

Local rather than systemic effects

Question 10

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

Answer 10

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

Question 11

What is the effect of histamine on capillaries?

What are the receptors and locations?

Answer 11

H1- endothelial cells (increase Ca) release of factors that relax-
H2- smooth muscle cells (increase cAMP)

This causes dilation and hypotension

Question 12

What is the effect of histamine on larger vessels?

Answer 12

contraction– this is overshadowed by the effects on capillaries which dilate and cause hypotension

Question 13

What is the effect of histamine on extravascular smooth muscle?

Answer 13

H1- contract
H2 -relax

Which one “wins” depends on teh site

Question 14

What is the effect of histamine on bronchi?

Answer 14

Constriction/bronchospasm– H1 dominates

Question 15

What is the effect of histamine on endothelial cells?

Answer 15

H1–> contraction–> separation and increased permeability to plasma–> edema

Question 16

What is the effect of histamine on gastric mucousa?

Answer 16

H2- acid secretion

Question 17

What is the effect of histamine on nerve endings/CNS?

Answer 17

H1– increased Ca–> itch/pain

Question 18

What are the effects of histamine on presynaptic modulation?

Answer 18

H3- inhibits by decreasing cAMP and Ca. –> modulated cognition, awakeness, homeostatic function

Question 19

What is the effect of histamine on the immune system?

Answer 19

H4–> enhanced activation of mast cells, autocrine enhancement of mast cells, recruitment of immune cells to site of inflammation

Question 20

What is the prominent location of H3 receptors?
What is their major function?
What 4 diseases are H3 antagonists being looked at to treat?

Answer 20

They are found predominantly in the CNS and act by feedback mechanism to block the release of presynaptic histamine

1. narcolepsy
2. parkinsons
3. alzheimer’s
4. ADHD

Question 21

Where is the prominent location of H4 receptors?
What is their major function?
What 3 things are antagonists being looked at to treat?

Answer 21

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:

1. allergic rhinitis
2. atopic dermatitis
3. inflammatory and autoimmune disorders

Question 22

What are H1 agonists used for?

Answer 22

1. Bronchial reactivity testing
2. Nerve integrity testing
3. positive control for skin tests of allergies

Question 23

What are H2 agonists used for?

Answer 23

1. test gastric secretory function

Question 24

How do first and second generation H1 receptor antagonists differ in effectiveness and deliver?

Answer 24

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

Question 25

What are the side effects of first line H1 antagonists like diphenhydramine?

Answer 25

1. sedation (first line only) 2. GI disturbances - vomiting, loss of appetite 3. antimuscarinic activity (dry mouth, urinary retention)

Question 26

What are the major uses of H1 antagonists?

Answer 26

1. immediate hypersensitivity reactions (although INEFFECTIVE in bronchial asthma and anaphylaxis) 2. motion sickness - due to anticholinergic properties 3. Urticaria (drowsiness might even be beneficial) 4. nausea

Question 27

What are the 3 ways histamine released during an immediate hypersensitivity reaction?

Answer 27

1. Antigen mediated degranulation : - antigen interacts with IgE on cell surface - phosphatidylinositol turnover - increased intracellular Ca - extrusion of secretory granule content by exocytosis 2. Other releasing agents: cytotoxic, polysaccharides, lectins, anaphylatoxins, venom (polybasic compounds), weakly basic compounds (drugs) 3. cell injury (mechanical, thermal, radiation

Question 28

What preformed substances are released from stored granules in a hypersensitivity reaction?

Answer 28

``` Histamine heparin proteoglycan neutral proteases acid hydrolases SO2 dismutase eosinophil chemotatic factor neutrophil chemotactic factor ```

Question 29

What chemical mediators are generated upon cellular activation in hypersensitivity reactions?

Answer 29

1. PGD2 2. 5-HETE 3. LTC4, D4 (slow reacting substance of anaphylaxis) 4. PAF

Question 30

Why do histamines only partially block reactions involving hypersensitivity?

Answer 30

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.

Question 31

What does cromolyn sodium do? Who uses it? What are drawbacks?

Answer 31

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.

Question 32

What is the major H2 receptor antagonist? | What are the therapeutic uses?

Answer 32

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) 1. duodenal and gastric ulcers 2. prevent ulceration with maintenance doses 3. GERD 4. Zollinger Ellison syndrome 5. High doses of aspirin

Question 33

What is Zollinger-Ellison syndrome?

Answer 33

It is elevated gastrin due to non-beta cell tumor in the pancreas

Question 34

What is the effect of prostaglandins on stomach acid release?

Answer 34

Decreased prostaglandins increase acid secretion because prostaglandins inhibit the H2 channels from increasing cAMP

Question 35

What drug interactions do ranitidine cause?

Answer 35

Decreased stomach acid changes the bioavailability and rate of absorption of many drugs