Histamine and Antihistamine Agents

Question 1

Histamine structure

Answer 1

Imidazole heterocycle and ethylamine side chain

Question 2

Biosynthesis of histamine

Answer 2

Catalysis of L-histidine (amino acid)

Question 3

Histamine location

Answer 3

Found mainly in skin and mucosal cells of bronchi, intestines, etc.
Stored in mast cells and basophilic granulocytes

Question 4

H1 receptor

Answer 4

Widespread throughout body (CNS, respiratory smooth muscles, GI tract, etc.)
Stimulates phospholipase C
Involved in CNS (sleeping/waking, food intake, emotions, memory, learning, etc.), immune response, and other physiologic processes (itching, vasodilation, hypotension, tachycardia, etc.)

Question 5

H2 receptor

Answer 5

Stimulates cAMP
Mediates many of the same physiological responses as H1 receptor
Mediates gastric acid secretion (unique to this receptor)
Plays a role in allergy, autoimmunity, malignant disease, and graft rejection

Question 6

H3 receptor

Answer 6

Mainly found in CNS

Lesser role in peripheral nerve tissues

Question 7

H4 receptor

Answer 7

Immune response (can produce white blood cells, involved in allergic inflammatory response)
Transmits intracellular signals similar to H3 receptor

Question 8

General allergic response

Answer 8

Histamine is released from mast cells and basophils in response to antigen
Early allergic response: H1 and H2 (headache, hypotension, tachycardia, flushing), H1 and H3 (cutaneous itch, nasal congestion)
Late allergic response: stimulation of cytokine production and lymphocyte movement and response

Question 9

3 ways to terminate histamine action

Answer 9

Cellular uptake
Desensitization of cells
Metabolism (enzymatic inactivation; most common termination mechanism)

Question 10

Antihistamine generations

Answer 10

1st generation: H1 receptor blocking

2nd generation: non-sedating, derivatives of 1st gen drugs, more specific

Question 11

Antihistamine mechanism of action

Answer 11

Inverse agonists: stabilize inactive form of H1 receptors to shift equilibrium towards inactive state
Some block histamine release

Question 12

1st generation antihistamine SAR

Answer 12

2 aryl groups
Connecting X atom (O, N, C)
Carbon chain (usually ethyl)
Terminal amine

Question 13

Antihistamine usage

Answer 13

Treat allergies, colds, vertigo

Side effects: drowsiness/sedation (blockage of H1 receptors), cardiotoxic

Question 14

1st generation antihistamine subtypes

Answer 14

Aminoalkyl ethers (ex- Benadryl)
Ethylenediamines
Piperazines
Propylamines (most active H1 antagonists)
Phenothiazines (also used as antipsychotics)
Dibenzocycloheptenes/heptanes

Question 15

Differences between 1st and 2nd generation antihistamines

Answer 15

2nd gen: less sedation effects and less binding to non-target proteins that create side effects, larger N-tertiary amine substitutions, don’t accumulate in CNS

Question 16

Examples of 2nd generation antihistamines

Answer 16

Claritin, allegra, zyrtec

Question 17

Mast cell stabilizers

Answer 17

Inhibit activation of mast cells and release of histamine

Can also inhibit chemotaxis (WBC movement)

Question 18

Dual-acting antihistamines

Answer 18

Both H1 receptor action and mast cell stabilization

Question 19

H2 antagonists

Answer 19

Treatment of acid-peptic disorders

Decrease secretion of acid in gastric mucosa by parietal cells

Question 20

H2 antagonist SAR

Answer 20

Methylation of 5-position of imidazole ring: improved selectivity for H2 receptor
Increased length of side chain
Replacement of guanidino with methyl thiourea (Burimamide) or cyano-imino group (Cimetidine; improved potency and decreased toxicity)

Question 21

Proton pump inhibitors

Answer 21

Lower gastric acid secretion independently of histamine action
Example: prilosec

Question 22

H3 agonists

Answer 22

Possible therapeutic for learning and memory impairment, ADHD, obesity, epilepsy