L 25 and 26 antihistamines

Question 1

synthesis of histamines

Answer 1

-synthesized in mast cells and basophils: an important mediator of inflammation
-stored in granules for rapid release in response to : antigen cell lysis

Question 2

metabolism of histamines

Answer 2

-N-methylation on an imidazole nitrogen by histamine N-methyl transferase
-oxidation by diamine oxidase
-imidazoleacetice acid 5’-phosphoribosyl transferase

Question 3

localization of histamine: distribution of mast cells

Answer 3

high numbers in; skin, nose, mouth, lungs, intestinal mucosa

Question 4

localization of histamine: storage granules

Answer 4

-histamine is complexed with polysaccharides, heparin sulfate, chondroitin sulfate, and proteases-

Question 5

localization of histamines: non-mast cell histamine

Answer 5

-nerve terminals in some areas of brain (neurotransmitters)
-fundus of stomach: specialized cells store histamines for stimulation of acid secretion

Question 6

causes of histamine release from mast cells and basophils: antigen mediated

Answer 6

-binding of antigen (allergens) to antibodies bound to the cell surface (IgE)
-other inflammatory agents are also released (kinins, serotonin, leukotrienes, prostaglandins)

Question 7

causes of histamines release from mast cells and basophils: non-antigen mediated

Answer 7

-thermal or mechanical stress
-cytotoxic agents; venoms
-various drugs (high doses morphine)

Question 8

mechanism of mast degranulation requires

Answer 8

-binding to IgE antibodies to FCER
-binding to antigen to IgE antibodies
-clustering of FCER receptors
-influx of Ca2+ via Ca2+ release activated channels (CRAC)

Question 9

mechanism of histamine release

Answer 9

-binding antigen to antibody molecules causes as increase in cytoplasmic Ca2+ concentrations
-beta-adrenergic agonists can inhibit antigen-induce histamine release while acetylcholine can stimulate histamine release from mast cells

Question 10

drugs that prevent histamine release

Answer 10

-cromolyn sodium: RX (mastocytosis oral)
OTC (allergic rhinitis nasal spray)
-nedocromil: RX (allergic conjunctivitis eye drops)

Question 11

histamine receptors

Answer 11

-affects of histamines are due to histamine receptors
-four histamine receptor subtypes are all G-protein coupled

Question 12

H1 receptor

Answer 12

-distributed throughout CV, respiratory systems, GI smooth muscle
-linked to phosphoinositol pathway, activation caused contraction of smooth muscles

Question 13

H1 receptors are linked to

Answer 13

-vasodilation:
Hist + H1 in vascular endothelial cells —> increase NO release –> NO diffuse to vascular smooth muscles —> increase cGMP —-> decrease Ca2+
-sensory nerves:
hist+ H1 in cutaneous or nasal muscosal nerve endings (sneezing and itching pruritus

Question 14

H2 receptors

Answer 14

-distrubuted in CV systems, GI smooth muscle, and stomach

Question 15

H2 receptor linked to relaxation of vascular smooth muscles and gastric secretion

Answer 15

hist + H2–> increase in adenylate cyclase –> increase cAMP

Question 16

H1 and H2 colocalization

Answer 16

-vascular smooth muscles and endothelium
-H1 in vascular endothelium- increase NO increase contraction of endothelial cells
-H2 in vascular muscle- relaxation (vasodilation)

Question 17

H3 receptors

Answer 17

-located mainly in the CNS- couples to Gi/Go
-auto receptor in neurons that use histamines as a neurotransmitter

Question 18

H3 receptor linked to inhibition of neurotransmitter release

Answer 18

hist—-> H3—–>decrease Ca2+ influx through voltage gated channels
-aslo inhibition of adenylyl cyclase

Question 19

H4 receptor

Answer 19

-located on mast cells, basophils, eosinophils- coupled to Gi/Go
-linked to histamine-induced chemotaxis
-promising target for future antiinflammatory drugs

Question 20

pharmacology of histamine: cardiovascular

Answer 20

a. Heart- moderate increase in rate and force of contraction (H2 increase in SA conduction; reflex tachycardia)
b. Vasodilation- (H1 in endothelium; H2 in sm. muscle)

Question 21

pharmacology of histamines: respiratory

Answer 21

H1 mediated constriction of bronchial sm. Muscle

Question 22

pharmacology of histamines: acid release in stomach

Answer 22

H2 mediated release from parietal cells in stomach

Question 23

Pharmacology of histamines: anaphylaxis

Answer 23

Hypotension and loss of fluid to the interstitial space decrease in effective blood volume; swelling

Question 24

histamine regulation of the vasculature: vasodilation

Answer 24

-endotehlium (high-affinity H1 receptor, via NO pathway)
-smooth muscle (lower/ moderate affinityH2 receptors, via PKA pathway)
-exception; histamine constricts veins

Question 25

histamine regulation of the vasculature: increase capillary permeability

Answer 25

-H1 mediated endothelial contraction
-tight junction disruption
-release plasma proteins, fluid
-occurs in small vessels
-results in edema
-enhances immune cells ability to respond to antigen

Question 26

histamine affects the skin triple response

Answer 26

1. Red spot at the point of injection (immediate)
2. Red flare radiating ~ 1 cm from injection site (~ 10 s.)
3. Wheal (raised welt) at site of injection (1-2 min.)

Question 27

other skin pathologies caused by histamines

Answer 27

-urticaria: hives, rash, edematous welts
-dermatographia: redness or welts with mechanical stimulation
-flushing (erythema): redness in skin due to vasodilation

Question 28

histamine affects in the lungs

Answer 28

-h1 receptor
-Ca2+ mobilization
-SM contraction
-bronchoconstriction

Question 29

anaphylaxis: massive release of histamines

Answer 29

-hypersensitivity/ allergic reaction to various allergens (food, bites, medication, etc)
-severe-life threatening
-histamine and other autocoids release
-skin, respiratory, GI, CV, etc
-treatment: epinephrine injection or used of antihistamines is often not effective

Question 30

general in antihistamines H1 receptor antagonists

Answer 30

Many, many different compounds available (23-24) ~120 products including combinations

Question 31

antihistamines: H1 receptor antagonist vs H2 receptor antagonist

Answer 31

1. H1 antagonists: referred to as antihistamines
   do not bind H2 receptors
2. H2 antagonists: referred to as acid blockers
   do not bind H1 receptors

Question 32

antihistamines: H1 receptor antagonist mechanism of action

Answer 32

competitive antagonist

Question 33

H1 receptor antagonist

Answer 33

-predominantly inverse agonist
-First generation antihistamines (alkylamines, ethanolamines, ethylenediamines, phenothiazines, piperadines, piperazines)