Histamine

Question 1

Synthesised from

Answer 1

L-histadine

Question 2

Distribution

Answer 2

Present in almost all mammalian tissues.
High levels in - mast cells (skin,lung,intestinal mucosa), basophils (blood), histaminocytes (gastric mucosa), CNS (histaminergic neurones).
Stored in secretory granules.

Question 3

Release from mast cells and basophils

Answer 3

1. Antigen/antibody reactionss - Antigen binds to IgE, histamine is released.
2. Tissue damage - burns, plant/insect stings, radiation
3. Drugs - d-turbocurarine, morphine.
   All modes of secretion involve Ca2+ dependant exocytosis.

Question 4

Histamine receptors

Answer 4

4 subtypes.
H1, H2, H3, H4.
H3 discovered in CNS, H4 discovered in immune cells, both recent discoveries.

Question 5

Actions of histamine

Answer 5

Vasodilation (NO pathway)
Vasoconstriction (smooth muscle action)
Increased vascular permeability

Question 6

Vasodilation

Answer 6

I.v injection of histamine leads to activation of H1 receptors on endothelial cells initiates NO production and activation of H2 receptors in arterial smooth muscle, both cause vasodilation. H1>H2

Question 7

Vasoconstriction

Answer 7

Large arteries and veins constrict due to H1 direct action on smooth muscle (small veins and arteries have less/no smooth muscle so no vasoconstrictive effects)

Question 8

Increased vascular permeability

Answer 8

Increased inflow due to vasodilation but decreased outflow due to vasoconstriction of veins causes increased venular hydrostatic pressure. Post-capillary venule endothelial cells contract forming intracellular gaps. Both aftions are H1 and increase vascular permeability.
This leads to the leak of plasma proteins,fluids and leukocytes into interstitial space causing oedema, this is hood as it recruits immune mediators.

Question 9

Classic triple response

Answer 9

Flush
Flare
Wheal
All H1 mediated

Question 10

Flush

Answer 10

Direct arteriolar dilation at site of histamine

Question 11

Flare

Answer 11

Axon reflex causing dilation of surrounding vessels by substace p release from sensory nerve fibres

Question 12

Wheal

Answer 12

Local oedema at histamine release site due to leak of fluid into interstitial space.

Question 13

Actions on the heart

Answer 13

Positive inotropic action
Positive chronotropic action
Both H2.
Reflex tachycardia due to baroreceptor reflex In response to falling BP.

Question 14

Actions on smooth muscle

Answer 14

Gut - contraction (H1)

Bronchi - contraction (H1) ( not in asthma, that is mediated by leukotrienes)

Question 15

Role in allergy

Answer 15

Mainly in exudative types (runny nose, eyes etc.)

Due to increased vascular permeability. (H1)

Question 16

Actions on nerves

Answer 16

In the CNS histamine is a neurotransmitter, it is excitatory on H1 receptors and inhibitory on H2 receptors.
There is also a negative feedback mechanism reducing histamine release from histaminergic neurons (H3 autoreceptor).
In the periphery histamine activates sensory fibres producings itch and pain, and the classical axon reflex triple response (H1)

Question 17

Actions on gastric acid secretion

Answer 17

Direct stimulation of parietal cells hydrogen phosphate atpase (H2).
Synergistic action with ACh or gastrin evoked secretion.

Question 18

H1 receptors

Answer 18

Linked via Gq to activation of phospholipase c, which increases intracellular Ca conc.

Question 19

H2 receptors

Answer 19

Linked via Gs to adenylate cyclase, increases cAMP, increase intracellular Ca conc.

Question 20

H3/4 receptors

Answer 20

Linked via Gi to adenylate cyclase, decreasing cAMP, inhibiting the inhibition of histamine release.

Question 21

B2 receptor agonists

Answer 21

Inhibits release of histamine from mast cells
Also blocks LTC4 and LTD4 as they come from mast cels
Used in asthma.

Question 22

Sodium cromoglycate

Answer 22

Mast cell stabiliser

Inhibits calcium dependant exocytosis.

Question 23

H1 receptor antagonists

Answer 23

Diphenhydramine, mepyramine
Competitive antagonists
Used in exudative allergy types
Antihistamines

Question 24

Side effects of H1 antagonists

Answer 24

Dry mouth - anticholinergic effect
Sedation - most important, advantage for travel sickness, disadvantage for driving, potentiated by alcohol.
Loritidine is highly iknised so cannot cross BBB, no sedatory effects.

Question 25

H2 receptor antagonists

Answer 25

Cimetidine, ranitidine
Competitive.
Block positive inotropic and chronotropic effects
Block H2 vasodilation
Block gastric agid secretion
Used to treat peptic ulcers