Histamine Flashcards
Synthesised from
L-histadine
Distribution
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.
Release from mast cells and basophils
- Antigen/antibody reactionss - Antigen binds to IgE, histamine is released.
- Tissue damage - burns, plant/insect stings, radiation
- Drugs - d-turbocurarine, morphine.
All modes of secretion involve Ca2+ dependant exocytosis.
Histamine receptors
4 subtypes.
H1, H2, H3, H4.
H3 discovered in CNS, H4 discovered in immune cells, both recent discoveries.
Actions of histamine
Vasodilation (NO pathway)
Vasoconstriction (smooth muscle action)
Increased vascular permeability
Vasodilation
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
Vasoconstriction
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)
Increased vascular permeability
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.
Classic triple response
Flush
Flare
Wheal
All H1 mediated
Flush
Direct arteriolar dilation at site of histamine
Flare
Axon reflex causing dilation of surrounding vessels by substace p release from sensory nerve fibres
Wheal
Local oedema at histamine release site due to leak of fluid into interstitial space.
Actions on the heart
Positive inotropic action
Positive chronotropic action
Both H2.
Reflex tachycardia due to baroreceptor reflex In response to falling BP.
Actions on smooth muscle
Gut - contraction (H1)
Bronchi - contraction (H1) ( not in asthma, that is mediated by leukotrienes)
Role in allergy
Mainly in exudative types (runny nose, eyes etc.)
Due to increased vascular permeability. (H1)
Actions on nerves
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)
Actions on gastric acid secretion
Direct stimulation of parietal cells hydrogen phosphate atpase (H2).
Synergistic action with ACh or gastrin evoked secretion.
H1 receptors
Linked via Gq to activation of phospholipase c, which increases intracellular Ca conc.
H2 receptors
Linked via Gs to adenylate cyclase, increases cAMP, increase intracellular Ca conc.
H3/4 receptors
Linked via Gi to adenylate cyclase, decreasing cAMP, inhibiting the inhibition of histamine release.
B2 receptor agonists
Inhibits release of histamine from mast cells
Also blocks LTC4 and LTD4 as they come from mast cels
Used in asthma.
Sodium cromoglycate
Mast cell stabiliser
Inhibits calcium dependant exocytosis.
H1 receptor antagonists
Diphenhydramine, mepyramine
Competitive antagonists
Used in exudative allergy types
Antihistamines
Side effects of H1 antagonists
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.
