YW - Histamine Flashcards
What are Histamine and 5-HT ? (3)
- Both biogenic amines
- Small molecules (mol wt ≈100) that act as local hormones or autacoids
- Important as neurotransmitters, local hormones in the vasculature and smooth muscle
What are 2 issues associated with histamine?
Allergy:
- A sensitivity to a specific substance (allergen), that is contacted through the skin, inhaled into the lungs or injected
Peptic ulcer
- A break in the lining of the stomach, first part of the small intestine, or occasionally the lower esophagus.
Describe the structure of Histamine
Imidazole ring - 2 x methyl groups - Amine group
Where is histamine synthesized, and what triggers its upregulation?
Histidine → Histamine
Histidine decarboxylase
- Found in mast cells, rapidly growing tissues, gastric mucosa cells
- Upregulated in stress and infections
Name dietary sources of histamine (2)
- Histidine decarboxylase found in several bacteria
- Histamine found in red wine, yeast extracts, smoked fish and meat
Dietary histamine does not contribute to the body’s pool of histamine
Describe the metabolism of histamine (2)
Histamine → N-Methylhistamine → N-Methylimidazole-Acetic Acid
Enzyme:
- N-Methyltransferase
- MAO-B
Histamine → Imidazoleacetic Acid → Imidazoleacetic acid Riboside
Enzyme:
- Diamine Oxidase
- +Ribose
Where is histamine stored
Mast Cells
→ Lung - 15µg/g tissue
→ Skin - 6-8µg/g tissue
→ Gut - 60-80 µg/g tissue
→ Stomach - 10µg/g tissue
What are constituents of mast cell granules? (3)
- Mast cell granules contain histamine bound to a proteoglycan core, usually heparin
- The granules also contain proteolytic enzymes such as tryptase and chymase
- Activation of the mast cells causes the granules to fuse with the cell membrane and release their contents.
How is histamine released from mast cells?
IgE dependent release
- Mast cells have receptors for IgE on their cell surface
- These bind IgE and when the cell is re-exposed to allergen IgE is crosslinked and the mast cell granules are released
The IgE-dependent release of histamine is associated with the symptoms of allergic disease
What are 2 other ways mast cells are activated?
Mast cells can be activated by bacterial products such as lipopolysaccharide (LPS)
They are also activated by complement peptides such as C3a and C5a.
- Both these mechanisms involve specific receptors on the mast cell surface
Histamine release occurs during bacterial infections and initiates an inflammatory response which recruits other elements of the immune system to destroy the bacteria
What are 2 examples of non-specific histamine release?
1) A number of basic drugs such as morphine and tubocurarine release histamine by non-receptor actions
2) Histamine is also released following trauma to the tissues
- This includes UV radiation, burns, and changes in osmolarity
Name histamine receptors and their locations
H1 - wide distribution in the cardiovascular system, smooth muscle and peripheral nerves
H2 - regulates gastric acid secretion in the stomach, increases the rate and output of the heart
H3 - found in the CNS
H4 - found on inflammatory cells
What are the effects of H1 receptor activation? (4)
Vasodilation - Redness/Heat
Increased vascular permeability - Swelling
Stimulation of peripheral nerves - Pain/Itch, Release of Neurotransmitters
Smooth muscle contraction - Asthma
- Histamine causes bronchial smooth muscle contraction
- Asthmatics are more susceptible to small doses of histamine
- Histamine is also able to contract smooth muscle in the GI and reproductive tracts
How does histamine affect the cardiovascular system?
Histamine acts on the heart to increase the rate and force of contraction
Dilation of arterioles causes a fall in peripheral resistance
- Veins are constricted increasing pressure in the venules
- Capillaries are dilated
- Arteries are constricted
Small doses vs Large doses of histamine in the CVS?
Small doses of histamine
- Cause a drop in peripheral resistance leading to a drop in blood pressure
Large doses of histamine
- Cause a profound decrease in blood pressure and a loss of fluid from the capillaries can cause circulatory collapse (Anaphylactic Shock)
What are the actions of histamine in the skin?
Inject Histamine →
- Reddening as capillaries dilate
- Blanching and Swelling as fluid moves into the tissues
- Pain or Itch as peripheral nerves stimulated
- Redness from neuronal stimulation
What is the classical H1 antagonist and what are its side effects?
Mepyramine
- It is orally available and has an excellent safety profile
- Side effects include drowsiness and effects on cholinergic receptors.
What is an example of a newer H1 antagonist and a certain problem associated with it?
Newer H1 antagonists such as cetirizine have been developed and cause fewer problems with drowsiness
- Cannot cross BBB (fewer problems)
Uses of H1 receptor antagonists (4)
- Treatment of allergies -oral, topical applications
- Sedative actions
- Local anaesthetic actions
- Motion sickness - safe though they can cause drowsiness
