Histamine and 5-HT are both what?
What is this?
A biogenic (produced or brought about by living organisms) substance with one or more amine group
What size is histamine and 5-HT?
How do they act?
They are small molecules
Molecular weight of roughly 100
They act as local hormones or autacoids
What is histamine and 5-HT important for?
As neurotransmitters, local hormones in vasculature and in smooth muscle
Tell me about how histamine is linked to human diseases
and what histamine is involved with each?
Allergy (H1): A sensitivity to a specific substance (allergen), that is contacted through the skin, inhaled into the lungs or injected
Peptic ulcer (gastric ulcer) (H2): A break in the lining of the stomach, first part of the small intestine, or occassionally the lower oesophagus
Tell me the structure of Histamine, label the groups at each terminus?
What is the pKa of the terminal groups and how is this affected in physiological conditions?
- pKa is defined as the pH where a drug exists as 50% ionized and 50% unionized
- on C terminus the ring like structure is called an Imidazole ring
- Under physiological conditions there is a pH of about 7, so in this case the ring would be neutral, but the N terminus would be NH3+
What is the source of histamine?
Tell me about the synthesis of histamine?
Histidine has an extra COOH group on N terminus, so simply need to remove COOH to form histamine
Tell me about the dietary sources of histamine?
- 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 (as is destroyed by bodies acid)
Metabolism of histamine
Tell me where histamine can be stored and how much in those locations?
In the cytoplasm of mast cells, there are mast cell granuels. What do these contain?
Mast cell granules contain histamine bound to a proteoglycan core, usually heparin. Might help protect from degradation so isn’t metabolized
What happens when the mast cell is in a resting state and an activated state?
- Under certain conditions the mast cells can be activated to release the granules to the environment
- 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 (histamine also released and all contributed to biological consequences)
State 3 factors which causes release of histamine from the mast cell due to activation of the cell?
- IgE dependent release
- Other stimuli
- Non-specific release
Tell me about IgE dependent release of histamine?
- 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
Tell me how other stimuli cause release of histamine from the mast cells?
- 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
Tell me about non-specific release of histamine from the mast cells
- A number of basic drugs such as morphine and tubocurarine (NMJ drug) release histamine by non-receptor actions.
- Histamine is also released following trauma to the tissues. This includes UV radiation, burns, and changes in osmolarity
Tell me about the type of histamine receptors and where they are generally located in the body?
H1 - wide distribution in cardiovascular system, smooth muscle and peripheral nerves
H2 - regulates gastric acid secretion in the stomach, increases rate and output of the heart
H3 - found in the CNS
H4 - found on inflammatory cells
The comparison between the different histamine receptors in the body
The actions of the histamine receptor, H1, are mainly located in the vasculature system. Tell me some of these actions?
What do these actions cause?
- Vasodilation (causes redness and heat)
- Increased vasculature permeability (causes swelling)
- Stimulation of peripheral nerves (causes pain/itch)
- Smooth muscle contraction (causes asthma)
Vasodilation, caused by H1
Increased vascular permeability caused by H1
Stimulation of peripheral nerves, caused by H1
Smooth muscle contraction, caused by H1
Tell me some actions of histamine on the cardiovascular system?
Generally and specifically on the heart, arterioles, veins, capillaries and arteries
- Histamine acts on the heart to increase 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 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)
Tell me about the wheal-and-flare reaction of histamine when injected in the skin?
Whats the classical H1 antagonist?
How is it given?
What are some sideeffects?
- The classical H1 antagonist is mepyramine
- It is orally available and has an excellent safety profile.
- Side effects include drowsiness and effects on cholinergic receptors.
Whats a newer H1 antagonist thats now available? Why was this one developed?
Newer H1 antagonists such as cetirizine have been developed and cause fewer problems with drowsiness (more specific to the peripheral H1 receptor)
Tell me some uses of H1 receptor antagonists?
- Treatment of allergies -oral, topical applications
- Sedative actions
- Local anaesthetic actions
- Motion sickness - safe though they can cause drowsiness
Tell me some actions of histamine on the H2 receptor?
- Stimulates gastric acid secretion
- Regulates cardiac output and rate
- Modulates actions of immune cells
Tell me the regulations of gastric acid involving the histamine receptor H2?