Histamine and 5-HT Flashcards
Similarities between histamine and 5-HT
biogenic amines
small molecules
local hormones in vasculature and smooth muscle
neurotransmitters
Diseases caused by histamine?
Allergies (H1) Peptic Ulcers (H2)
pKa of Imidazole ring?
5.74
Uncharged at physiological pH
pKa of amino group?
9.8
Charged at physiological pH
Where is histidine decarboxylase found?
In mast cells, rapidly growing tissues and gastric mucosa cells.
Where is histamine stored?
In mast cells.
Lung - 15ug/g tissue
Skin - 5ug/g tissue
Gut - 60ug/g tissue
Stomach - 10ug/g tissue
What does histamine bind to?
Heparin (proteoglycan core)
What is in the mast cell granules?
Proteolytic enzymes - tryptase and chymase
How do the mast cell granules get released in allergic disease?
IgE dependent release
Mast cells bind IgE and when re-exposed, gets crosslinked and the mast cell granules are released.
Allergic disease
How do other stimuli trigger granule release?
Bacterial products (LPS) can activate.
Complement peptides can activate.
Specific receptors cause histamine release during bacterial infections
Non specific release of granules?
Morphine and tubocurarine.
Released following trauma to tissues.
H1 receptor location?
Cardiovascular system
Smooth muscle
Peripheral system
H2 receptor location?
Regulates gastric acid secretion in stomach
Increases rate/output of heart
H3 receptor location?
CNS
H4 receptor location?
Inflammatory cells
Effect of H1 receptors?
- Increase in vascular permeability at sites of inflammation (proteins escape - swelling)
- Vasodilation (redness/heat)
- Peripheral nerve stimulation (pain/itch)
- Smooth muscle contraction (asthmatics are more susceptible)
Gq -> phospholipase C
Effect of H2 receptors?
- Increase in release of gastric acid
- Regulates cardiac output and rate
- Modulates actions of immune cells
Gs
Wheal and flaring?
Wheal - swelling
Flaring - red patch
Effect of histamine on bp?
Constricts large vessels and dilates small vessels.
Drop in peripheral resistance and bp.
Loss of fluid from capillaries –> circulatory collapse –> anaphylactic shock
H1 antagonists?
Mepyramine - drowsiness
Cetrizine - no drowsiness as can’t pass BBB
Treat allergies, sedative action, local anaesthetic actions.
Gastric acid secretion?
Prostaglandins and Histamine have opposing effects on HCl secretion
H2 antagonists?
Cimetidine.
Inhibits cytochrome p450 and can retard the metabolism of a range of different drugs.
Widely used to treat the symptoms of gastric ulcers and in reflux oesophagitis.
H3 antagonists?
Thioperamide
Include control of sleep/wake cycles
Control of food/water intake
H3 receptor effects?
Release in the brain follows a distinct circadian pattern
H4 receptor effects?
Regulate cytokine networks
Mast cells & tumours?
Often found with tumours.
Not sure if they facilitate tumour development or if part of the host defence.
Mast cells & fetus?
Growing fetus produces lots of histamine
Another name for 5-Hydroxytrptamine?
Serotonin
Where is 5-HT found?
CNS, GI tract and in platelets
Which diseases are linked to 5-HT?
Depression and migraines
Where is 5-HT synthesised?
CNS
Where is 5-HT stored?
Enterochromaffin cells in gut, 90% of it is stored here
5-HT & platelets?
Taken up by platelets as they pass through intestinal circulation and stored in granules - not synthesised
How much 5-HT in an avg adult?
10mg
Which drugs alter 5-HT levels?
Fenfluramine - appetite supressant depletes CNS levels
Ecstasy - release of 5-HT in CNS followed by tissue levels dropping
Carbohydrate diet affects 5-HT?
Boosts levels. Promotes wellbeing and sleepiness.
How many 5-HT 1 receptor types?
5, affect cAMP Mainly in CNS Neural inhibition Vasoconstriction Mood & behaviour, thermoregulation, feeding, sleep
How many 5-HT 2 receptor types?
3, up IP3 and DAG
CNS and periphery
How many 5-HT 3 receptor types?
1, internal cationic channel
Peripheral NS - evoke pain
Brain - vomit reflex
5-HT 4-7 types?
up cAMP
Most effective migraine drug?
sumatriptan - 5-HT 1D agonist.
Methiothepin?
5-HT 1 antagonist on all subtypes
LSD?
Agonist at central 5-HT2 receptors
Hallucinations.
Antagonist at peripheral 5-HT2 receptors
5-HT 2 antagonists?
Methysergide
Ketotifen
5-HT 3 antagonist?
Ondansetron
Anti-emetic - control severe vomiting and nausea with cancer chemotherapy
5-HT 4 receptor?
Found in CNS, main role is regulating GI motility
5-HT 4 agonist?
Tegaserod
Relieve IBS
5-HT in migraines?
Cause vasoconstriction in cerebral arteries. 5-HIAA found in urine of patients with migraines.
5-HT in gut?
Stimulates GI motility directly (2) via smooth muscle receptors and indirectly via (3 and 4) on enteric neurons
Stimulates fluid secretion and elicits nausea and vomiting
Peristalsis
5-HT in circulation?
Can act indirectly via NO release from endothelial cells - inhibits noradrenaline release
Injection of 5-HT causes a rise in blood pressure - flushing
5-HT in platelets?
2 receptors on platelets, trigger the release of more 5-HT and causing them to become sticky. Platelet plug.
