BIOL 2048 - Histamine and 5HT

histamine and 5HT similarities

• biogenic amines

• small 100mw

• local hormones or autocoids (self drugs)

• neurotransmitters, local hormones

overactivation of histamine

CONDITIONS ASSOCITED W/ OVERACTIVATION

• Allergy: sensitivity to specific conditions occurs through skin, inhaled or injected. Associated w H1 receptor

• Peptic Ulcer: break in the lining of the stomach, small intesting or oesophagus caused by overacitve histamine. Related to H2

structure and synthesis of histamine

STRUCTURE

• has an imidazole ring w a pKa of 5.74 which is usually uncharged at pH

• amino acid group w a pKa of 9.8 which is usually charged at physiological pH

SYNTHESIS

• synthesised from histidine

• histidine decarboxylase which removes the amino acid

• enzyme found in mast cells, rapidly growing tissues or gastric mucosal cells

• enzyme upregulated in stress

• histamine found in food but doesn’t contribute to the body’s pool as its degraded

metabolism and storage of histidine

METABOLSIM

• rapidly metabolised via 2 routes

STORAGE

• stored in mast cells —> long lived tissue resident cells that contain up to 1000 granules per cell (3-4pg/cell)

• also stored in

  • lung (15ug)

  • skin (6-8ug)

  • gut (60-80ug)

  • stomach (10ug)

• upon stimulation granules released

• granules contain histamine bound to a proteoglycan core, usually heparin

• the granules also contain enzymes such as tryptase and chymase

release of histamine

1. IGE DEPENDENT RELEASE

   • when IgE present it binds to receptors on mast cells and causes the release of histamine

   • associated w allergy

2. OTHER STIMULI

   • activated by bacterial products like liposaccharides

   • activated by complement peptides C3a and C5a

   • both require specific receptors on CSM

   • occurs in infection

3. NON SPECIFIC RELEASE

   • a number of basic drugs such as morphine tubocurarine cause release of histamine

   • also can be released following trauma to tissues including UV radiation, burns, changes in osmolarity

H1 receptors

NOTE: ALL HISTAMINE RECEPTORS ARE GPCRS

H1

• wide distribution in CV system, smooth muscle and peripheral nerves

• causes

• vasodilation associated w heat and redness

• increased vascular permeability

  • —> causes fluid, clotting proteins, complement and antibodies to move into the surrounding circulation

• stimulation of peripheral nerves:

  • stimulation of the CNS which causes pain and itch.

  • Also causes the release of vasodilators into the system

• smooth muscle contractions:

  • histamine causes bronchial smooth muscle contraction associated w asthma

  • histamine able to contract smooth muscle in the GI and reproductive tract

actions of histamine on the skin, CV system, brain

SKIN

• wheal and flare reactions

• pain and itch due to stimulation of PNS

• reddening as capillaries dilate

• blanching and swelling as fluid moves into the tissue

• redness from neuronal stimulation

CV SYSTEM

• small doses of histamine causes a drop in the peripheral resistance —> low bp

• large doses of histamine cause a profound decrease in BP and a loss of fluid from the capillaries —> circulatory collapse (anaphylactic shock)

BRAIN

• can act as a nt, found in histaminergic neurons

H1 receptor antagonists

• classical H1 antagonist is mepyramine

• orally available, excellent safety

• side effects include drowsiness and effects on cholinergic receptors

• newer H1 antagonist such as cetirizine —> doesn’t cross BBB so fewer drowsiness side effects

• used to treat allergies, sedatives, and for motion sickness

• Alternative method of inhibition: some drugs used to stabilise the membrane of the mast cells to block the release of histamine

• most antihistamines non competitive inhibitors —> stabilise the inacvtive conf.

• anti adrenergic and anti serotonin effects as the receptor is the same class of GPCR

H2 receptor action

1. STIMULATE GASTRIC ACID SECRETION

• H2 receptor in gastric mucosa

• activation of mast cells controlled by muscarinic receptor (uses Ach) and the gastrin receptor which recognises gastrin

• histamine binds to receptors on parietal cells —> activation of proton pump

• treatment of peptic ulcer: target H2 receptor or gastrin receptor

• prostaglandins can inhibit the release of gastric acid

1. CARDIAC SYSTEM

• histamine increases rate and force of contraction

• also releases NAdr from adrenergic nerves

1. OTHER EFFECTS

• H2 receptors found on a no of cells in the immune system like mast cells and lymphocytes

• may provide a negative feedback inhibiting the release of histamine from degranulating mast cells

H2 receptor antagonists

• cimetidine

• orally availible, very safe

• inhibits cytochrome p450 and can retard the metabolism of anticoagulants and tricyclic antidepressants

• used to treat gastric ulcers, reflux oesophagitis, anti cancer activity

actions of histamine on H3

• no H3 receptor antagonists clinally used

• thioperamide used in research

• potential use of antagonists include control of sleep wake cycle and sedation, control of food and water intake, thermoregulation

actions of H4

• H4 receptors on inflammatory cells

• appear to regulate cytokine networks in the inflammatory response

• antagonists and other agonists not clear

5HT location, structure and source

LOCATION

• 5 hydroxy tryptamine

• found in CND, Gi tract and vascular system

STRUCTURE

• indole ring, hydroxyl group, amino group

SOURCE

• found in bananas, strawberries, pineapple and tomatoes

• doesn’t affect the body’s pools of 5HT but is rapidly metabolised and excreted in urine

synthesis of 5HT

• synthesised in the enterochromaffin cells in the gut

• 90% of teh bodys 5HT found in the gut

• can be stored in platelets but not synthesised there

• avg adult contains 5mg of 5HT

metabolism of 5HT

DRUGS THAT INCREASE THE CONCENTRATION OF 5HT

• fenfluramine inhibits apetite and decreases 5HT

• ecstasy increases 5HT

• carbohydrate rich diet boosts levels of 5HT

receptors

• many receptors - at least 7 main types as well as subtypes

• all GPCR apart from 3 ligand gated ion channels

• for all receptors apart from 2, the second messenger is cAMP but for 2 its IP3/DAG

5HT 1 RECEPTOR

• mainly found in CNS

• controls mood, behaviour, thermoregulation, feeding and sleep

• activation = vasoconstriction and neural inhibiton

• associated w migraine

5HT 2 RECEPTOR

• occurs in CNS, widely distributed in periphery

• lysergic acid dimethylamine (LSD) acts as an agonist at the central 5HT2 receptors causing hallucinations

• LSD is an antagonist of 5HT2 receptors in periphery

5HT 3 RECEPTORS

• antagonists such as ondansetron are used as antiemetics

• they are effective at controlling severe vomiting and nausea that come w chemotherapy

• may be anxiolytic drugs

5HT 4 RECEPTORS

• found in the CNS but their main physiological role is regulating GI motility

• 5HT4 receptor agonists used to relieve abdominal discomfort associated with chronic idiopathic constipation

5HT in the body

MIGRAINE

• known to cause vasoconstriction in cerebral arteries

• 5HIAA found in the urine of patients w migraine

5HT IN GUT

• can regulate fluid secretion and motility of the gut

IN CIRCULATION

• causes constriction of arterioles

• but this is followed by dilation as 5HT triggers the release of NO and inhibits the release of noradrenaline from the sympathetic nerve terminal

IN PLATELETS

• can act on receptors and trigger platelet aggregation or growth