YW - Histamine and 5-HT Flashcards
What are the main 3 actions of histamine on the H2 receptor?
- Stimulates gastric acid secretion
- Regulates cardiac output and rate
- Modulates actions of immune cells
What common disease is associated with H2 receptor overactivity?
Peptic Ulcer (overproduction of gastric acid)
Describe the mechanism of histamine (H2) in and the regulation of gastric acid
Mechanism of histamine (H2)
Binding of Gastrin to GR and Acetylcholine to MR produces Histamine in MC-like cells
REGULATION OF GASTRIC ACID
- Block gastrin binding to GR
- Block histamine binding to H2 receptor
How does histamine (H2) affect the cardiac system? (3)
Histamine stimulates isolated (in vitro) heart preparations to increase rate and force of contraction
- This is due to direct actions on the cardiac muscle but also indirect actions via the release of noradrenaline from the adrenergic nerves
The response of the heart in vivo is largely regulated by autonomic reflexes due to change in blood pressure
Where else are H2 receptors found and what is their effect?
H2 receptors are found on a number of cells in the immune system including mast cells and lymphocytes.
- They may provide a negative feedback inhibiting the release of histamine from degranulating mast cells
Name a classical H2 receptor antagonist and its mechanism of action
The classical H2 receptor antagonist is cimetidine
- It is orally available and has an excellent safety profile.
Cimetidine inhibits cytochrome P450 and can retard the metabolism of a range of different drugs such as anticoagulants and tricyclic antidepressants.
- This will potentiate the actions of these drugs
What are 3 uses of H2 receptor antagonists?
- Widely used to treat the symptoms of gastric ulcers
- Also used in reflux oesophagitis
- Some H2 antagonists have anti-cancer activity
Where is the Histamine (H3) receptor found and what are its actions?
Histamine is found in the brain and functions as a neurotransmitter
- Histaminergic neurones originate in the hypothalmus and extend to virtually all parts of the brain
- Histamine release in the CNS follows a distinct circadian pattern with release occuring during the day but not at night
What are the potential uses of H3 receptor antagonists? (2)
There are no H3 receptor antagonists in clinical use.
- Potential uses of H3 receptor antagonists include control of sleep/wake cycles and sedation.
- Other possible uses include control of food and water intake and thermoregulation
Actions of histamine (H4)
H4 receptors have been identified on inflammatory cells
- They appear to regulate cytokine networks in the inflammatory response
Agonists/antagonists of H4 receptors not fully elucidated
What is the role of histamine in tumors, and what is its assumed role in embryo-uterine interactions?
Mast cells are often found associated with tumours.
- It is not clear if they are facilitating tumour development (eg heparin from mast cell granules increasing angiogenesis) or part of the host defence against the tumour
Histamine has been assumed to contribute to embryo-uterine interactions due to its vasoactive, differentiation and growth-promoting properties
What is 5-HT, and where is it found?
5-Hydroxytryptamine (5-HT) is also known as serotonin
- It is found in the CNS, the GI tract and in platelets
- It is an important neurotransmitter and plays key roles in the GI tract and the vascular system
What are the effects of too much or too little serotonin?
Too Much Serotonin
- Anxiety
- Insomnia
- Sexual Dysfunction
Not Enough Serotonin
- Depression
- OCD
- Panic
Structure of 5-HT (Serotonin)
Hydroxyl Group – Indole Ring – butyl group – Amino group
Describe the 2-step synthesis of 5-HT
1) Tryptophan → 5-Hydroxytryptophan
- Tryptophan Hydroxylase (Addition of -OH group)
2) 5-Hydroxytryptophan → 5-Hydroxytryptamine
- L-aromatic acid decarboxylase (Removal of COOH group)
Dietary sources of 5-HT
5-HT is found in bananas, strawberries, pineapples and tomatoes
- Dietary intake of 5-HT does not affect the body’s pools of 5-HT but is rapidly metabolised and excreted in the urine
Metabolism of 5-HT (2)
1) 5-Hydroxytryptamine → Intermediate
- Monoamine oxidase (NH2 → CHO)
2) Intermediate → 5-Hydroxyindole acetic acid (5-HIAA)
- Aldehyde dehydrogenase (CHO → COOH)
How many receptor families are there of 5-HT?
7 receptor families
5-HT1 receptors
- These occur mainly in the CNS (5-HT1D receptors are also on cerebral blood vessels)
- Activation of these receptors results in neural inhibition and vasoconstriction
5HT1 receptors are important in mood and behaviour, thermoregulation, feeding and sleep
Agonist- Sumatriptan
Antagonists- None are currently in clinical use
- Methiothepin
5-HT2 receptors
- 5-HT2 receptors occur in the CNS and are also widely distributed in the periphery
Agonist- Lysergic acid diethylamine (LSD) in CNS
- Causing hallucinations
However LSD acts as an antagonist in the periphery
Antagonists-
- Methysergide
- Ketotifen
LSD inhibits the firing of the 5-HT containing neurons of the raphe nuclei
5-HT3 receptors
- 5-HT3 receptors are found mainly in the peripheral nervous system where they evoke pain
- 5-HT3 receptors are also found in the brain where they are involved in the vomiting reflex
Uses of 5-HT3 antagonists
5-HT3 antagonists such as ondansetron are used as anti-emetics
- Control severe vomiting and nausea
5-HT4 receptors
- 5-HT4 receptors are found in the CNS but their main physiological role appears to be in regulating GI motility
Agonist- Tegaserod (used to relieve abdominal discomfort and bloating)
5-HT in migraine and gut
5-HT in migraine
- 5-HT is known to cause vasoconstriction in the cerebral arteries
- 5-HIAA is found in the urine of patients with migraine
5-HT in gut
- 5-HT stimulates GI motility both directly via 5-HT2 receptors on the smooth muscle cells and indirectly via 5-HT3 and 5-HT4 receptors on enteric neurons
- 5-HT also stimulates fluid secretion and elicits nausea and vomiting by stimulating 5-HT receptors in the stomach
5-HT in CVS and platelets
5-HT in the cardiovascular system
- 5-HT has direct effects but can also act indirectly via release of Nitrogen oxide (NO) from the endothelial cells and inhibiting noradrenaline release from the sympathetic nerve terminals
- Injection of 5-HT leads to an initial rise in blood pressure as the large vessels constrict followed by a fall as the arterioles dilate
5-HT in platelets
The 5-HT acts on 5-HT2 receptors on the platelet surface triggering the release of more 5-HT and causing the platelets to become ‘sticky’
- 5-HT serves as a vasoconstrictor and helps to regulate hemostasis and blood clotting
- Serotonin also is a growth factor for some types of cells, which may give it a role in wound healing.
Which drugs alter 5-HT levels? (2)
Fenfluramine
Appetite Suppressant
- Depletes 5-HT levels in the CNS
Ecstasy
- Causes the release of 5-HT in the CNS followed by a drop in tissue levels of 5-HT
A carbohydrate rich diet can boost levels of 5-HT promoting feelings of well-being and sleepiness
