Serotonin and Anti-Serotonins

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Serotonin and Anti-Serotonins




LEC 7 .


Serotonin (5-HT) & Antiserotonins :

Before the identification of 5-hydroxy tryptamine (5-HT) it was known that when blood allowed to clot, a vasoconstrictor substance is released. This substance was called serotonin.

Serotonin is an endogenous amine & one of the neurotransmitters.

Basic Pharmacology of (5-HT):

1)Chemistry and pharmacokinetics:

5-HT is widely distributed in nature, being found in plant & animal tissues, venoms & stings. It is an indolethylamine formed in biological systems from the amino acid L- tryptophan by the hydroxylation of the indol ring followed by decarboxylation of the amino acid.

Tryptophan by tryptophan hydroxylase 5-hydroxy tryptophan by L-aromatic a.a. decarboxylase5-hydroxy tryptamine ( serotonin) ---by MAO 5-hydroxy indol acetic acid

Hydroxylation can be blocked by p-chlorophenylalanine & p-chloramphetamine (used experimentally to reduce 5-HT synthesis in case of carcinoid tumor).

- After synthesis the free amine is either stored or rapidly inactivated (usually by oxidation catalysed by MAO).

- In mammals (including human beings) over 90% of the 5-HT in the body is found in the enterochromaffin cells of the G.I.T.

- In blood I 5-HT is found in platelets ( they concentrate the amine by an active carrier mechanism ).

- 5-HT is also found in brain stem ( raphe nuclei cells) which synthesize, store & release 5-HT as a transmitter (contain serotonergic - tryptaminergic cell bodies) & involved in sleep, temperature regulation, perception of pain & regulation of (BP).

- 5-HT may be involved in conditions such as depression, anxiety & migraine.

- 5-HT is also found in mast cells.

- The final product of 5-HT synthesis is 5-hydroxy indol acetic acid (is a measure of 5-HT synthesis).

- The 24 hr. excretion of 5-HIAA can be used as diagnostic test for tumors that synthesize excessive quantities of 5-HT ( carcinoid tumor).

- Bananas contain large amounts of 5-HT & must be prohibited during such diagnostic tests.

2) Pharmacodynamics:

a. Mechanism of action: actions of 5-HT are mediated through receptors located in or on the surface membranes of the target cells.

• Three subsets of 5-HT receptors are present:

1- 5-HT1 receptors (5-HT1A, 5-HT1B, 5-HT1C ) are found in brain peripheral tissues & are associated with inhibition of neurotransmitter release, contraction & relaxation of smooth muscles.

2- 5-HT2 receptors : also heterogenous as 5-HT1 receptors & found at the same location, they produce effects such as excitation of neurons, contraction of smooth muscles & aggregation of platelets.

3- 5-HT3 receptors: associated with nerve depolarization & transmitter release.

4-There are Others ..... to 5-HT7

b. Tissue & organ systemic effects:

1) Cardiovascular system:

- 5-HT directly cause the contraction of smooth muscles.

- It’s a powerful vasoconstrictor except in skeletal muscles & heart, where it dilates blood vessels.

- 5-HT can also elicit reflex bradycardia by activation of chemoreceptor nerve endings.

- A triphasic blood pressure response is often seen following an I. V. injection of 5-HT :

I) A decrease in BP & heart rate caused by chemoreceptor response.

II) An increase in BP due to vasoconstriction.

III) A decrease in BP due to vasodilation in vessels supplying skeletal muscles.

- 5-HT has a vasoconstrictor effect resulting in increased capillary filling ( cause flush after 5-HT adminstration ).

- 5-HT causes blood platelets to aggregate by activating surface 5-HT receptors.

2) G.I.T:

• 5-HT causes contraction of GIT smooth muscles, it increases tone & facilitates peristalsis.

• The above action is caused by a direct action of 5-HT on the smooth muscles & a stimulating action on intestinal ganglia.

• 5-HT has a little inhibitory effect on GIT secretions.

• 5-HT has an important physiological role as a local hormone controlling GIT motility.

• Overproduction of 5HT (in carcinoid tumor) is associated with severe diarrhea.


• 5-HT has a small direct stimulant effect on bronchial smooth muscle ( in normal subjects).

• In patients with carcinoid tumor, it causes episodes of asthmatic bronchiolar obstruction (due to elevated levels of 5HT)

4-Nervous system:

• 5-HT is a potent stimulant of pain & itch sensory nerve endings (insect & plant stings).

• 5-HT is a powerful activator of chemosensitive ending located in the coronary vascular bed (activation causes Bezoid-Jarwish reflex)

Clinical pharm. of 5HT:

• Serotonin agonists: 5HT has no clinical application as a drug. Several receptor subtype-selective agonists proved to be of value (i.e. Buspirone: a 5HTla agonist an effective nonbenzodiazipine anxiolytic, also Dexfenfluramine: a selective 5HT agonist used as appetite suppressant, Sumatriptan a 5HTld agonist used as treatment of acute migraine).

Sumatriptan: Sumatriptansuccinate is an effective treatment for migraine attacks (6 mg S/C or 25mg orally) and causes relief in majority of patients with efficacy equal or greater than other treatments.

• Adverse Effects: are mild such as: dizziness, muscle weakness, neck pain & injection site reaction.


Ischemic coronary art. Disease & angina


Its duration is shorter than the duration of the headache, so several doses are required with a prolonged migraine attack.

-proved for only two doses /24hs; also expensive

Serotonin receptor antagonists

-cyproheptadine is a competitive 5HT-recptor blocking agent, ergot alkaloids are partial agonist at the 5HT-receptor.

-cyproheptadine has potent H1-receptor blocking actions. It has 5H receptor affinity; it prevents the smooth m. effects of histamine &5HT, but has no effect on gastric secretion stimulated by histamine.


1. Treatment of smooth m. manifestations of carcinoid tumor.

2. Post gastrectomy dumping syndrome

3. Drug of choice in cold-induced uriticaria

Dose: 12-16 mg/day in three to four divided doses.

Ketanserin: blocks 5-HT1C & 5-HT2 receptors, also blocks vascular α1 Adrenoceptors . Prevent platelets aggregation ( blocks 5-HT2 receptors on them), it lowers BP with an unknown mechanism ( may involve α1 ).

Ritanserin : 5-HT2 antagonist with a little or no α effect. It alters bleeding time & reduce thromboxane formation presumably by altering platelet function.

Ondansetron: a 5-HT3 antagonist used to prevent nausea & vomiting associated with surgery & cancer chemotherapy.

Granisetron :can reduce or prevent severe nausea & vomiting associated with cancer chemotherapy.


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