Pharmacology
Serotonin and Anti-Serotonins
PHARMACOLOGY
SEROTONIN AND ANTI-SEROTONINS
Dr.AHMED AL-ZOHYRI
LEC 7 .
TOTAL LEC. NO . 11
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Pharmacology
Serotonin and Anti-Serotonins
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
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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 5HT adminstration ).
- 5-HT causes blood platelets to aggregate by activating surface 5-HT receptors.
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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.
3-Respiration:
• 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 subtypeselective 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.
Contraindications:
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Ischemic coronary art. Disease & angina
Disadvantages:
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.
Indications:
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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