Pharmacology
Serotonin and Anti-Serotonins
1
Dr. Mohammed Qasim Mal-Allah
Page 1
PHARMACOLOGY
SEROTONIN AND ANTI-SEROTONINS
Dr. Mohammed Q. M.al-Allah
LEC 3 .
Pharmacology
Serotonin and Anti-Serotonins
2
Dr. Mohammed Qasim Mal-Allah
Page 2
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.
decarboxylase5-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
Pharmacology
Serotonin and Anti-Serotonins
3
Dr. Mohammed Qasim Mal-Allah
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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-HT
1
receptors (5-HT
1
A, 5-HT
1
B, 5-HT
1
C ) are found in brain peripheral tissues & are
associated with inhibition of neurotransmitter release, contraction & relaxation of
smooth muscles.
2- 5-HT
2
receptors : also heterogenous as 5-HT
1
receptors & found at the same location,
they produce effects such as excitation of neurons, contraction of smooth muscles &
aggregation of platelets.
3- 5-HT
3
receptors: associated with nerve depolarization & transmitter release.
4-There are Others ..... to 5-HT
7
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 ).
Pharmacology
Serotonin and Anti-Serotonins
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Dr. Mohammed Qasim Mal-Allah
Page 4
- 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.
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 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.
Pharmacology
Serotonin and Anti-Serotonins
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Dr. Mohammed Qasim Mal-Allah
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• Adverse Effects: are mild such as: dizziness, muscle weakness, neck pain & injection
site reaction.
Contraindications:
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 H
1
-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-HT
1
C & 5-HT
2
receptors, also blocks vascular α
1
Adrenoceptors .
Prevent platelets aggregation ( blocks 5-HT
2
receptors on them), it lowers BP with an
unknown mechanism ( may involve α
1
).
Ritanserin : 5-HT
2
antagonist with a little or no α
effect. It alters bleeding time & reduce
thromboxane formation presumably by altering platelet function.
Ondansetron: a 5-HT
3
antagonist used to prevent nausea & vomiting associated with
surgery & cancer chemotherapy.
Granisetron :can reduce or prevent severe nausea & vomiting associated with cancer
chemotherapy