Pharmacology of 50HT

1. Pharmacology of
5-Hydroxytryptamine(5-HT) and
5-HT-antagomists
Prof. Awad Giumma Abdellatif ALI
Department of pharmacology, University of
Benghazi

2. Serotonin
was the name given to an unknown vasoconstrictor substance found in
the serum after blood had clotted. It was identified chemically as 5-
hydroxytryptamine in 1948 and shown to originate from platelets. It
was subsequently found in the gastrointestinal tract and central nervous
system (CNS), and shown to function both as a neurotransmitter and as
a local hormone in the peripheral vascular system
Serotonin is available in:
-plants like (banana)
-animal tissues
- venoms and stings
Serotonin is present in diet , but most is metabolized before entering
the blood
Biosynthesis and metabolism of 5-HT:

3. Biosynthesis and metabolism of 5-HT:

4. 5-HT is formed from dietary tryptophan, which is converted to 5-hydroxytryptophan
(in chromaffin cells and neurons, but not in platelets) by tryptophan hydroxylase,
then to 5-HT by a non-specific decarboxylase
5-HT is often stored in neurons and chromaffin cells as a cotransmitter together with
various peptide hormones, such as somatostatin, substance P or vasoactive intestinal
polypeptide.
Distribution
5-HT occurs in the highest concentrations in three organs
1- In the wall of the intestine:. Over 90% of the total amount in the body is present in
the enterochromaffin cells in the gut .
2- In blood. 5-HT: is present in high concentrations in platelets, which accumulate it
from the plasma by an active transport system and release it when they aggregate at
sites of tissue damage.
3-In the CNS: 5-HT is a transmitter in the CNS and is present in high concentrations in
localised regions of the midbrain.
5-HT is transported into cells by a specific transport system
Transformation of serotonin into melatonin is carried out primarily in the pineal
gland. The concentration of melatonin in the pineal gland presents circadian
variations: it follows the variations of N-acetyl transferase activity, increasing during
the night and decreasing during the day, darkness and light playing a regulatory role.
Light inhibits melatonin biosynthesis

5. Degradation occurs mainly by monoamine oxidase, with the
formation of an aldehyde intermediate. This is followed by
0xidation to 5-hydroxyindoleacetic acid (5-HIAA), which is
excreted in urine.
The level of 5-HIAA is significantly increased in CARCINOID
SYNDROME.
Carinoid Syndrome:
Is a malignant tumor of chromaffin cells, which usually
arising in small intestine and metastasizing to the liver. This
tumor secretes excessive amount of 5-HT , prostaglandins
and bradykinins.
Symptoms of carcinoid tumor or syndrome:
1- diarrhea
2- intestinal colic.
3- bronchoconstriction.
4- 20 fold increase in the urinary excretion of 5-HIAA

6. Family Type Mechanism Action
5-HT1 Gi/Go-protein coupled.
Decreasing cellular levels
of cAMP.
Inhibitory
5-HT2 Gq/G11-protein coupled.
Increasing cellular levels
of IP3 and DAG.
Excitatory
5-HT3
Ligand-
gated Na+ and K+ cation
channel.
Depolarizing plasma
membrane.
Excitatory
5-HT4 Gs-protein coupled.
Increasing cellular levels
of cAMP.
Excitatory
5-HT5 Gi/Go-protein coupled.[6] Decreasing cellular levels
of cAMP.
Inhibitory
5-HT6 Gs-protein coupled.
Increasing cellular levels
of cAMP.
Excitatory
5-HT7 Gs-protein coupled.
Increasing cellular levels
of cAMP.
Excitatory
Serotonin receptors subtypes

7. Receptor
Sub-Type
Sites of Expression Functions
5HT1A vasculature, CNS
aggression, anxiety,vasoconstriction, appetite, memory, mood,
cardiovascular tone, heart rate, respiration, pupillary dilation, pain sensation,
sexual behavior, erectile function, emesis, thermoregulation, sleep, addictive
behaviors
5HT1B vasculature, CNS
locomotion, aggression, anxiety, blood pressure (vasoconstriction), memory,
mood, learning, sexual behavior, erectile function, addictive behaviors
5HT1D vasculature, CNS blood pressure (vasoconstriction), locomotion, anxiety
5HT1F CNS involved in migraine headaches
5HT2A
gastrointestinal tract, smooth
muscles, vasculature, CNS,
PNS, platelets
anxiety, blood pressure (vasoconstriction), thermoregulation, appetite,
learning, memory, mood, cognitive abilities, sexual behavior, sleep, addictive
behaviors
5HT2B
gastrointestinal tract, smooth
muscles, vasculature, CNS,
PNS, platelets
gastrointestinal, motility, blood pressure (vasoconstriction), appetite, anxiety,
sleep
5HT2C
GIT, smooth muscles, CNS,
vasculature,PNS, platelets
anxiety, locomotion, GIT motility, blood pressure (vasoconstriction), appetite,
mood, sexual behavior, erectile function, thermoregulation, sleep, addictive
behaviors
5HT3 GIT, CNS, PNS anxiety, GITmotility, emesis learning, memory, addictive behaviors
5HT4 GIT, CNS, PNS
respiration, appetite, gastrointestinal motility, learning, memory, mood,
anxiety
5HT5A CNS locomotion, sleep
5HT6 CNS cognitive abilities, learning, memory, anxiety, mood
5HT7 GIT,vasculature, CNS
(vasoconstriction), respiration, thermoregulation, sleep, memory, mood,
anxiety

8. 5-HT1A
CNS:(autoreceptors)
-Raphe nuclei
-Hippocampus
-Neuronal inhibition
-Behavioural effects:
sleep, feeding,
thermoregulation,
anxiety
Inhibition of
adenylcyclase
→ ↓cAMP
8-OH-DPAT
Buspirone (PA)
Spiperone
Methiothepin
Ergotamine
5-HT1B -CNS Presynaptic inhibition
Behavioral effects:
locomotion
Inhibition of
adenylcyclase
→ ↓cAMP
-5-carboxamido-
Tryptamine
-sumatriptan
Methiothepin
5-HD1D Cranial blood vessels Cerebral
vasoconstriction
Inhibition of
adenylcyclase
→ ↓cAMP
Sumatriptan
5-HT1E Cortex Inhibition of
adenylcyclase
→ ↓cAMP
5-HT2A -CNS
-PNS
-Smooths muscles
-Platelets
-Neuronal excitation
and behavioral effects
-Smoothmucsle
contraction(gut and
bronchi .etc)
-Platelets aggregations
++of PLC→↑IP3
and DAG
alpha-Me-5-HT Ketanserin
Cyproheptadine
Pizotifen(non-
selective)
Recceptor Location Main effects Secondary
messenger
Agonists antagonists

9. Recceptor Location Main effects Secondary
messenger
Agonists antagonists
5-HT2B Stomach fundus Contraction ++of PLC→↑IP3
and DAG
alpha-Me-5-HT Ly53857
5-HT2C Choroid plexus CSF secretion ++of PLC→↑IP3
and DAG
alpha-Me-5-HT
LSD
Methysergide
5-HT3 PNS
CNS
Neuronal excitation
Emesis
anxiety
Ligand gated Na
and K operated
ion channel
2-Me-5-HT.
Clorophenyl -
biguanide.
Ondansetron
Tropisetron
Granisetron
5-HT4 PNS
CNS
GIT
Neuronal excitation
GIT motility
+of Adenyl
cyclase→↑cAMP
5-methoxy –
treptamine.
Metoclopramide
GR113808
5-HT5A Hippocampus Inhibition of adenylcyclase
→ ↓cAMP(Gi/Go)
Unknown Unknoon
5-HT5B --------- ------------------ + (Gi)
↓adenylcyclase
→ ↓cAMP
---------------- ---------------
5-HT6 CNS Anxiety, mood,memory,
learning
+ Gs →+
adenylcyclase
→↑cAMP
E55888
5-HT7 CNS
Blood vessels
GIT
Anxiety, mood, sleep
Vasoconstriction,
thermoregulation
+ Gs →+of
adenylcyclase
→↑cAMP
RA-7 Clonazepine
Olanazepine
amitriptilyne

10. Pharmacological actions of serotonin:
Serotonin has profound effects on the gastrointestinal, cardiovascular ,respiratory ,
and peripheral and central nervous system function
1-On smooth muscle:
-serotonin causes contraction of the smooth muscles of→ stomach, intestine, uterus,
and bronchial smooth muscles mainly via 5-HT2 receptor activation(++ of
phospholipase C/Ip3 system).
2- Cardiovascular system:
-Vasoconstriction of renal, placental,uterine,umbilical, and pulmonary blood
vessels.(N.B large blood vessels, both arteries and veins are usually constricted by 5-
HT and this is mainly through direct effect on 5-HT2A receptors)
-Vasoconstriction of the large intracranial blood vessels (5-HT1-stimulation.
- Vasodiltation of skeletal muscle beds.
-Action on heart:
Serotonin has a positive initropic and chronotropic action by 5-HT4 receptor
stimulation and could take part in the genesis of certain rhythm disorders. It has a
positive inotropic effect.
-Action on blood pressure:
It is complex, according to experimental conditions, serotonin gives either
hypotension, or hypertension, or no modification

12. 3-Digestive effects:
•Serotonin has an emetic effect by stimulation of 5-HT3 receptors. These receptors
are located particularly on the vagal terminations in the digestive tract and in area
postrema (chemoreceptor trigger zone), which is accessible to peripheral circulating
serotonin. Their stimulation elicits nausea and vomiting, and 5-HT3 antagonists are
used to avoid vomiting induced by antineoplastic treatments. 5-HT has an ulcerative
action, its administration to animals in high doses induces gastric.
NB:LOS=The lower oesophageal sphincter

13. •Serotonin increases intestinal motility, probably by stimulation of 5-
HT4 and 5-HT3 receptors: in human beings, injected by intravenous
route, it increases duodenum and small intestine motility. This effect
explains diarrhea observed in patients with carcinoid syndrome.
4-Migraine:
Migraine is a disease characterized by repeated accesses of headache
in which vasomotor phenomena and serotonin play a determining
part. In the first prodromic phase, there is a vasoconstriction, and in
the second painful phase, a vasodilation. This vasodilation is reduced
by vasoconstrictive drugs.
5-Myocardial ischemia:
Serotonin released from platelets seems to worsen the myocardial
ischemia by vasoconstriction.

14. 6-Effect on Platelets:
Serotonin causes platelets aggragation by activation of platelets
surface 5-HT2A receptors

15. 7-Central effects:
•Effects of serotonin on the central nervous system are numerous,
complex and difficult to systematize, but of considerable importance
from a pharmacological point of view because many drugs act by its
intermediary.
•Serotonin is involved in the regulation of sleep, mood
(antidepressant action), temperature, appetite (appetite suppressant
effect).
Over stimulation of 5-HT2 receptors could induce productive
and negative symptoms of psychotic disorders. LSD or
lysergide, agonist of 5-HT2 receptors and also of D1 and D2
dopaminergic receptors, has hallucinogenic properties
8-Other actions:
-Stimulation of catecholamine from adrenal gland
-Stimulation of the sensory nerves, which contribute to pain
response
-Regulation of the release of ACTH, groth hormones,
prolactin, leutilizing hormone, FSH, and TSH

16. 5-HT Agonists:
•Buspirone:
It is a partial agonist for 5-HT1A and Used as anxiolytic
•Sumatriptan:
Is a selective 5-TH1D and 5-HT1B agonist. These receptors are found in cerebral and
meningeal and mediate vasoconstriction.
Bioavailability of sumatriptan is about 15% but other triptans e.g natratriptan,
elemotriptan, rizatriptan and almotriptan have 40-80% bioavailability.
The t1/2 of sumatriptan, almotriptan, eletriptan , rizatriptan and zolmatriptan is
about 2-3 hours whereas the t1/2 of natratriptan is 6 hrs
Sumatriptan is poorly absorbed therefore it is given by subcutaneous or nasal
administration.
Uses of triptans:
In treatment of migraine
Adverse effects of sumatriptan:
1- injection site reaction 2-unpleasant taste with nasal adminitration
Chest pressure (resolved within 30 min)
3- weakness, drowsiness, dizzines and fatigue.
ContraIndications: Hypertension, and pregnancy

17. Tegaserod, a newer 5-HT4 partial agonist, is used for irritable bowel syndrome
with constipation
Cisapride, a 5-HT4 agonist, was used in the treatment of gastroesophageal
reflux and motility
Ergot Alkaloids: are 5-HT1B/1D agonists
Are derivatives of lysergic acid
They are 2 types: a. Amino acid alkaloids: e.g ergotamine ,ergotoxine
and b. Amine alkaloids. E.g ergometrine
1- Ergotamine:
-has also partial α-receptor agonist activity.
-is poorly absorbed and caffeine increases its absorption
- contracts smooth muscle of uterus(oxytotic action)
Uses:
In acute attack of migraine
Adverse effects:
Nausea, vomiting, anginal pain, and abortion
in case of pregnant women.
Contraindications:
-Peripheral vascular disease -coronary heart disease - hypertension
- Pregnancy - liver and kidney disease

18. 2- Ergometrine:
It is a partial 5-HT receptor agonist
Has no α-adrenergic effect
Has potent oxytocic action.
Used for prevension and treatment of postpartum hemorrhage
5-HT receptors Antagonists:
1-Ketanserin:
-Is A 5-HT2A antagonist and has α1-receptor antagonistic activities
Ketanserin lowers blood pressure in patients with hypertension, causing a reduction
comparable to that seen with b adrenergic-receptor antagonists or diuretics
-Ketanserin inhibits 5-HT-induced platelet aggregation
2-Ritanserin, another 5-HT2 antagonist, has little or no a-blocking action. It has
been reported to alter bleeding time and to reduce thromboxane formation,
presumably by altering platelet function
3-Ondansetron is the prototypical 5-HT3 antagonist. This drug and its analogs are
very important in the prevention of nausea and vomiting associated with surgery and
cancer chemotherapy