This presentation is about the neurotransmitter 5-HT (serotonin), we focused on its definition, biosynthesis, storage and destruction, with mentioning its both central and peripheral effects, and lastly the serotonin receptors in the human body, as well as their agonist and antagonists.

1. 5-HYDROXYTRYPTAMINE
Hawler Medical University
College of Medicine
Department of Pharmacology
Prepared by:
Zanyar Sabah
Aram Majeed
Ibrahim Hussein

2. Contents
• Definition
• Biosynthesis
• Storage
• Destruction
• Central effects
• Peripheral effects
• 5-hydroxytryptamine receptors
• 5-hydroxytryptamine receptor agonists
• 5-hydroxytryptamine receptor antagonists

3. 5-HYDROXYTRYPTAMINE
• Serotonin was the name given to the vasoconstrictor substance which
appeared in the serum when blood clotted and Enteramine to the
smooth muscle contracting substance present in enterochromaffin
cells of gut mucosa.

4. • In early 1950s both were shown to be 5-Hydroxytryptamine ( 5-HT ) .
About %90 of body’s content of 5-HT is localized in the intestines,
most of the rest in the platelets and brain.

5. • It is also found in wasp and
scorpion sting , and is widely
distributed in invertebrates
and plants (banana, pear,
pineapple, tomato, stinging nettle,
cowage).

7. Biosynthesis, Storage and Destruction
5-HT occurs in the highest concentrations in three situation in the body.
• In the wall of intestine about %90 of the total amount in the body is
present in enterochromaffin cells, which are cells derived from neural
crest .
• Similar to those of the adrenal medulla , that are interspersed with
mucosal cells , mainly in the stomach and small intestine . Some of 5-
HT also occurs in nerve cells of myenteric plexus , where it functions
as an excitatory neurotransmitter

8. Biosynthesis, Storage and Destruction
• In blood 5-HT is present in high concentration in platelets which
accumulate it from the plasma by an active transport system and
release it when they aggregate at sites of tissue damage.
• In the CNS 5-HT is a transmitter in the CNS and is present in high
concentrations in localised region of the midbrain . Though 5-HT is
present in diet , most of this is metabolized before entering the blood
stream.

9. Biosynthesis, Storage and Destruction
• Endogenous 5-HT arises by biosynthesis , which follows a pathway
similar to that of noradrenaline , except the precursor amino acid is
tryptophan instead of tyrosine .
• Tryptophan is converted to 5-Hydroxy tryptamine ( in chromaffin cells
and neurons, but not in platelets ) by the action of tryptophan
hydroxylase ( an enzyme confined to 5-HT producing cells ) .

10. Biosynthesis, Storage and Destruction
• The 5-hydroxytreptophan is then decarboxylated to 5-HT , by a
ubiquitous amino –acid decarboxylase that also participates in the
synthesis of cathecholamines and histamine .
• Platelets (and neurons) possess a high affinity 5-HT uptake
mechanism , and platelets become loaded with 5-HT as they pass
through the intestinal circulation , where the local concentration is
relatively high .

11. Biosynthesis, Storage and Destruction
• 5-HT is often stored in neurons and chromaffin cells as a co-
transmitter together with various peptide hormones , such as
somatostatin.
• Substance P or vasoactive intestinal polypeptide (VIP). Degradation
of 5-HT occurs mainly through oxidative deamination , catalysed by
monoamine oxidase , followed by oxidation to 5-hydroxyindoleacetic
acid ( 5-HIAA ) .

12. Biosynthesis, Storage and Destruction
• The pathway being the same as that of noradrenaline catabolism . 5-
HIAA is excreted in the urine and serves as an indicator of 5-HT
production in the body , this is used for example , in the diagnosis of
carcinoid syndrome .

13. Pharmacological
effects
1- Central effects
Hallucinatory effects
Many hallucinogenic drugs (e.g. LSD) are agonists at
5-HT2A receptors and depress the firing of brain-stem 5-HT
neurons, these neurons exert an inhibitory influence on cortical
neurons

14. Sleep, wakefulness and mood
There is evidence that 5-HT may be involved in the control of mood and the
use of tryptophan to enhance 5-HT synthesis has been tried in depression,
with equivocal results
Feeding and appetite
Antagonists acting on 5-HT2 receptors, including several antipsychotic drugs
used clinically, also increase appetite and cause weight gain. On the other
hand, antidepressant drugs that inhibit 5-HT uptake cause loss of appetite.

15. Sensory transmission
After lesion of the raphe nuclei or administration of para-
chlorophenylalanine animals show exaggerated responses to many
forms of sensory stimulus.
5-HT also exerts an inhibitory effect on transmission in the pain
pathway.

16. Other possible roles
Other putative role of 5-HT include various autonomic and endocrine
functions such as the regulation of body temperature, blood pressure,
vomiting and sexual function.

17. Pharmacological effects
2- Peripheral effects
Gastrointestinal Tract
Stimulates motility
Nausea and vomiting

18. Smooth muscle
Contraction, to a minor extent in humans
Blood vessels
Size, species, prevailing sympathetic activity
Arteries and veins constricted
Arterioles dilate while venules constrict
If 5-HT is injected IV, BP first then

19. Platelet
Platelet aggregation via 5-HT2A receptors and they release more 5-HT.
Nerve endings
Stimulates nociceptive sensory nerve endings via 5-HT3 receptors.
Glands
Inhibits gastric secretions but increases mucus secretion.

20. 5-Hydroxytryptamine
Receptors
Seven families of 5-HT receptors
(5-HT1, 5-HT2, 5-HT3,
5-HT4, 5-HT5, 5-HT6, 5-HT7 )

21. All 5-HT receptors are G protein coupled receptors, except 5-HT3 which
is a Ligand gated ion channel, its activation elicits fast depolarization.
Function through:
5-HT1 : decreasing cAMP production
5-HT2 : produce IP3/DAG
5-HT4,7 : increasing cAMP production

22. 5-HT1 receptors
Occur mainly in the brain
The 5-HT1A subtype is particularly important in the brain, in relation to
mood and behaviour.
The 5-HT1D subtype, which is expressed in cerebral blood vessels, is
important in migraine and is the target for Sumatriptan.

23. 5-HT2 receptors
Particularly important in the periphery
Stimulate IP3 /DAG formation
The 5-HT2A subtype is functionally the most important, mediates
smooth muscle contraction and platelet aggregation.

24. 5-HT3 receptors
Occur mainly in the PNS, particularly on nociceptive sensory neurons
and autonomic and enteric neurons,
5-HT3 receptors also occur in the brain, particularly in the
area postrema, a region of the medulla involved in the vomiting reflex.

25. 5-HT4 receptors
Occur in the brain, as well as in peripheral organs such as the GIT,
bladder and heart.
Their main physiological role appears to be in the GIT where they
produce neuronal excitation and mediate the effect of 5-HT in
stimulating peristalsis.

26. 5-Hydroxytryptamine Receptor Agonists
Selective 5-HT1A agonists :
8-hydroxy-2-(di-npropylamino) tetralin (8-OH DPAT) highly selective agonist
but not used clinically
Buspirone, Gepirone, Ipasapirone : potent 5-HT1A agonists used in treating
anxiety.
Given orally at a dosage of 15 mg/day
the drug is rapidly absorbed
half-life of about 2.5 hours
The mean peak plasma concentration (Cmax) is approximately 2.5 μg/L, and
the time to reach the peak is under 1 hour, however it takes days or weeks to
produce its effect.
The absolute bioavailability of buspirone is approximately 4%.

27. Side effects:
Mainly nausea, dizziness, headache, restlessness but no sedation or
loss of coordination.

28. 5-HT1D receptor agonists
Sumatriptan, used for treating migraine
Pharmacokinetics:
Administered subcutaneously, orally, and intranasally.
Orally, single dose of 25, 50, or 100 mg, if patient has a partial response
to the initial dose, a single additional dose may be taken after 2 h up to
a max of 200 mg/day
Subcutaneous 6 mg initially. May repeat once after 1 h (max, 6 mg per
single dose or 12 mg/day).
Intranasal Administer a single dose of 5, 10, or 20 mg in one nostril. The
dose may be repeated once after 2 h (max, 40 mg/day).

29. Total plasma clearance is rapid, with an elimination half-life of around 2
hours.
Bioavailability for subcutaneous, oral, and intranasal administration is
97%, 15%, and 15.8%, respectively.
Metabolized by MAO-A
Contraindicated in patients with severe hepatic impairment, patients
with history or symptoms of ischemic heart disease, cerebrovascular
syndromes (strokes) or peripheral vascular syndromes (ischemic bowel
disease).

30. 5-HT4 receptor agonists
Metoclopramide
which stimulate coordinated peristaltic activity (prokinetic action), are
used for treating gastrointestinal disorders, increase motility
Pharmacokinetics:
Given orally at a dose of 5-10 mg, is rapidly and well absorbed,
bioavailability is 80% ± 15.5%, plasma half life or 4-5 h and peak plasma
concentrations occur at about 1 to 2 h.
85% eliminated in the urine.

31. Side effects :
Fatigue, motor restlessness, spasmodic torticollis, occulogyric crisis,
also can cause galactorrhoea and disorders of menstruation.
Contraindications :
Metoclopramide should not be used whenever stimulation of
gastrointestinal motility might be dangerous, e.g., in the presence of
gastrointestinal hemorrhage, mechanical obstruction, or perforation.
patients with pheochromocytoma, should not be used in epileptics or
patients receiving other drugs, which are likely to cause extrapyramidal
reactions

32. • Tegaserod is more selective and is used to treat irritable bowel
syndrome.
Tegaserod at dosages of 1 to 12 mg/day exerts pharmacodynamic
actions in the upper and the lower gastrointestinal tract, accelerating
small bowel and colonic transit in patients with IBS.
It is rapidly absorbed following oral administration, peak plasma
concentrations are reached after approximately 1 hour. Absolute
bioavailability is about 10% under fasted conditions, food reduces the
bioavailability of tegaserod by 40 to 65%.
Tegaserod is approximately 98% bound to plasma proteins, primarily to
alpha(1)-acid glycoprotein

33. • Approximately two-thirds of the orally administered dose of
tegaserod is excreted unchanged in faeces, with the remainder
excreted in urine,

34. 5-Hydroxytryptamine Receptor Antagonists
5-HT2 receptor antagonists :
Cyproheptadine: primarily blocks 5-HT2A receptor, used in controlling
the symptoms of carcinoid tumors.
Methysergide & Dihydroergotamine: used mainly for migraine
prophylaxis.
Ketanserin: 5HT2 (blockade of 5HT2A is stronger than of 5HT2C) and α1
antagonist, used as antihypertensive.
Clozapine: partial antagonist at 5-HT2A/2C receptor,
Risperidone: is a combined 5-HT2A + dopamine D2 antagonist,

35. Clozapine and Risperidone are both used in treatment of schizophrenia.
Are recent (atypical) antipsychotics
They can be given orally or IM injection, They take days or weeks to
show their effects
The absorption of clozapine is almost complete, but the
oral bioavailability is only 60 to 70%.The time to peak concentration
after oral dosing is about 2.5 hours, and food does not appear to affect
the bioavailability of clozapine. The elimination half-life of clozapine is
about 14 hours at steady state conditions (varying with daily dose).
Clozapine is extensively metabolized in the liver, via the cytochrome
P450 system, to polar metabolites suitable for elimination in the urine
and feces.

36. Side effects :
Clozapine is usually used only in patients that have not responded to
other anti-psychotic treatments due to its danger of causing
agranulocytosis.
Common side effects include extreme constipation, night-
time drooling, muscle stiffness, sedation, tremors, hyperglycemia,
and weight gain.
The risk of developing extrapyramidal symptoms such as tardive
dyskinesia is below that of typical antipsychotics.

37. 5-HT3 receptor antagonists :
Ondansetron, Granisetron, Tropisetron:
These agents have an important place in treating emesis linked with
chemotherapy.
Long duration of action.
Can be administered as a single dose prior to chemotherapy.
Are extensively metabolized in the liver.
Elimination is through the urine.
Common side effect is headache.

38. 5-HT mixed agonist and antagonist : Lysergic acid diethylamide (LSD)
Is a potent hallucinogen, activates 5-HT1A, 5-HT2A/2C, 5-HT5-7, also
antagonizes 5-HT2A receptors in the ileum.

39. • Other related drugs :
SSRI : specifically inhibit serotonin reuptake, have 300-3000 fold
selectivity, drug of choice in treating depression.
Example : Fluoxetine, citalopram, fluvoxamine, paroxetine, sertraline,
Indication : Depression, obsessive compulsive disorder, panic disorder,
generalized anxiety and bulimia nervosa.

40. Mechanism of action of SSRIs

41. • Pharmacokinetics :
All the SSRIs are well absorbed after oral administration.
All have large volume of distribution.
Plasma half lives range between 16-36 h but Fluoxetine have a half life
of 50 h.
Fluoxetine and paroxetine are inhibitors of enzyme CYP2D6.
Excretion is primarily through the kidneys, except Paroxetine and
Sertraline undergo 35% fecal excretion, 50% renal excretion.
Dosage should be adjusted downward in hepatic impairment.

42. Adverse effects :
Nausea, vomiting, diarrhea,
Headache, restlessness, fatigue, sleep disturbances.
Should be used cautiously in children and teenagers, 1 out of 50
children become suicidal as a result of SSRI treatment,

43. Summary
Receptor Location Effect
1A CNS Neuronal inhibition, behavioural effects:
sleep, feeding, thermoregulation, anxiety.
1B CNS, Presynaptic inhibition,
Vascular smooth muscle Pulmonary vasoconstriction
1D CNS, Cerebral vasoconstriction
Blood vessels Behavioural effects: locomotion
2A CNS, PNS, Neuronal excitation
Smooth muscle Smooth muscle contraction
platelets Platelet aggregation
2B Gastric fundus Contraction

44. Summary
Receptor Location Effect
2C CNS, Cerebrospinal fluid secretion
Choroid plexus
3 PNS Neuronal excitation (autonomic, nociceptive n)
CNS, Emesis, anxiety
4 CNS, PNS (GIT) Neuronal excitation, Gl motility
5 CNS Not known
6 CNS Not known
7 CNS, GIT Not known
Blood vessels

45. References
1- Rang H P, Dale M M, Ritter J M, Moore P K, Pharmacology. 5th
Ed.Churchill Livingstone:London;2003
2- Richard D.howland & Mary J.mycek. Lippincott's Illustrated Reviews:
Pharmacology, 3rd Ed.USA:Lippincott Williams & wilkins; 2006
3- Tripathi K D, Eseentials of medical pharmacology. 6th Ed. Jaypee:New
Delhi; 2007