![5-HT RECEPTORS
- There are four families of 5-HT
receptors (5-HT1, 5-HT2, 5-HT3, 5-
HT 4-7).
- Some of the subtypes have been
functionally correlated.
- All 5-HT receptors are G protein
coupled receptors [ functions
through decreasing or increasing
cAMP production].
- Decrease cAMP production: 5-HT1
- Increase cAMP production: 5-HT4, 5-
HT6, 5-HT 7
- Generating IP3/DAG: 5-HT](https://image.slidesharecdn.com/serotonin-1-250120094542-54cf9cd0/85/Detailed-Pharmacology-of-Serotonin-5-HT-11-320.jpg)
![5-HT3 Receptor
They are found in the CNS,
especially in the Chemoreceptive
area and vomiting centre.
Also found in peripheral sensory
and enteric nerves.
These receptors mediate excitation
via 5-HT gated cation channels.
Antagonist acting at this receptor
have proved to be extremely useful
anti-emetic drugs.
M.O.A Location Function ANTAGONIST
Ligand
gated ion
channel
Receptor
(Na+
, K+
,
CA2+
entry into
cell)
- Peripheral
nerves
(nociceptive
neurons)
- Area Prostema
(CTZ)
* medulla
oblongata
[Vomiting centre]
Nociception
(pain
sensation)
Emesis
(vomiting)
-Ondansetron
-Tropisetron
(anti-emetic)](https://image.slidesharecdn.com/serotonin-1-250120094542-54cf9cd0/85/Detailed-Pharmacology-of-Serotonin-5-HT-17-320.jpg)
Detailed Pharmacology of Serotonin (5-HT)
- 1. 5-HYDROXYTRYPTAMINE NIMS INSTITUTE OF PHARMACY NIMS UNIVERSITY Submitted to: Mr. Junaid Tantray Assistant Professor Nims Institute of Pharmacy Presented by: Michelle Laribha Mawrie (PharmD 2nd year)
- 2. OVERVIEW HISTORY INTRODUCTION BIOSYNTHESIS, STORAGE & METABOLISM DEGRADATION & ELIMINATION RECEPTORS & SUB-TYPES 5-HT RECEPTOR AGONISTS & ANTAGONISTS ACTIONS OF 5-HT & PHYSIOLOGICAL ROLES MIGRAINE & ITS DRUG THERAPY CONCLUSION
- 3. HISTORY In 1935, Vittorio Erspamer showed that an extract from Enterochromaffin cell made intestine contract. Two years later, Erspamer was able to show that it was a previously unknown amine, which he name as Enteramine. In 1948, Maurice M. Rapport, Arda Green and Irvine Page of the Cleveland Clinic discovered a vasoconstrictor substance in blood serum and name it SEROTONIN. Serotonin (5-HT) was synthesized in 1951. In 1957, Gaddum & Picarelli proposed two distinct 5-HT receptor subtypes- M type (neurotropic) & D type (musculotropic) receptors. - However, a new classification system was later developed to classify serotonin receptors.
- 4. INTRODUCTION 5-Hydroxytryptamine or Serotonin is a monoamine neurotransmitter. It has a popular image as a contributor to feelings of well-being and happiness. Its biological function is complex, touching on diverse functions including mood, cognition, learning, memory and numerous physiological processes such as vomiting and vasoconstriction. Serotonin was the name given to the vasoconstrictor substance which appeared in the serum when blood clotted & Enteramine to the smooth muscle contracting substance present in enterochromaffin cell of gut mucosa. In the early 1950s both were shown to be 5- hydroxytryptamine.
- 5. - Serotonin is synthesized from the amino acid tryptophan, which is derived from the diet. - Serotonin secreted from the enterochromaffin cells eventually finds its way out to tissues into the blood. - There, it is actively taken up by blood platelets, which stores it. - When the platelets binds to a clot, they disgorge serotonin, where it serves as a vasoconstrictor and helps to regulate hemostasis and blood clotting.
- 6. OCCURENCE AND DISTRIBUTION OF 5-HT : Widely distributed in nature. It is also found in wasp and scorpion sting, and is widely distributed in invertebrates and plants (banana, pear, pineapple, tomato, etc). Play role in several diseases eg; Carcinoid syndrome( tumor of enterochromaffin cells). Functions as a neurotransmitter and local hormone.
- 7. In the walls of the intestine:- - Enterochromaffin cells (90 % of total amount in the body). - Nerve cells of myenteric plexus (control motor functions of intestine) where it functions as an excitatory neurotransmitter. In blood:- - Occur in high concentration in platelets. - Platelets accumulate 5-HT from plasma by an active carrier mediated transport mechanism. - Released when platelets aggregate at sites of tissue damage. In the CNS:- - Found in high concentration in specific areas of the midbrain. - In the pineal gland, 5-HT serves as a precursor of melatonin (a melanocyte- stimulating hormone).
- 8. SYNTHESIS & DEGRADATION OF 5-HT 5-HT is Beta-aminoethyl-5-hydroxyindole. Serotonin synthesis begins with the uptake of the essential amino acid L-tryptophan from the blood. Tryptophan (amino acid) is converted into 5- Hydroxytryptophan (5-HTP) with the help of enzyme Tryptophan hydroxylase. Now, this 5-hydroxytryptophan (5-HTP) is converted into Serotonin (5- hydroxytryptamine) with the help of enzyme decarboxylase.
- 9. - After release, 5-HT is metabolized by monoamine oxidase(MAO) and a small proportion by dehydrogenase enzyme. - It leads to the formation of 5-Hydroxy Indole Acetic Acid (5-HIAA), a metabolite of 5HT. - 5-HIAA excreted in urine. - Used as an indicator of 5-HT production in the body & in the diagnosis of Carcinoid syndrome.
- 10. UPTAKE AND TERMINATION OF SEROTONIN 5-HT is actively taken up by an amine pump Serotonin Transporter (SERT), a Na+ dependent carrier, which operates at the membrane of platelets and serotonergic nerve endings. The pump is inhibited by selective serotonin reuptake inhibitors (SSRIs) and tricyclic anti- depressants (TCAs). Platelets do not synthesize 5-HT but acquire it by uptake during passage through intestinal blood vessels.
- 11. 5-HT RECEPTORS - There are four families of 5-HT receptors (5-HT1, 5-HT2, 5-HT3, 5- HT 4-7). - Some of the subtypes have been functionally correlated. - All 5-HT receptors are G protein coupled receptors [ functions through decreasing or increasing cAMP production]. - Decrease cAMP production: 5-HT1 - Increase cAMP production: 5-HT4, 5- HT6, 5-HT 7 - Generating IP3/DAG: 5-HT
- 12. 5-HT1 Receptors Occur mainly in the brain. Subtypes are distinguished on the basis of regional distribution and pharmacological specificity. Function as inhibitory pre-synaptic receptors (AUTORECEPTOR) & as post-synaptic receptor. G- protein coupled receptor and linked to inhibition of adenylate cyclase.
- 13. Receptor subtype M.O.A Location Function Agonist 5-HT1A G-protein coupled receptor(Gi), adenylyl cyclase inhibition ( cAMP) - Raphe Nucleus (Autoreceptor, blocks the release of 5-HT) - Hippocampus (post synaptically) Inhibit 5-HT firing Reduce aggression & impulsitivity, Increase cognitive ability - Buspirone - Gepirone (anti-anxiety) 5-HT1B G-protein coupled receptor(Gi), adenylyl cyclase inhibition ( cAMP) - Basal Ganglia (Autoreceptor) - Hippocampus - Pulmonary blood vessels - Bone Inhibit 5-HT firing Increase Cognition & learning Vasoconstriction Osteoblastic activity 5- HT1D G-PCR (Gi), cAMP - Cranial Blood Vessels Blood vessel constriction 5-HT1E G-PCR (Gi), cAMP Corpus Striatum - 5-HT1F G-PCR (Gi), cAMP Brain & Periphery -
- 14. 5-HT1B & 5-HT1D Agonists : 5-HT1B : Increase Dopamine release: - Inhibit vasodilation - Inhibit Nociception 5-HT1D : Vasoconstriction In acute migraine headaches, triptans are effective medication that bind to 5-HT1B & 5-HT1D receptors in cranial vessels which leads to vasoconstriction.
- 15. 5-HT2 Receptors All stimulate Phospholipase C (PLC). Stimulation increase levels of IP3 and DAG. More important in the periphery than CNS. Cause Neuronal Excitation. Modulate behaviour, mediate platelet aggregation, smooth muscle contraction, vasoconstriction and vasodilation.
- 16. Receptor subtype M.O.A Location Function DRUGS Agonist 5-HT2A G- PCR (activate Phospholipas e C, PLC) - Cerebral Cortex - Platelets - Smooth muscles(blood vessels) Excitation( increase cognition),hallucinat ion Aggregation Vasoconstriction ( BP) - Clozapine (anti-psychotic) - Sarpogrelate (anti-platelet) - Ketanserine (anti- hypertensive) HALLUCINOGENS - Lisergic acid dithalamine(LSD) - Lesuride - Amphetamine derivative 5-HT2B G- PCR (activate phospholipas e C, PLC) - Stomach Contraction - - 5-HT2C G- PCR (activate phospholipas e C, PLC) -Choroid Plexus -Hypothalamus -Urinary bladder - Decrease food intake, increase body temp. Decrease urination(activate sympathetic nervous system) - - Lorcaserine, Fenfluramine (anti-obesity)
- 17. 5-HT3 Receptor They are found in the CNS, especially in the Chemoreceptive area and vomiting centre. Also found in peripheral sensory and enteric nerves. These receptors mediate excitation via 5-HT gated cation channels. Antagonist acting at this receptor have proved to be extremely useful anti-emetic drugs. M.O.A Location Function ANTAGONIST Ligand gated ion channel Receptor (Na+ , K+ , CA2+ entry into cell) - Peripheral nerves (nociceptive neurons) - Area Prostema (CTZ) * medulla oblongata [Vomiting centre] Nociception (pain sensation) Emesis (vomiting) -Ondansetron -Tropisetron (anti-emetic)
- 18. 5-HT4 Receptor They are found in the Gastrointestinal tract and play very important role in intestinal motility. M.O.A Location Function AGONIST - G-PCR (Gs)stimulatory protein - activate adenylyl cyclase - excitatory effect - GIT - Heart (Atria) - Hippocampus - Adrenal gland Increase GI motility Increase Heart rate Improve cognition Increase cortisol & aldosterone release In constipation & IBS - Rezapride, Cisapride, Metoclopromide( can work as 5-HT3 antagonist)
- 19. Receptor M.O.A Location Function 5-HT5 G-protein coupled receptor(Gi), adenylyl cyclase inhibition ( cAMP) Hippocampus not known 5-HT6 G-protein coupled receptor(Gs),stimulatory protein - activate adenylyl cyclase Corpus striatum not known 5HT7 G-protein coupled receptor(Gs),stimulatory protein - activate adenylyl cyclase Hypothalamus not known
- 20. 5-HT Receptor Agonists D-Lysergic acid diethyl amide(LSD) - Synthesized as an ergot derivative, an extremely potent hallucinogen. - It is a non-selective 5-HT agonist activates 5- HT receptors (5-HT1A, 5HT2A/2C and 5-HT5-7) in specific brain areas. Azapirones - Buspirone, Gepirone and ipsapirone are novel class of anti-anxiety drugs which do not produce sedation. - They act as partial agonist of 5-HT1A receptors in the brain. Sumatriptan and other triptans - Selective 5-HT1D/1B agonists. - Constrict cerebral blood vessels and have emerged as the most effective treatment of acute migraine attacks. Cisapride - Prokinetic drug, a selective 5-HT4 agonists. - Increases GI motility.
- 21. 5-HT Receptor Antagonists Clozapine - A typical anti-psychotic drug. - It exert inverse agonist activity at cerebral 5- HT2A/2C receptors which may account for its efficacy in schizophrenia. Ketanserin - It has selective 5-HT2 receptor blocking property. - Blockade of 5-HT2A is stronger than 5-HT2C. - It antagonizes 5-HT induced vasoconstriction, platelet aggregation and contraction of airway smooth muscle. Risperidone - A typical anti-psychotic drug. - It is a combined 5-HT2A + dopamine D2 antagonist. - Similar to Clozapine. Ondansetron - A selective 5-HT3 antagonist. - Remarkable efficacy in controlling nausea and vomiting.
- 22. PATHOPHYSIOLOGICAL ROLES OF 5-HT Neurotransmitter: It is a neurotransmitter in brain & is involved in sleep, temperature regulation, thought, cognitive function, behaviour and mood, vomiting & pain perception. Precursor of melatonin in pineal gland: regulates biological clock & maintain circadian rhythm. Nausea and vomiting: evoked by cytotoxic drugs or radiotherapy, is mediated by release of 5-HT (5-HT3 receptors in gut & area prostema). Migraine: It initiates vasoconstriction phase of migraine & participates in neurogenic inflammation of cranial blood vessels. Haemostasis: It causes platelet aggregation & clot formation at site of injury to blood vessel. Intestinal motility: Enterochromaffin cell & 5-HT containing neurons regulate peristalsis & local reflexes in gut. Carcinoid tumor: Bowel hypermotility & bronchoconstriction in carcinoid is due to 5-HT release in massive amount.
- 23. MIGRAINE & ITS DRUG THERAPY Migraine can be defined as episodic headache, typically unilateral, associated with vomiting and visual disturbances. Major cause is due to excessive vasodilation in cerebral blood vessels. Vasodilation causes vascular leakage that trigger inflammation. Inflammation transmit pain signal to brain HEADACHE
- 24. PHASE 1 (Prodrome) - Yawning - Lethargy - Photophobia, Phonophobia - Changes in temperature perception PHASE 2 (Aura) - Visual impairment - Auditory impairment - Sensory impairment (numbness) PHASE 3 (Migraine attack) - Unilateral pain - Pulsatile -other symptoms: nausea, vomiting, vertigo, loose motion, photophobia & phonophobia. PHASE 4 (Postdrome) - Exhaustion - Dizziness - Irritability Sign & symptoms: 4 phases
- 25. MIGRAINE TREATMENT ACUTE THERAPY: - treat headache that has already started. NSAIDS: Ibuprofen, Ketorolac & Naproxen Anti-histamine: Diphenhydramine Steroids: Dexamethasone 5-HT1B/1D Receptor agonist: Sumatriptan, Naratriptan, Rizatriptan & Zolmitriptan Ergot alkaloids: Dihydroergotamine PROPHYLACTIC THERAPY: - reduce the frequency and severity of future migraines. Beta blockers: Propranolol, Metoprolol Anti-convulsant: Topiramate, Valproate Tricyclic anti-depressant: Increase 5-HT level Calcitonin gene related peptide(CGRP) antagonist: Erenumab Botulinium toxin