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Serotonin and anti serotonin drugs
This document details serotonin (5-HT) receptors, their roles, and the pharmacological actions of various serotonin-related drugs. It discusses the clinical applications of these drugs, particularly in treating migraines, and outlines different types of agonists and antagonists, including their adverse effects and contraindications. Additionally, it provides insight into the mechanisms of migraine and the therapeutic strategies for prophylaxis and acute management.
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Serotonin and anti serotonin drugs
- 1. Serotonin and Anti-serotonin drugs DrNaser Tadvi
- 2. Objectives • Describe serotonin(5HT) receptors including serotonin & antiserotonin drugs • Explain important clinical applications of serotonin related drugs. • Explain the drugs used in the treatment & prophylaxis of migraine
- 3. Serotonin • Monoamine neurotransmitter •Synthesized from tryptophan • 90 % present in gastro-intestinal enterochromaffin cells and 10 % in platelets and brain. • Role in mood, sleep, sexual activity, thermoregulation, pain. • Precursor for synthesis of melatonin
- 4. Synthesis and degradationof 5- HT
- 5. 5 HT receptors TypeReceptor mechanism 5 HT1 Gi coupled ↓ cAMP 5 HT2 Activation of PLC 5 HT3 Ligand gated ion channel (Nicotinic family of Na+/K+ channel proteins 5 HT4 Gs coupled , ↑ cAMP 5 HT5 Gi coupled ↓ cAMP 5 HT6 Gs coupled , ↑ cAMP 5 HT7 Gs coupled , ↑ cAMP
- 6. 5 HT1 Receptors TypeDistribution Function 5 HT1A Brain stem, raphe nuclei and Hippocampus Inhibition of release in CNS Anxiety, thermoregulation 5 HT1D Basal Ganglia and Substantia nigra Regulate dopaminergic tone 5 HT1D/1B Cranial Blood vessels Constricts cranial blood vessels Inhibit release of inflammatory neuropeptide All are autoreceptors and inhibit the firing of neurons or release of 5 HT
- 7. 5 HT 2Mainly CNS Smooth muscles Platelets Excitatory platelet aggregation , Antinociception 5 HT 2A (Major post junctional receptor) • Vascular and visceral smooth muscle • Platelets • Cerebral neurons (Mainly prefrontal cortex) Contraction Platelet aggregation Activation, Behavioural effects 5 HT 2B Stomach fundus Contraction 5 HT 2C • Choroid plexus • Vascular endothelium CSF secretion Vasodilation (EDRF Release) 5 HT2 receptors
- 8. 5 HT3 -7receptors Type Distribution Function 5 HT3 Mainly PNS on nociceptive sensory neuron Area postrema,Nucleus Tractus solitarius Excitation of nociceptive neuron Emesis 5 HT4 CNS (Hippocampus) Mucosa and plexuses of smooth muscles of Gut Neuronal excitation ↑ GI motility 5 HT5 CNS Hippocampus Not known 5 HT6 CNS Not known 5 HT7 CNS , Hypothalamus, GIT, blood vessels Not known
- 9. Pharmacological Actions • CNS –Regulation of mood, behavior, sleep – Pain perception – Thermoregulation • CVS – Contraction of vascular smooth muscle except in skeletal muscle and heart – IV injection causes triple response
- 10. • GIT – Stimulatesperistalsis – ↑ mucus production ↓acid and pepsin • Others – Stimulates perception of pain and itch by activating 5HT3 receptors – Constricts bronchial smooth muscle by facilitating Ach release from bronchial vagal nerve endings – ↓ food intake Pharmacological Actions
- 11. 5 HT receptoragonists 1. Buspirone: 5HT 1A used in anxiety 2. Sumatriptan: 5HT 1B/D used in migraine 3. Cisapride, mosapride: 5 HT4 used in GERD 4. Dexfenfluramine: Non selective 5HT2 Agonist (BANNED) 5. Lorcaserin: 5HT2C used in obesity
- 12. 5 HT receptorantagonists • Cyproheptadine: 5 HT2A • Methysergide: 5HT2A/2C • Ketanserin: 5HT2A/2C • Clozapine: 5HT2A/2C (D2 to lesser extent) • Risperidone: 5HT2A+ D2 antagonist • Ondansetron: 5 HT3 antagonist
- 13. • Cyproheptadine: – 5HT 2A receptor blocking property – Famous for increasing apetite – H1 antihistaminic , anticholinergic & sedative – Uses: • allergies, appetite stimulant, serotonin syndrome, carcinoid syndrome, priapism – Adverse effects: • Dryness of mouth, weight gain, drowsiness 5 HT receptor antagonists
- 14. • Methysergide: – Potent5 HT 2A-2c antagonist, non emetic non oxytocic – Used in migraine prophylaxis, carcinoid, post gastrectomy dumping – Most serious side effect: retro – peritoneal fibrosis.
- 15. 5 HT receptorantagonists • Ketanserin: • Selective 5 HT2 receptor blocking property • Effective antihypertensive drug • A/E: Dizziness, tiredness, nausea & dry mouth • Additional H1, α1, dopaminergic blocking • Ritanserin: More selective 5 HT2A receptor blocker , reduces TXA2
- 16. • Ondansetron, dolasetron,granisetron: – 5 HT3 receptor antagonists used as antiemetics • Antipsychotics: (5HT2 antagonists) – Clozapine, Risperidone 5 HT receptor antagonists
- 17. Ergot alkaloids • Naturalergot alkaloids – Ergometrine – Ergotamine • Synthetic – Dihydroergotamine – Dihydroergotoxine – Bromocriptine
- 18. Ergot related drugs •Ergotamine : – Partial agonist & antagonist at , 5 HT1 & 5 HT2 receptors – Produces sustained vasoconstriction , visceral smooth muscle contraction , vasomotor centre depression – Chronic exposure can cause gangrene • Bromocriptine: • D2 agonist inhibits prolactin release • Ergometrine: – Oxytocic drug
- 19. Ergot related drugs •Adverse events: – Nausea, vomiting, – abdominal pain , muscle cramps , – weakness, paresthesia, – Chest pain – coronary artery & other vascular spasm • Contraindications: – Sepsis, IHD, PVD, Pregnancy, liver & kidney disease
- 20. Serotonergic drugs: actions& uses Sr. no Receptor Drug action Drug example Clinical disorder 1. 5HT1A partial agonist Buspirone, ipsapirone Anxiety, Depression 2. 5 HT1B/1D Agonist Sumatriptan Migraine 3. 5 HT2A/2C Antagonists Methysergide, Trazadone, Risperidone, ketanserin Migraine Depression Schizophrenia 4. 5 HT3 Antagonists Ondansetron Chemotherapy , radiotherapy induced emesis 5. 5 HT4 Agonists Cisapride, tegaserod GIT disorders
- 21. Migraine • Severe throbbing,pulsatile headache usually unilateral, associated with nausea, vomiting, sensitivity to light and sound, flashes of light, loose motion etc. • Pathophysiology – Pulsatile dilation of temporal and other cranial vessels – Perivascular neurogenic inflammation – Spreading depression of cortical electric activity
- 22. Characteristics of Migraine,cluster and Tension type headache
- 23. Drugs for Migraine •Mild Migraine (NSAIDS and antiemetics) – Ibuprofen 400 mg TDS – Paracetamol 500 mg TDS – Naproxen 500 mg TDS – Antiemetics: Metoclopramide 10 mg oral/ Domperidone 10 mg Oral • Moderate migraine – NSAIDS combination / triptans like sumatriptan + antiemetic • Severe : triptans/ ergotamine + Prophylaxis + antiemetic
- 24. Prophylaxis of migraine •Necessary when attacks are frequent ( 2 or more attacks per month) • Aim is to abolish attack totally • Discontinue every 4-6 months and observe • Drugs for prophylaxis of migraine – Propranolol 40 mg BD – Amitryptilline 25 mg BD – Flunnarizine – Valproic acid, gabapentin , topiramate (Anti-epileptics)
- 25. Sumatriptan • Mechanism ofaction in migraine – Selective 5HT 1B/1D receptor agonist – Constriction of dilated extracerebral blood vessels – Inhibition of release of 5HT and inflammatory neuropeptides around the affected vessels – Supression of neurogenic inflammation • Dose: 50 -100 mg
- 26. Sumatriptan • Adverse effects –Dose related: Tightness of chest, feeling of heat, paresthesias, dizziness, weakness – Risk of Myocardial infarction, seizure and death • Contraindications: – Ischemic heart disease, epilepsy, hypertension, pregnancy, hepatic and renal imairment Other triptans: Rizatriptan, zolmitriptan, naratriptan, almotriptan
- 27. Summary • Serotonin receptoragonists • Serotonin receptor antagonists • Clinical application of these • Migraine
- 28. Further reading • Essentialsof Medical Pharmacology KD Tripathi 8th edition • Lippincott’s illustrated Pharmacology 6th edition
- 29. • Which ofthe following drugs for headache is contraindicated in patients with peripheral vascular disease? A. Ergotamine. B. Aspirin. C. Acetaminophen. D. Naproxen E. Ibuprofen.
Editor's Notes
- #4 Serotonin was the name given to vasoconstrictor substance that appeared in serum when the blood clotted, and enteramine to the smooth muscle contracting substance present in the enterochromaffin cells of gut mucosa. In early 1950s both were shown to be same (5 HT). 90 % BODYS CONTENT PRESENT IN HE ENTEROCHROMAFFIN CELLS OF stomach and intestines . Most of the rest is in platelets and brain. Also found in wasp and scorpion sting, widely distributed in invertebrates and plants (banana, pear, pineapple, tomato, stinging nettle) Diverse Physiological and pharmacological roles in body Neurotransmitter in CNS Regulator of smooth muscle function in GIT and Regulator of Platelet function.
- #5 5HT is formed by dietary tryptophan which is converted to 5 hydroxytryptophan by tryptophan hydroxylase and then to 5 hydroxytryptamine by L amino acid decarboxylase. Decarbosylase is non specific acts on dopa as well as 5hydroxy-tryptophan. To produce DA and 5 HT respectively. Like NA 5 ht is uptaken activrly by a amine pump serotonin transporter (SERT)a Na+ dependent carrier . Which operates at the membrane of the platelets. Pump inhibited by SSRIs and TCA . 5ht is stored in storage vehicles and its uptake at VMAT 2 is inhibited by reserpine
- #6 7 Types All except 5 HT3 are G protein coupled 5 HT3 are ligand gated cation channels 5HT1 (decrease cAMP) , 5 HT 4,6,7 (↑cAMP ) 5 HT5 Gi Inhibit adenyl cyclase
- #7 5 HT 1 A: Antidepressant Buspirone 5HT 1D : Dopaminergic
- #8 Located in smooth muscles- vascular as well as visceral and platelets Ketanserin, cyprohepatidine and methysergide are specific antagonists
- #9 5 HT 3 are located exclusively on neurons and mediate neurotransmitter release – parasympahetic, sympathetic sensory and enteric Central: facilitate dopamine and 5 HT release, inhibit Ach and noradrenaline release
- #11 Diarrhoea
- #12 Azapirones: Buspirone, gepirone, ipsapirone Lorcaserin: Belviq
- #13 Cyproheptadine: 5 HT2A (H1 and Muscarinic blocking also)
- #14 Pizotifen: 5 HT 2A, 2c antagonist , antihistaminic & anticholinergic actions was used in migraine prophylaxis.
- #16 Ketanserin : raynauds disease and hypert Antagonizes vasoconstriction, platelet aggregation, contraction of airway smooth muscle
- #17 Methysergide is chemically related to ergot alkaloids
- #24 Mild migraine Cases having fewer than one attack per month of throbbing but tolerable headache lasting upto 8 hours which does not incapacitate the individual may be classified as mild migraine. Moderate migraine Migraine may be labelled as moderate when the throbbing headache is more intense, lasts for 6–24 hours, nausea/vomiting and other features are more prominent and the patient is functionally impaired. One or more attacks occur per month. Severe migraine These patients suffer 2–3 or more attacks per month of severe throbbing headache lasting 12–48 hours, often accompanied by vertigo, vomiting and other symptoms; the subject is grossly incapacitated during the attack.