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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 Dr Naser Tadvi
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
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
Synthesis and degradation of 5- HT
5 HT receptors Type Receptor 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
5 HT1 Receptors Type Distribution 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
5 HT 2 Mainly 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
5 HT3 -7 receptors 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
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
• GIT – Stimulates peristalsis – ↑ 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
5 HT receptor agonists 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
5 HT receptor antagonists • Cyproheptadine: 5 HT2A • Methysergide: 5HT2A/2C • Ketanserin: 5HT2A/2C • Clozapine: 5HT2A/2C (D2 to lesser extent) • Risperidone: 5HT2A+ D2 antagonist • Ondansetron: 5 HT3 antagonist
• Cyproheptadine: – 5 HT 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
• Methysergide: – Potent 5 HT 2A-2c antagonist, non emetic non oxytocic – Used in migraine prophylaxis, carcinoid, post gastrectomy dumping – Most serious side effect: retro – peritoneal fibrosis.
5 HT receptor antagonists • 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
• Ondansetron, dolasetron, granisetron: – 5 HT3 receptor antagonists used as antiemetics • Antipsychotics: (5HT2 antagonists) – Clozapine, Risperidone 5 HT receptor antagonists
Ergot alkaloids • Natural ergot alkaloids – Ergometrine – Ergotamine • Synthetic – Dihydroergotamine – Dihydroergotoxine – Bromocriptine
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
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
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
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
Characteristics of Migraine, cluster and Tension type headache
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
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)
Sumatriptan • Mechanism of action 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
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
Summary • Serotonin receptor agonists • Serotonin receptor antagonists • Clinical application of these • Migraine
Further reading • Essentials of Medical Pharmacology KD Tripathi 8th edition • Lippincott’s illustrated Pharmacology 6th edition
• Which of the following drugs for headache is contraindicated in patients with peripheral vascular disease? A. Ergotamine. B. Aspirin. C. Acetaminophen. D. Naproxen E. Ibuprofen.