Serotonin and anti serotonin drugs

Serotonin pharmacology with receptors, agonists and antagonists on these receptors and drug therapy of migraine covered in this lecture

1. Serotonin and Anti-serotonin drugs Dr Naser 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 degradation of 5- HT

5. 5 HT receptors Type Receptor mechanism 5 HT 1 Gi coupled ↓ cAMP 5 HT 2 Activation of PLC 5 HT 3 Ligand gated ion channel (Nicotinic family of Na+/K+ channel proteins 5 HT 4 Gs coupled , ↑ cAMP 5 HT 5 Gi coupled ↓ cAMP 5 HT 6 Gs coupled , ↑ cAMP 5 HT 7 Gs coupled , ↑ cAMP

6. 5 HT 1 Receptors Type Distribution Function 5 HT 1A Brain stem, raphe nuclei and Hippocampus Inhibition of release in CNS Anxiety, thermoregulation 5 HT 1D Basal Ganglia and Substantia nigra Regulate dopaminergic tone 5 HT 1D / 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 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 HT 2 receptors

8. 5 HT 3 -7 receptors Type Distribution Function 5 HT 3 Mainly PNS on nociceptive sensory neuron Area postrema,Nucleus Tractus solitarius Excitation of nociceptive neuron Emesis 5 HT 4 CNS (Hippocampus) Mucosa and plexuses of smooth muscles of Gut Neuronal excitation ↑ GI motility 5 HT 5 CNS Hippocampus Not known 5 HT 6 CNS Not known 5 HT 7 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 Stimulates peristalsis ↑ mucus production ↓acid and pepsin Others Stimulates perception of pain and itch by activating 5HT 3 receptors Constricts bronchial smooth muscle by facilitating Ach release from bronchial vagal nerve endings ↓ food intake Pharmacological Actions

11. 5 HT receptor agonists Buspirone : 5HT 1A used in anxiety Sumatriptan: 5HT 1 B/D used in migraine Cisapride , mosapride : 5 HT 4 used in GERD Dexfenfluramine: Non selective 5HT 2 Agonist (BANNED) Lorcaserin : 5HT 2C used in obesity

12. 5 HT receptor antagonists Cyproheptadine: 5 HT 2A Methysergide : 5HT 2A/2C Ketanserin : 5HT 2A/2C Clozapine: 5HT 2A/2C (D 2 to lesser extent) Risperidone: 5HT 2A + D 2 antagonist Ondansetron: 5 HT 3 antagonist

13. Cyproheptadine : 5 HT 2A receptor blocking property Famous for increasing apetite H 1 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 : 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.

15. 5 HT receptor antagonists Ketanserin : Selective 5 HT 2 receptor blocking property Effective antihypertensive drug A/E: Dizziness, tiredness, nausea & dry mouth Additional H 1 , α 1 , dopaminergic blocking Ritanserin : More selective 5 HT 2A receptor blocker , reduces TXA 2

16. Ondansetron , dolasetron , granisetron : 5 HT 3 receptor antagonists used as antiemetics Antipsychotics: (5HT 2 antagonists) Clozapine, Risperidone 5 HT receptor antagonists

17. Ergot alkaloids Natural ergot alkaloids Ergometrine Ergotamine Synthetic Dihydroergotamine Dihydroergotoxine Bromocriptine

18. Ergot related drugs Ergotamine : Partial agonist & antagonist at  , 5 HT 1 & 5 HT 2 receptors Produces sustained vasoconstriction , visceral smooth muscle contraction , vasomotor centre depression Chronic exposure can cause gangrene Bromocriptine : D 2 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 HT 1B/1D Agonist Sumatriptan Migraine 3. 5 HT 2A/2C Antagonists Methysergide, Trazadone , Risperidone , ketanserin Migraine Depression Schizophrenia 4. 5 HT 3 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 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

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 receptor agonists Serotonin receptor antagonists Clinical application of these Migraine

28. Further reading Essentials of Medical Pharmacology KD Tripathi 8 th edition Lippincott’s illustrated Pharmacology 6 th edition

29. 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.