Serotonin & Serotonergic drugs

1. Serotonin & Serotonergic drugs Dept. of Pharmacology CIPS

2. Serotonin • Page & coworkers name serotonin to an unknown vasoconstrictor substance in serum in 1976. • Chemically - 5- hydroxytryptamine (5-HT) • Widely distributed in mammals, plants and insects • Chromaffin cells of GIT (>90%), • 8% in blood platelets • 2% in CNS • Neurons in brain make their own; none from body crosses Blood Brain Barrier (BBB). • Specific region of brain & platelets. • It is also present in plant like tomato, banana & pineapple lower animals (mollusks, arthropods, snake and bee venom/sting)

3. Regulatory role of serotonin : • Primarily involve in regulation of tone & motility of gastrointestinal tract • Act as precursor molecule for melatonin • Its deficiency causes depression & excess cause excitation. • Involved in hemostasis (platelets), Carcinoid syndrome (tumor of serotonin producing cells) Role in brain: • Act as a neurotransmitter in tryptaminergic nerves (raphe nucleus in the brainstem) • Regulate appetite, body temperature etc. • Pain perception, e.g. Headache, Migraine Sleep/Wakefulness Various behaviors/mood normal/abnormal, depression, schizophrenia, etc. • Neuro-endocrine regulation – controls release of several anterior pituitary hormones, prolactin.

4. COOH OH COOH CH NH2 NH2 CH N N Tryptophan OH H CH NH2 Synthesis and metabolism Tryptophan hydroxylase Rate limiting step 5-Hydroxytryptophan 5-OH Tryptophan decarboxylase N 5-Hydroxytryptamine

5. OH H 5-Hydroxytryptamine NH2 CH N Mono amine oxidase CH2 CH2 COOH CHO 5-OH Indole Acetaldehyde N N Aldehyde dehydrogenase 5-Hydroxy Indole Acetic Acid Excreted in urine

6. Carrier mediated uptake…… • In addition to metabolism carrier mediated uptake take place to terminate the action • 5-HT transporter proteins are present on outer membrane of platelets and serotonergic neurons. • Due to deficiency of tryptophan hydroxylase 5-HT can’t synthesized in platelets but it is taken up from the circulation by active transport through serotonin transporter proteins.

7. Drugs affecting on tryptaminergic system • 5-HT Precursor – ↑Tryptophan in diet ↑ 5-HT production • Synthesis inhibitors – p-chloro-phenylalanine (PCPA) inhibit tryptophan hydroxylase - ↓ 5-HT production • Storage inhibitors – (selectively release the 5-HT) Fenfluramine, dexfenfluramine • Uptake inhibitor – selective serotonin reuptake inhibitors (SSRI). Fluoxetine, Paroxetine, • Neuronal degradation – 5-6 di-hydroxytryptamine selectively destroys tryptaminergic neurons in brain. • Inhibit metabolism: MAO inhibitors Clorgyline, Selegiline • Promote release:p-chloroamphetamine - then depletes the storage

8. Mechanism of action • Interaction with tryptaminergic receptors • These receptors are of seven types (5-HT1, 5-HT2 ,….5-HT7) • 5-HT1 and 5-HT2 have (A - D) subtypes • 5-HT1A 5-HT1B….5-HT1D • 5-HT2A 5-HT2B….5-HT2D

10. Pharmacological Effects on different system Cardiovascular system : Multiple direct and indirect effects: • Direct vasoconstriction (large arteries) and • Indirect vasodilatation in small blood vessels due to • Partially by release of relaxing factors (NO and PGI2–mediators) • partially by inhibiting EN/NE release from sympathetic nerve terminals. • Heart: direct ionotropic and chronotropic effects • Reflex mechanisms due to stimulation of sensory nerve endings in baro-receptors, chemo-receptors and in vagal afferents in coronary circulation (BezoldJarrisch reflex) → Bradycardia and hypotension

11. Triphasicresponse: A rapid intravenous injection of 5-HT • Initial rise in systemic arterial blood pressure • Short period of pressoreffect • Prolong fall in systemic blood pressure due to vasodilatation Gastrointestinal tract: • Entero-chromaffin cells in the mucosa main 5-HT in body • ↑ GIT motility • partly through direct effect on the smooth muscle cells (5-HT2receptor) • partly as a result of indirect excitatory effect on enteric neurons (5-HT3&5-HT4receptors). • Also stimulates vomiting (5-HT3 receptors on vagal afferents and centrally) on 5-HT receptors. • 5-HT inhibit gastric acid and pepsin, secretion however increase mucus production thus it has ulcer protective property.

12. Respiratory system: • Bronchoconstrictionstimulation of aortic and carotid chemo-receptors result increase in respiration rate and minute volume. Other system: • It produces vasoconstriction in renal and splanchic beds, placental, uterine, umbilical, and to a lesser degree to pulmonary vessels while vasodilatation of skeletal muscle beds. Platelets: • The main function of is to prevent leakage • Platelets have 5-HT2 receptors in the membrane on interaction • it increases the platelet aggregation and • vasoconstriction to leakage site thereby promotes hemostasis.

13. Brain : • Neurotransmitter in serotonergic neuron (raphe nuclei, pons & medulla) • These neurons mainly regulate appetite, mood, sleep body temperature, thought, pain perception, vomiting & behaviors (normal and abnormal). • 5-HT poorly cross blood brain barrier however direct injection in brain produces sleepiness, change in body temperature, vomition & appetite. • Serotonin stimulates adrenal gland (autonomic ganglia) for release catecholamine.

14. Serotonin receptor Agonists • Sumatriptan: 5-HT1D agonist; contraindicated in patients with angina • Buspirone: 5-HT1A agonist for anxiety • Cisapride: 5-HT4 agonist to ↑ GI motility and decrease GIT reflux • 5HT3receptor agonists – Painful stimulation (Experimental purpose)

15. Antagonists of serotonin • Cyproheptadine: migraine, appetite stimulant in young animals and control skin allergies (In carcinoid) • Katanserin: used as antihypertensive • Methysergide: - In carcinoid, migraine. • Clozapine: for schizophrenia. • Metoclopramide, Ondansetron and Granisetron are currently available as anti-emetic for chemotherapeutic induced nausea and vomiting (5-HT3 antagonists). • Ergot Alkaloids • Alpha-blockers like phenoxybenzamine

16. Cyproheptadine • 5-HT2A blocking property • Also H1antihistamic, anticholinergic and sedative action • Famous for increasing appetite Uses: • Allergic reactions like hay fever • Serotonin syndrome • Carcinoid syndrome • Priapism (fluoxetine) • Appetite stimulation in children Adverse effects: weight gain, drowsiness, dry mouth etc.

17. Ketanserine • Selective 5-HT2 receptor blocker • Additional H1, α1 and dopaminergic blocking action • Negligible action on other 5-HT receptors • Antagonizes vasoconstriction, platelet aggregation and airway constriction actions of 5-HT • Used as antihypertensive agent • Other drugs like – clozapine, risperidone and ondansetron will be discussed elsewhere !

18. Ergot Alkaloids and derivatives • Ergot alkaloids ----toxic effects • First isolated by Dale & Barger in 1906 from fungus Clavicepspurpurea ---- on rye and other grains • They have long been recognized as abortifacientsand poisonings produced an intense burning sensation & gangrenous condition in the limbs as a result of persistent peripheral vasoconstriction. Classification of ergot alkaloids • Natural – Derivatives of the tetra-cyclic compounds (lysergic acid). • Amine alkaloids – Ergometrine • Amino acid alkaloids - Ergotamine, Ergotoxine • Semi-synthetic– Bromocriptine, Methysergide, Dihydro-ergotamine • Synthetic– (non lysergic acid derivative) Metergotine

19. MIGRAINE • Severe, throbbing, pulsating headache usually unilateral headache (few hours to a few days in duration) • Associated with nausea, vomiting, sensitivity to light and sound, flashes of light, loose motion and others Types: • Classical with aura • Without aura (common) Pathophysiology: • Pulsatile dilatation of temporal or certain cranial vessels • Vascular theory: initial vasoconstriction or shunting of blood through carotid arterio-venous anastomosis causing cerebral ischaemia • Neurogenic theory: depression of cortical electrical activity followed by depression • Migraine attack associated with (based on histological studies): • sterile neurogenicperivascular edema • inflammation (clinically effective antimigraine medication reduce perivascular inflammation)

20. Pharmacotherapy of Migraine • Three types: Mild, Moderate and Severe Mild: NSAIDS and Antiemetics (optional) Ibuprofen (400 mg 8 hrly) Paracetamol(500 mg 8 hrly) Naproxen (250 mg 8 hrly) Mefenamicacid (500 mg 8 Hrly) Diclofenac (50 mg 8 Hrly) Antiemetics: Metoclopramide(10 mg oral or IV); Domperidone(10 mg oral) Moderate: Intense throbbing headache lasting for 6 – 24 Hrs, nausea and vomiting and functionally impaired patient • NSAIDs • Antiemetics • Specific drugs like ergots and others (sumatriptan) Severe: More than 2-3 attacks per month lasting for 12 – 48 hrs, often vertigo and vomiting and patient is completely incapacitated • NSAIDS cannot relieve symptoms • Specific antimigraine drugs like ergot alkaloids and triptans • Also prophylactic regimens

21. Ergotamine • Most effective ergot alkaloid MOA: • Partial agonist of 5-HT1B/1D • Constriction of dilated temporal vessels • Constriction of carotid AV shunt channels • Reduction of neurogenic inflammation and leakage of plasma in duramater Doses: oral/sublingual (1 mg every half an hourly) till relief – 6 mg/ day Kinetics: only 1% Bioavailability orally – high first pass metabolism • Given by SL route and rectal • Metabolized in liver and excreted in bile • Sequestrated to tissues and long lastin effect • Crosses BBB ADRs: Nausea, vomiting, abdominal pain, muscle cramps etc. Also chest pain, vascular spasm etc.

22. DHE • Almost equally effective as ergotamine • Preferred for parenteral administration • Erratic oral absorption – combined with caffeine 100 mg for enhancing oral absorption Ergo status in Migraine: • Not popular anymore • Regular use is hazardous • No prophylactic value – precipitate on discontinuation • Dull headache • Combination with caffeine, paracetamol, belladona etc. are available

23. Selective 5-HT1B/1Dagonist Sumatriptan • Selective agonist of 5-HT1B/1D receptor • No interaction with other 5-HT receptors • No interaction with adrenergic, dopaminergic and cholinergic receptors, GABA MOA: • Blockade of 5-HT1D/1B mediated constriction dilatation of extracerebral blood vessel • Constriction of arteriovenous shunt of carotid artery • Inhibition of release of 5-HT and inflammatory neuropeptides around the affected vessels – supression of neurogenic inflammation • Supression of impulse transmission in trigeminovascular system Kinetics: • Poorly absorbed from GIT, bioavailability – 10 – 15% only • Complete absorption after subcutaneous administration • Metabolized by MAO-A and excreted in urine, t1/2 is 2-3 Hrs

24. Administration & Doses: • Onset of acute attack • Better tolerated than ergotamine • 50 to 100 mg as initial dose and repeated after 24 Hrs if required • Should not be given is first dose fails • SC dose – 12 mg (1 ml) stat and repeated if required Adverse effects: Dose related - Tightness of chest, feeling of heat, paresthesiaof limbs, dizziness and weakness (short lasting) – common with SC route • Risk of MI and seizure and death Contraindications: IHD, epilepsy, hypertension, pregnancy, hepatic and renal impairment (Rizatriptan, zolmitriptan, naratriptan, almotriptan)

25. Prophylaxis of Migraine • Necessary when attacks are frequent – 2 (two) or more attacks per month • Aim is to abolish attack totally • Discontinue every 4 - 6 months and observe • Beta-adrenergic blockers – Propranolol (40 mg BD), timolol etc. (not metoprolol or atenolol) • TCAs: Amitryptylline (25 – 50 mg BD) • Calcium channel blockers: Verapamil – not used now (flunnarizine – weak Ca channel blocker is effective) • Anticonvulsants: Valproic acid (400 – 1200 mg/day), gabapentin (300 – 1200 mg per day) and newer topiramate (25 mg OD) – effective

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