Serotonin or 5-hydroxytryptamine • Widely distributed amine (animals + plants) • In humans, present in GI enterochromaffin cells (90%), platelets and brain. • Synthesized from tryptophan (in diet) in two steps. • Platelets do not synthesize but take up from blood (active uptake process in platelets and nerve terminals). • Cell storage in granules similar to catecholamines. (Rate limiting) COOH C OH COOH Tryptophan hydroxylase NH2 C N NH2 N Tryptophan In diet. Active CNS transport C 5-Hydroxytryptophan 5-OH Tryptophan decarboxylase COOH OH H N C 5-Hydroxy Indole Acetic Acid NH2 N 5-OH Indole Acetaldehyde 5-Hydroxytryptamine Synthesis and Metabolism • Competition at the level of brain and neuronal uptake • Rate limiting enzyme not saturated usually • No end-product negative feedback • 5-OHTr decarboxylase same as DOPA decarboxylase • 5-OHIAA actively extruded from CNS (probenecid-sensitive) and excreted in urine. Interference with the system • Inhibit uptake into CNS (other AA’s) • Inhibit synthesis: p-chlorophenylalanine (irreversible) • Inhibit neuronal re-uptake: cocaine, SSRA (e.g. fluoxetine), TCA (e.g. imipramine) • Inhibit storage-deplete: reserpine Non-selective • Inhibit metabolism: MAO inhibitors • Promote release: p-chloroamphetamine - then depletes (e.g. fenfluramine to ↓ appetite) Serotonin Receptors • • • • • At least 15 types and subtypes Multiple transduction mechanisms 5HT-1A: role in anxiety/depression 5HT-1D: role in migraine 5HT-2: role in CNS various behaviors, and in cardiovascular system • 5-HT3: role in nausea and vomiting esp. due to Chemotherapy. Endogenous Function • • • • Central neurotransmitter Precursor of melatonin GI tract: uncertain; motility? In carcinoid tumors: large amounts released leading to diarrhea, bronchoconstriction and edema • Platelets: 5-HT2 receptors → aggregation and vasoconstriction Serotonin Pharmacological Effects • Respiratory system: bronchoconstriction if asthmatic; stimulation of aortic and carotid chemoreceptors → ↑ RR and minute vol. • GI tract: small intestine very sensitive to serotonin → intense rhythmic contractions due to direct and indirect (ganglia in wall) effects. Also stimulates vomiting (5-HT3 receptors on vagal afferents and centrally). Serotonin Pharmacological Effects -2 • 1. 2. 3. 4. Cardiovascular system: Multiple direct and indirect effects: Direct vasoconstriction (large arteries) and indirect vasodilation (NO and PGI2 – mediated) Heart: direct inotropic and chronotropic effects Reflex mechanisms due to change in BP Stimulation of sensory nerve endings in baroreceptors and in vagal afferents in coronary circulation (Bezold Jarrisch reflex) → bradycardia and hypotension Serotonin in the Central Nervous System • Pain perception • Sleep/Wakefulness • Various behaviors normal/abnormal: depression, schizophrenia, obsessive compulsive behavior, etc. • Neuroendocrine regulation – controls hypothalamic cells involved in release of several anterior pituitary hormones. Migraine • Clinical Presentations: – Often accompanied by brief aura (visual scotomas, hemianopia) – Severe, throbbing, usually unilateral headache (few hours to a few days in duration) • Migraine Pathophysiology: – Vasomotor mechanism -- inferred from: • increased temporal artery pulsation magnitude • pain relief (by ergotamine) occurs with decreased artery pulsations – Migraine attack associated with (based on histological studies): • sterile neurogenic perivascular edema • inflammation (clinically effective antimigraine medication reduce perivascular inflammation) Migraine: Drug Treatment – Ergotamine: best results when drug administered prior to the attack (prodromal phase) -- less effective as attack progresses • combined with caffeine: better absorption • potentially severe long-lasting Vasoconstriction. – Dihydroergotamine (IV administration mainly): may be appropriate for intractable migraine – Nonsteroidal antiinflammatory drugs (NSAIDs) – Sumatriptan: alternative to ergotamine for acute migraine treatment; not recommended for patients with coronary vascular disease risk. • formulations: subcutaneous injection, oral, nasal spray • selective serotonin-receptor agonist (short duration of action) • probably more effective than ergotamine for management of acute migraine attacks (relief: 10 to 15 minutes following nasal spray) Migraine: Prophylaxis – Methysergide • effective in about 60% of patients • NOT effective in treating an active migraine attack or even preventing an impending attack. • Methysergide toxicity: retroperitoneal fibroplasia, subendocardial fibrosis. Recommend 3-4 week drug holiday every six months – Propranolol - Most common for continuous prophylaxis • best established drug for migraine attack prevention. – Amitriptyline (TCA) • most frequently used among the tricyclic antidepressants – Valproic acid (Antiepileptic) • effective in decreasing migraine frequency. – Nonsteroidal antiinflammatory drugs (NSAIDs) • used for attack prevention and aborting acute attack Serotonin in Migraine • • 1. 2. 3. 4. 5. Neurogenic vs. Vascular theories Several drugs that modulate the serotonin system are effective in migraine: Cyproheptadine/methysergide prophylaxis Sumatriptan, ergotamine - acute MAO inhibitors and TCA – both Caffeine (↑ cAMP?) Reserpine worsens migraine PAIN Unknown Trigger antidromic Activation Cortex Orthodromic conduction Thalamus Blood Vessel Trigeminal neuron autonomic nausea Mast cell Inhibitory receptor (5-HT1D) Trigem. Nucleus caudalis Serotonin Agonists • Sumatriptan: 5-HT1D agonist; contraindicated in patients with angina • Fluoxetine: Selective serotonin uptake inhibitors for depression and other indications • Buspirone: 5-HT1A agonist for anxiety • Cisapride: 5-HT4 agonist to ↑ GI motility and decrease G-E reflux (Removed from US market due to fatal arrhythmias) • LSD: 5HT1A – hallucinogen • Ergot alkaloids: 5-HT1 and 2 and other receptors Serotonin Antagonists • Methysergide and Cyproheptadine. 5HT2 antagonists. In carcinoid, migraine. • Ketanserin: 5HT2 and Alpha antagonist – used as antihypertensive. • Ondansetron: 5-HT3 antagonist for chemotherapy induced nausea and vomiting • Clozapine: 5HT2A/2C antagonist: for schizophrenia.