Lesson 28 - Pharmacology of Serotonin PDF

Lesson 28 Pharmacology of Serotonin 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 INDEX 1. Introduction 2. Functional aspects 3. Clinically used drugs 4. Drugs used for migraine 5. Carcinoid syndrome  1. Introducti...

Lesson 28 Pharmacology of Serotonin 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 INDEX 1. Introduction 2. Functional aspects 3. Clinically used drugs 4. Drugs used for migraine 5. Carcinoid syndrome  1. Introduction Serotonin 5-hidroxitriptamine (5-HT) Amine synthesized from the aa Tryptophan Synthesis: Enterochromaffin cells of the GI tract and 5-HT neurons of the CNS Location in greater concentration: 1. Intestinal wall: enterochromaffin cells of the intestine + nerve cells of the myenteric plexus 2. Blood: platelets* 3. CNS: Localized regions of the midbrain *Part of the 5-HT secreted by enterochromaffin cells enters the bloodstream, where it is reuptaken by platelets through an active transport system. 5-HT acts on vessel dilation and helps regulate homeostasis and platelet aggregation processes.  1. Introduction Serotonin 5-hidroxitriptamine (5-HT) Function both as a neurotransmitter and as a local hormone in the peripheral vascular system Metabolism closely parallels that of noradrenaline Degradation occurs mainly by monoamine oxidase, and is excreted in urine. 5-HT does not cross the BBB 1. Introduction Serotonin Release of 5-HT: 1. Enterochromaffin cells → by nervous, chemical (gastrin) and mechanical (compression) stimuli 2. 5-HT passes into the blood → liver and endothelium (mainly pulmonary); metabolized by MAO (monoamine oxidase) and AD (amino acid-decarboxylase) into 5-HIAA 3. The fraction that does not transform → platelets → platelet aggregation 4. Serotonergic neurons → depolarization and Ca2+ input. It acts on receptors; reuptake by the nerve ending itself. MAO: Monoaminooxidase AD: amino acid-decarboxylase 5-HIIAA: 5-hydroxyindoleacetic acid 2. Functional aspects Serotonin Main actions: Increased GI motility Contraction of other types of smooth muscle (bronchi, uterus) Platelet aggregation Stimulation of nociceptive peripheral nerve endings Stimulation/inhibition of CNS neurons In the CNS: appetite control, sleep, mood, hallucinations, stereotypic behavior, pain perception, and vomiting Clinical conditions associated with disturbed 5-HT include: Migraine Carcinoid and serotonin syndrome Pulmonary hypertension Mood disorders and anxiety 2. Functional aspects HALLUCINATORY EFFECTS Many hallucinogenic drugs (e.g. LSD) are agonists of 5-HT2A receptors. The psychostimulant properties of MDMA (‘ecstasy’) are due partly to its ability to increase the release 5-HT Some antipsychotic drugs are antagonists of 5-HT2A receptors in addition to blocking D2 receptors (atypical antipsychotic or second generation)  2. Functional aspects FEEDING AND APPETITE 5-HT induces saciety: antagonists acting on 5-HT 2C receptors, including several antipsychotic drugs used clinically, also increase appetite and cause weight gain. Antidepressant drugs that inhibit 5-HT uptake (SSRIs) cause loss of appetite 2. Functional aspects Serotonin the NT of happiness MOOD There is strong evidence that 5-HT, as well as noradrenaline, may be involved in the control of mood. 2. Functional aspects SENSORY TRANSMISSION 5-HT also exerts an inhibitory effect on transmission in the pain pathway, both in the spinal cord and in the brain. There is a synergistic effect between 5-HT and analgesics such as MORPHINE. 5-HT receptors location Metoclopramide (CTZ) 3. Clinically used drugs 5-HT reuptake inhibitors (fluoxetine) used as antidepressants and anxiolytic agents 5-HT 1B/D/F receptor agonists, such as sumatriptan, used to treat migraine 5-HT 2 antagonists, such as pizotifen , used to treat migraine 5-HT 3 receptor antagonists, such as ondansetron, used as antiemetic agents Antipsychotic drugs (e.g. Clozapine) which owe their efficacy at least partly to an action on 5-HT 2 receptors 5-HT4 receptor agonists that stimulate coordinated peristaltic activity could be used for treating gastrointestinal disorders (metoclopramide) Other 5-HT2 antagonists are used to control the symptoms of carcinoid tumours  PHARMACOLOGICAL TREATMENT OF MIGRAINE 4. Migraine pathophysiology It is a chronic neurological pathology characterized by an intracranial pain, pulsatile. It is usually recurrent and is accompanied by sensory alterations such as photophobia and phonophobia VASODILATION MEDIATORS: NO, Ach, VIP The word ‘’Migraine’’ derives from the Ancient Greek: ἡμικρανία (hēmikranía) ἡμι- (hēmi-, meaning "half") κρανίον (kraníon, meaning "skull"). INFLAMMATORY MEDIATORS: hēmikranía meaning "pain on one side of the head" CGRP, P substance  4. Migraine pathophysiology VASODILATION MEDIATORS: NO, Ach, VIP Neurological Dysfunction and Activation of Trigemino- Vascular System: Migraine involves activation of the trigemino-vascular system, releasing neuropeptides (like CGRP) that cause vasodilation and neurogenic inflammation, leading to pain. Cortical Spreading Depression: A wave of reduced neuronal INFLAMMATORY MEDIATORS: activity spreads across the cortex, linked to aura and causing CGRP, P substance vascular and inflammatory changes. Pain Modulation and Neurotransmitters: Pain control mechanisms are altered, increasing trigeminal neuron excitability. Reduced 5-HT levels contribute to pain pathway sensitization, and many migraine drugs target 5-HT1B/D/F receptors. Genetic, Environmental, and Hormonal Factors: Migraine has genetic links, with triggers from environment (stress, diet) and hormonal imbalances (e.g., estrogen), affecting onset and duration. 4. Migraine pathophysiology Phases of Migraine THERAPEUTIC AIM: inhibit vasoconstriction 1st Phase Cerebral vasoconstriction Ischemia (aura) Antagonists of 5-HT 2 receptor 2nd Phase Cerebral vasodilation THERAPEUTIC AIM: Pain inhibit vasodilation and inflammation Agonists 5-HT 1B/D/F receptor  4. Drugs used for migraine PROPHYLACTIC AGENTS: in patients with a predisposition to migraine CENTRALLY ACTING DRUGS 1. Antihistamines Pizotifen is a non-sedating antihistamine that also has some anticholinergic actions and is also a 5-HT 2A/2C receptor antagonist 2. Antiepileptic Drugs Valproate 3. Antidepressants ATC: Amitriptyline, Nortriptyline SSRIs: Fluoxetine MAOIs: Phenelzine 4. Drugs used for migraine PROPHYLACTIC AGENTS NSAIDs NAPROXEN and FENOPROFEN, can be used for the prevention and treatment of migraine. They are also effective when given at the beginning of the migraine attack. CARDIOVASCULAR AGENTS→β-Blockers PROPRANOLOL , METOPROLOL and TIMOLOL are first-line agents for migraine prophylaxis. 5. Drugs used for migraine ERGOT DERIVATIVES ERGOTAMINE, DIHYDROERGOTAMINE Ergotamine and its derivatives have been the only specific drugs for the symptomatic treatment of migraine until this last decade. Claviceps Purpurea (Rye ergot) History and fun facts Claviceps purpurea (known commonly as ergot) is a fungus that grows on rye and other grains. The fungus produces toxic alkaloids, including ergotamine and lysergic acid (LSD). In medieval Europe people would inadvertently consume grains infected with Claviceps purpurea. This caused ergotism, which led to symptoms of delirium and hallucinations (convulsive ergotism) and dry gangrene in the limbs (gangrenous ergotism). This condition, known as St. Anthony’s Fire, had a profound social impact, often linked to supernatural beliefs. 5. Drugs used for migraine ERGOT DERIVATIVES ERGOTAMINE, DIHYDROERGOTAMINE Mechanism of action Ergotamine acts on migraine by one of two proposed mechanisms: 1) agonism of 5-HT1D receptors located on intracranial blood vessels, leads to vasoconstriction, which correlates with the relief of migraine headache. 2) activation of 5-HT1D receptors on sensory nerve endings of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release Ergotamine is also an 1-adrenoreceptor agonist, inducing periferical vasoconstriction Clinical use: Only current use of ergotamine is in the treatment of attacks of migraine or cluster headaches unresponsive to simple analgesics Sometimes formulation with caffeine and the antihistamine/anticholinergic drug cyclizine which has antiemetic properties. CONTRAINDICATION: concomitant use of ergot alkaloids and β-blockers can cause severe peripheral ischemia 5. Drugs used for migraine ERGOT DERIVATIVES METHYSERGIDE Methysergide was formerly used for migraine prophylaxis, and for treating the symptoms of carcinoid tumours. It is seldom used today because of potentially serious toxicity problems Sometimes still employed for the treatment of cluster headaches which are refractory to other drugs Mechanism of action:Antagonist of 5-HT2 receptor in the CNS 4. Drugs used for migraine ERGOT DERIVATIVES ADRs: ERGOTAMINE Nausea and vomiting Contraindicated in patients with coronary artery disease or peripheral vascular disease Peripheral vasoconstriction, including coronary vessels Uterine contractions with possible fetal damage METHYSERGIDE Also causes nausea and vomiting Most serious side effect is retroperitoneal and mediastinal fibrosis, which impairs the functioning of the gastrointestinal tract, kidneys, heart and lungs Contraindicated in pregnant women: TERATOGENIC! 4. Drugs used for migraine TRIPTANs (5-HT1B/D/F agonist) SUMATRIPTAN, RIZATRIPTAN, ZOLMITRIPTAN, ALMOTRIPTAN Mechanism of action Peripheric level: CGRP Neurogenic inflammation Vasoconstriction → useful in the second phase of migraines Central level: Transmission 4. Drugs used for migraine TRIPTANs (5-HT1B/D/F agonist) Indications Mainly used to treat acute migraine but also may be given to provide prophylactic treatment of predictable attacks of migraine. (e.g. menstrual migraine) ADRs: Paresthesia Asthenia, dizziness, drowsiness, nausea and vomiting Coronary Vasoconstriction, arrhythmias CAUTION:in patients with hypertension, ischaemic heart disease, cerebrovascular disease or peripheral vascular disease. ALMOTRIPTAN first and only triptan agent approved for use in both adults and adolescents 4. Drugs used for migraine TRIPTANs (5-HT1B/D/F agonist) Interactions MAOIs Shouldn’t be used within 24 hours of administration of an ergot alkaloid. SSRI use increases the risk of triggering serotoninergic syndrome Serotoninergic syndrome: is a potentially serious condition caused by an excess of serotonin in the central nervous system. Symptoms: Neurological symptoms: agitation, confusion, hallucinations, hyperactivity. Muscle symptoms: rigidity, tremors, exaggerated reflexes, lack of coordination. Autonomic symptoms: high fever, excessive sweating, fast heart rate, high BP 4. Drugs used for migraine DITANS LASMIDITAN It is a new non-triptan drug, highly effective in aborting migraine attacks Selective 5HT 1F -receptor agonist (only CNS) Clinical use: Oral administation for the treatment of acute migraine: not suitable for migraine prophylaxis. ADRs: Dizziness, drowsiness and nausea It does not have the cardiovascular toxic effects as normal triptans  4. Drugs used for migraine Drugs Acting on the CGRP System GEPANTS→RIMEGEPANT, UBROGEPANT small-molecule CGRP antagonists shown efficacy as a prophylactic drug, and during the acute phase of migraine ADRs No cardiovascular effects. Nausea ,dizziness and vomiting (rimegepant ) or dry mouth and drowsiness Anti-CGRP mabs→EPTINEZUMAB, FREMANEZUMAB, GALCENEZUMAB Binds CGRP and thereby blocks the binding of CGRP to the CGRP receptor Administered SC or IV Inhibit the inflammatory response 4. Drugs used for migraine ACUTE ATTACK 1st line: ANALGESICS (paracetamol) , NSAIDs 2nd line: TRIPTANs (5-HT1B/D/F agonist) SUMATRIPTAN (short half life) ALMOTRIPTAN RIZATRIPTAN ZOLMITRIPTAN (nasal administration available) ERGOTAMINE 4. Drugs used for migraine PROFILAXIS β-adrenergic antagonists Calcium Antagonists Antiepileptic 5-HT2 antagonists Others (amitriptyline, fluoxetine...) TREATMENT OF CARCINOID SYNDROME 5. Carcinoid syndrome Rare disorder associated with malignant tumours of enterochromaffin cells, which usually arise in the small intestine and metastasise to the liver. These tumours secrete a variety of chemical mediators as 5-HT, substance P and other agents Symptoms: Flushing, abdominal cramps, diarrhea, bronchoconstriction ,hypotension, dizziness. More severe cognitive impairment may develop and sometimes fibrotic stenosis of heart valves, leading to cardiac failure 5. Carcinoid syndrome Diagnosis By measuring the urinary excretion of the main metabolite of 5-HT, 5- HIAA. This may increase by as much as 20-fold when the disease is active Treatment Control of the symptoms: CYPROHEPTADINE (antagonist of 5-HT2 receptors).