Serotonin and Its Clinical Applications

Serotonin (5-Hydroxytryptamine)

• Serotonin is a neurotransmitter with various physiological roles
• Serotonin agonists and antagonists have clinical applications
• About 90% of body serotonin is found in enterochromaffin cells, 8% in platelets, and 2% in the CNS

Objectives

• Describe serotonin agonists and antagonists
• Describe the uses of serotonin agonists and antagonists
• List adverse effects of serotonin agonists and antagonists

Autacoids

• Autacoids are a group of chemical substances with varied biological effects
• They are synthesized by different tissues and have localized effects
• Serotonin is one of these substances
• These substances have little to no presence in the serum

Introduction

• Serotonin is a crucial neurotransmitter with diverse physiological roles
• Serotonin agonists and antagonists are used for various clinical purposes
• Examples are in treating anxiety or migraine

Biosynthesis of Serotonin

• Serotonin is synthesized from the amino acid L-tryptophan
• This involves decarboxylation, a biochemical process
• Melatonin is a product of serotonin metabolism

Fate of Serotonin

• Serotonin is metabolized by monoamine oxidase (MAO) into 5-hydroxyindoleacetic acid (5-HIAA)
• 5-HIAA is water-soluble and can be detected in urine
• Elevated 5-HIAA levels can indicate conditions like carcinoid syndrome or ingestion of bananas, and is used diagnostically

Physiological Roles of Serotonin in the Body

• Involved in temperature regulation
• Influences appetite
• Affects pain perception
• Plays a role in carcinoid syndrome, migraine headaches, and depression
• Influences anxiety levels
• Impacts intestinal motility
• Regulates vomiting
• Involved in sleep, though it's a precursor to melatonin
• Plays a role in thinking and cognition

Too Much or Too Little Serotonin

• Excessive serotonin levels lead to potentially serious conditions (serotonin syndrome)
• Low serotonin levels correlated with depression, anxiety, and other mental health issues

Mode of Action of 5-HT

• Serotonin exerts its effects by binding to various receptor subtypes (7)
• Six subtypes are G-protein-coupled receptors
• 5-HT3 is an ion channel-coupled receptor

Pharmacologic Action of 5-HT

Effect on Cardiovascular System

• Serotonin creates a triphasic response, involving initial bradycardia (decreased heart rate), decreased cardiac output, and decreased blood pressure
• Vasoconstriction, leading to increased blood pressure
• Subsequent vasodilation in skeletal muscle vessels causes a blood pressure decrease

Effect on Respiratory System

• In healthy individuals, serotonin has a minor stimulating effect on bronchioles
• In conditions like carcinoid tumors, bronchospasm can be observed.
• Serotonin can induce hyperventilation through the chemoreceptor reflex or bronchial sensory nerve stimulation

Effect on Gastrointestinal Tract

• Serotonin strongly stimulates smooth muscle in the GI tract, raising tone and promoting peristalsis
• 5-HT4 receptor activation enhances GI motility through acetylcholine (ACh) release

Effect on Nervous System

• Serotonin acts as a neurotransmitter in the central nervous system (CNS)
• It significantly affects pain and itch sensation, influencing symptoms from insect and plant stings

Effect on Gland Secretion

• Serotonin has an inhibitory effect on exocrine gland secretions

Effect on the Uterus

• High doses of serotonin can lead to fetal distress through impaired placental blood flow

Serotonin Receptor Agonists

• Buspirone: An agonist for the 5-HT1A receptor used in anxiety treatment
• Triptans: (Almotriptan, Eletriptan, Frovatriptan, Naratriptan, Rizatriptan, Sumatriptan, Zolmitriptan) - Agonists of 5-HT1D/1B receptors, primarily for migraine
• Cisapride: A 5-HT4 agonist formerly used for GERD treatment
• Tegaserod: A partial 5-HT4 agonist used for irritable bowel syndrome (IBS) with constipation
• Dexfenfluramine: An appetite suppressant acting on 5-HT2 receptors
• Fluoxetine: An antidepressant influencing serotonin activity
• Lorcaserin: A 5-HT2C receptor agonist used for obesity treatment

Disadvantages of Triptans

• Short duration of action
• Expensive

Contraindications of Triptans

• Ischemic heart disease (IHD)
• Patients with peripheral vascular disease
• Those with severe hepatic or renal impairment
• Wolfram-Parkinson-White syndrome

Serotonin Receptor Antagonists

• Cyproheptadine: Potent 5-HT2 receptor blocker and H1 receptor blocker with sedative effects (used in cold urticaria, appetite stimulant, migrane prophylaxis)
• Ketanserin: Blocks 5-HT2A and a1-adrenergic receptors, inhibits platelet aggregation. Used in treating hypertension
• Ondansetron: Prototypical antagonist of 5-HT3 receptors, primarily used in preventing nausea and vomiting associated with surgery and chemotherapy

The Ergot Alkaloids

• Bromocriptine: Used for acromegaly and hyperprolactinemia
• Ergometrine: Used for post-partum hemorrhage (PPH)
• LSD: A hallucinogenic agent
• Methysergide: Used in migraine prophylaxis
• Dihydroergotoxin: Used in treating cerebral insufficiency/Alzheimer's

Serotonin Syndrome

• Occurs with overdose or concurrent use of serotonin-increasing drugs
• Characterized by muscle rigidity, hyperthermia, arrhythmias, hypertension, and headache

Home Work Questions

• List some 5-HT receptor antagonists
• Describe serotonin's bodily distribution
• Explain the role of 5-HT agonists in migraine treatment

This quiz covers the essential functions of serotonin, including its role as a neurotransmitter and the clinical significance of serotonin agonists and antagonists. Participants will delve into the biosynthesis, physiological roles, and adverse effects associated with these compounds. Perfect for students of pharmacology and neuroscience.