39. 5-HYDROXYTRYPTAMINE AGONISTS AND ANTAGONISTS

Introduction

5-Hydroxytryptamine (5-HT), also known as serotonin, is an important chemical messenger found in the brain, gastrointestinal tract and platelets. It regulates mood, sleep, appetite, behaviour, pain, migraine and gut motility. Drugs that act on serotonin receptors are used for conditions like migraine, anxiety, vomiting and gastric motility disorders.

Distribution, Synthesis and Metabolism

About 90% of serotonin is present in the gastrointestinal tract, especially in enterochromaffin cells. It is also found in platelets, CNS, lungs and pineal gland.

Synthesis: Serotonin is made from the amino acid tryptophan. It is converted into 5-hydroxytryptophan and then into serotonin. After release, serotonin is broken down by monoamine oxidase (MAO) into 5-HIAA, which is excreted in urine.

Serotonin Receptors

There are seven major types of 5-HT receptors (5-HT1 to 5-HT7). Most are G-protein–coupled receptors except 5-HT3, which is a ligand-gated ion channel.

5-HT1 Receptors

  • Mainly in CNS; inhibitory receptors reducing cAMP.
  • 5-HT1A/1B regulate mood and behaviour.
  • 5-HT1D causes cerebral vasoconstriction — target for migraine therapy.

5-HT2 Receptors

  • Located in smooth muscles and platelets.
  • Mediates vasoconstriction, bronchoconstriction and platelet aggregation.
  • Important in asthma, thrombosis and vascular tone regulation.

5-HT3 Receptors

  • Found in vagal afferents and GI tract.
  • Cause nausea, vomiting and pain sensation.
  • Target of antiemetic drugs like ondansetron.

5-HT4 Receptors

  • Located in GI tract and CNS.
  • Increase gastric emptying and GI motility.
  • Agonists used in reflux disease and constipation-predominant IBS.

Pharmacological Actions of Serotonin

Central Nervous System

  • Regulates mood, sleep, behaviour and appetite.
  • Imbalance linked to depression, anxiety, OCD and psychosis.
  • Acts as a precursor of melatonin in pineal gland.

Cardiovascular System

  • Causes vasodilation of skin, skeletal muscle and cardiac vessels.
  • May produce slight vasoconstriction in some vessels.
  • Decreases blood pressure and causes bradycardia.

Platelets

  • Stored in platelets and released at injury sites.
  • Promotes platelet aggregation.

Gastrointestinal Tract

  • Increases intestinal peristalsis (via 5-HT2, 5-HT3 and 5-HT4).
  • Increases gastric acid secretion → nausea, vomiting and diarrhea.

Respiratory System

  • Can cause bronchoconstriction (important in asthmatics).

5-HT Receptor Agonists

Serotonin itself is not used clinically, but selective agonists have therapeutic value.

1. Buspirone

Partial agonist at 5-HT1A receptors. Used as an anxiolytic. Does not cause sedation or dependence like benzodiazepines.

2. Triptans (5-HT1D Agonists)

Most important group of 5-HT agonists used for the acute treatment of migraine. They reverse migraine by causing selective cerebral vasoconstriction and inhibiting trigeminal nerve transmission.

  • Sumatriptan
  • Zolmitriptan
  • Rizatriptan
  • Eletriptan
  • Naratriptan

Adverse effects: Tingling, chest tightness, dizziness. Avoid in coronary artery disease and uncontrolled hypertension.

3. 5-HT4 Agonists

  • Cisapride, Renzapride: Increase gastric motility; limited use due to cardiac risks.
  • Tegaserod: Used in IBS with constipation.

4. Dexfenfluramine & Sibutramine

Suppress appetite by increasing serotonin levels. Withdrawn or restricted due to cardiac and neurological toxicity.

5. LSD (Lysergic Acid Diethylamide)

A non-selective 5-HT agonist; potent hallucinogen and drug of abuse.

5-HT Receptor Antagonists

These drugs block specific serotonin receptors and have several clinical uses.

1. Ketanserin

  • 5-HT2A antagonist
  • Used as an antihypertensive
  • Blocks platelet aggregation

2. Sarpogrelate

  • Selective 5-HT2A antagonist
  • Used for vasospastic disorders such as Raynaud’s disease

3. Ritanserin

  • 5-HT2A antagonist
  • Reduces platelet aggregation; limited availability

4. 5-HT3 Antagonists

Potent antiemetics used in:

  • Chemotherapy-induced vomiting
  • Postoperative nausea
  • Radiation therapy

Examples: Ondansetron, Granisetron, Dolasetron.

5. Cyproheptadine

Blocks 5-HT2A and H1 receptors. Used in:

  • Skin allergies
  • Carcinoid syndrome
  • Migraine prophylaxis
  • Increasing appetite in children

6. Ergot Alkaloids

Have partial agonist–antagonist actions on 5-HT receptors.

  • Ergotamine, Dihydroergotamine: Used in migraine attacks.
  • Methysergide: Used earlier in migraine prophylaxis.
  • Ergometrine: Uterine stimulant for postpartum haemorrhage.
  • Bromocriptine: Used for Parkinsonism and endocrine disorders.

Contraindicated in: Pregnancy, coronary artery disease, peripheral vascular disease, hypertension.

Detailed Notes:

For PDF style full-color notes, open the complete study material below:

Share your love