5-HT modulating drugs,

drugs for migraine (PH 1.16)

 Serotonin
• ? Neurotransmitter
• 5-Hydroxytryptamine
• ? Synthesis
Stored in vesicles: VMAT - 2
Serotonin transporter (SERT) – active reuptake
Drugs that inhibit this transport?

• Distribution
Gut mucosa (enterochromaffin cells)
Platelets
Brain
Serotonin
• Auto-receptors?
• Four families: 5-HT1, 5-HT2, 5-HT3, 5-HT4-7

Features:
• 5-HT1: Auto-receptors (inhibitory activity in the brain)
• 5-HT2: visceral, vascular smooth muscle, platelet aggregation
• 5-HT3: Ion channel – neuronal depolarization, peristalsis
• 5-HT4: intestinal secretions, augments peristalsis
 Serotonin: Actions
Cardiovascular system
• Vasoconstriction, Vasodilation - ?????
• Blood pressure ?
• Heart: indirect effect on heart rate, via blood
pressure alteration

Glands
• Inhibits gastric secretion, increases mucous
production
Serotonin: Actions
Visceral smooth muscles
• Stimulation
• Peristalsis, diarrhoea
• Bronchial constriction (less than histamine)

Platelets
• Weak aggregatory action

CNS
• Sleep!
 Serotonin: Pathophysiological role

• Pathogenesis of depression, anxiety, other

behavioural disorders
• Maintenance of circadian rhythm (melatonin)
• Normal hormonal release and balance
• Vomiting
• Migraine - vasoconstriction
• Platelet aggregation (minor role, amplifies the
process)
• Carcinoid syndrome
Drugs affecting Serotonin system:
Serotonin Antagonists
CYPROHEPTADINE
• 5-HT2a blocker
• + Antihistaminic, Anticholinergic properties
• Sedation +
• Appetite +
• Uses: carcinoid syndrome, post-gastrectomy
dumping syndrome
 Drugs affecting Serotonin system:
ERGOT ALKALOIDS
• Natural alkaloids: Ergometrine, Ergotamine, Ergotoxine
• Semisynthetic derivatives: Dihydroergotamine, Dihydroergotoxine,
Methysergide
• What does it do?
• Partial agonist/ Antagonist at Alpha adrenergic receptors, 5-HT1, 5-
HT2 receptors
• Effects: vasoconstriction, sc contraction
• Chronic exposure – thrombosis, vascular stasis, gangrene
 Drugs affecting Serotonin system:
ERGOT ALKALOIDS

• SE: Nausea, pain abdomen, vascular spasm

• Contraindication: Ischemic heart disease,
peripheral vascular disease, hypertension,
pregnancy

Preparations:
• Ergotamine, Dihydroergotamine– migraine
• Ergometrine – to control post partum
hemorrhage
Migraine
 Drugs for acute attack of Migraine
Depends on the severity
• Mild: NSAIDs, anti-emetic if needed
• Moderate: NSAIDs / Triptan
• Severe: Triptan + prophylactic medication

Antimigraine agents:
• Ergot derivatives
• Triptans
 TRIPTANS: Selective 5-HT1D/1B agonists

How do they act?

• 5-HT 1D/1B mediated constriction – arterio venous shunts
• Inhibits inflammatory neuropeptide release

Drugs: Sumatriptan, Rizatriptan

• Used only in severe attacks of migraine

• Poor oral bioavailability – given as s.c injection

 Prophylaxis of migraine

• Beta adrenergic blockers

• Tricyclic antidepressants
• Calcium channel blockers
Flunarizine
• Anti-convulsant drugs
Valproic acid, gabapentin, Topiramate