Serotonin pharmacology with receptors, agonists and antagonists on these receptors and drug therapy of migraine covered in this lecture

1. Serotonin and Anti-serotonin
drugs
Dr Naser Tadvi

2. Objectives
• Describe serotonin (5HT) receptors including
serotonin & antiserotonin drugs
• Explain important clinical applications of
serotonin related drugs.
• Explain the drugs used in the treatment &
prophylaxis of migraine

3. Serotonin
• Monoamine neurotransmitter
• Synthesized from tryptophan
• 90 % present in gastro-intestinal
enterochromaffin cells and 10 % in
platelets and brain.
• Role in mood, sleep, sexual activity,
thermoregulation, pain.
• Precursor for synthesis of melatonin

4. Synthesis and degradation of 5- HT

5. 5 HT receptors
Type Receptor mechanism
5 HT1 Gi coupled
↓ cAMP
5 HT2 Activation of PLC
5 HT3 Ligand gated ion channel (Nicotinic family of
Na+/K+ channel proteins
5 HT4 Gs coupled , ↑ cAMP
5 HT5 Gi coupled
↓ cAMP
5 HT6 Gs coupled , ↑ cAMP
5 HT7 Gs coupled , ↑ cAMP

6. 5 HT1 Receptors
Type Distribution Function
5 HT1A Brain stem, raphe nuclei
and Hippocampus
Inhibition of release in CNS
Anxiety, thermoregulation
5 HT1D Basal Ganglia and
Substantia nigra
Regulate dopaminergic tone
5 HT1D/1B Cranial Blood vessels Constricts cranial blood vessels
Inhibit release of inflammatory
neuropeptide
All are autoreceptors and inhibit the firing
of neurons or release of 5 HT

7. 5 HT 2 Mainly CNS
Smooth muscles
Platelets
Excitatory
platelet aggregation , Antinociception
5 HT 2A
(Major post
junctional
receptor)
• Vascular and visceral
smooth muscle
• Platelets
• Cerebral neurons (Mainly
prefrontal cortex)
Contraction
Platelet aggregation
Activation, Behavioural effects
5 HT 2B Stomach fundus Contraction
5 HT 2C • Choroid plexus
• Vascular endothelium
CSF secretion
Vasodilation (EDRF Release)
5 HT2 receptors

8. 5 HT3 -7 receptors
Type Distribution Function
5 HT3 Mainly PNS on nociceptive
sensory neuron
Area postrema,Nucleus
Tractus solitarius
Excitation of nociceptive neuron
Emesis
5 HT4 CNS (Hippocampus)
Mucosa and plexuses of
smooth muscles of Gut
Neuronal excitation
↑ GI motility
5 HT5 CNS
Hippocampus
Not known
5 HT6 CNS Not known
5 HT7 CNS , Hypothalamus, GIT,
blood vessels
Not known

9. Pharmacological Actions
• CNS
– Regulation of mood, behavior, sleep
– Pain perception
– Thermoregulation
• CVS
– Contraction of vascular smooth muscle except in
skeletal muscle and heart
– IV injection causes triple response

10. • GIT
– Stimulates peristalsis
– ↑ mucus production ↓acid and pepsin
• Others
– Stimulates perception of pain and itch by
activating 5HT3 receptors
– Constricts bronchial smooth muscle by facilitating
Ach release from bronchial vagal nerve endings
– ↓ food intake
Pharmacological Actions

11. 5 HT receptor agonists
1. Buspirone: 5HT 1A used in anxiety
2. Sumatriptan: 5HT 1B/D used in migraine
3. Cisapride, mosapride: 5 HT4 used in GERD
4. Dexfenfluramine: Non selective 5HT2 Agonist
(BANNED)
5. Lorcaserin: 5HT2C used in obesity

12. 5 HT receptor antagonists
• Cyproheptadine: 5 HT2A
• Methysergide: 5HT2A/2C
• Ketanserin: 5HT2A/2C
• Clozapine: 5HT2A/2C (D2 to lesser extent)
• Risperidone: 5HT2A+ D2 antagonist
• Ondansetron: 5 HT3 antagonist

13. • Cyproheptadine:
– 5 HT 2A receptor blocking property
– Famous for increasing apetite
– H1 antihistaminic , anticholinergic & sedative
– Uses:
• allergies, appetite stimulant, serotonin syndrome,
carcinoid syndrome, priapism
– Adverse effects:
• Dryness of mouth, weight gain, drowsiness
5 HT receptor antagonists

14. • Methysergide:
– Potent 5 HT 2A-2c antagonist, non emetic non
oxytocic
– Used in migraine prophylaxis, carcinoid, post
gastrectomy dumping
– Most serious side effect: retro – peritoneal
fibrosis.

15. 5 HT receptor antagonists
• Ketanserin:
• Selective 5 HT2 receptor blocking property
• Effective antihypertensive drug
• A/E: Dizziness, tiredness, nausea & dry mouth
• Additional H1, α1, dopaminergic blocking
• Ritanserin: More selective 5 HT2A receptor blocker ,
reduces TXA2

16. • Ondansetron, dolasetron, granisetron:
– 5 HT3 receptor antagonists used as antiemetics
• Antipsychotics: (5HT2 antagonists)
– Clozapine, Risperidone
5 HT receptor antagonists

17. Ergot alkaloids
• Natural ergot alkaloids
– Ergometrine
– Ergotamine
• Synthetic
– Dihydroergotamine
– Dihydroergotoxine
– Bromocriptine

18. Ergot related drugs
• Ergotamine :
– Partial agonist & antagonist at , 5 HT1 & 5 HT2 receptors
– Produces sustained vasoconstriction , visceral smooth
muscle contraction , vasomotor centre depression
– Chronic exposure can cause gangrene
• Bromocriptine:
• D2 agonist inhibits prolactin release
• Ergometrine:
– Oxytocic drug

19. Ergot related drugs
• Adverse events:
– Nausea, vomiting,
– abdominal pain , muscle cramps ,
– weakness, paresthesia,
– Chest pain
– coronary artery & other vascular spasm
• Contraindications:
– Sepsis, IHD, PVD, Pregnancy, liver & kidney disease

20. Serotonergic drugs: actions & uses
Sr.
no
Receptor Drug action Drug example Clinical disorder
1. 5HT1A partial agonist Buspirone,
ipsapirone
Anxiety,
Depression
2. 5 HT1B/1D Agonist Sumatriptan Migraine
3. 5 HT2A/2C Antagonists Methysergide,
Trazadone,
Risperidone,
ketanserin
Migraine
Depression
Schizophrenia
4. 5 HT3 Antagonists Ondansetron Chemotherapy ,
radiotherapy induced
emesis
5. 5 HT4 Agonists Cisapride,
tegaserod
GIT disorders

21. Migraine
• Severe throbbing, pulsatile headache usually
unilateral, associated with nausea, vomiting,
sensitivity to light and sound, flashes of light, loose
motion etc.
• Pathophysiology
– Pulsatile dilation of temporal and other cranial vessels
– Perivascular neurogenic inflammation
– Spreading depression of cortical electric activity

22. Characteristics of Migraine, cluster and Tension
type headache

23. Drugs for Migraine
• Mild Migraine (NSAIDS and antiemetics)
– Ibuprofen 400 mg TDS
– Paracetamol 500 mg TDS
– Naproxen 500 mg TDS
– Antiemetics: Metoclopramide 10 mg oral/ Domperidone
10 mg Oral
• Moderate migraine
– NSAIDS combination / triptans like sumatriptan +
antiemetic
• Severe : triptans/ ergotamine + Prophylaxis +
antiemetic

24. Prophylaxis of migraine
• Necessary when attacks are frequent ( 2 or more
attacks per month)
• Aim is to abolish attack totally
• Discontinue every 4-6 months and observe
• Drugs for prophylaxis of migraine
– Propranolol 40 mg BD
– Amitryptilline 25 mg BD
– Flunnarizine
– Valproic acid, gabapentin , topiramate (Anti-epileptics)

25. Sumatriptan
• Mechanism of action in migraine
– Selective 5HT 1B/1D receptor agonist
– Constriction of dilated extracerebral blood vessels
– Inhibition of release of 5HT and inflammatory
neuropeptides around the affected vessels
– Supression of neurogenic inflammation
• Dose: 50 -100 mg

26. Sumatriptan
• Adverse effects
– Dose related: Tightness of chest, feeling of heat,
paresthesias, dizziness, weakness
– Risk of Myocardial infarction, seizure and death
• Contraindications:
– Ischemic heart disease, epilepsy, hypertension,
pregnancy, hepatic and renal imairment
Other triptans: Rizatriptan, zolmitriptan, naratriptan, almotriptan

27. Summary
• Serotonin receptor agonists
• Serotonin receptor antagonists
• Clinical application of these
• Migraine

28. Further reading
• Essentials of Medical Pharmacology KD
Tripathi 8th edition
• Lippincott’s illustrated Pharmacology 6th
edition

29. • Which of the following drugs for headache is
contraindicated in patients with peripheral
vascular disease?
A. Ergotamine.
B. Aspirin.
C. Acetaminophen.
D. Naproxen
E. Ibuprofen.