Serotonin, Serotonin Receptor Agonists and Antagonists

Question 1

General Characteristics of Serotonin

Function
Localisation
Synthesis and Breakdown

Answer 1

As Autacoid:

Function:
Local Hormone (Autacoid)
Neurotransmitter

Localisation:
Intestine (synthesis): Enterochromaffin cells + neurons
Platelets: active uptake from plasma (role in aggregat)
CNS (synthesis): Neurons

Synthesis and Breakdown: Both completed in 2 steps
Tryptophan–> tryptophan hydroxylase–>
5 Hydroxytryptophan–> DOPA decarboxylase–>
5-Hydroxytryptamine (serotonin)

Serotonin–> Monoamine Oxidase–>
Aldehyde Dehydrogenase—> 5 Hydroxyindolactate
(carbonic acid) –> excreted renally

Question 2

Serotonin Receptors

Types and Effects

Answer 2

5-HT1 R
Gi coupled–> decrease cAMP
Vasoconstriction, neural and vasomotor inhibition

5-HT2 R
Gq coupled–> increase IP3/DAG
SM constriction, NO mediated vasodil, platelet aggregat

5-HT3 R
Cation (+) selective ion channel (ionotropic)
Excitation of CTZ

5-HT4 R
Gs coupled–> increase cAMP
Neural excitation, positive chrono and inotopic

Question 3

Main Effects of Serotonin (and via which R)

Answer 3

SM Contraction:
5-HT2 R–> bronchus, uterus, intestines

Vascular Effects:
Vasoconstriction: 5HT2A: Splanchus/ Kidney
5HT1B/D: Meninges/ Lung
Vasodilation: Endothelium dependent (NO mediated)
5-HT2A: Skeletal Muscles/ Meninges

Oedema Formation:
Dilation of arterioles (precapillary), constriction of
venules (postcapillary), increase permeability

Platelet Aggregation:
5HT2A R

Excitation of Sensory Nerve Ending
5 HT3 R–> Na influx and depolarisation –> AP
Pain, itching, autonomic reflexes (vomiting)

Excitation of CTZ
5 HT3 R–> vomiting

CNS Effects
Modulation of mood, sleep wake cycle, appetite, pain

Question 4

Pathophysiological Roles of Serotonin

Answer 4

Intestinal Motility
Hemostasis
Inflammation
Vomiting
Vasospastic Diseases
Migrane
Carcinoid Tumor (Enterochromaffin cells)
Depression/ Anxiety/ Schizophrenia

Question 5

5- HT1A Receptor Agonists

Drug Names and Characteristics

Answer 5

Anxiolytic Drugs: Buspirone and Gepirone
Partial Agonists–> neural inhibition

Antihypertensive Drugs: Urapidil
Central Sympatholytic Effect: decrease vasomotor
activity
Peripheral Effect: nonselective alpha 1 antagonist
No reflex tachy due to weak beta 1 antagonism

Used in emergency cases of an hypertensive crisis

Question 6

5 HT 1B/D Receptor Agonist

Drug Names and Characteristics

Answer 6

Drugs for Migrane Attacks

Sumatriptan, Naratriptan, Rizatriptan
Vasoconstriction (meninges), inhibition of neurogenic
inflammation (red. neuropeptides), decrease excitability
of trigemial nociceptors
Side Effects: Vasospasm, arrythmia, dizziness
Oral, rectal, nasal, subcutaneous
MAO A Inhibitors may compromise metabolism

Ergotamine
Partial agonist at 5 HT 1B/D R and alpha R (strong
vasoconstriction)
Uterine contraction–> th for postpartum bleeding
Side Effects: vasospasm, hypertension, vomiting
Not to be used during pregnancy
Oral, rectal, inhaled, subcutaneous, IM

Dihydroergotamine
Pure alpha R antagonist

Question 7

5 HT2A/2C R Agonist

Drug Names and Characteristics

Answer 7

LSD –> Hallucinogenic Agent, not used th (yet…)

Lorcaserin–> decreases appetite–> obesity th?

Question 8

5 HT4 R Agonist

Drug Names and Characteristics

Answer 8

Prokinetic Drugs
Cisapride, Metoclopramide
Increase gastic motility–> th of ex diabetic
neuropathy, gastroparesis
Increase tone of lower esophageal sphincter—>
GERD th
Metoclopramide also a D2 antagonist–> antiemetic

Partial Agonist
Tegaserod
Th of IBS with constipation; positive heart effects:
may increase risk for AMI and stroke

Question 9

5 HT2A/2C Receptor Antagonists

Drug Names and Characteristics

Answer 9

Ketanserin and Ritanserin: for vasospastic diseases,
Ketanserin also alpha and H1 block

Pizotifen: migrane prevention, atropine like side effects
(M block)

Methysergide: Migrane prevention, side effect: vomiting

Mianserin, Mirtazepine: also alpha 2 block, for depression

Clozapine, Olanzepine, Risperidone, Sertindole, Quetapine: newer atypical antipsychotics, also D2 antag

Question 10

Why are 5HT2A/2C Antagonists useful in migrane prevention

Answer 10

Act before endothelium allows NOS and NO

Question 11

5 HT3 Receptor Antagonists

Drug Names and Characteristics

Answer 11

Odansetron, Tropisetron, Dolasetron
   for antiemetics (chemo induced vomiting)

Question 12

Drugs Acting on Serotonergic Neurons

Answer 12

Reserpine
Irreversible inhibition of tryptophan hydroxylase

Amphetamine Like Drugs
Cause 5HT release–> appetite lowering
But–> pulmonary hypertension

Cocaine, TCA, SSRI

MAO A Inhibitors: inhibit serotonin breakdown