MODULE 4:

Histamine and Serotonin

Antihistaminic Agents

Serotonin Modifiers and the Ergot Alkaloids

 Histamine

• Most histamine is synthesized & stored in mast cells &

basophils.

• Released in response to Agns & Abds, bacterial products,

xenobiotics & other stimulus

• Also released via interaction of IgE-antigen complex with

membranes of storage cells
 Histamine
• In gastric mucosa, Histamine is released from
enterochromaffin-like cells via gastrin & acetylcholine.
Histamine Receptors: H1

Locations: Responses:
• Vascular Smooth • Relaxation
Muscles

• Extravascular Smooth • Contraction

Muscles

• CNS
• Wakefulness &
Pruritus

• Vomit Center • Emesis

• Vestibular System • Disruption

Histamine Receptors: H2 & H3

H2
Location: Response:
• Parietal Cells • Increased Gastric HCl

H3

Location: Response:
• Auto-receptors • Decreased
histamine release
Ethanolamines
1. Diphenhydramine
Also used for:
• Parkinson’s Disease
• Sedative-hypnotic
• Anti-emetic

2. Dimenhydrinate
• Anti-emetic
• Sedative-Hypnotic

3. Doxylamine
• Sedative-Hypnotic
Ethanolamines

4. Carbinoxamine

5. Clemastine
 First Generation Antihistamines:
Ethylenediamines
1. Tripelennamine

2. Pyrilamine

3. Antazoline
• Ocular decongestant
 First Generation Antihistamines:
Cyclizines
1. Cyclizine & Meclizine
• Used primarily in the prophylaxis & treatment of motion
sickness

2. Chlorcyclizine
• Used for allergic conditions

3. Buclizine
• Found in Appebon® and Propan®

4. Hydroxyzine
• Sedative-Hypnotic
 First Generation Antihistamines:
Alkylamines/Propylamines
(Monoaminopropyl Derivatives)
1. Pheniramine
• Least potent; Ocular decongestant

2. Chlorpheniramine
• Usually combined with Phenylephrine + Paracetamol (Bioflu®,
Neozep®)

3. Brompheniramine (+ Phenylephrine: Dimetapp®)

• More potent than Chlorpheniramine

4. Dimethindene (Fenistil Gel®)

• Applied topically
 Phenothiazines

1. Promethazine
• Added with other anti-psychotics
• Anti-emetic

2. Cyproheptadine
• Has significant anti-serotoninergic effect
 Second Generation
Antihistamines
• First Members include Terfenadine & Astemizole: Obsolete

1. Fexofenadine
• 1o oxidative metabolite of Terfenadine
• Devoid of K+ channel blocking effect of Terfenadine
2. Acrivastine
• Decongestant with pseudoephedrine
3. Loratadine
• Chemically resembles phenothiazines & TCA’s
Second Generation
Antihistamines
4. Cetirizine
• Metabolite of Hydroxyzine

5. Ebastine

6. Mizolastine

New Generation:
• Desloratadine
• Levocetirizine
• Bilastine, Rupatadine
Serotonin/5-HT
Melatonin

Concentration is light-
dependent.

5-hydroxyindole-O-
methyltransferase

5-HT
Degradation
Serotonin Receptors: 5-HT1
5-HT1A
Key Location: Responses:
• CNS • Sedation, anxiety
modulation
• Facilitation of sex drive
and arousal (especially in
females)

5-HT1B/1D
Key Location: Responses:
•Cerebral blood •Vasoconstriction
vessels
5-HT1F
Key Location: Responses:
•CNS •Decrease extravasation
into the dura
Serotonin Receptors: 5-HT2
5-HT2
Responses:
Key Locations:

• Vasoconstriction
• Blood vessels

• Mood regulation
• CNS
• Cognitive function
• Hypothalamus
• Hyperthermia

• Increased peristalsis
• GIT
Serotonin Receptors: 5-HT2
5-HT2A
Responses:
Key Locations:

• Vasoconstriction
• Cerebral blood vessels

• Mood regulation
• CNS
• Cognitive function
• Decreased sex drive in
females

• GIT
• Increased peristalsis

• Uterus
• Contraction
Serotonin Receptors: 5-HT2

5-HT2B
Key Location: Responses:
• Heart • Heart valve distortion,
cardiac hypertrophy

5-HT2C

Key Location: Responses:

•CNS (Hunger center) •Decreased cravings
 Serotonin Receptors: 5-HT3
Dominant Locations:
• CNS, GIT

STIMULUS
Key 5-HT4 Effects
Dominant Locations:
• Same with 5-HT3

Effects:
• Increased GIT motility

5-HT5 to 5-HT7
• Structurally resembles 5-HT4 but are dominantly located
in the brain and functional roles are unclear.
 Drugs that can precipitate Serotonin
Syndrome
• SSRIs
• Antidepressants
• MAOIs
• Linezolid
• Tramadol
• Meperidine
• Fentanyl
• Ondansetron
• Sumatriptan
• MDMA
• LSD
• St. John's Wort
• Ginseng
Serotonin Agonists
1. 5-HT1A
• Buspirone (partial agonist): Sedative-hypnotic and Anxiolytic

• Flibanserin: For female HSDD

• Bremelanotide: Melanocortin Receptor Agonist, for pre-

menopausal HSDD

2. 5-HT1B/1D
• Sumatriptan, Naratriptan, Rizatriptan, Zolmitriptan,
Almotriptan, Frovatriptan & Eletriptan: For migraine HA
Serotonin Agonists
3. 5-HT1F: Lasmiditan
Other new therapies for migraine HA:

• *Erenumab: Calcitonin Gene-Related Peptide (CGRP)

antagonist for migraine prophylaxis

• *Ubrogepant: CGRP antagonist for acute migraine HA

• *Fremanezumab and Galcanezumab: CGRP inhibitors

Serotonin Agonists
3. 5-HT2A
• Ergotamine (Partial Agonist): For migraine HA
• Methylergometrine and Ergometrine (Partial Agonist):
Oxytocic

4. 5-HT2C
• Lorcaserin: Anti-obesity Agent

5. 5-HT4
• Tegaserod, Cisapride, Prucalopride, Mosapride: For
constipation-dominant irritable bowel syndrome (IBS-C)
Serotonin Antagonists
1. 5-HT2
• Phenoxybenzamine and Cyproheptadine: For Carcinoid
Syndrome

2. 5-HT2A
• Methysergide (Partial Agonist): Tocolytic

3. 5-HT3
• Ondansetron, Granisetron, Ramosetron, Tropisetron,
Dolasetron and Palonosetron: Anti-emetic for
Chemotherapy-Induced N&V (CINV)
• Alosetron: for IBS

4. Telotristat Ethyl: Trp-5-Hydroxylase Inhibitor for

Carcinoid Syndrome
 Ergot Alkaloids
• Produced by Claviceps purpurea, which infects grasses and
grains under damp growing or storage conditions.

• Activates adrenoceptors, dopamine receptors, 5-HT receptors,

and other receptor types.

• Accidental ingestion of ergot alkaloids in contaminated grain is

known as ergotism.

• Effects of poisoning: dementia with hallucinations, prolonged

vasospasm and stimulation of uterine smooth muscle.
Ergot Alkaloids
1. Bromocriptine, Pergolide and Cabergoline
• Has central and pituitary dopamine receptor
agonistic activity

2. Ergonovine/Ergometrine &
Methylergonovine/Methylergometrine

3. Ergotamine

4. LSD
• Agonizes dopamine and serotonin receptors in the
CNS

5. Methysergide