This document summarizes information about histamine, serotonin, and ergot alkaloids. It discusses their structures, physiological roles as neurotransmitters or hormones, receptor types, and mechanisms of action. It also describes clinical uses of antihistamines, serotonin agonists and antagonists, and ergot alkaloids in conditions like allergies, migraine, nausea, and postpartum hemorrhage. Key points covered include the four types of histamine receptors (H1-H4), serotonin's seven receptor families (5-HT1-7), and how ergot alkaloids structurally resemble biogenic amines and affect various receptors.

1. Histamine, Serotonin,
& the Ergot alkaloids
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Presenter: Akash Agnihotri

2. Introduction
• Many tissues contain substances
• Cause physiologic effects:
Histamine & Serotonin (5-hydroxytryptamine,5-HT)
 Biological amines
 Function as neurotransmitters
 With endogenous peptides (prostaglandins, leukotrienes and cytokines)
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Reddening of skin
Itching or pain
Bronchospasm
Autacoids

3. Histamine
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Imidazoline ring
Amine ring
Ethylene group
Present in practically all tissues,
with significant amounts in lungs,
skin, blood vessels, and GI tract

4. Histamine producing cells & stimuli
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Complement-
C3a and C5a “anaphylatoxins”
Many cytokines,
including IL-3, IL-18, IL-
33, and Stem cell factor
(SCF) promote
histamine synthesis

5. Histamine producing cells & stimuli
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6. Major physiologic actions of histamine
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7. Histamine receptors
• Four types of histamine receptor have been identified
• H1, H2, H3, and H4
• All are G protein–coupled receptors but their downstream signaling
systems differ
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8. H1 Receptor- pain pathway
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PLC: Phospholipase C;
PIP2:
phosphatidylinositol
4,5‐ bisphosphate;
PKC: Protein kinase C;
DAG: Diacylglycerol;
IP3: Inositol
triphosphate;
CaM: Calmodulin

9. Histamine receptors
H2 receptors
• Link to Gs to activate the adenylyl cyclase–cyclic AMP–PKA pathway
• Activation of H2 receptors also can activate MAP (mitogen-activated
protein) kinase and inhibit the Na+/H+ exchanger
H3 and H4 receptors
• Couple to Gi/o to inhibit adenylyl cyclase and decrease cellular cyclic
AMP
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10. Overview of Histamine receptors
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11. H1 Antihistamines
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• Neutral at physiologic pH
• Readily cross the blood–brain barrier, where
they block actions of histaminergic neurons
in the CNS
• Less selective to H1 receptor (comparatively)
• May additionally bind cholinergic, -
adrenergic, and serotonergic receptors at
therapeutic doses

12. H1 Antihistamines
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13. H1 Antihistamines
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• Ionized at physiologic pH
• Do not appreciably cross the blood–brain
barrier
Partial sedation

14. H1 antihistamines at histamine, adrenergic,
cholinergic, and serotonin-binding receptors
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15. H1 antihistamines: Therapeutic uses
• Allergic and inflammatory conditions
• Caused by IgE antibody
• Oral antihistamines: drug of choice in controlling symptoms of allergic rhinitis
and urticaira
• Ophthalmic antihistamines
• Azelastine, olopatadine, ketotifen: useful for treatment of allergic conjunctivitis
• Motion sickness and nausea
• Along with scopolamine;
• Diphenhydramine, Dimenhydrinate, Cyclizine, meclizine, and promethazine
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16. H1 antihistamines: Pharmacokinetics
• Oral H1 -antihistamines are well absorbed from the GI tract
• Reach peak plasma concentrations in 2–3 hours
• Mostly, metabolized by the liver
• As inhibitors of hepatic cytochrome P450 enzymes
• H1–antihistamines may affect the metabolism of other drugs utilizing
the cytochrome P450 system
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17. H1 antihistamines: Drug interactions
• Combination with ketoconazole, itraconazole, or macrolide antibiotics
such as erythromycin
Lethal ventricular arrhythmias
(Terfenadine or Astemizole)
Prolong the QT-interval
Mechanism: blockade of hERG (human-ether-a-go-go related gene)
potassium channel (Ikr) – blockade of cardiac repolarization
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18. H2 Antihistamines
• Drugs that blocked acid secretion and no H1 agonist or antagonist
effects
• 4 H2 receptor antagonists are available:
• Cimetidine
• Ranitidine
• Famotidine
• Nizatidine
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19. H2 Antihistamines- Mechanism
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Inhibit basal,
food-stimulated,
and nocturnal
secretion of gastric
acid
Reducing acid
secretion by
approximately 70%

20. H2 Antihistamines- Therapeutic uses
• Peptic Ulcers:
• Recurrence is common if H.pylori is present
• Acute stress ulcers:
• Given as an IV infusion to prevent and manage acute stress ulcers
• Cimetidine, Ranitidine, and Famotidine (Available in IV formulations)
• Gastroesophageal reflux disease:
• PPIs are now used preferentially in the treatment of GERD
Pharmacokinetics: Distribute widely throughout the body (including
breast milk & placenta)
• Nizatidine has the little First-pass metabolism than others
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21. H2 Antihistamines- Clinical comparisons
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22. H2 Antihistamines- Adverse effects
• <3% of patients: Diarrhea, headache, fatigue, myalgias, and constipation
• Especially in patients in the ICU who are elderly/renal/hepatic
dysfunction
• Mental status changes (confusion, hallucinations, agitation)- (For Cimetidine)
• Cimetidine may cause gynecomastia or impotence in men and
galactorrhea in women
• inhibits metabolism of estradiol, and increases serum prolactin levels
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23. H2 Antihistamines- Drug interactions
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Cimetidine interferes with several important
hepatic cytochrome P450 drug metabolism
pathways, including those catalyzed by
CYP1A2, CYP2C9, CYP2D6, and CYP3A4

24. H3 Antihistamines
• H3 receptors are presynaptic autoreceptors on histaminergic neurons
• Originated in hypothalamus & project throughout CNS
Activation of H3 receptor
Neuronal firing at the level of cell bodies/dendrites
Histamine release from depolarized terminals
Thus, H3 agonists decrease histaminergic transmission, and antagonists
increase it
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25. H3 Antihistamines
• H3 antagonists/inverse agonists have a wide range of central effects
• Promote wakefulness
• Improve cognitive function (e.g., enhance memory, learning, and attention)
• Reduce food intake
Thioperamide: 1st specific H3 antagonist available experimentally
But equally effective at the H4 receptor
Clobenpropit, ciproxifan and proxyfan: other imidazole derivatives
but the imidazole ring enhances binding to the H4 receptor
Tiprolisant: more selective nonimidazole H3 antagonist
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26. H3 Antihistamines
Pitolisant
• 1st H3 receptor-targeting drug to reach market
• Approved for the treatment of narcolepsy
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27. H4 Antihistamines
• H4 receptor antagonists are currently under clinical evaluation for their
potential therapeutic exploitation in inflammatory disorders such as
atopic dermatitis, as well as in vestibular disease
Seliforant
• Currently in Phase II clinical trials for the treatment of acute unilateral
vestibulopathy
Adriforant
• In Phase II clinical trials for the treatment of moderate to severe atopic
dermatitis
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28. Serotonin (5-HT)
• A monoamine neurotransmitter
• A local hormone in gut
• A component of platelet clotting process
• Found in-
• High concentration in ECL cells throughout the GI tract
• In storage granules in platelets, and throughout the CNS
• Functions-
• Vasoconstriction, inhibition of gastric secretion, and stimulation of smooth
muscle contraction
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29. Serotonin (5-HT)
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• Stored in vesicles, vesicular
monoamine transporter (VMAT)
• Released by exocytosis of the vesicle
in response to an action potential
• Actively taken up by an amine pump
serotonin transporter (SERT)
• This pump is inhibited by selective
serotonin reuptake inhibitors and
TCAs

30. Serotonin (5-HT)- Receptors
• 7 families of 5-HT receptor subtypes, with numeric subscripts 1 through
7 (5-HT1 to 5-HT7)
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5-HT1
5-HT1a
5-HT1b
5-HT1c
5-HT1d
5-HT1e
5-HT1f
5-HT2
5-HT2a
5-HT2b
5-HT2c
5-HT3
Recently
renamed
5-HT3A
5-HT4-7
Coupled with Gi/Go
Inhibit adenylyl cyclase
Gq protein→
activate phospholipase C and
function through generation of IP3/DAG
Gs protein,
activates adenylyl
cyclase
Ligand-gated ion channel

31. Serotonin (5-HT)- Receptors- 5-HT1
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8-OH-DPAT, 8-hydroxy-di-propylaminotetralin, cAMP, cyclic adenosine monophosphate;
EPSP, excitatory postsynaptic potential; IP3, inositol trisphosphate

32. Serotonin (5-HT)- Receptors- 5-HT2
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8-OH-DPAT, 8-hydroxy-di-propylaminotetralin, cAMP, cyclic adenosine monophosphate;
EPSP, excitatory postsynaptic potential; IP3, inositol trisphosphate

33. Serotonin (5-HT)- Receptors- 5-HT3-7
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8-OH-DPAT, 8-hydroxy-di-propylaminotetralin, cAMP, cyclic adenosine monophosphate;
EPSP, excitatory postsynaptic potential; IP3, inositol trisphosphate

34. Serotonin Pharmacology
Serotonin has no clinical applications as a drug. However, several
receptor subtype-selective agonists have proved to be of value
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35. 5-HT1 Partial Agonists
• Buspirone, Ipsapirone, Gepirone- 5-HT1A Partial agonists
• useful as antianxiety drugs
• Dexfenfluramine, a selective 5-HT agonist, was widely used as an
appetite suppressant
• but withdrawn because of cardiac valvulopathy
• Lorcaserin, selective 5-HT2c agonist
• Use as a weight-loss medication but has been withdrawn in 2020
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36. 5-HT1B/1D Partial Agonists
• Triptans- Sumatriptan, Naratriptan, Almotriptan
• Cause constriction of cranial vessels
• Useful for the treatment of acute migraine attacks
• Sumatriptan for migraine headaches is also marketed in a fixed-dose
combination with naproxen
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37. Pharmacokinetics of Triptans
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38. Serotonin Agonists- For migraine
• Lasmiditan:
• Recently approved drug, 2019
• Selective 5-HT1F agonist, has significant antimigraine efficacy
• Lower affinity than triptans but better CV safety
• 3 monoclonal antibodies:
• Erenumab, Fremanezumab and Galcanezumab
• Binds to the CGRP receptor and prevents activation by the peptide
• Ubrogepant is small molecule, Calcitonin Gene-Related Peptide (CGRP)
receptor antagonist that is orally active
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39. Other serotonin agonists
• Cisapride, Mosapride, Renzapride, Tegaserod
• 5-HT4 agonist
• used in the treatment of gastroesophageal reflux and motility disorders
• Tegaserod- Partial 5-HT4 agonist
• For management of irritable bowel syndrome and constipation
• Prucalopride
• high-affinity 5-HT4 agonist, are used for irritable bowel syndrome with
constipation
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40. Serotonin antagonists
Nonselective and interact with receptors for other signal molecules as
well:
• Ergot derivatives- Ergotamine, LSD (Lysergic acid diethylamide), 2-
bromo LSD, methysergide
• Adrenergic α blockers- Phenoxybenzamine
• Antihistaminic- Cyproheptadine, cinnarizine chlorpromazine
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41. Serotonin antagonists
Cyproheptadine
• Phenothiazine H1 antihistaminic agent as well as 5-HT2 blocking actions
• Major clinical applications- Treatment of smooth muscle manifestations of
carcinoid tumor
• Cold-induced urticaria
• Carcinoid tumor: Neuroendocrine tumor; begin in digestive tract
• Octreotide or Lanreotide- Somatostatin analogs
• Primary antisecretory drugs used in carcinoid syndrome
• Telotristat, inhibitor of tyrosine hydroxylase- reduce production of serotonin- in
combination with Octreotide (Recently approved)
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42. Serotonin antagonists
Ketanserin:
• Blocks 5-HT2 receptors on smooth muscle and platelets
• Antagonizes platelet aggregation promoted by serotonin
• Also, potently blocks vascular α1 adrenoceptors
• Approved in Europe for hypertension and vasospastic conditions, but
not in USA
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43. Serotonin antagonists
Ondansetron, Granisetron, Dolasetron, and Palonosetron
• 5-HT3 antagonist
• Used in prevention of nausea and vomiting associated with surgery and
cancer chemotherapy
Alosetron
• 5-HT3 antagonist that has been approved for the treatment of patients
with severe IBS with diarrhea (Only for women)
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44. Serotonin antagonists
Adverse effects of 5-HT3 antagonists:
• Most commonly- headache, dizziness, and constipation
• First-generation agents cause a small but statistically significant
prolongation of the QT interval
• FDA has advised that these agents should not be administered to
patients with prolonged QT or other QT-prolonging drugs
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45. Ergot Alkaloids
• Ergot alkaloids are produced by Claviceps purpurea, a fungus that
infects grasses and grains—especially rye
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• Ergot alkaloids are produced by Claviceps purpurea, a fungus that
infects grasses and grains—especially rye
In Ayurveda- ”Annaamaya”, or “Sraavikaa”
Versatile fungus
• Synthesizes histamine, Acetylcholine,
Tyramine, more of unique ergot alkaloids
• Affects: Adrenoceptors, Dopamine receptors,
5-HT receptors

46. Ergot Alkaloids
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47. Structural similarity of ergoline ring with
biogenic amine receptors
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48. Receptor mediated actions of ergot
alkaloids
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49. Properties of ergot alkaloids and related
compounds
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Natural

50. Ergot alkaloids- Clinical pharmacology
Migraine:
• Ergot derivatives are highly specific for migraine pain
• Ergotamine tartrate is available for oral, sublingual, rectal suppository,
and inhaler use
• Combination with caffeine to facilitate absorption (100mg in 1mg of ET)
Postpartum Hemorrhage:
• Used only for control of postpartum uterine bleeding
• Oxytocin is the preferred agent for control of postpartum hemorrhage
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51. Ergot alkaloids- Clinical pharmacology
Diagnosis of Variant Angina:
• Ergonovine intravenously- used to produce prompt vasoconstriction
during coronary angiography- to diagnose variant angina
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52. References
1. Katzung, B. G. (2020). Basic and clinical pharmacology. Mc Graw Hill.
2. Ritter, J., Flower, R. J., Henderson, G., Loke, Y. K., MacEwan, D. J., & Rang, H. P. (2020).
Rang and Dale's pharmacology.
3. Goodman LS. Goodman and Gilman's the pharmacological basis of therapeutics. New
York: McGraw-Hill; 2018.
4. Harvey RA, Clark M, Finkel R, Rey J, Whalen K. Lippincott’s illustrated reviews:
Pharmacology. Philadelphia; 2020.
5. David E Golan’s “Principles of pharmacology” 4th edition. 2017.
6. Huang H, Li Y, Liang J, Finkelman FD. Molecular regulation of histamine synthesis.
Frontiers in immunology. 2018 Jun 20;9:1392.
7. Obara I, Telezhkin V, Alrashdi I, Chazot PL. Histamine, histamine receptors, and
neuropathic pain relief. British Journal of Pharmacology. 2020 Feb;177(3):580-99.
8. Tiligada E, Ennis M. Histamine pharmacology: from Sir Henry Dale to the 21st century.
British Journal of Pharmacology. 2020 Feb;177(3):469-89.
9. Sharma N, Sharma VK, Manikyam HK, Krishna AB. Ergot alkaloids: a review on therapeutic
applications. European Journal of Medicinal Plants. 2016 Apr 21:1-7.
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53. Thank You
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