Histamine,Serotonin and ergot alkaloids with recent advances.

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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