Histamine, Serotonin,&

the Ergot Alkaloids

By

M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Sciences

Histamine, Serotonin, & the Ergot Alkaloids

Histamine introduction Storage & Release Receptor Subtypes Functions Organ System Effects Toxicity &

Contraindications Antagonists

Serotonin Introduction Carcinoid Syndrome Organ System Effect Cardiovascular system GI Tract CNS

Migraine Vomiting Ergot Alkaloids

Introduction Clinical Uses Drug Pictures

M.H.Farjoo

Introduction

Biologically active amine Synthesized from Histidine Autacoid member (Local Hormone) Has Physiologic & Pathologic Functions Occurs in:

Plants Animal tissues Some venoms and stinging secretions.

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Autacoids

Histamine Serotonin Prostaglandins Leukotrienes Thromboxanes Endogenous peptides Cytokines

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Storage & Release Of Histamine

Stored in: Mast cells / basophiles Brain Fundus of the stomach

Released by: Immunologic reactions Chemical and mechanical injuries

Receptor Subtype Distribution Postreceptor

MechanismPartially Selective

AgonistsPartially Selective

Antagonists

H1Smooth muscle, endothelium, brain

Gq, IP3, DAG 

Histaprodifen Cetirizine

H2

Gastric mucosa, cardiac muscle, mast cells, brain

Gs, cAMP 

AmthamineCimetidine, ranitidine, tiotidine 

H3 Presynaptic: brain, myenteric plexus, other neurons

Gi, cAMP 

R--Methylhistamine, imetit, immepip 

Thioperamide, iodophenpropit, clobenpropit,1 tiprolisant1

 

H4

Eosinophils, neutrophils, CD4 T cells

Gi, cAMP 

Clobenpropit, imetit, clozapine

Thioperamide

Not yet clinically important

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Histamine Functions

Can be Physiologic and/or Pathologic. Important mediator of immediate allergic and

inflammatory reactions (triple response). Has an important role in gastric acid secretion. Functions as a neurotransmitter / neuromodulator. Plays a role in chemotaxis of white blood cells.

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Organ System Effects Of Histamine

Nervous System Cardiovascular System Bronchiolar Smooth Muscle Gastrointestinal Tract Uterus Secretory Tissue

powerful stimulation of sensory nerve endings, especially those mediating pain and itching.decrease in systolic and diastolic

blood pressure and an increase in heart rate. Flushing, sense of warmth, headache

bronchoconstriction

contraction of intestinal smooth muscle, large doses of histamine may cause diarrheaAbortion in pregnant women

with anaphylaxisstimulation of gastric acid, pepsin & intrinsic factor. Increases secretion in the small and large intestine

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Toxicity & Contraindications of Histamine

Toxicity: (observed after the ingestion of spoiled fish) Flushing Hypotension Tachycardia Headache Wheals Bronchoconstriction Gastrointestinal upset

Contraindications: Asthmatics Patients with active ulcer disease or GI bleeding

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Histamine Antagonists

Physiologic Antagonists Epinephrine (for anaphylaxis)

Release Inhibitors Receptor Antagonists

H1 Receptor Antagonists first-generation second-generation

H2 Receptor Antagonists

stronger sedative effectsmore likely to block autonomic receptors. eg: Hydroxyzine

Longer duration of action hence once daily administration but more expensive

Drugs Anticholinergic Activity Comments

FIRST-GENERATION ANTIHISTAMINES 

  Carbinoxamine +++  Slight to moderate sedation

  Dimenhydrinate  +++Marked sedation; anti-motion sickness activity

  Diphenhydramine +++ Marked sedation; anti-motion sickness activity

  Hydroxyzine nd Marked sedation

  Cyclizine –Slight sedation; anti-motion sickness activity

  Meclizine –Slight sedation; anti-motion sickness activity

Drugs Anticholinergic Activity Comments

FIRST-GENERATION ANTIHISTAMINES Brompheniramine + Slight sedation

Chlorpheniramine +Slight sedation; common component of OTC "cold" medication

 Promethazine (Phenergan) +++ Marked sedation; 

antiemetic; block   

Cyproheptadine + Moderate sedation; also has antiserotonin activity

SECOND-GENERATION ANTIHISTAMINES Fexofenadine –  Loratadine  – Longer actionCetirizine  –  

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H1 Receptor Antagonists

Mechanism of action Non histamine receptor blocking effects:

Sedation Antinausea and Antiemetic Actions Antiparkinsonism Effects Anticholinoceptor Actions Adrenoceptor-Blocking Actions Local Anesthesia

Diphenhydramine, Dimenhydrinate,Promethazine

Diphenhydramine, Dimenhydrinate, Promethazine. Can cause urinary retention, blurred vision

Promethazine. may cause orthostatic hypotension

Diphenhydramine, Dimenhydrinate,Promethazine

Diphenhydramine, Promethazine (more potent than procaine)

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H1 Receptor Antagonists Cont,d

Clinical Uses Allergic Reactions Motion Sickness and Vestibular Disturbances Nausea and Vomiting of Pregnancy

Toxicity Drug Interactions Contraindications

Drug allergy!!!. Relatively common after topical use of H1 antagonistsLethal ventricular arrhythmias

with terfenadine in combination with ketoconazole, erythromycin or grapefruit juice

Combined use with sedative or autonomic blocking drugs

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H2 Receptor Antagonists

Will be discussed in the relevant section

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Introduction

Serotonin is: A Neurotransmitter in CNS A local hormone in the gut A component of the platelet clotting process A potent stimulant of pain and itch nerves

A central (CNS) modulator of: Migraine Vomiting Mood, sleep, appetite, temperature, blood pressure

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Carcinoid Syndrome

Over 90% of the serotonin in the body is found in enterochromaffin cells in GI tract.

Carcinoid tumor secrets serotonin and is a neoplasm of enterochromaffin cells.

Carcinoid syndrome causes subendocardial fibroplasia and valvular or electrical malfunction.

In patients whose tumor is not operable, a serotonin antagonist is a useful treatment.

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Carcinoid Syndrome

Cyproheptadine is a H1 and 5-HT2 blocker.

It also has antimuscarinic effects and causes sedation.

It is used in the treatment of the smooth muscle manifestations of carcinoid tumor and in cold-induced urticaria.

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Carcinoid Syndrome

5-hydroxyindoleacetic acid (5-HIAA) is a metabolite of serotonin.

The excretion of 5-HIAA is a measure of serotonin synthesis.

The 24-hour excretion of 5-HIAA can be used as a diagnostic test for carcinoid tumor.

Banana contains large amounts of serotonin and must be prohibited during such tests.

M.H.Farjoo

Organ System Effect

Serotonin has no clinical applications as a drug but receptor selective agonists are of value.

For example buspirone, a 5-HT1A agonist, has anxiolytic effects.

Except 5-HT3 which is an ion channel, all serotonin receptors are G-protein coupled.

Receptor Distribution Agonists Antagonists

5-HT1A  Raphe nuclei, hippocampus Buspirone

5-HT1BSubstantia nigra, globus pallidus, basal ganglia

Sumatriptan  

5-HT1D  Brain Sumatriptan  

5-HT1E Cortex, putamen    

5-HT1F Cortex, hippocampus  

5-HT1P  Enteric nervous system

5-HT2APlatelets, smooth muscle, cerebral cortex

5-HT2B  Stomach fundus

5-HT2CChoroid, hippocampus, substantia nigra

5-HT3Area postrema, sensory and enteric nerves

Granisetron, Ondansetron, Tropisetron

5-HT4CNS and myenteric neurons, smooth muscle

Cisapride, Metoclopramide

 

5-HT5A,B  Brain    

5-HT6,7  Brain  Clozapine (5-HT7)

M.H.Farjoo

Cardiovascular system

Serotonin is a powerful activator of chemosensitive endings located in the coronary vascular bed.

Activation of 5-HT3 receptors on these afferent vagal nerve endings causes chemoreceptor reflex (Bezold-Jarisch reflex).

The reflex response consists of marked bradycardia and hypotension.

Except in skeletal muscle and heart, serotonin contracts other vascular beds through 5-HT2 receptors.

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Gastrointestinal tract

Serotonin stimulates peristalsis via:

This action is caused by the action on 5-HT2 receptors.

Agonists of 5-HT4 receptors in the ENS (Cisapride, Metoclopramide) increases acetylcholine and has a "prokinetic" effect.

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Migraine

The mechanisms of action of drugs used in migraine are poorly understood.

Two hypotheses explain the actions of these drugs. activating 5-HT1D/1B receptors on nerve endings inhibits

the release of vasodilating peptides. the vasoconstrictor actions of direct 5-HT agonists

prevents vasodilation and stretching of the pain endings.

Triptans 5-HT1 agonists (eg: sumatriptan) are first-line therapy for severe migraine and are effective on cluster headache.

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Migraine Most adverse effects are mild but chest discomfort

occurs in 1-5% of patients, They are contraindicated in patients with coronary

artery disease and in patients with angina. their duration of effect is often shorter than the

duration of the headache. Several doses is required during a prolonged migraine

but the adverse effects limit the maximum dose.

M.H.Farjoo

Migraine

Many other different drugs are also used in migraine.

Propranolol, amitriptyline, verapamil, valproic acid and topiramate are effective for the prophylaxis of migraine.

They are of no value in the treatment of acute migraine.

NSAIDs such as aspirin and ibuprofen are often helpful in controlling the pain of migraine.

M.H.Farjoo

Vomiting

5-HT3 receptors participate in the vomiting reflex.

They are particularly important in vomiting caused by anti cancer drugs.

Ondansetron is the prototypical 5-HT3 antagonist. This drug is very important in the prevention of

nausea and vomiting associated with surgery and cancer chemotherapy.

M.H.Farjoo

Introduction of Ergot Alkaloids

Alkaloid’s Chemistry Produced by a fungus that infects grain especially rye Affect many kinds of receptors. Ergot poisoning signs & symptoms (ergotism) :

Dementia with hallucinations

Prolonged vasospasm, which may result in gangrene Stimulation of uterine smooth muscle, which in pregnancy

may result in abortion

Amine alkaloids Peptide alkaloids

Lysergic acid diethylamide (LSD)

Ergot Alkaloid AdrenoceptorDopamine Receptor

Serotonin Receptor (5-HT2)

Uterine Muscle

Bromocriptine – +++ – 0

Ergonovine ++ – (PA) +++  

Ergotamine – – (PA) 0 + (PA) +++

LSD 0 +++ – –++ in CNS

+

Methysergide +/0 +/0 – – – (PA) +/0

* PA means partial agonist (both agonist and antagonist effects can be detected)

Introduction of Ergot Alkaloids (Cont,d)

Peptide alkaloidsAmine alkaloids

M.H.Farjoo

Clinical Uses of Ergot Alkaloids

Migraine Hyperprolactinemia Postpartum Hemorrhage (if Oxytocin fails) :

Uterus at term is very sensitive to ergot alkaloids Induce powerful and prolonged contracture of uterus. Should never be given before delivery. Only for control of late uterine bleeding Ergonovine maleate 0.2 mg is the agent of choice It is usually effective within 1–5 minutes

Bromocriptine

Ergotamine

SummaryIn English

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