Download - Histamine, serotonin, & the ergot alkaloids
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
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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.
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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)
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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.
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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.
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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.
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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
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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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