histamine and histamine antagonists-08
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Histamine and anti histamines
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Synthesis and storage and release of
histamine
Mechanism of Synthesis:
histamine is synthesized by decarboxylation of the
amino acid histidine by the action of the enzyme
histidine decarboxylase. Once formed, histamine is stored at the site of
synthesis.
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Site of synthesis and storage:
Histamine is synthesized and stored in the following
sites:
1- Neurons in the brain2- Enterochromaffin cells in the gastric mucosa
3- Mast cells
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Sources of histamine release in the body
1- Mast cellsMast cells are of two types:
1- connective tissue mast cells (especially around blood vessels and in the skin)
2- mucosal mast cells (lungs, digestive tract, mouth, conjunctiva and nose)
Release of histamine from mast cells
1- Immune mediated2- Non immune mediated (chemical and mechanical release)
They synthesize andstore histamine in granules
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Release of histamine from mast cells (1)
Immune mediated release = hypersensitivity reactions2 stages:
1- First exposure to an antigen (inhalation,ingestion)
results in the formation of antibodies (type IgE)
specific for that antigen. These antibodies are fixed on mast cells
2- Subsequent exposure to the same antigen
(may occur after a variable period, days,months)
Results in binding of the antigen to its specific IgE on mast cells and cross linking of IGE
receptors. This results in release of histamine
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Non-immune mediated release = Chemical andmechanical release
Certain drugs such as morphine and tubocurarine,
can displace histamine from mast cells. This type ofrelease does not require prior exposure.
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2- Non mast cell sources of histamine in
the body1- Brain: (functions as neurotransmitter)
2- Enterochromaffin cells (EC) in the stomach
(function: stimulates HCL secretion by parietal cells of
the stomach)
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Pharmacological actions of histamine
The pharmacological actions of histamine depend onthe tissue and type of receptor present at the area
of release
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Effect of histamine release
(pathophysiologic release)
Source of release Receptor Site of receptor Effect
Mast cells
(hypersensitivity)
H1 Smooth muscles 1. Bronchoconstriction
2. Contraction of GIT
H1 Endothelium 1. Vasodilatation
2. Increased capillary
permeability leading to
edema
H1 Sensory nerve endings 1. Pain and itch
H2 Smooth muscles of blood
vessels (only in large
doses)
1- Vasodilatation
H4 Immune active cells (as
eosinophils)
1. Chemotaxis
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Effect of histamine release (physiologic
release)
Source of release Receptor Site of receptor Effect
ECL - cells in the
stomach
H2 Oxyntic cells of the
stomach
1. HCL secretion
Brain
(histaminergicneurons cell bodies
of these neurons are
found in the
hypothalamus and
axons extend to all
areas of the brain)
H1 and H2 Post synaptic neurons at
all areas of the rain
1. 1- Arousal
2. Decreased appetite
H3 Presynaptic histaminergic
neurons in the brain
1. Inhibit histamine
release producing sleep
2. Modulate the release
of other
neurotransmitters
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Termination of Histamine Action
1. Cellular uptake
2. Metabolism by histamine N-methyltransferase and
histaminase enzymes in the liver.3. Very little amount is excreted
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Symptoms associated with histamine
release from mast cells
Mild cutaneous release
Moderate release
Severe release (anaphylactic)
erythema, urticaria, and/or itching
skin reactions, tachycardia, moderate
hypotension, mild respiratory distress
severe hypotension, ventricularfibrillations, cardiac arrest, bronchospasrespiratory arrest
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Urticaria
(due to the release of histamine)
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Reduction of the effects of released
histamine
1. Physiologic antagonists:Epinephrine has smooth muscle actions opposite to
histamine but by actiong on different types of receptors.It is used in conditions of massive release of histamine
2. Histamine release inhibitors:Reduce immunologic release of histamine from mast cells
a) Mast cell stabilizers: Cromolyn and nedocromil
b) Beta 2 adrenergic agonists
3. Histamine receptor antagonists
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Pharmacokinetics:
1- First Generation Agents:
Rapidly absorbed from the GIT
Widely distributed
Cross blood-brain barrier
Extensively metabolized by the cytochromeP450 and metabolites are active and are excretedby the kidney
Duration of action 4-6 hours.
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Pharmacokinetics:
2- Second GenerationRapidly absorbed from the GITWidely distributedDo not cross the blood-brain barrier (less lipidsoluble)Elimination: Cetirizine (urine) and fexofenadine (bile)
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Pharmacological Properties
I- Effects related to reversible competitive antagonism of H1
receptors (present in both first and second generations)
1- On smooth Muscles:
inhibit effects of histamine on smooth muscles, especially the constriction
of the bronchi.
2- On blood vessels:
inhibit the vasodilator effects that are mediated by activation of H1
receptors on endothelial cells (synthesis/release of NO and other
mediators). Residual vasodilation is due to H2 receptors on smooth
muscle and can be suppressed by administration of an H2 antagonist.
3- On capillary permeability:
inhibit the increased capillary permeability and formation of edema
brought about by histamine.
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II- Effects not related to blockade of H1 receptors (present in
some of the first generation drugs)
1- Anticholinergic Effects: Many of the first-generation H1 antagonists inhibit responses to acetylcholine
that are mediated by muscarinic receptors (have atropine-like actions) e.g.,
promethazine. The second-generation H1 antagonists have no effect on
muscarinic receptors.
Anticholinergic effects include dry mouth, blurred vision, constipation and
urinary retention
Perhaps because of their anticholinergic effects, some of the H1 antagonists
have suppressant effects on drug-induced parkinsonism symptoms.
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Effects not related to blockade of H1 receptors
(present in some of the first generation drugs)
2-On the central nervous system:
Therapeutic doses of most of the first generation histamine H1 receptor
antagonists produce CNS depression manifest as sedation.
Excitation rather than sedation may occur in children and rarely in adults
Overdoses produce central excitation resulting in convulsions, particularly in
children. Individual variability as regards the CNS exist. Some of the first generation drugs can prevent motion sickness
The second-generation ("nonsedating") H1 antagonists do not affect the CNS
because they do not cross the blood-brain barrier when given in therapeutic
doses.
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Summary of effects not related to reversible
competitive antagonism of H1 receptors
Anticholinergicactivity Sedation Other actions
First generation
Carbinoxamine +++ Slight to moderate -
Diphenhydramine +++ Marked Anti-motion sickness
Dimenhydrinate +++ Marked Anti-motion sickness
Cyclizine - Slight Anti-motion sickness
Chlorpheniramine + Slight -
Promethazine +++ Marked 1. Antiemetic
2. Alpha adrenergic blocker
Second generation
Fexofenadine - -
Loratadine - - Long duration of antihistamine action
Cetirizine - - Mast cell stabilizer
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Uses:
1- Prevention and treatment of allergic diseases as allergicrhinitis and chronic urticaria : both first and secondgenerations (but the non-sedating drugs are preferred)
Histamine H1 receptor antagonists are ineffective in
bronchial asthma as other mediators of allergy arepresent
2-Treatment of atopic dermatitis: Sedative histamine H1receptor antagonists are preferred.
3- Motion sickness: diphenhydramine, dimenhydrinate orcyclizine.
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Adverse effects:
1- Sedation (with first generation)1. Anticholinergic action in the form of dry mouth, blurred
vision, tachycardia, constipation and urinary retention
occur with diphenhydramine, dimenhydrinate or cyclizine,
chlorpheniramine, promethazine and carbinoxamine.2. Sedation occurs with the first generation drugs
3. Excitation and convulsions (mostly in children treated with
first generation drugs)
4. Allergy
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Drug interactions
1) Co administering first generation H1 antihistaminestogether with cytochrome P450 inducers such as the
benzodiazepines will decrease their activity.
2) Co administering first generation H1antihistamines with drugs that competitively inhibit
P450 such as the macrolides, antifungals or calcium
antagonists will increase their activity.
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Drug interactions
3) First generation H1 antihistamines produce additive CNSdepression with CNS depressants as:
1. opioids
2. sedatives
3. narcotic analgesics4. Alcohol
4) First generation H1 antihistamines produce additive
anticholinergic action with anticholinergic drugs
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Cromolyn and Nedocromyl
Not absorbed orally Given as powder by inhalation for prophylaxis
against bronchial asthma and allergic rhinitis
Inhibit histamine release by inhibiting chloridechannels on mast cells
Side effects are local in the form of dry mouth,
throat irritation, cough or wheezes.
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