Histamine

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 Histamine
• Formed by the decarboxylation of the amino acid
histidine by histidine decarboxylase
• Present abundantly in lungs, skin and GIT
• Histamine is found largely in the mast cells and basophils
• In the GIT, in specialized cells called histaminocytes,
which exist in the acid-secreting glands of the stomach
(parietal cells)

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 Histamine

• Release
– IgE causes mast cell degranulation (immunological
response) causing asthma, rhinitis and itching

• Chemical Release
– Chocolate, Egg, Milk, Snakes and bees venom and
drugs such as morphine

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 Histamine Receptors
Receptor Distribution Mechanism Agonist Antagonist

H1 Smooth Muscles, IP3, DAG 1. Histamine 1. Mepyramine

brain endothelium 2. 2-methyl histamine 2. Diphenhydrami
3. Betahistidine ne

H2 Gastric Mucosa cAMP 1. 4-methyl histamine 1. Ranitidine

Cardiac Muscles 2. Betazole 2. Famotidine
Brain 3. Impromidone

H3 Presynaptic brain G-coupled -methyl-histamine Thioperamide

neurons Ca 2+ influx

H4 Eosinophil and
Neutrophil

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Pharmacological effects of Histamine

• Effects on Smooth Muscles

– Histamine induces contraction of intestinal and
bronchial muscles via stimulation of H1 r eceptors,
and the uterus via stimulation of H2 receptors

• Stimulation of Sensory Nerves

– Histamine causes pruritis and pain due to
stimulation of sensory nerves

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Pharmacological effects of Histamine

• Effect on Cardiovascular System

– Vasodilation by a combined H1 and H2 response leads to
decreased peripheral resistance and flushing
– Histamine can produce shock through hypotension and
reduced blood volume, due to increasing vascular
permeability and decreased venous return
– Increases inotropic response by promoting Ca2+ influx
– Increase heart rate by Baroreflex-mediated mechanisms

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Pharmacological effects of Histamine

• Secretory Effects of histamine

– Histamine targeting parietal cells is a potent
gastric secretagogue (via H2 receptors)

• Triple Response Phenomenon

– Red Spot (Capillary Dilation)
– Wheal (edema fluid)
– Red Flare (arteriole dilation)

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Triple Response

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 H1 Receptor Blockers
• H1 antagonists include
– First Generation
– Second Generation
– Both categories are orally active and are metabolized by the liver
using the cytochrome P 450 drug-metabolizing system
– The average duration of pharmacological action is 4-6 hours
– Meclizine and several second generation drugs are longer acting,
with effects lasting 12-24 hours

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 H1 Receptor Blockers
First Generation Agents Second Generation Agents

• Clemastine Fumarate • Acrivastine

• Diphenhydramine HCl • Cetirizine HCl
• Chlorpheniramine Maleate • Astemizole
• Loratidine
• Terfenadine
• Fexofenadine

Marked sedating as well as Have less penetration to CNS and

anticholinergic side effects reduced antcholinergic activity

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 First Generation Anti-histaminics
• The pharmacological objective in the use of these medications
is to treat or prevent symptoms of allergic reaction
• H1 receptor blockers prevent bronchiolar, GIT smooth muscle
contraction
• They prevent allergy mediated type of reactions such as
allergic rhinitis, hives, sting reactions, urticaria, pruritis and
other allergic dermatitis

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 Non-Histamine Receptor : Mediated effects

• First-Generation H1 receptor blockers may

exert effects mediated via blockade of many
other receptor systems:
– Muscarinic Cholinergic Receptors
– -adrenergic Receptors
– Serotonergic Receptors

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 Non-Histamine Receptor : Mediated effects

• Sedation
– Is a common side effect for first Generation H1- blockers
– They cross Blood Brain Barrier, therefore cause Sedation

• Atropine Like effects (Anti Cholinergic effects)

– Blurred Vision (loss of Accomodation)

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 Non-Histamine Receptor : Mediated effects

• Atropine Like effects (Anti Cholinergic effects)

– Urinary Retention
– Therefore, patients who may have benign prostatic
hypertrophy may exhibit significant worsening of their
clinical state due to anti-muscarinic effects.

• Alpha adrenergic blocking effects

– Orthostatic (postural) hypotension

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 Non-Histamine Receptor : Mediated effects

• Anti-emetic/Anti-nausea
– Treatment of Motion Sickness
– Example:
• Dimenhydrinate

• Meclizine

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 Side Effects
• Central Side Effects
– Dizziness, Tinnitus, Headache, Fatigue and Sedation

• Antimuscarinic Side Effects

– Dry Mouth, Blurred Vision, Constipation, Urinary Retention

• Allergic Dermatitis
– In case of topical preparations

• Orthostatic (postural) hypotension

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 Second Generation Anti-histaminics

• Many of the newer (2nd generation)

antihistamines are more specific for histamine
receptors and are primarily used for allergic
rhinitis

Less Longer duration

sedation of action
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 Drug Interactions
• Terfenadine or Astemizole are contraindicated in
patients taking cytochrome P450 enzyme inhibitors
such as ketoconazole, itraconazole
• As their serum concentration may reach toxic level
causing ventricular arrhythmias which may be
potentially fatal
• Fexofenadine, a metabolite of terfenadine is safer

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 Drug Interactions
Terfena
Terfena
dine
dine
Or
Or
Astemiz
Astemiz
ole
ole

Ventricular
Arrythmias

CYP
CYP 450
450
inhibitors
inhibitors
Ketocona
Ketocona
zole
zole
Itraconaz
Itraconaz
ole
ole

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 Therapeutic Uses

• Dermatosis

• Allergic Rhinitis
• Motion Sickness and Vertigo
– Meclizine, Cyclizine and Promethazine

• Insomnia (Sleeping Aid)

• Not effective as monotherapy for bronchial asthma

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 Mast Cell Stabilizers
• Mast Cell stabilizers are common medications used to prevent or
control certain allergic reactions
• They block a calcium channel essential for mast cell degranulation,
stabilizing the cell and thereby preventing the release of histamine and
related mediators
• One suspected pharmacodynamic mechanism is the blocking of IgE-
regulated calcium channels
• Without intracellular calcium, the histamine vesicles cannot fuse to the
cell membrane and degranulate

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 Mast Cell Stabilizers
• Examples
– Cromolyn Sodium

– Nedocromil

– Ketotifen Fumarate

• As Inhalers they are used to treat Asthma, As Nasal Sprays

they are used to treat Hay Fever (Allergic Rhinitis) and As
eye drops they are used to treat allergic Conjunctivitis

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 Cromolyn Sodium
• Cromolyn is a synthetic compound that is used to
prevent some allergic reactions
• Cromolyn is inhaled to prevent the episodes of Asthma
due to allergy
• Cromolyn is also used just before exposure to
conditions or substances that cause bronchospasm
(wheezing or difficulty in breathing)
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 Cromolyn Sodium

• Cromolyn will not help an asthma or

bronchospasm attack that has already started
• It is also used as a nasal inhaler to treat
seasonal allergic rhinitis (inflammation of the
lining of the nose) and as an ophthalmic (eye)
of the eyelids
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 H2 Receptor antagonists

• Cimetidine, Ranitidine, Famotidine and

Nizatidine
• Competitive antagonists of histamine at H2
receptors  Reduce cAMP concentration 
prevent the release of three gastric
secretagogues (Histamine, Gastrin and ACh)
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 Therapeutic Uses

• Peptic Ulcers (Gastric and Duodenal)

• Zollinger-Ellison Syndrome

• Gastroesophageal reflux
• Heart Burns (low doses)

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Peptic Ulcer

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 Side Effects
• Mostly encountered with Cimetidine
– Cimetidine binds to the CYT P450 thereby inhibit the metabolism of
drugs that use mixed function oxidases (Eg: Theophylline, Phenytoin,
Warfarin, Lidocaine, Some tricyclics, and Benzodiazepines)
– Newer H2 blockers have reduced interactions with CYT P450
– Anti-androgenic activity manifested as a decrease in sexual function
(impotence) and gynecomastia in males
– CNS disturbances and confusion especially in elderly

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 Thank You

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