Histamine and Antihistamines

A. Histamine Synthesis
 Function Location Type
Causes:
vasodilation
Bronchoconstriction
bronchial smooth muscle
contraction separation of
endothelial cells
(responsible for hives), Found on:
and pain and itching due • Smooth muscle H1 histamine
to insect stings; • Endothelium receptor
• CNS tissue
the primary receptors
involved in allergic rhinitis
symptoms and motion
sickness;

sleep regulation.
Primarily stimulate Located on parietal H2 histamine
gastric acid secretion cells receptor
Decreased
Found on central
neurotransmitter
nervous system and
release: histamine, H3 histamine
to a lesser extent
acetylcholine, receptor
peripheral nervous
norepinephrine,
system tissue
serotonin
Found primarily in
the basophils and in
the bone marrow. It
Plays a role in H4 histamine
is also found on
chemotaxis. receptor
thymus, small
intestine, spleen, and
colon.
B. Release of histamine can occur by two
processes:

1. Energy- and Ca2+-dependent

degranulation reaction. The release of
histamine from mast cells is induced by:
A. immunoglobulin E (IgE) fixation to mast
cells (sensitization) and subsequent
exposure to a specific antigen;
B. complement activation (mediated by
immunoglobulin G or immunoglobulin M)
may also induce degranulation.
2. Energy- and Ca2+-independent release
(displacement).
• Displacement is induced by:
A. drugs such as morphine, tubocurarine,
guanethidine, and amine antibiotics.
B. mast cell damage, which is caused by noxious
agents such as venom or by mechanical
trauma, can release histamine.
Mechanism of action

A. Histamine (H1)-receptors
– H1-receptors are found in the brain, heart,
bronchi, gastrointestinal tract, vascular
smooth muscles, and leukocytes.

– H1-receptors are membrane bound and

coupled to G-proteins, specifically Gq/11, and
their activation causes:
– increase in phospholipase A2 and D activity
– increases in diacylglycerol and intracellular Ca2+
– increased cyclic guanosine 5′-monophosphate (cGMP)
– Activation of H1-receptors in the brain
increases wakefulness.

– Activation of H1-receptors in vessels causes

vasodilation and an increase in permeability.

– Activation of H1-receptors typically stimulates

nonvascular smooth muscle.
B. Histamine (H2)-receptors
1. H2-receptors are membrane bound; they are
found in the brain, heart, vascular smooth
muscles, leukocytes, and parietal cells.
2. The response of H2-receptors is coupled via
Gαs to increased cyclic AMP (cAMP)
production.
3. Activation of H2-receptors:
• increases gastric acid production
• causes vasodilation
• generally relaxes smooth muscles.
C. Histamine (H3)-receptors

1. H3-receptors are found in the central nervous

system (CNS) and peripheral nervous system
(PNS) at presynaptic nerve terminals.

2. H3-receptors are membrane bound and

coupled to Gi/o; their activation increases
intracellular Ca2+ and decreases cAMP.
3. Stimulation of H3-receptors
– on nerve cells causes a decrease in
histamine release
– in the CNS, stimulation of H3 modulates the
release of dopamine, acetylcholine,
serotonin, and norepinephrine.
– Activation of H3-receptors on the vagus
nerve decreases acetylcholine (ACh) release.
D. Histamine (H4)-receptors
1. H4-receptors are found on hematopoietic cells
and in the spleen, thymus, and colon.
2. Stimulation of H4 receptors increases
chemotaxis of mast cells and leukocytes cells
toward sites of inflammation.
3. H4 receptors are coupled to Gi/Go and thereby
inhibit the production of cAMP and increase
intracellular Ca2+
Histamine agonists

• Histamine, betazole, and impromidine.

– Betazole has approximately tenfold greater

activity at H2-receptors than at H1-receptors.

– Impromidine is an investigational agent; its

ratio of H2 to H1 activity is about 10,000.

– Methimepip is an H3-specific agonist.

• The uses of histamine agonists are primarily
diagnostic.

• These agents are used:

1. in allergy testing to assess histamine sensitivity
2. in the test of gastric secretory function
• The adverse effects of these agents can
be quite severe; they include:
• flushing
• a burning sensation
• hypotension
• tachycardia
• bronchoconstriction.
 Clinical Uses of Antihistamines
• Allergic rhinitis (common cold)
• Allergic conjunctivitis (pink eye)
• Allergic dermatological conditions
• Urticaria (hives)
• Angioedema (swelling of the skin)
• Puritus (atopic dermatitis, insect bites)
• Anaphylactic reactions (severe allergies)
• Nausea and vomiting (first generation H1-
antihistamines)
• Sedation (first generation H1-antihistamines)
Histamine (H1)-receptor antagonists
• Competitive inhibitors.

• Classification:

1. First-generation agents
2. Second-generation agents
 First-generation agents
• Groups:
1. Alkylamines
2. Ethanolamines
3. Ethylenediamines
4. Piperazines
5. Tricyclics
First-generation agents

1.Alkylamines
– Alkylamines include
– Chlorpheniramine
– Brompheniramine

– These agents produce slight sedation.

2. Ethanolamines
– Include
– diphenhydramine
– doxylamine
– clemastine
– dimenhydrinate
(combination of diphenhydramine and 8-
chlorotheophylline)
– Ethanolamines produce marked sedation;
– doxylamine is marketed only as a sleeping aid.
– Ethanolamines also act as antiemetics.
3. Ethylenediamines

– Include:
– pyrilamine and antazoline.

– Ethylenediamines produce
moderate sedation and can cause
gastrointestinal upset.
4. Piperazines
– include meclizine and cyclizine.
– Piperazines produce marked adverse
gastrointestinal effects and moderate
sedation.

– These agents have

A.antiemetic
B.antivertigo activities.
5. Phenothiazines
– include promethazine.
– Phenothazines produce marked sedation.
– These agents have antiemetic activity.
– Phenothiazines are also weak α-
adrenoceptor antagonists.
6. Methylpiperidines
– include cyproheptadine.
– have antihistamine, anticholinergic, and
antiserotonin activities.
2. Second-generation agents

2. Piperidines
Loratadine [Claritin]
Desloratadine [Clarinex]
– Poor CNS penetration: reduced sedation
– Little or no anticholinergic activity
– Desloratadine:
• is the active metabolite of loratadine
• has about 15-fold greater affinity for the H1
receptor than the parent compound
Fexophenadine
– is structurally different than the other
piperidine antihistamines,
– sedative activity is low but dose dependent.
2. Clemastine
• is a second-generation ethanolamine
• longer duration of action than
dimenhydramine
• it has some antiemetic activity.

3. Alkylamines:
A. acrivastine.
• Acrivastine is not associated with cardiac
effects.
B. Cetirizine [Zyrtec]
– Cetirizine is not associated with cardiac
abnormalities.
– Cetirizine has poor penetration into the
CNS.
– Cetirizine is less sedating;
– it is ineffective for motion sickness or
antiemesis.
 Pharmacologic properties
of Histamine (H1)-receptor antagonists
• well absorbed after oral administration.

2nd 1st
generation generation
30 min 30 min Onset

3-24 hours 3-8 hrs Duration

• H1-receptor antagonists are lipid soluble; most first-
generation agents cross the blood— brain barrier.

• H1-receptor antagonists are metabolized in the liver;

• many induce microsomal enzymes and alter their own

metabolism and that of other drugs.
Pharmacologic Actions

• Many H1-receptor antagonists, especially the

ethanolamines, phenothiazines, and
ethylenediamines, have muscarinic—cholinergic
antagonist activity.

• Most of these agents are effective local anesthetics,

probably because of a blockade of sodium channels in
excitable tissues.

• Dimenhydrinate and promethazine are potent local

anesthetics.
• H1-receptor antagonists relax histamine-induced
contraction of bronchial smooth muscle and have some
use in allergic bronchospasm.

• These agents block the vasodilator action of histamine.

• H1-receptor antagonists inhibit histamine-induced

increases in capillary permeability.

• These agents block mucus secretion and sensory nerve

stimulation.
• H1-receptor antagonists, especially the first-generation
agents, frequently cause CNS depression (marked by
sedation, decreased alertness, and decreased appetite).

• In children and some adults, these agents stimulate the

CNS.
 Therapeutic Uses
1. Treatment of allergic rhinitis and conjunctivitis.

• Clemastine is approved for the treatment of rhinorrhea.

• Many antihistamines are used to treat the common cold,
based on their anticholinergic properties, but they are
only marginally effective for this use.
• Diphenhydramine also has an antitussive effect not
mediated by H1-receptor antagonism.
2. Treatment of urticaria and atopic dermatitis,
including hives

3. Sedatives. Several (doxylamine, diphenhydramine)

are marketed as over-the-counter (OTC) sleep aids.

4. Prevention of motion sickness

5. Appetite suppressants
 Adverse effects
• (significantly reduced with second-generation agents)
• Sedation, dizziness, and loss of appetite.
• These agents can cause gastrointestinal upset, nausea,
and constipation or diarrhea.
• H1-receptor antagonists produce anticholinergic effects
(dry mouth, blurred vision, and urine retention).

• Two second-generation H1 antagonists, astemizole and

terfenadine (a prodrug of fexofenadine) were
discontinued or removed from the market because they
were associated with Q-T prolongation and ventricular
tachycardias.
 Histamine (H2)-receptor antagonists
• Cimetidine [Tagamet]
• Ranitidine [Zantac]
• Famotidine [Pepcid AC]
• Nizatidine [Axid]

Competitive antagonists at the H2-receptor,

which predominates in the gastric parietal cell.
• Used in the treatment of:

1. Gastrointestinal disorders, including

heartburn and acid-induced indigestion.

2. These agents promote the healing of gastric

and duodenal ulcers.

3. Used to treat hypersecretory states such as

Zollinger-Ellison syndrome.
Pharmacokinetics

• The bioavailability of H2-antagonists goes from

50% for ranitidine and famotidine to
approximately 90% for nizatidine and advised
dosages take this into account.
• They are taken especially in the evening to
reduce night gastric acidity.
• Their elimination is primarily renal.
• Cimetidine inhibits cytochrome P-450 and
increases the concentrations and the effects of
many other drugs.
Adverse effects

• H2 antagonists are generally well-tolerated, except for

cimetidine where all of the following adverse drug
reactions (ADRs) are common.
• Infrequent ADRs include hypotension.
• Rare ADRs include: headache, tiredness, dizziness,
confusion, diarrhea, constipation, and rash.

• Additionally, cimetidine may also cause gynecomastia in

males, loss of libido, and impotence, which are
reversible upon discontinuation.
 The chromones:
• Cromolyn [Intal]
• Nedocromil sodium [Tilade]
• These are administered by inhalation.

• They inhibit the release of histamine and other

autocoids from the mast cell.

• Each is used prophylactically in the treatment of

asthma
• they do not reverse bronchospasm.
• Adverse effects:
– confined to the site of application
– Include:
– sore throat
– dry mouth.

• Nedocromil sodium
– more effective in reducing bronchospasm
caused by exercise or cold air.