This document discusses histamine and antihistamines. It provides details on histamine including its synthesis, storage, receptors, and role in allergic reactions and inflammation. It then describes first and second generation antihistamines that act as H1 receptor antagonists to relieve symptoms of allergic rhinitis, urticaria, and other conditions by blocking the effects of histamine. The patient described has seasonal allergic rhinitis, so a second generation antihistamine with fewer side effects would be most suitable. First generation antihistamines that cause drowsiness should be avoided.

1. Antihistaminic
Dr. Sumit Kumar Mahato
Senior Resident
Department of Pharmacology

2. Case study
A taxi driver aged 30 years presented with sudden onset running and
itchy nose, bouts of sneezing, partial nasal blockage, redness and
watering from the eyes, but no fever, bodyache or malaise. He gave
history of similar episodes occurring off and on during the spring
season.
A diagnosis of seasonal allergic rhinitis was made and the doctor
decided to prescribe antiallergic medication.
 Which antiallergic medicine would be suitable for this patient?
Which antiallergic drugs should be avoided?

3. Histamine and Antihistaminics
• Autacoid : Greek term
autos—self, akos—healing substance or remedy
• These are substances produced by wide variety of cells that act locally at the site of production.
• Autacoids are involved in a number of physiological and pathological processes including
inflammatory and immunological reactions.
• Autacoids are classified as
Autacoids
Amines
1.Histamine
2. Serotonin
Lipids
1.Prostaglandin
2. Leukotriens
3. Platelet activating Factor
Peptide
1. Bradykinin
2. Angiontensin
3. Kallidin

4. Histamine
• Histamine, meaning ‘tissue amine’ (histos—tissue)
• Its pharmacology was studied in detail by Dale
• Implicated as a mediator of hypersensitivity reaction and tissue injury reactions.
• Present mostly within storage granules of mast cells.
• Tissues rich in histamine are skin, gastric and intestinal mucosa, lungs, liver and
placenta.
• Non-mast cell histamine occurs in brain, epidermis, gastric mucosa and growing
regions.

5. Histamine continues……
• Turnover of mast cell histamine is slow, while that of non-mast cell histamine is
fast.
• Histamine is also present in blood, most body secretions, venoms and
pathological fluids

6. Synthesis, Storage and Destruction
Histamine is synthesized from amino acid histidine by histidine decarboxylase
and stored in mast cells, Complexed with polysulfated anion, heparin, along with
an anionic protein.
 If not stored, it is rapidly inactivated by amine oxidase enzymes
Histamine releases in response to some stimuli, destruction of cells due to cold,
bacterial toxins, bee sting venoms, or trauma. Allergies and anaphylaxis also
trigger release of histamine.

7. Mechanism of action
• Histamine act primarily by binding to its one or more of four types of histamine
receptors, H1, H2, H3, and H4 receptors
• H1 and H2 receptors are widely expressed and are the targets of clinically useful
drugs.
• H3 receptors are pre-synaptic in location and inhibit the release of histamine. and
H4 receptors are present in hematopoietic cells like eosinophils, basophils and
mast cells. Promote chemotaxis

8. Histamine Receptors
H1 H2 H3 H4
Receptor type GPCR GPCR GPCR GPCR
Effector
Pathway
Coupled to Gq
IP3/DAG/Ca2+
Coupled Gs
activate the adenylyl
cyclase–cyclic AMP–
PKA pathway
Couple to Gi/o
Inhibit adenylyl
cyclase and
decrease cellular
cyclic AMP
Couple to Gi/o
inhibit adenylyl
cyclase and
decrease cellular
cyclic AMP
Tissue
distribution
Smooth muscle,
Endothelial cell,
CNS
Gastric Parietal cell,
Cardiac Cell, Mast
cell, CNS
CNS- Presynaptic Haemopoietic cell
Antagonist Chlorpheniramine Ranitidine Tiprolisant ----------

9. Pharmacological Actions
1. Blood vessels:
 Histamine causes marked dilatation of smaller blood vessels, including arterioles, capillaries
and venules.
Dilation of small blood vessels result in flushing and hypotension.
Fall in blood pressure is mediated by both H1 (early; by release of NO) as well as H2 (delayed
and persistent; direct action on smooth muscles of blood vessels) receptors.
Increases capillary permeability and result in edema through stimulation of H1 receptors
Injected s.c elicits triple response
 Red spot
 Flare
 Whea

10. Pharmacological action continued…….
2. Heart:
 Histamine increases the force of contraction of both atrial and ventricular
muscle.
Increases heart rate by increasing diastolic depolarization in the sinoatrial (SA)
node, also directly slows atrioventricular (AV) conduction.
 The direct cardiac effects of histamine given intravenously are overshadowed
by baroreceptor reflexes due to reduced blood pressure
3. Extravascular Smooth Muscle.
Histamine directly contracts due to activation of H1 receptors on smooth
muscle by increasing intracellular Ca2+ and relaxes various extravascular
smooth muscles due to activation of H2 receptors.

11. 3. Peripheral Nerve Endings:
Histamine stimulates various nerve endings and sensory effects. In the
epidermis, causes itch & Pain, in the dermis evokes pain often accompanied by
itching.
4. Glands :
Through direct action on H2 receptor present in parietal cells increases gastric
secretion—primarily of acid but also of pepsin
5. Autonomic ganglia and adrenal medulla :
Stimulates and release Adr, which leads to a secondary rise in BP

12. Pathophysiological Roles:
1. Gastric secretion:
Histamine mediate secretion of HCl in the stomach by Nonmast cell
present in gastric mucosa, known as ‘histaminocytes’ close to the
parietal cells
feeding,vagal stimulation, cholinergic drugs and gastrin activates the proton pump (H+K+
ATPase) through H2 receptors
2. Allergic phenomena
 It is one of the mediators. following an AG : AB reaction they are released and lead to
immediate type of hypersensitivity reactions,
Urticaria, angioedema, bronchoconstriction and anaphylactic shock are associated with it

13. • Allergic phenomenon includes
1. Urticaria
2. Angioedema
3. Bronchoconstriction
4. Anaphylactic shock
5. Allergic rhinitis

14. Pathophysiological Roles……………..
3. As transmitter:
Act as afferent transmitter for sensation of itch and pain at sensory nerve
endings
4. Inflammation:
 As a mediator of vasodilatation during inflammation, promotes adhesion of
leukocytes to vascular endothelium by expressing adhesion molecule P-selectin
& sequestrating leukocytes at the inflammatory site.
Uses of histamine
Betahistine
 It is an orally active H1 selective histamine analogue, used to control vertigo in
patients of Meniere’s disease.

15. H1 Anti-Histaminics
These drugs act as competitive antagonists at H1 receptors. These may be classified
into first generation and second generation compounds on the basis of CNS penetration
and anticholinergic properties
Pharmacological Actions
1. Antagonism of histamine
 Effectively block histamine induced bronchoconstriction, contraction of intestinal and
other smooth muscle
2. Antiallergic action:
Manifestations of immediate hypersensitivity (type I reactions) are suppressed.
Urticaria, itching and angioedema are well controlled. Anaphylactic fall in BP is only
partially prevented.

16. 3. CNS
Earlier generation produce variable degree of CNS depression owing to penetrate
the blood-brain barrier and its affinity for the central H1 receptors.
Some H1 antihistamines are effective in preventing motion sickness.
Promethazine controls vomiting of pregnancy and also reduces tremor, rigidity
and sialorrhoea of parkinsonism
4. Anticholinergic action : Many H1 blockers in addition antagonize muscarinic
actions of Ach

17. First generation antihistaminic
Highly sedating Moderately sedating Mildly sedating
Diphenhydramine Pheniramine Chlorpheniramine
Dimenhydrinate Cyproheptadine Mepyramine
Promethazine Meclizine Cyclizine
Hydroxyzine Buclizine Clemastine
Doxepin Cinnarizine

18. Pharmacokinetics
H1-receptor blockers are well absorbed after oral administration & have high
bioavailability
After a single oral dose, the onset of action occurs within 1 to 3 hours, Peak serum levels
is achieved in 1 to 2 hours, average plasma half-life is 4 to 6 hours, duration of action last
for 24 hours
Drug Interactions
Increased effect of CNS depressants
 MAO inhibitors increase anticholinergic effect
First gen. antihistaminics decrease effectiveness of cholinesterase inhibitors used in
Alzheimer`s disease like donepezil and rivastigmine

19. Side effect
Side effects of first generation H1 antihistaminics are frequent, but generally mild
and show marked Individual variability
 CNS – sedation, diminished alertness, motor incoordination, fatigue,
insomnia.
 GI – Epigastric distress, alteration of bowel movement, weight gain & increase
appetite.
 Urinary hesitancy
 Drowsiness, respiratory depression in nursing infants
 Acute overdose produces central excitation, tremors, hallucinations, muscular
incordination,convulsions, flushing, hypotension, fever and some other features
of belladonna poisoning

20. Second Generation Antihistaminics
Second generation antihistaminics (SGAs) defined as those H1 receptor blockers
having following properties:
Absence of CNS depressant property: Minimal or no drowsiness and sedation
Higher H1 selectivitiy: No anticholinergic side effects
Additional antiallergic mechanisms apart from histamine blockade

21. Antihistaminics………..
•
Second Generation Antihistaminics
Fexofenadine Loratadine
Desloratadine Cetirizine
Levocetirizine Mizolastine
Rupatadine
H2 Antagonist:
 Cimetidine
 Ranitidine
 Famotidine
H3 Antagonist:
Pitolisant (tiprolisant)
approved for Narcolepsy
H4 Antagonist
Antagonists of these receptors are
being developed
for allergic conditions

22. Therapeutic Uses
Allergic rhinitis & common cold
Allergic dermatitis, itching, urticaria
Wasp stings/ bite: pain and itching decreases
Mild blood transfusion reactions
Allergic conjunctivitis
Motion sickness: Dimenhydrinate, Promethazine
Morning sickness: Doxylamine

23. Uses…
Vertigo: cinnarizine
Appetite stimulant: Cyproheptadine
Drug induced parkinsonism: Diphenhydramine
Acute muscle dystonia: Promethazine
As sedative, hypnotic, anxiolytic: Hydroxyzine