This presentation includes histamine physiology, receptors, actions, classification of antihistaminics, uses and averse effects.

1. Antihistamines

2. Histamine
• Histamine is a hydrophilic molecule consisting of
imidazole ring and an amino group connected by two
methylene groups.
• Synthesized by decarboxylation of amino acid histidine
• Histamine is present in storage granules of mast cells & also
found in skin, lungs, liver, gastric mucosa etc.

3. The different Histamine receptors

4. Pharmacological actions
• CVS:
– Dilates arterioles, capillaries, venules,
• IV injection- decreased BP
• Intradermal- Triple response
Stimulating H1, H2, H3 Receptors
Red spot
Wheal
Flare(Reflex
arteriolar dilatation)

5. Pharmacological actions (Contd)
• Visceral smooth muscles:
– Bronchospasm, abdominal cramps
• Secretions:
– Increased gastric secretion (H2)
– Increased nasal secretions (H1)
• Sensory Nerve Endings: Itching
• CNS:
– Wakefulness on intra Cerebroventricular Injection

6. Classification of H1 Antagonists

7. Antihistaminics
(Pharmacokinetics)
• Absorption: Antihistaminics (H1 receptor
antagonists) are well absorbed from oral and
parenteral routes
• Distribution: widely in the body and enter brain.
Newer compounds penetrate the brain poorly.
• Metabolism: In liver
• Excretion: In urine

8. Antihistaminics
(Pharmacological actions)
• Smooth Muscle: Inhibit most of the effects of histamine on
smooth muscles, especially the constriction of respiratory
smooth muscle
• Capillary Permeability. H1 antagonists strongly block the
increased capillary permeability and formation of oedema
and wheal brought about by histamine.
• Flare and Itch. The flare component of the triple response
and the itching caused by intradermal injection of histamine
are two different manifestations of the action of histamine on
nerve endings. H1 antagonists suppress both.

9. • Immediate Hypersensitivity Reactions (Anaphylaxis and Allergy):
Oedema formation and itch are effectively suppressed. Other effects,
such as hypotension, are less well antagonized. Bronchoconstriction
is reduced little, if at all.
• Central Nervous System:
• The first-generation H1 antagonists can both stimulate and depress
the CNS.
– Stimulation  Restless, nervous, sleeplessness & convulsions
– Central depression  Diminished alertness, slowed reaction times, and
somnolence are common manifestations.
• The second-generation ("nonsedating") H1 antagonists do not cross
the blood-brain barrier appreciably.

10. • Anticholinergic action: Many H1 blockers in addition antagonize
muscarinic actions of Ach.
1 High Anticholinergic action: Promethazine, Diphenhydramine,
Pheniramine, Cyproheptadine
2 Low Anticholinergic action: Chlorpheniramine, Hydroxyzine,
3 Minimal/No Anticholinergic action: Fexofenadine, Loratadine,
Cetrizine, levocetrizine
• Local anesthetics: some drugs like Pheniramine have strong membrane
stabilizing property. But not used clinically.

11. Therapeutic Uses of H1- Antagonists
• Urticaria
• Pruritus and prurigo
• Allergic rhinitis
• Allergic Dermatitis
• Allergic conjunctivitis
• Common cold

12. First generation H1 antihistamines
• Competitive inhibitors of histamine action at tissue level
• First generation antihistamines are sedative because they are
lipophilic & easily cross blood brain barrier .
• Additional anticholinergic activity, some possess anti
serotoninergic activity and many of them also inhibit neuronal
uptake of norepinephrine
• Also have local anesthetic effect, but carry risk of irritation
and sensitization

13. First generation antihistamines
Diphenhydramine (Benedryl)
• Ethanolamine derivative
• Dose: 25mg, 50mg
• Oldest and most effective antihistamine on the market
• Also inhibits the reuptake of serotonin, which led to the search for viable
antidepressants with similar structures
Chlorpheniramine (Avil)
• Alkylamine class
• Originally used to prevent allergic conditions
• Shown to have antidepressant properties and inhibit the reuptake of serotonin
• Dose : 4mg, 12mg

14. Hydroxyzine (Atarax)
• In addition to treating itches and irritations, its an anitemetic, a weak
analgesic and an anxiolytic (treat anxiety)
• It shows greatest degree tolerance to itself & also to other
antihistamines
• Dose: 10mg, 25mg
Promethazine (Phenegran)
• This drug has extremely strong anticholinergic and sedative effects
• It was originally used as an antipsychotic, however now it is most
commonly used as a sedative or anti nausea drug (also severe
morning sickness) and requires a prescription
• Dose: 12.5mg ,25mg ,50mg

15. Cyproheptadine
• This drug both an antihistamine and an antiserotonergic agent
• It is a 5-HT2 receptor antagonist and also blocks calcium channels
• Used to treat hay fever and preferred for cold urticaria, other
physical urticaria
• It interfere with hypothalamic function ,may causes increased
appetite & weight gain
• It is also rarely used to treat SSRI induced sexual dysfunction and
also Cushing’s Syndrome (high level of cortisol in the blood) and
migraine headaches
• Dose: 4mg

16. Adverse effect
 CNS
-sedation
- hyperexcitability
-impaired cognitive function
-increase appetite
 GIT
-dry mouth
-constipation
 Genitourinary
-dysuria
- urinary retension
 CVS
-tachycardia
-arrhythmias
 Other
-blurred vision

17. Second generation H1-receptor antagonists
• Antagonists at H1 receptors
• Competitive antagonists though some are noncompetitive at
higher doses
• High therapeutic index
• Poorly lipophilic - do not cross blood brain barrier
• Highly selective with little or no anticholinergic activity
• Additional antiallergic mechanisms of some, like inhibition of late
phase allergic reaction by acting on leukotrienes or anti platelet
factor activating effect

18. Cetrizine
• Cetirizine, a piperazine derivative
• Carboxylated metabolite of hydroxyzine
• Marked affinity for peripheral H1 receptors; penetrates brain
poorly
• Minimal sedative and anticholinergic effects in recommended
dosage
• Drug interaction and contraindications
- no significant drug interaction
- Reduced dosage recommended in impaired LFT &RFT
- no significant cardiac adverse effect

19. • Cetirizine at doses of 5 and 10 mg strongly inhibited the skin
wheal and flare caused by the intradermal injection of histamine
• Onset within 20 minutes in 50% of subjects and within one hour
in 95% of subjects
• No tolerance to the antihistamines(suppression of wheal and
flare response) effects after repeated dosage
• Late phase recruitment of eosinophils, neutrophils and basophils,
components of the allergic inflammatory response, was inhibited
by cetirizine at a dose of 20 mg

20. Loratadine (Claritin)
• Piperidine tricyclic H1 antihistamine
• It has long lasting effects and does not cause drowsiness because it
does not cross the BBB
• Major metabolite is desloratadine
• Dose :10mg
• Lower dosage recommended in chronic renal &hepatic disease

21. Levocetirizine (Zyzal)
• This drug is the active enantiomer of cetirizine and is believed to be
more effective and have fewer side effects.
• Also it is not metabolized and is likely to be safer than other drugs
due to a lack of possible drug interactions .
• More potent than loratadine
• It is licensed for patient over 6yrs of age at dose of 5mg daily for
urticaria

22. Desloratadine (Clarinex)
• It is the active metabolite of Loratadine
• 5 time more potent thane loratadine
• Not metabolized via CYP enzyme pathway ,so safely
administered with macrolide & azoles
• 5mg daily above 13yrs (2.5mgdaily 6-12yrs,1.25mg for 2-
5yrs)

23. Fexofenadine (Allegra)
• Piperidine chemical class
• It was developed as an alternative to Terfenadine
• Terfenadine is prodrug ,causes serious cardiotoxicity
• Fexofenadine was proven to be more effective and safe
• Currently recommended dose 60-180mg twice a day
• No need of dosage adjustment in eldely ,or pt with renal
,hepatic impairment

24. Ketotifen
• Second generation non competitive H1 antihistamine & mast cell
stabilizer
• It is calcium channel blocker ,prevent release of histamine from mast
cell
• It is also functional leucotriene antagonist
• Indication-CIU, mastocytosis, neurofibromatosis associated pruritus
• Dose: 1mg bd
• It may take 10wk to respond completely.

25. Doxepine
• Tricyclic antidepressant drug with H1 &H2 antihistamine activity.
• Formulation :5% cream,
oral 10mg,25mg,50mg,75mg
• Indication: systemically for severe urticaria
Topically for allaying pruritus in eczematous dermatitis
• Drug interaction : Should not administered with other antidepressan
• Contraindication: severe heart disease .

27. H1 Antihistamines in
Pregnancy & Lactation
• Chlorpheniramine –pregnacy category B
• Cetirizine and loratadine- Pregnancy Category B
• Fexofenadine and desloratadine- Pregnancy Category C
• Fexofenadine and loratadine - compatible with breast feeding
• Cetirizine -not been evaluated in lactating women( based on studies
in dogs, appreciable concentrations in milk may occur). For this
reason, use of cetirizine in nursing mothers is not recommended