Histamineandantihistaminics

1. HISTAMINE AND ANTIHISTAMINICS

2. Autacoid(self healing)
Amine Autacoids Lipid derived Peptide derived
 Histamine
 Serotonin
 Prostaglandins
 Leukotrienes
 PAF
 Plasma kinins
 Angiotensin

3. Histamine
• Histamine: Tissue amine
N N
NH2
H
1
2
3
4
5
Histamine
1. Present mostly in mast cells:
 Skin, lungs, GIT Mucosa, liver,
placenta
2. Non mast cell histamine:
Brain, Gastric Mucosa, Epidermis.
β imidazolylethylamine

4. Histamine
 Histamine is a biogenic amine present in many animal
and plant tissues
 Also present in blood, body secretions, venom &
stinging nettle, pathological fluids
 One of the mediators involved in inflammatory &
hypersensitivity reactions
 Present within storage granules of mast cells.

5. Synthesis, storage & metabolism of histamine
• Synthesized by decarboxylation of amino acid
histidine
• Degrades rapidly by oxidation & methylation

6. Mechanism of antigen-antibody reaction
induced release of histamine from mast cell

7. Mechanism of Action of Histamine
Histamine
H1 Receptors (Gq) H2 Receptors(Gs) H3 Receptors(Gi/Go)
(presynaptic auto
receptors)
↑ Ca2+
• Smooth muscle
contraction
• Increased capillary
permeability
• Vasodilation
• Sensory nerve endings
pain & itching
↑ cAMP
• ↑ Gastric acid
secretion
• Blood vessels:
vasodilation
• Increased capillary
permeability
• ↓ histamine
release
• ↓secretion
• Vasodilation
↓ cAMP

8. 1. Blood vessels:
 Marked dilatation of smaller BV including arterioles, capillaries &
venules
 S.C inj- flushing, ↑HR & CO, No fall in BP
 Rapid IV inj – Fall in BP
 Dilatation of cranial vessels – Pulsatile HA
 Vasodilatation by H1→mediated by EDRF (NO)
 Vasodilatation by H2 → located directly on the vascular SM
Pharmacological actions

9. Pharmacological actions
2. CVS:
– Dilates arterioles, capillaries, venules,
• IV injection- decreased BP
• Intradermal- Triple response Red spot
(Capillary dilatation)
Wheal (exudation of
fluid from capillaries
& venules)
Flare (Reflex
arteriolar dilatation)

10. Pharmacological actions…
3. Visceral smooth muscles:
– Bronchoconstriction, abdominal cramps & colic
4. Glands:
– Increased gastric secretion (H2)
– Increased nasal secretions (H1)
5. Sensory Nerve Endings: Itching
6. CNS: doesn’t cross BBB
– Intracerebroventricular Injection →↑BP, cardiac
stimulation, behavioural arousal, hypothermia, vomiting.

11. Therapeutic Uses
• Betahistine
– To control vertigo in Meniere`s disease 8 mg tab ½
tablet QID (Vasodilatation in internal ear)
– Contraindicated in asthmatics and ulcer patients.
Histamine releasers
 Stings and venom
 Ag-Ab reaction
 Drugs
 d-tubocurarine
Morphine
Atropine, vancomycin

12. Adverse effects of histamine release
• Itching, Urticaria
• Flushing
• Hypotension
• Tachycardia
• Bronchospasm
• Angioedema
• Wakefulness
• Increased acidity (Gastric acid secretion)

13. Classification of H1 ANTAGONISTS
Antihistamines Drugs (First generation/ Conventional H1
antihistamines)
1. HIGHLY SEDATIVE Diphenhydramine, Dimenhydrinate
Promethazine , Hydroxyzine
2. MODERATELY SEDATIVE Pheniramine
Cyproheptadine
Meclozine (Meclizine), Cinnarizine
3. MILD SEDATIVE Chlorpheniramine (CPM)
Dexchlorpheniramine
Triprolidine , Clemastine

14. Second generation H1 antihistamines
1. Fexofenadine
2. Loratadine
3. Desloratadine
4. Cetirizine
5. Levocetirizine
6. Azelastine
7. Mizolastine
8. Ebastine
9. Rupatadine

15. Pharmacological actions
1. CNS depression: (More with first generation)
– Sedation and drowsiness
– Some have antiemetic and antiparkinsonian effects
2. Antiallergic action – type 1 HSV reaction
3. Anticholinergic actions (More with first generation)
• Antagonize muscarinic actions of ACh
– Dryness of mouth , Blurring of vision
– Constipation
– Urinary retention

16. Pharmacological Actions
4. Antagonism of histamine:
Block the histamine induced bronchoconstriction, triple
response, fall in BP, release of adrenaline.
5. Local anaesthetic: Membrane stabilizing property
Pheniramine, promethazine, diphenhydramine
6. BP: fall in BP on IV injection (direct smooth muscle
relaxation)

17. PHARMACOKINETICS
• Well absorbed oral and parenteral routes
• Metabolized- Liver
• Excretion – Urine
• Widely distributed in the body and enter brain.
• DOA → 4 – 6hours
• Except Meclozine, CPM, loratadine, cetrizine &
fexofenadine → 12 – 24hours
• Newer drugs doesn’t cross BBB – less sedative

18. Preparations & dosage (Daily)
Drug Dose
1. Diphenhydramine 25-50 mg oral
2. Dimenhydrinate 25-50 mg oral
3. Promethazine 25-50 mg oral, 1mg/kg IM
4. Chlorpheniramine 2-4 mg oral
5. Pheniramine 25- 50 mg oral/im
6. Cinnarizine 25-150 mg oral
7. Cyprohepatidine 4 mg oral

19. Therapeutic uses
1. Allergic rhinitis & common cold
2. Allergic dermatitis, itching, urticaria
3. Wasp stings/ bite: pain and itching
decreases
4. Mild blood transfusion reactions
5. Allergic conjunctivitis
6. Motion sickness: dimenhydrinate, promethazine
7. Morning sickness: promethazine

20. 8. Vertigo: cinnarizine
• Cinnarizine inhibits vestibular sensory nuclei in the inner ear
• Suppresses postrotatory labyrinthine reflexes, by reducing
stimulated influx of Ca2+ from endolymph into the vestibular
sensory cells
8. Chronic urticaria
9. Appetite stimulant: cyprohepatidine
10.Drug induced parkinsonism:
Diphenhydramine,
Therapeutic uses…..

21. 12. Preanaesthetic medication -Promethazine
13. Cough
• CPM, diphenhydramine and promethazine (Afford symptomatic relief)
14. Parkinsonism
• Promethazine – Anticholinergic and Sedative property.
15. Acute muscle dystonia - Promethazine, Diphenhydramine or
hydroxyzine.
Therapeutic uses….

22. Adverse effects
1. Sedation, diminished alertness & concentration, light
headedness, motor incoordination, fatigue, tendency to
fall asleep
2. Impairment of psychomotor performance.
3. Anticholinergic effects
4. Epigastric distress & HA
5. Dermatitis on local use
6. Cyclizine, meclizine, fexofenadine: teratogenicity
(animals)
7. Acute overdose – central excitation, tremors,
hallucination, convulsion, flushing, hypotension.

24. Second generation H1 Blockers
(Non Sedative: Less anticholinergic property)
• Fexofenadine
• Astemizole
• Loratidine
• Desloratidine
• Cetrizine
• Levocetrizine
• Azelastine
• Ebastine
• Rupatadine
Uses:
• Allergic rhinitis
• Allergic Dermatitis
• Allergic conjunctivitis
• Urticaria
• Common cold
• Dermatographism
• Atopic eczema
• Hey fever
• Pollinosis

25. Advantages of second generation
antihistaminics
1. Absence of CNS depressant property.
2. No impairment of psychomotor performance , produce no
subjective effects, no sedation.
3. Do not potentiate alcohol or benzodiazepines.
4. Higher H1 selectivitiy
5. No anticholinergic side effects.
6. Additional antiallergic mechanisms apart from histamine blockade
7. Inhibit late phase allergic reaction by acting on leukotrienes
8. or by antiplatelet activating factor effect

26. Banned antihistaminics
1. Terfenadine
 First non-sedating SGA that was withdrawn
 Due to polymorphic VT (torsades de pointes) due to higher
doses
 When it was co-administered with CYP3A4
inhibitors(erythromycin, clarithromycin, ketoconazole,
itraconazole)
 Blockade of delayed rectifier k+ channels in the heart at
higher concentrations.
2. Astemizole is another SGA banned for the same reason

27. 1. Fexofenadine
1. Active metabolite of terfenadine
2. Does not prolong QTc interval.
3. No interaction with CYP3A4 inhibitors
4. Free of arrhythmogenic potential
2. Loratadine
1. Long & fast acting
2. Lacks CNS depressant
3. Partly metabolized by CYP3A4 & t½ of 17 hour
4. No cardiac arrhythmia
5. Seizures are reported
6. Uses: Urticaria and atopic dermatitis
3. Desloratadine
1. Active metabolite of loratadine
2. Cardiac safety are documented
4. Cetrizine
1. Metabolite of hydroxyzine
2. Upper respiratory allergies, pollinosis
3. Urticaria and atopic dermatitis;
4. Used as adjuvant in seasonal asthma

28. 5. Levocetirizine
1. Active R(–) enantiomer of cetirizine.
2. Effective at half the dose
3. Less sedation
6. Azelastine
1. Good topical activity
2. Nasal spray - seasonal and perennial allergic rhinitis
3. Side effects- Stinging in the nose, altered taste
perception, weight gain
7. Mizolastine 1. Non-sedating antihistaminic,
2. Effective in allergic rhinitis and urticaria
8. Ebastine 1. Converted to the active metabolite carbastine.
2. Non-sedating
3. Nasal and skin allergies.
4. Prolong Q-Tc interval and CYP3A4 interaction

30. VERTIGO
 Labyrinthine suppressants
• (a) Antihistaminics (with anticholinergic action)—cinnarizine,
dimenhydrinate, diphenhydramine, promethazine.
• (b) Anticholinergics—atropine, hyoscine.
• (c) Antiemetic phenothiazines— prochlorperazine,
thiethylperazine.
 Vasodilators
• They improve blood flow to labyrinth and brainstem—betahistine,
nicotinic acid.

31. VERTIGO
 Diuretics
• They decrease labyrinthine fluid pressure—acetazolamide, thiazides,
furosemide.
 Anxiolytics, antidepressants - diazepam, amitriptyline
• These drugs appear to modify the sensation of vertigo
 Corticosteroids
• They suppress intra labyrinthine edema due to viral infection or other
causes.

32. THANK YOU