Histamine & antihistaminics

• Greek: autos—self, akos—healing substance
or remedy.
• Autocoids.

Autocoids
• Self healing substances.
• Also called as local hormones.
• Mostly released in response to injury &
immunological insult.

• Amine autacoids: Histamine, 5-HT (Serotonin).
• Lipid derived autacoids: PGs, LTs, PAF.
• Peptide autacoids: Plasma kinins (Bradykinin),
Angiotensin etc.
• Others: Cytokines (ILs, TNFα, GM-CSF, etc.) &
several peptides viz gastrin, somatostatin, VIP etc.

HISTAMINE & ANTIHISTAMINICS
Dr. M Kanhaiah
Dept of Pharmacology

Histamine
(Tissue amine)
 High levels in skin, bronchial & intestinal
mucosa, CSF, bone marrow etc
 Released from mast cells & basophils
(Type I hypersensitivity...LTs, PAF>>>Hist)
 GPCRs

• Decarboxylation of L-histidine
• Mast cells (predominant sites of storage)
• Stimuli for its release (IgE mediated release,
chemical & mechanical)

Histamine releasers
 Tissue damage (trauma, sting, venoms)
 Polymers (Dextran, PVP)
 Some basic drugs;
 d-tubocurarine, morphine, vancomycin, SCh, hydralazine etc
 Vancomycin-induced red-man syndrome, involving hypotension & flushing
of upper body & face
 Heat, cold, sunlight, x-ray
 Ag-Ab reaction involving IgE antibodies

Histamine Release Inhibitors
• β2 agonists
• Methylxanthines
• Mast cell stabilizers (cromoglycate, ketotifen)

H1 Gq coupled (IP3, DAG, Ca2+)
H2 Gs coupled (cAMP)
H3 Gi coupled
H4 Gi
Receptors

H1 activation
 Capillary dilation (via NO & PGI2) - fall in BP
 Capillary permeability – edema
 Bronchial smooth muscle contraction (Gq)
 Activation of peripheral nociceptive receptors via
Substance-P (pain & pruritus)
 Decreased AV nodal conduction (Gi)

• Exocrine secretions
• Adrenal medulla (secondary rise in BP)
• Maintenance of wakefulness
– H1 antagonists cause sedative action by blocking this
function in hypothalamus & midbrain

• Betahistine:
• It is an orally active, somewhat H1 selective
histamine analogue.
• Used to control vertigo in pts of Meniéré’s disease:
(by causing vasodilatation in the internal ear).
• It is contraindicated in asthmatics & ulcer patients.

H2 activation
 Gastric acid secretion increased – ulcers
 Increased SA & AV-nodal rate
 Positive chronotropic & inotropic

• H4 receptors primarily are found in cells of hematopoietic origin (eosinophils,
dendritic cells, mast cells, monocytes, basophils, & T cells)
• Activation of H4 receptors is associated with induction of cellular shape change,
chemotaxis, secretion of cytokines and upregulation of adhesion molecules
• H4 antagonists may be useful inhibitors of allergic and inflammatory responses

H1 antagonists
Drug M block Sedation Antimotion Other characteristics
Diphenhydramine +++ +++ +++ Widely used OTC
Promethazine +++ +++ ++ Some α block & LA
action
Chlorpheniramine ++ ++ ++ Possible CNS
stimulation
Meclizine ++ ++ ++++ Highly effective in
motion sickness
Hydroxyzine ++ +++ ++ Used as sedative
Loratadine +/- 0 0 No CNS entry
Fexofenadine +/- 0 0 No CNS entry

SECOND GENERATION ANTIHISTAMINICS (SGA) or NEWER ANTIHISTAMINICS
 Higher H1 selectivity
 Devoid of anticholinergic side effects
 Absence of CNS depression
 Some have additional antiallergic
properties (act on LTs & PAF)

Advantages:
 Do not impair psychomotor function (driving etc).
 No sleepiness.
 Do not potentiate CNS depressants.
 Additional anti-allergic properties.

Fexofenadine:
 Active metabolite of Terfenadine.
 Terfenadine & Astemizole are withdrawn now due to TdP.
 Doesn’t prolong QTc interval (less propensity for Torsades de Pointes)
 No interaction with CYP3A4 inhibitors.
 Not entirely safe in pts with long QT, Bradycardia / hypokalemia.
 Doesn’t cross BBB.
 Free of atropinic (anti-cholinergic) side effects.

Loratidine:
 Long & fast-acting selective H1 antagonist
 Devoid of CNS depression
 No cardiac arrhythmias in overdose
 Seizures have been reported

Cetirizine:
 Metabolite of Hydroxyzine
 Poor CNS entry
 Subjective somnelence at higher doses
 No interaction with CYP3A4 inhibitors
 Additional antiallergic actions (inhibits histamine release from platelets &
eosinophil chemotaxis)
 High & longer concentrations in skin (superior efficacy in urticaria / atopic
dermatitis)
 OD dose despite elimination t½ of 10 hrs.

Levocetirizine:
 Active R(-) enantiomer of Cetirizine
 Effective at half dose
 Few side effects

Azelastine:
 Newer drug with good topical activity
 Additional antiallergic properties (inhibits histamine release & reaction due to LTs,
PAF)
 Bronchodilating property
 Active metabolite (longer-acting)
 Metabolism inhibited by CYP3A4 inhibitors
 Nasal spray in rhinitis provides quick relief lasting 12 hrs
 Weight gain observed after oral use

Other SGAs:
 Mizolastine
 Ebastine
 Desloratadine
 Rupatidine

Uses:
Allergic disorders:
 Do not suppress AG:AB reaction but blocks histamine’s actions.
 Effectively control itching, urticaria, allergic conjunctivitis etc.
 Efficacy is secondary to Adrenaline (life saving drug) in
laryngeal edema & anaphylaxis.
 Ineffective in Bronchial Asthma (LTs & PAF play role).
 Type I hypersensitivity to drugs is suppressed (NOT anaphylaxis &

 Motion sickness (Promethazine, Diphenhydramine, Cyclizine)
 Nausea & vomiting of pregnancy/radiation sickness (Promethazine)
 Preoperative sedation (Promethazine, Hydroxyzine)
 OTC for cold (Sx relief by anticholinergic-sedative actions)
 Parkinson’s disease (Orphenadrine, Promethazine)
 Acute EPS caused by antipsychotics/D2 blockers (Promethazine)

 Pruritus (older preparations are much effective)
 Vertigo (Cinnarizine)
 Cough (Sx relief by sedative-anticholinergic action e.g.
Chlorpheniramine, Diphenhydramine, Promethazine)

ADRs:
 Sedation
 Synergism with other CNS depressants (Alcohol, Barbiturates,
Opiates, BZDs etc)
 Anti muscarinic side effects (dry mouth, blurred vision)
 Arrhythmias (H1 & M2 receptor-mediated)
 Careful while using in pts with BPH & Glaucoma

H2 Blockers
• Primarily used in peptic ulcer, GERD & other
gastric hypersecretory states

Histamine & antihistaminics

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