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Antihistamines

Histamine

Chemical Messenger having a wide range of cellular responses, causing allergies, inflammatory reactions, increased gastric acid secretion, acting as a neurotransmitter in brain

Synthesized from HISTADINE through decarboxylation.

Stored in mast cells

Released in response to various stimuli like after insect bites, can be released in response to bees sting, and in anaphylactic reaction.

Histamine Receptor Subtypes

—  H1 – Most abundant, present in:

  1. Smooth muscles, responsible for smooth muscle contraction
  2. Endothelium, vasodilatation of blood vessels
  3. Brain neurotransmitters

Act through hydrolysis of inositol triphosphate diacyl glycerol second messenger system.H1 receptors are present on post synaptic neurons.

—  H2 

  1. Gastric mucosa, increase gastric acid secretion
  2. Cardiac muscle, produce hypotension, producing reflex tachycardia
  3. Mast cells,
  4. Brain

H2 receptors act through stimulation of cAMP 2nd messenger system. H2 receptors are also present on post synaptic neurons.

H3 and H4 are present pre-synaptically.

  H3 – Presynaptic: brain, myenteric plexus, other neurons

Act through inhibition of cAMP

  H4 – Eosinophils, neutrophils, CD4 T cells

Play a role in allergies.

Antihistamines

By antihistamines we mainly refer to H1 blockers. H2 blockers are called the drugs which decrease gastric acid secretion.

Classification of Antihistamines

Antihistamines are broadly divided into two groups:

  1. 1st generation antihistamines
  2. 2nd generation antihistamines

Drugs having hysteric signs are included in 2nd generation,, rest are in 1st generation.

Ethanolamines

  •        Carbinoxamine maleate
  •        Clemastine fumarate
  •        Dimenhydrinate
  •        Diphenhydramine HCl

Ethylaminediamine

  •        Tripelennamine HCl
  •        Pyrilamine Maleate
  •        Antazoline

Piperazine Derivatives

  •        Hydroxyzine HCl
  •        Cyclizine HCl
  •        Meclizine HCl
  •        Cetrizine*

Alkylamines

  •    Brompheniramine maleate
  •    Chlorpheniramine maleate
  •    Pheniramine
  •    Acrivastine*

Phenothiazine

  •    Promethazine HCl

Piperidine

  •             Fexofenadine*
  •             Levocabastine*
  •             Loratidine*

Miscellaneous

  •              Cyproheptadine
  •              Pheniramine
Structure of antihistamines

Structure resembles that of histamine.

Have ethylamine or carbon chain

Linked with Tertiary amine group through glycosidic bond.

To amine group, two aromatic groups are attached.

Mechanism of Action

—  1st Generation block H1 receptors competitively

—  2nd Generation block H1 receptors non-competitively

Pharmacological Actions
  1. Smooth Muscles

Block vasodilatation in endothelial smooth muscles. However, they are not effective in preventing bronchoconstriction because there are leukotrines and platelet activating factors involved.

  1. Capillary Permeability

Prevent capillary permeability, thus effective in preventing edema.

  1. Triple response

Antihistamines are effective in preventing triple response seen after intradermal injection of histamine, in which there is redness due to dilatation of small vessels and there is veil formation i.e. edema.

Flare is the redness around wheel. Antihistamines are effective in preventing all components of triple response.

  1. Exocrine glands

Decrease secretions of endocrine glands, including lacrimal gland, but not effective in decreasing gastric secretions.

  1. Allergy

Prevent triple response, but not effective in preventing bronchoconstriction and hypotension.

  1. Anticholinergic Effects

Most of 1st generation antihistamines are capable of antagonizing muscarinic receptors, having anticholinergic effects including

  • blurring of vision,
  • dilatation of pupils,
  • urinary retention,
  • constipation and
  • tachycardia.

Among 1st generation antihistamines, Promethazine has strongest anticholinergic activity and Mepyramine has least anticholinergic activity.

  1. Motion Sickness

Vestibular apparatus has M1 and H1 receptors, so antihistamines and anticholinergics are effective in motion sickness.

Drugs used are  Diphenhydramine and Dimenhydrinate.

1st generation antihistmaines having anticholinergic activity are effective in motion sickness.

  1. Local Anesthetic Effect

1st generation antihistamines possess local anesthetic effect in higher doses. They can block sodium channels and this local anesthetic effect is equal to procaine and lignocaine.

  1. Adrenoceptor blocking effect

1st generation antihistamines block alpha 1 receptors producing postural hypotension and flushing.

Mostly seen with Promethazine and Diphenhydramine.

  1. Serotonin blocking effect

1st generation antihistamines have ability to antagonize serotonin receptors e.g. Cyproheptadine.

  1. Appetite stimulant effect

Because of blockage of serotonin receptors, Cyproheptadine has appetite stimulant effect.

  1. Central Nervous System

1st generation antihistamines cross BBB and produce CNS depressant effect,

  • Sedation
  • Drowsiness
  • Dizziness
  • Fatigue

Almost all 1st generation antihistamines produce CNS depression except Fenandamine which produces CNS stimulation. 2nd generation antihistamines do not cross BBB.

Pharmacokinetics

Usually given through oral route and parenteral route. Topical preparations are available in form of nasal drops, eye drops. Levocabastine can be given topically.

  • Peak plasma concentration

Usually in 1-2 hours.

  • Duration of action

1st generation up to 6 hours

2nd generation up to 24 hours

However, Astimazole has more than 24 hours.

1st generation antihistamines are widely distributed as are lipid soluble. 2nd generation have far less distribution.

  • Metabolism

Antihistamines are metabolized by CYT P450. Most are metabolized by cyt CA4.

As a result converted into metabolites, e.g. Loratidine is converted into Desloratidine, Hydroxyzine is converted into Cytrazine and Terphendadrine is converted into Fexophendaine.

Mostly excreted in urine in form of metabolites. However, Cytrazine and Acrevestine are excreted as such. Sexophenadine is eliminated in feces.

Therapeutic Uses
  1. Allergy

All kinds of allergies,

  1. acute allergies,
  2. acute rhinitis
  3. acute conjunctivitis
  4. chronic allergies
  5. chronic urticarial
  6. drug induced allergies
  7. contact dermatitis
  8. insect bites
  9. serum sickness
  1. Common Cold

Provide symptomatic release and decrease secretions.

  1. Anti Emetic Effect
  1. Pregnancy induced vomiting
  2. Radiation induced vomiting
  3. Cancer chemotherapy induced nausea, vomiting
  4. Motion sickness

Diphenhydramine and Dimenhydrinate are used.

  1. Meniere’s disease

Idiopathic disease of inner ear, affecting hearing and balance.

Promethazine and Dimenhydrinate are used.

  1. Parkinsonism

Antihistamines effect rigidity and tremors and decreases cholinergic activity. Drugs used are Orphenadrine and Diphenhydramine.

  1. Sedative, Hypnotic, Anxiolytic, Pre anesthetic medication

Can be used for sedation, hypnosis, anxiolytic effect. Can be given as pre anesthetic medication. Mostly Promethazine and Diphenhydramine are used.

  1. Appetite Stimulant

Block serotonin receptors, having appetite stimulant effect (Cyproheptadine)

  1. Carcinoid Syndrome

Cyproheptadine is used having serotonin blocking effect.

There is group of symptoms secondary to carcinoid tumor, flushing, diarrhea, bronchoconstriction.

Adverse Effects
  1. Central Nervous System

1st generation antihistamines cross BBB and produce CNS depression except Phenadrine which produces CNS stimulation. 2nd generation do not cross BBB being devoid of CNS effects.

  1. Gastrointestinal Tract
  • Can produce abdominal discomfort
  • Can alter  bowel habits
  • Anorexia
  • Cycloheptidine has appetite stimulant effect.
  1. Cardiovascular Effects

Two drugs Astamizole and Terphenadrine prolong QT interval, can produce ventricular arrhythmias. These drugs should not be given to individuals taking enzyme inhibitors.

  1. Anticholinergic effects

1st generation antihistamines can enter cholinergic receptors, producing anti cholinergic effects:

  • Dilatation of pupil
  • Dryness of mouth
  • Urinary retention
  • constipation
  1. Allergy

Topical preparations can produce allergic manifestations:

  • Dermatitis
  • Articaria
  • Rash
  1. Hematological Complications

Can produce:

  • Hemolytic anemia
  • leukopenia
  1. Teratogenic

With Piperazine derivatives, teratogenic effects are seen in experimental animals (not in humans).

  1. Mutagenicity

Some antihistamines have been found to be mutagenic, can induce fibrosarcomas and melanomas in experimental animals.

Drug Interactions
  1. Sedative Hypnotics

Can potentiate the effects

  1. Alcohol

Can potentiate the effects

  1. MAO Inhibitors

MAO inhibitors can enhance anticholinergic effects of antihistamines

  1. Ketoconazole, Itraconazole, Erythromycin

These are enzyme inhibitors, when these are combined, metabolism of antihistamines is reduced.

Astamizole and Terphenaline cardiac effects are enhanced.

  1. Grape fruit juice

Enzyme inhibitor.

Slight over dosage

With slight overdosage, there is sedation.

High Doses

In higher doses, CNS stimulation and anticholinergic effects are enhanced.

  1st generation 2nd generation
Name of drug    
Chemical properties Aromatic groups and ethylamine group Aromatic group
Mechanism of action Competitive antagonism of H1 Non competitive antagonism
Pharmacological actions Can cross BBB causing CNS depression(except Pheniramine) Cannot cross BBB so no CNS effects
Pharmacokinetics

Distribution

Metabolism

Lipid soluble so distributed in all compartments

No active metabolite

Less lipid soluble so cannot enter CNS, CSF

Mostly converted to active metabolite e.g.

Terfenadrine à Fenofexadine

Loratidine à Desloratidine

Local Anesthetic/Membrane Stabilizing Activity Local anesthetic having effect like procaine and lidocaine No effect
Adrenoceptor blockage Alpha 1 blockage None
Duration of action Short (4-6 hours) except Meclizine 12-24 hours Long 12-24 hours except Estemizole more than 24 hours.
Anticholinergic effect Present Absent

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