Allergy and Antiallergic agents (antihistaminic agents)

By

Dr. N. C. Baruah

Allergy and hypersensitivity

• Histamine is an endogenous substance (autocoids)

• Synthesized in the Golgi apparatus and stored in secretory granules of mast cells and basophils

• Released by the stimulation of antibody IgE (reagin)

• This is an Inflammatory responses to allergens.

• The common allergens are Pollen grains, Dust, Molds, Drugs etc.

The prime physiological actions of Histamine

• Histamine dilates the smooth muscle of the blood vessels but contracts the bronchiolar smooth muscle.

• Histamine is the primary stimulant for gastric acid and pepsin secretion (through H2 receptors on the parietal cells)

• Histamine is a neurotransmitter (through pre-synaptic H3 receptors) in the CNS and pns.

Pathological actions

• Histamine causes allergy and hypersensitivity reactions in the response of an allergen or foreign substances such as,

Anaphylaxis

Seasonal allergies

Urticaria

Hay fever

biosynthesis of histamine

Histamine is biosynthesized from l-histidine L Histidine Histamine

• It is metabolized by MAO and N-methyl transferase.

Histidine decarboxylase

Histidine decarboxylase

Histamine L-Histidine

Acute release of histamine

• Ig E Antigens

• Mast cell HA

HA HA

HA

HA

Ү Ү Ү

PGs, LTs, Histamine Protease, Other mediators

Acute inflammatory and hypersensitivity reactions

IgE-mediated Histamine releasers

• Some substance stimulate the secretion of histamine by sensitizing reagin

• Foods : Egg or some protein foods

• Drugs :Penicillins, Sulfonamides etc

• Venoms : Bee, Snake, Fire ant

Triple response of Lewis

• Histamine produces a triple response in the epithelial tissues when applied intradermally.

• 1. Red spot develops within seconds due to direct vasodilating effect of histamine

• 2. Brighter red flare extending beyond the original red spot due to histamine induced axon reflexed vasodilatations.

• 3. Red Wheal in the original redspot due to increased capillary permeability by the histamine

Clinical symptoms associated with histamine release

• Urticaria, itching and erythema as mild cutaneous reactions.

• Histamine may cause tachycardia, hypotension, arrhythmia and respiratory disturbances.

• Histamine in severe conditions cause acute hypotension, cardiac arrest, bronchospasm and respiratory arrest.

Types of allergy

• 1. Allergy caused by activated T-cells Repeated exposure to toxin initiate helper and killer T-cells.

Allergen-T-cell mediated allergy.

• 2. Due to immunoglobulin-E (IgE or Reagin)

– Allergen-Reagin mediated allergy .

• Anaphylaxis

• Urticaria

• Hay fever

First generation antihistamines:

• Aminoalkylethers (Ethanolamines): The active

drugs from this group are

• Diphenhydramine,

• Dimenhydrinate,

• Bromodiphenhydramine,

• Doxylamine,

• Carbinoxamine,

• Clemastine, and

• Diphenylpyraline.

1st Generation antiallergic agents

• Aminoalkylethers (Ethanolamines)

• Diphenhydramine and Dimenhydrinate

• Used in allergic reactions, common cold, insomnia, motion sickness, pruritis of skin, and as Antitussive.

Doxylamine Carbinoxamine

used in seasonal rhinitis, allergic dermatitis, motion sickness

Ethylenediamines

• The members of the group are

• Tripelennamine (Pyribenzamine),

• Pyrilamine ,

• Methapyrilene,

• Thonzylamine and

• Antazoline .

• Uses are same as ethanolamines

Tripelennamine (Pyribenzamine) Pyrilamine maleate

Piperazines (Cyclizines)

• The piperazines are also ethylenediamines derivatives, and have intermediate antihistaminic activity but are potent sedatives. The drugs from this group are

• Cyclizine,

• Chlorcyclizine,

• Meclizine,

• Buclizine,

Piperazines

Buclizine Meclizine

Chlorcyclizine Cyclizine

Propylamines (Monoaminopropyl or Alkylamines derivatives)

• The active drugs of this group are, • Pheniramine maleate • Chlorpheniramine maleate • Dexchlorpheniramine, • Brompheniramine, • Pyrrobutamine, • Triprolidine, • Phenindamine • Used in allergic rhinitis and in common cold

Chlorpheniramine maleate Pheniramine maleate

Phenindamine tartrate Triprolidine

Phenothiazines

• The drugs of this group are

• Promethazine,

• Trimeprazine,

• Methdilazine

• Uses: antiemetic, in motion sickness

Trimeprazine Promethazine

Used in motion sickness

Dibenzocycloheptenes and dibenzocycloheptanes

• The active drugs

• Cyproheptadine and

• Azatadine

Cyproheptadiene Azatadine

Uses of first generation antiallergic agents

• The first generation antiallergic agents are used in allergic reactions, which are associated with histamine release, as in anaphylaxis, allergic rhinitis, allergic dermatitis and in motion sickness (Promethazine). The antiallergic agents are also used to stop nausea and vomiting (as antiemetic) and as sedative and Antitussive.

Side-effects of 1st generation antiallergic agents:

• The first generation antihistaminic agents are low molecular weight lipophilic compounds that can easily cross the blood brain barrier so produce depressive effect as sedation. These agents potentiate the action of central nervous system depressant drugs (opioids, sedatives, narcotic analgesics and alcohol).

Second generation antihistamines

• The first second generation drugs Astemizole and

Terfenadine were receptor selective but found cardiotoxic after prolong use.

• The newer second generation antihistamine agents are the derivatives of first-generation drugs.

• They contain larger polar groups to the terminal tertiary amine, or substituent of one of the aromatic rings.

• The Acrivastine is a derivative of Triprolidine; Cetirizine and Levocetirizine are oxidative products of hydroxyzine; Desloratadine is a metabolite of Loratadine; and Fexofenadine is oxidative product of Terfenadine.

• They do not accumulate in the CNS because of their hydrophilic properties.

Second generation antihistamines

Fexofenadine HCl

Terfenadine

Astemizole Loratadine

Acrivastine

Uses & Side effects of second generation antihistaminic agents

• Uses of second generation antihistamines are similar to the first generation drugs but the are free from most of the adverse effects.

• Side-effects

• The second generation antiallergic drugs are high molecular and low lipid soluble compounds which have low penetrability to blood brain barrier, which have low affinity for the cerebral H1 receptors. So the second generation antihistaminic is devoid of CNS side effects.