By Omar Durani Prof. Buynak 04/13/06

Allergy = An abnormally high sensitivity to certain substances, such as pollens, foods, or microorganisms. Common indications of mild allergy may include sneezing, itching, and skin rashes. A severe allergic reaction is known as an anaphylactic shock which can be life- threatening (airway constriction & extreme hypotension. Immediate medical attention needs to be administered.

People with allergies have immune systems that overreacts when exposed to substances. These substances (ex. Pollen) causes the body to respond with release of Histamine which is main proponent of allergic reactions in individuals.

Discovered in 1911 by Sir Henry Dale, identified as a potent vasoactive substance in guinea pigs and dogs through experiments. Soon recognized to be major mediator of allergic reactions such as rhinitis, asthma, urticaria (hives), pruritis (itching) and anaphylaxis HISTAMINE ACTIVE SITE Histamine stored in special granules, and to exert its action, must be released. Mast Cells – Tissue Basophils – Blood

Histamine released from: Tissue injury, allergic reactions, drugs (antibiotics, toxins). Histamine once released interacts with specific receptors on the cell surface. There 4 histamine receptors found on cells: H1 Receptor: Endothelial and smooth muscle cells, adrenal medulla, brain; histamine increases Ca2+ intake. H1 receptor is the target of Antihistamines H2 Receptor: Gastric mucosa cells; histamine induces gastric acid released. A form of antihistamine drugs bind to H2 receptors to treat for GERD (ex. Nexium, Prevacid) H3 Receptor: CNS neurotransmitter properties as a neural presynaptic receptor; may somehow regulate histamine release. H4 Receptor: Found in immune active cells and involved in their chemotaxis.

These are drugs that directly compete with histamine for specific receptor sites. Antihistamines compete for typically H1 and H2 receptors. Common structural features of classical antihistamine* - ETHYLAMINE GROUP - 3 O AMINE - LINKED TO 2 AROMATIC GROUPS X = N, R1 = R2 = small alkyl groups X = C X = CO Chirality at X can increase both the potency and selectivity for H1-receptors For maximum potency, the two aromatic rings should be orientated in different planes.

BLOCK action of histamine at the receptor sites Compete with histamine for binding at unoccupied receptors. If histamine is already bound, antihistamines cannot remove histamine. The binding of H1 blockers to the histamine receptors prevents the adverse consequences of histamine stimulation: Vasodilation Increased gastrointestinal and respiratory secretions Increased capillary permeability Absorbed well by GI tract with a maximum absorption – 1-2 Hr and a high safety margin.

Cardiovascular (small blood vessels) Histamine effects: Dilation Increased permeability (allowing substances to leak into tissues) Antihistamine effects: Prevent dilation of blood vessels Prevent increased permeability

Immune System Histamine effects: Mast cells release histamine and other substances, resulting in allergic reaction. Antihistamine effects: Bind to histamine receptors, preventing histamine from causing the allergic response. Smooth Muscle Histamine effects: Stimulate salivary, gastric and bronchial secretions. Antihistamine effects: Prevent salivery, gastric and bronchial secretions.

Antihistamines effects… Skin: Block capillary permeability itching Anticholinergic: Drying effect that reduces nasal, salivary, and lacrimal gland secretions (runny nose, tearing, and itching eyes) Sedative: Some antihistamines cause drowsiness (1 st generation antihistamines)

Management of: Seasonal allergic rhinitis (Hay fever) Nasal allergies Allergic reactions to food, microbes, dust, etc. Motion sickness Sinus congestions Sleep disorders

1 st Generation or Traditional antihistamines 2 nd Generation or Non-sedative antihistamines

Older drugs Work both peripherally and centrally Have anticholinergic effects, and in some cases more effective than nonsedating agents Examples: diphenhydramine (Benadryl), chlorpheniramine (Chlor-Trimeton)

Different Classes: 1. Alkylamines - (Chlor Trimeton®) 2. Ethanolamines - Diphenhydramine HCl (Benadryl®) 3. Ethylenediamines 4. Piperazines – Hydroxyzine HCl (Atarax®) 5. Phenothiazines - Promethazine HCl (Phenergan®) 6. Piperadines - Azatadine (Optimine®)

Nonsedating antihistamines Developed to eliminate side effects, (sedation) Bulky and not as lipophilic and thus does not readily cross BBB, fewer CNS side effects Longer duration of action (increases compliance) Better specificity for H1 and/or H2 receptor to block histamines effects Examples: fexofenadine (Allegra) loratadine (Claritin)

CNS depression (mainly in first generation agents). Appetite loss, nausea and vomiting, constipation or diarrhea. Insomnia Tachycardia dry mouth blurred vision Urinary retention Secreted in breast milk and can cross the placenta.

Ash, Schild. Receptors Mediating Actions of Histamine. J. Pharmacol, Bachert, C. "Histamine: a Major Role in Allergy?" Abstract. Clinical and Experimental Allergy 28 (1998): Huttrer CP, Leonard F. Histamine Antagonists. Washington DC: National Research Council Hardman JG, Limbird LE (ed’s). Goodman & Gilman’s The Pharmacological Basis of Therapeutics. McGraw-Hill, NY, NY; 1996, p 673.