ANTI-ALLERGY Medication About 1 in 10 suffer from some type of allergy: pollen, poison ivy, food, cosmetics, drugs (penicillin), chemicals About 1 in 15 suffer asthma: NA ALLERGY DEATHS: ~ 5000/y ASTHMA ~100/y FOOD ~40-100/y STINGS ~300/y PENICILLIN Pollen, for example, contains an ANTIGEN (ALLERGEN) which reacts with one of the antibody proteins in the blood eg. IgE (Immunoglubulin E)

Antigen-Antibody complex causes release of stored HISTAMINE from mast cells, which then goes to H-1 sites, and triggers the inflammation cycle that causes hay fever symptoms: 1. Dilates blood capillaries: skin red, warm and itchy Capillaries leak water and plasma proteins: swelling, inflammation and HIVES Bronchial muscle spasms and constriction: ASTHMA Stimulates glands: produces nasal fluids, mucus, tears, saliva (opposite effect of atropine) 5. Dilated blood vessels: blood pressure drop but normally no effect on heart

Strategies: AVOID, DESENSITIZE, or block receptor sites with anti-histamine HISTAMINE: note the N-C-C-C-N sequence/shape Older anti-histamines: side effect DROWSINESS (mild sleeping pills) Pyribenzamine Phenergan Benadryl Chlortripolon

Also used in travel (motion sickness) pills: eg. Dramamine, Gravol, etc. all use a salt of benadryl and a chlorinated caffeine derivative Other ones are Cyclizine, Meclizine (Calmonal, Anti-vert, Sea-Legs) Dramamine (OTC) Cyclizine Meclizine (dimenhydrinate) “Marzine, Marezine” “Bonamine”

2nd Generation ALLERGY DRUGS (LESS DROWSY): SELDANE Seldane does not cross the blood brain barrier: non-sedating First prescription antihistamine to relieve the symptoms of allergic rhinitis (1985) without causing drowsiness After Seldane was approved, FDA began receiving reports of fatal and serious instances of cardiac arrhythmias: Drug interactions between Seldane and erythromycin or ketoconozole – in the presence of these antibiotics, Seldane accumulated in the blood, resulting in serious cardiac side effects Withdrawn from the market in 1997 Hismanal: similar side effects, more interactions: withdrawn 1999

ALLEGRA (fexofenadine) is a metabolism product of Seldane without the side effects REACTINE (cetirizine) is another popular non-drowsy antihistamine

Other anti-histamines: Desloratadine: Aerius (Can) Clarinex (US) Loratidine: Claritin Azatidine: Optimime Trinalin Cyproheptidine: veterinary use

OTHER APPROACHES CROMOLYN (Nalcrom, Allergochrom, Nasalcrom, Opticrom) Powder sprayed into nose: prevents release of stored histamine from mast cells not a cure, management at bad times of year also available orally as Nalcrom for food allergies: 200 mg x 4 / day, 20 min before meals

LEUCOTRIENE RECEPTOR ANTAGONISTS Leucotrienes are produced in a similar manner to the prostaglandins, and they promote powerful wind-pipe contractions and inflammation Accolate (zafirlukast) Astra-Zeneca blocks the leucotriene D4 and E4 receptors [LTD4 and E4] (2 x 20mg/day)

Salbutamol (Ventolin) ~3h Salmeterol (Serevent) ~12h THE BRONCHODILATOR DRUGS FOR ASTHMA (doses usually ~ 50-100mg/spray) Salbutamol (Ventolin) ~3h Salmeterol (Serevent) ~12h

b-agonists: activate adenylcyclase enzyme = increases c-AMP (cyclic adenosine monophosphate) c-AMP activates phosphorylation of HO-containing amino acids (tyrosine, serine and threonine) which causes the enzyme to change shape = release of Ca2+ ions from their storage sites = relaxation of muscles Lungs have PDE-4's that destroy c-AMP so one strategy is to look for PDE-4 inhibitors that maintain higher levels of c-AMP (compare with effects of Viagra on PDE-5 to keep c-GMP elevated) Egs. of long acting b-agonists include Salmeterol and Foradil (formoterol, shown below)

Note: inhaled corticosteroids in low doses are considered a better long term strategy than using beta-agonists Eg. Flovent (Advair, Flonase, Flunase....) = fluticasone propionate: