Transcript 12 Allergy Drugs

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
2. Capillaries leak water and plasma proteins: swelling,
inflammation and HIVES
3. Bronchial muscle spasms and constriction: ASTHMA
4. 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
NH2
HN
HISTAMINE: note the N-C-C-C-N sequence/shape
N
Older anti-histamines: side effect DROWSINESS
(mild sleeping pills)
N
H
S
O
N
N
NMe2
NMe2
N
NMe2
Pyribenzamine
NMe2
Phenergan
Cl
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)
O
O
N
NHMe2
+
O
Dramamine (OTC)
(dimenhydrinate)
N
N
Cl
N
Cl
N
N
N
N
Cyclizine
“Marzine, Marezine”
Meclizine
“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Withdrawn from the market in 1997
Hismanal: similar side effects, more interactions: withdrawn 1999
Terfen
HO
HO
[Non1997 -
N
metabolism
Fexof
HO
ALLEGRA (fexofenadine)
is a metabolism product of
Seldane without the side effects
REACTINE (cetirizine) is another
popular non-drowsy antihistamine
[most
COOH
HO
N
Other anti-histamines:
Desloratadine:
Loratidine:
Azatidine:
Cyproheptidine:
O
Aerius (Can) Clarinex (US)
Claritin
Optimime
Trinalin
veterinary use
O
N
N
N
N
NH
N
N
Cl
Cl
Claritin
Clarinex
Optimime
Cyproheptadine
OTHER APPROACHES
CROMOLYN (Nalcrom, Allergochrom, Nasalcrom, Opticrom)
HOCH
O
O
O
COO- Na+
2
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
ACCOLATE -Zafirlukast
N
O
O
NH SO2
NH
[Leucotriene receptor antagonist
20 mg pill instead of inhaled steroids]
O
MeO
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)
THE BRONCHODILATOR DRUGS FOR ASTHMA
(doses usually ~ 50-100mg/spray)
OH
NHR
HO
HO
R=
R = t-Bu
as sulfate
Salbuterol - VENTOLIN
(Albuterol, Salbutamol, many others)
[beta-agonist, mimics adrenaline
broncodilator
Salmeterol (Glaxo)
[Longer lasting]
O
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:
O
HO
F
S
O
O
F
O
F