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4 Antihistamines
Histamine H1 Antagonists
The term antihistamine historically refers to drugs that antagonize the actions of histamine at H1 receptors. Histamine is an important chemical mediator of hypersensitivity
4 (5-)-(2-aminoethyl)imidazole
H N
CH2CH2NH2 Ethylamine
Imidazole
4(5)-(2-aminoethyl) imidazole
(a) NX-tautomer
H N
At pH 7.4, histamine exists almost exclusively (96.6%) in a monocationic form Most histamine is synthesized and stored in mast cells and basophilic granulocytes Histamine is mediated by specific cell surface receptors (H1, H2, and H3)
NH2 HN N COOH
histidine decarboxylase
SAM SAH
NH2 H3C N N HN N
COOH
N-methyl histamine N-
MAO (brain)( -B ) DAO ( (peripheral) ) Aldehyde dehydorgenase
COOH H3C N N
HO HO
OH
Ar Ar' N N
Weaker action to H1 receptor moderate central analgesic effect causing disorder of gastrointestine local external use may cause skin hypersensity.
Ar' Ar O
R' N R
The first generation of H1 receptor antagonist display apparent analgesic and anticholinergic effects usually with side reaction like somnolence, dizzy, oral dryness. But incidence rate of gastrointestine reaction is low. Some of drugs could be applied in the treatment of insomnia. For those aminoether with two aromatic group the activity of Sisomer is usually higher than that of R-isomer.
Cl
Clemastine
Setastine
Compared to traditional antihistamines like ethyldiamines, aminoethers, tricyclics propylamines have stronger antihistamine action but weaker central analgesic, and less tendency of inducing somnolence.
Chlorphenamine Maleate
Stronger antihistamine action less dosage less side effect suitable for children. Mainly use for hypersensitive nasitis, skin mucosa hypersensitivity, urticaria, angiectatic nasitis, hay fever contact dermatitis and hypersensitivity caused by food and drugs. Side effect: somnolence, thirsty, diuresis.
S(+) -Chlorphenamine
One chiral center in Chlorphenamine there is a pair of optical isomer. The activity of S-isomer is twice stronger than that of racemate acute toxicity is also less. The activity of R-isomer is only 1/90 than that of racemate In clinic, racemate chlorphenamine maleate is used
Chemical Synthesis
Acrivastine Allyl acid make the compound more hydrophilic and it is more difficult for it to enter into central nerve system.Therefore, acrivastine displays no analgesic effect. The activity of E-isomer is great higher than that of Z-isomer.
If X = N Y = S then phenothiazine If X= C (sp2) Y is replaced with bioisostere, -CH=CH- then cyproheptadine Further modification of cyproheptadine produce loratadine
Loratadine
Cl N
N O O
Strong selective H1 receptor antagonist, but no anticholinergic activity and central nerve system inhibition, belong to second generation non-sedative antihistamines. The main difference compared to other tricyclics antihistamines, is the replacement of neutral aminoformate for basic tertiary amine. It is believed this is the reason of its decrease of central analgesic .
Cl
Ar' Ar N N R
Other than stronger H1 receptor antagonism effect they display other characteristic like relieving asthma effect, antikinetia action, and blocking action of Ca2+ ion channel .
Cetirizine Hydrochloride
O Cl N N O OH
.2HCl
Because of the easy ionization of Cetirizine, the drug is not easy to permeate blood brain barrier (BBB) , little amount of the drug is able to arrive central nerve system, it belongs to non-sedative antihistamine, it is one of the representative drug of second generation antihistamines.
The advantages of Zyrtec is that 1. Once-daily dosing 2. Rapid onset of activity (20-60 min) 3. Minimal CNS effects
Cl N
NH
Cl Cl(CH2)2OCH2CN K2CO3 N
Mizolastine
F
N N
N HN
F O N N F NaH CH 3I
N NaOCH 3
H N O
N N
N N N N
N O
N HN
SAR of Antihistamines
Ar X Ar'
X = O, C, or N N = 2 or 3
N N
R (CH2)n N R'