Description
Loratadine(79794-75-5) is a non-sedating antihistamine indicated for use in allergic rhinitis and chronic
urticaria. Its major advantage over other non-sedating antihistamines such as astemizole
and terfenadine is its very fast onset of action. Loratadine is claimed not to cross the
blood-brain barrier.
Chemical Properties
White Crystalline Solid
Originator
Schering Plough (USA)
Uses
A nonsedating-type histamine H1-receptor
Uses
antinflammatory, analgesic, antipyretic
Uses
Histamine H1 receptor antagonist; antihistamine.
Definition
ChEBI: Loratadine is a benzocycloheptapyridine that is 6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine substituted by a chloro group at position 8 and a 1-(ethoxycarbonyl)piperidin-4-ylidene group at position 11. It is a H1-receptor antagonist commonly employed in the treatment of allergic disorders. It has a role as a geroprotector, a H1-receptor antagonist, an anti-allergic agent and a cholinergic antagonist. It is an ethyl ester, a N-acylpiperidine, a tertiary carboxamide, an organochlorine compound and a benzocycloheptapyridine. It is functionally related to a desloratadine.
Indications
Loratadine (Claritin) is a long-acting, potent peripheral H1 blocker with minimal
sedative effects. It does not appear to have the same adverse cardiac effects as
the other nonsedating H1 antihistamines. It is indicated for allergic rhinitis and
chronic urticaria.
Manufacturing Process
Preparation of Loratadine
In a two-liter vessel provided with a thermometer, a reflux condenser and nitrogen atmosphere, dry tetrahydrofuran (343 ml) was placed, and cooled between 0 and -5°C. Titanium tetrachloride (28.5 ml, 49.5 g, 0.255 mol) was slowly added with stirring (17 min.), keeping the temperature in the above indicated range, a yellow suspension being formed. After the addition was finished, stirring was continued for 10 min. Then, zinc dust (34.5 g, 0.524 mol) was added with stirring in approximately 15 min. keeping the temperature in the above cited range, and after addition was finished, stirring was continued at this temperature for 20 min., a blue suspension being formed. Then, pyridine (17 ml, 0.21 mol) was added with stirring, keeping the temperature in the above range, and then, a solution of 8-chloro-5,6- dihydrobenzo[5,6]cyclohepta[1,2-b]pyridin-11-one (30.0 g, 0.123 mol) and ethyl 4-oxopiperidine-1-carboxylate (25.2 g, 0.147 mol) in anhydrous tetrahydrofuran (96 ml) was added in about 20 min., with stirring and keeping the temperature in the above cited range. The, thus obtained, dark brown mixture was stirred for 3 h keeping the temperature in the above cited range, then was allowed to heat to room temperature and kept at this temperature for 2 h and then heated to 40°C for 17 h. The tetrahydrofuran was distilled off
from the reaction mixture to give a black resin that was dissolved in
dichloromethane (300 ml) and acidified by addition of isopropanol/HCl 7.2 N
(97 ml). The mixture was stirred for 10 min, and the phases were separated,
being the aqueous one extracted with dichloromethane (150 ml). The
combined organic phases were washed 6 times with a mixture of water (125
ml) and 35% aqueous HCl (7.5 ml). Then, the organic phase was basified to
pH 7.5-8.0 by addition of 30% aqueous NH3. The mixture was stirred for 10
min and the phases were separated, and then washed 3 times with water
(250 ml). The organic phase was dried with anhydrous sodium sulfate, filtered
and the solvent eliminated in vacuo to give a residue (47.47 g) that was
treated with acetonitrile (97 ml). The solid was filtered and crystallized from
the same solvent to give pure Loratadine, m.p. 132-133°C (18.8 g, 40%
yield).
Brand name
Alavert (Wyeth); Claritin (Schering-Plough).
Therapeutic Function
Antihistaminic, Antiallergic
General Description
Loratadine, 4-(8-chloro-5,6-dihydro-11Hbenzo[5,6]-cyclohepta[1,2-b]pyridin-l 1-ylidene-1-carboxylic acid ethyl ester, is a white to off-white powder insoluble in water but very soluble in acetone, alcohols, and chloroform. Loratadine is structurally related to the antihistamines azatadine and cyproheptadine, and to some tricyclic antidepressants. It differs from azatadine, in that a neutral carbamate group has replaced the basic tertiary amino moiety, and a phenyl ring has been substituted with a chlorine atom. Loratadine is a selective peripheral H1-antihistamine with a receptor-binding profile like that of the other members of this series, except that it has more antiserotonergic activity. Thus, it produces no substantial CNS or autonomic side effects or cardiac toxicity.
Loratadine displays potency comparable with that of astemizole and greater than that of terfenadine. Loratadine is indicated for the relief of nasal and nonnasal symptoms of seasonal allergic rhinitis. In the presence of a CYP3A4 inhibitor ketoconazole, loratadine is metabolized to descarboethoxyloratadine predominantly by CYP2D6.
Biological Activity
Peripheral histamine H 1 receptor antagonist (K i = 35 nM); devoid of central effects. Orally active antiallergic agent.
Biochem/physiol Actions
Non-sedating histamine H1-receptor antagonist.
Pharmacokinetics
Good oral absorption, rapid and extensive metabolism in the liver, and excreted by urine and feces. After taking the medicine, the effect is fast, and some patients show the effect within 30 minutes. Tmax is 1.5 ~ 2 h, and the elimination half-life is 8 ~ 14 h. The half-life of the active metabolite decarboxymethylethoxyloratadine (DCL) is 17 ~ 24h. The half-life of the elderly and patients with liver disease may be longer. The binding rate of loratadine to plasma protein was 97% ~ 99%, and DCL was 73% ~ 76%. After 24 hours, about 27% of loratadine was excreted from urine, about 40% was eliminated from urine and 42% was excreted from stool after 10 days. With less milk secretion, it is safe to use drugs during lactation.
Clinical Use
Loratadine is related to the first-generation tricyclic antihistamines and to
antidepressants. It is nonsedating, and neither it nor its major metabolite, desloratadine
(descarboethoxyloratadine), is associated with the potentially cardiotoxic effects reported for
terfenadine and astemizole. On chronic dosing, the AUC (plasma concentration–time curve)
for the metabolite is greater than that for the parent drug, and its half-life is longer.
Metabolism
Molecular weight (daltons) 382.9 % Protein binding 97-99 % Excreted unchanged in urine 40 Volume of distribution (L/kg) No data Half-life - normal/ESRF (hrs) 12-15 / Unchanged
Dosage forms
10 mg daily. Patients with liver or renal impairment should be
started on a lower dose.
