Loratadine

Loratadine (INN)
Systematic (IUPAC) name
Ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate
Clinical data
Trade names Claritin
AHFS/Drugs.com monograph
MedlinePlus a697038
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
Legal status
Routes of
administration		 oral
Pharmacokinetic data
Bioavailability almost 100%
Protein binding 97–99%
Metabolism Hepatic (CYP2D6- and 3A4-mediated)
Biological half-life 8 hours, active metabolite desloratadine 27 hours
Excretion 40% as conjugated metabolites into urine
Similar amount into the feces
Identifiers
CAS Number 79794-75-5 YesY
ATC code R06AX13
PubChem CID 3957
IUPHAR/BPS 7216
DrugBank DB00455 N
ChemSpider 3820 YesY
UNII 7AJO3BO7QN YesY
KEGG D00364 YesY
ChEMBL CHEMBL998 YesY
Chemical data
Formula C22H23ClN2O2
Molar mass 382.88 g/mol
 NYesY (what is this?)  (verify)

Loratadine is a second-generation[1] peripheral histamine H1-receptors blocker[2] used to treat allergies. In structure, it is closely related to tricyclic antidepressants, such as imipramine, and is distantly related to the atypical antipsychotic quetiapine.[3]

Loratadine was discovered in 1981 and came to market in 1993.[4] It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[5] It is available as a generic drug and is marketed for its nonsedating properties. There is a version combined with pseudoephedrine, a decongestant; known as pseudoephedrine/loratadine.

Medical uses

Loratadine is indicated for the symptomatic relief of allergy such as hay fever (allergic rhinitis), urticaria (hives), chronic idiopathic urticaria,[6] and other skin allergies.[7] For allergic rhinitis (hay fever), loratadine is effective for both nasal and eye symptoms: sneezing, runny nose, itchy or burning eyes. Loratadine could be also used to treat mild to moderate pain from headaches.

Similarly to cetirizine, loratadine attenuates the itching associated with Kimura's disease.[8]

Forms

An example of a loratadine 10-mg tablet (Rx)

The drug is available in many different forms, such as: tablets, oral suspension, and syrup,[7] and in combination with pseudoephedrine.[9] Also available are quick-dissolving tablets, which are marketed as being faster to get into one's circulatory system, but require special handling to avoid degrading in the package.

Contraindications

Patients with severe hepatic (liver) disorders may need to start with a lower dose. No dose adaptation is necessary for elderly or renally (kidney) impaired patients.[7][2]

Loratadine is usually compatible with breast-feeding (classified category L-2 by the American Academy of Pediatrics).[10] In the U.S., it is classified as category B in pregnancy, meaning animal reproduction studies have failed to demonstrate a risk to the fetus, and no adequate and well-controlled studies in pregnant women have been conducted.[11]

Adverse effects

As a "nonsedating" antihistamine, loratadine causes less (but still significant, in some cases) sedation and psychomotor retardation than the older antihistamines because it penetrates the blood/brain barrier to a smaller extent. Although drowsiness is rare at the common 10-mg dose, patients should, nevertheless, be advised that it can occur and may affect performance of skilled tasks (e.g., driving). Patients who do experience drowsiness while taking loratadine should avoid the use of alcohol, as it can cause excessive drowsiness. Otherwise, loratadine and alcohol are unlikely to cause problems. Nevertheless, it would be in the patient's best interest to take caution when combining alcohol and any medication.[12]

Other possible side effects include headache and antimuscarinic effects such as urinary retention, dry mouth, blurred vision, and gastrointestinal disturbances.[7][2]

Interactions

Substances that act as inhibitors of the CYP3A4 enzyme such as ketoconazole, erythromycin, cimetidine, and furanocoumarin derivatives (found in grapefruit) lead to increased plasma levels of loratadine. This had clinically significant effects in controlled trials of higher-than-usual doses of loratadine (20 mg).

Antihistamines should be discontinued about 48 hr prior to skin allergy tests, since these drugs may prevent or diminish otherwise-positive reactions to dermal activity indicators.

Mechanism of action

Loratadine is a tricyclic antihistamine, which acts as a selective inverse agonist of peripheral histamine H1-receptors.[2] Histamine is responsible for many features of allergic reactions.

Pharmacokinetics

Loratadine is given orally, is well absorbed from the gastrointestinal tract, and has rapid first-pass hepatic metabolism; it is metabolized by isoenzymes of the cytochrome P450 system, including CYP3A4, CYP2D6, and, to a lesser extent, several others.[13][14] Loratadine is almost totally (97–99%) bound to plasma proteins. Its metabolite desloratadine, which is largely responsible for the antihistaminergic effects, binds to plasma proteins by 73–76%.[7]

Loratadine's peak effect occurs after one to two hours, and its biological half-life is on average 8 hours (range 3 to 20 hours) with desloratadine's half-life being 27 hours (range 9 to 92 hours), accounting for its long-lasting effect.[15] About 40% is excreted as conjugated metabolites into the urine, and a similar amount is excreted into the feces. Traces of unmetabolised loratadine can be found in the urine.[7]

History

Schering-Plough developed loratadine as part of a quest for a potential blockbuster drug: a nonsedating antihistamine. However, by the time Schering submitted the drug to the U.S. Food and Drug Administration (FDA) for approval, the agency had already approved a competitor's nonsedating antihistamine, terfenadine (trade name Seldane), and, therefore, put loratadine on a lower priority.[16]

Loratadine was approved by the FDA in 1993.[16] The drug continued to be available only by prescription in the U.S. until it went off patent in 2002. It was then subsequently approved for over-the-counter sales. Once it became an unpatented over-the-counter drug, the price dropped significantly.

Schering also developed desloratadine (Clarinex), which is an active metabolite of loratadine.

Availability

Loratadine is available under many brand names and dosage forms worldwide.[17]

Loratadine is marketed by Bayer (formerly Schering-Plough, later Merck & Co.) under several trade names (e.g., Claritin) and also by Shionogi in Japan. It is manufactured by Pfizer[18] among others.

In 1998, in an an unprecedented action, the American insurance company Anthem petitioned the FDA to allow loratadine and two other antihistamines to be made available over the counter (OTC) while it was still under patent; the FDA granted the request, which was not binding on manufacturers.[19] In the US, Schering-Plough made loratadine available OTC in 2002.[19] Loratadine is currently available in many countries OTC.[20]

See also

References

  1. ↑ Holdcroft, C. (1993). "Terfenadine, astemizole and loratadine: Second generation antihistamines". The Nurse practitioner 18 (11): 13–14. doi:10.1097/00006205-199311000-00005. PMID 8278087.
  2. 1 2 3 4 Mutschler, Ernst; Gerd Geisslinger; Heyo K. Kroemer; Monika Schäfer-Korting (2001). Arzneimittelwirkungen (in German) (8 ed.). Stuttgart: Wissenschaftliche Verlagsgesellschaft. pp. 456–461. ISBN 3-8047-1763-2.
  3. ↑ Kay GG, Harris AG (July 1999). "Loratadine: a nonsedating antihistamine. Review of its effects on cognition, psychomotor performance, mood and sedation". Clinical and experimental allergy: journal of the British Society for Allergy and Clinical Immunology. 29 Suppl 3: 147–50. doi:10.1046/j.1365-2222.1999.0290s3147.x. PMID 10444229.
  4. ↑ Corey, E.J. (2012). "Loratadine". Molecules and Medicine. John Wiley & Sons. ISBN 9781118361733.
  5. ↑ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  6. ↑ Pons-Guiraud, A; Nekam, K; Lahovsky, J; Costa, A; Piacentini, A (2006). "Emedastine difumarate versus loratadine in chronic idiopathic urticaria: A randomized, double-blind, controlled European multicentre clinical trial". European journal of dermatology : EJD 16 (6): 649–54. PMID 17229605.
  7. 1 2 3 4 5 6 Jasek, W, ed. (2007). Austria-Codex (in German) 1 (2007/2008 ed.). Vienna: Österreichischer Apothekerverlag. pp. 1768–71. ISBN 978-3-85200-181-4.
  8. ↑ Ueda, T; Arai, S; Amoh, Y; Katsuoka, K (2011). "Kimura's disease treated with suplatast tosilate and loratadine". European journal of dermatology : EJD 21 (6): 1020–1. doi:10.1684/ejd.2011.1539 (inactive 2015-11-29). PMID 21914581.
  9. ↑ Jasek, W, ed. (2007). Austria-Codex (in German) 1 (2007/2008 ed.). Vienna: Österreichischer Apothekerverlag. pp. 1731–34. ISBN 978-3-85200-181-4.
  10. ↑ Committee on Drugs (1 September 2001). "Transfer of drugs and other chemicals into human milk". Pediatrics 108 (3): 776–89. PMID 11533352.
  11. ↑ See, Sharon (November 15, 2003). "Desloratadine for Allergic Rhinitis". American Family Physician.
  12. ↑ Kristi Monson, PharmD. "Claritin and Alcohol". emedtv.com.
  13. ↑ Nelson, Wendel L. (2002). "Antihistamines and related antiallergic and antiulcer agents". In Williams, David H.; Foye, William O.; Lemke, Thomas L. Foye's principles of medicinal chemistry. Hagerstown, MD: Lippincott Williams & Wilkins. p. 805. ISBN 0-683-30737-1.
  14. ↑ Ghosal A, Gupta S, Ramanathan R, et al. (August 2009). "Metabolism of loratadine and further characterization of its in vitro metabolites". Drug Metab Lett 3 (3): 162–70. doi:10.2174/187231209789352067. PMID 19702548.
  15. ↑ Affrime, M; Gupta, S; Banfield, C; Cohen, A (2002). "A pharmacokinetic profile of desloratadine in healthy adults, including elderly". Clinical pharmacokinetics. 41 Suppl 1: 13–9. doi:10.2165/00003088-200241001-00003. PMID 12169042.
  16. 1 2 Hall, Stephen S. (2001-03-11). "The Claritin Effect; Prescription for Profit". The New York Times. Retrieved 2010-06-28.
  17. ↑ drugs.com Loratadine at drugs.com international listings Page accessed April 11, 2015]
  18. ↑ "Pfizer Prescription Products". Pfizer Inc. Retrieved March 9, 2010.
  19. 1 2 Cohen JP et al. Switching prescription drugs to over the counter. BMJ. 2005 Jan 1;330(7481):39-41. PMID 15626806 PMC 539854
  20. ↑ Association of the European Self-Medication Industry Database. Loratadine OTC regulation Page accessed April 11, 2015

External links

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