Loratadine

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Loratadine
Loratadine.svg
Loratadine - 3d, portrait orientation.png
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 namesClaritin
AHFS/Drugs.commonograph
MedlinePlusa697038
Pregnancy cat.B1 (AU) B (US)
Legal statusGSL (UK) OTC (US) OTC(Canada)
Routesoral
Pharmacokinetic data
Bioavailabilityalmost 100%
Protein binding97–99%
MetabolismHepatic (CYP2D6- and 3A4-mediated)
Half-life8 hours, active metabolite desloratadine 27 hours
Excretion40% as conjugated metabolites into urine
Similar amount into the feces
Identifiers
CAS number79794-75-5 YesY
ATC codeR06AX13
PubChemCID 3957
DrugBankDB00455
ChemSpider3820 YesY
UNII7AJO3BO7QN YesY
KEGGD00364 YesY
ChEMBLCHEMBL998 YesY
Chemical data
FormulaC22H23ClN2O2 
Mol. mass382.88 g/mol
 N (what is this?)  (verify)
 
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Loratadine
Loratadine.svg
Loratadine - 3d, portrait orientation.png
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 namesClaritin
AHFS/Drugs.commonograph
MedlinePlusa697038
Pregnancy cat.B1 (AU) B (US)
Legal statusGSL (UK) OTC (US) OTC(Canada)
Routesoral
Pharmacokinetic data
Bioavailabilityalmost 100%
Protein binding97–99%
MetabolismHepatic (CYP2D6- and 3A4-mediated)
Half-life8 hours, active metabolite desloratadine 27 hours
Excretion40% as conjugated metabolites into urine
Similar amount into the feces
Identifiers
CAS number79794-75-5 YesY
ATC codeR06AX13
PubChemCID 3957
DrugBankDB00455
ChemSpider3820 YesY
UNII7AJO3BO7QN YesY
KEGGD00364 YesY
ChEMBLCHEMBL998 YesY
Chemical data
FormulaC22H23ClN2O2 
Mol. mass382.88 g/mol
 N (what is this?)  (verify)

Loratadine (INN) is a second-generation[1] H1 histamine antagonist drug 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.[2]

Loratadine is marketed by Schering-Plough[needs update] under several trade names (e.g., Claritin) and also by Shionogi in Japan. It is available as a generic drug and is marketed for its nonsedating properties. In a version named Claritin-D or Clarinase, it is combined with pseudoephedrine, a decongestant; this makes it useful for colds, as well as allergies but adds potential side effects of insomnia, anxiety, and nervousness.

History[edit]

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.[3]

Loratadine was approved by the FDA in 1993.[3]The drug continued to be available only by prescription in the U.S. until it went off patent in 2002.[citation needed] 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.

Indications[edit]

Loratadine is indicated for the symptomatic relief of allergy such as hay fever (allergic rhinitis), urticaria (hives), chronic idiopathic urticaria,[4] and other skin allergies.[5] 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.[citation needed]

Similarly to cetirizine, loratadine attenuates the itching associated with Kimura's disease.[6]

Forms[edit]

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

The drug is available many different forms, such as: tablets, oral suspension, and syrup,[5] and in combination with pseudoephedrine.[7] 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.

Cautions and contraindications[edit]

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.[5][8]

Loratadine is usually compatible with breast-feeding (classified category L-2 by the American Academy of Pediatrics).[9] 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.[10]

Adverse effects[edit]

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.[11]

Other possible side effects include headache and antimuscarinic effects such as urinary retention, dry mouth, blurred vision, and gastrointestinal disturbances.[5][8]

Mechanism of action[edit]

Loratadine is a tricyclic antihistamine, which acts as a selective inverse agonist of peripheral histamine H1-receptors.[8] Histamine is responsible for many features of allergic reactions.

Pharmacokinetics[edit]

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.[12][13] 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%.[5]

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.[14] 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.[5]

Interactions[edit]

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).[citation needed]

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.

Legal status[edit]

In Canada, Mexico, the U.S., Australia, the UK, and many other countries, loratadine is available over the counter, as are some other second-generation antihistamines such as cetirizine. In the UK, larger quantities are "P-Line" and can be sold only in the presence of a pharmacist. However, packets of up to 14 tablets are available "off the shelf" (GSL).[15] In Norway, loratadine is available over the counter up to 7 tablets sold as Loratadin and Clarityn.

References[edit]

  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.  edit
  2. ^ 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. 
  3. ^ a b Hall, Stephen S. (2001-03-11). "The Claritin Effect; Prescription for Profit". The New York Times. Retrieved 2010-06-28. 
  4. ^ 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.  edit
  5. ^ a b c d e f Jasek, W, ed. (2007). Austria-Codex (in German) 1 (2007/2008 ed.). Vienna: Österreichischer Apothekerverlag. pp. 1768–71. ISBN 978-3-85200-181-4. 
  6. ^ http://www.ncbi.nlm.nih.gov/pubmed/21914581
  7. ^ Jasek, W, ed. (2007). Austria-Codex (in German) 1 (2007/2008 ed.). Vienna: Österreichischer Apothekerverlag. pp. 1731–34. ISBN 978-3-85200-181-4. 
  8. ^ a b c 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. 
  9. ^ Committee on Drugs (1 September 2001). "Transfer of drugs and other chemicals into human milk". Pediatrics 108 (3): 776–89. PMID 11533352. 
  10. ^ See, Sharon (November 15, 2003). "Desloratadine for Allergic Rhinitis". American Family Physician. 
  11. ^ Kristi Monson, PharmD. "Claritin and Alcohol". emedtv.com. 
  12. ^ 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.  Retrieved on 1 December 2009 through Google Book Search.
  13. ^ 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. 
  14. ^ 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. PMID 12169042.  edit
  15. ^ Medicines and Healthcare products Regulatory Agency: Recent reclassifications

External links[edit]