Hydroxyzine

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Hydroxyzine
Hydroxyzine.svg
Hydroxyzine-3d-sticks.png
Clinical data
Trade names Vistaril , Atarax
AHFS/Drugs.com Monograph
MedlinePlus a682866
Pregnancy
category
  • AU: A
  • US: C (Risk not ruled out)
Routes of
administration		 Oral, IM
ATC code N05BB01 (WHO)
Legal status
Legal status
  • AU: S4 (Prescription only)
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability High in-vivo
Protein binding 93%
Metabolism Hepatic
Biological half-life 20–24 hours[1]
Excretion Urine, Feces
Identifiers
CAS Number 68-88-2 YesY
PubChem (CID) 3658
IUPHAR/BPS 7199
DrugBank DB00557 YesY
ChemSpider 3531 YesY
UNII 30S50YM8OG YesY
KEGG D08054 YesY
ChEBI CHEBI:5818 YesY
ChEMBL CHEMBL896 YesY
ECHA InfoCard 100.000.630
Chemical and physical data
Formula C21H27ClN2O2
Molar mass 374.904 g/mol
3D model (Jmol) Interactive image
  (verify)

Hydroxyzine (/haɪˈdrɒksᵻziːn/) is a first-generation antihistamine of the diphenylmethane and piperazine class. It was first synthesized by Union Chimique Belge in 1956 and was marketed by Pfizer in the United States later the same year,[2] and is still in widespread use today.

Due to its antagonistic effects on several receptor systems in the brain, hydroxyzine has strong anxiolytic and mild antiobsessive as well as antipsychotic properties.[3] Today it is used primarily for the symptomatic relief of anxiety and tension associated with psychoneurosis and as an adjunct in organic disease states in which anxiety is manifested. Because of its antihistamine effects it can also be used for the treatment of severe cases of itching, hyperalgesia and motion sickness-induced nausea; it has also been used in some cases to relieve the effects of opioid withdrawal.[4][5] Even though it is an effective sedative, hypnotic, and anxiolytic, it shares virtually none of the abuse, dependence, addiction, and toxicity potential of other drugs used for the same range of therapeutic reasons. Hydroxyzine has also been used to potentiate the analgesia of opioids and to alleviate some of their side effects, such as itching, nausea, and vomiting.

Hydroxyzine preparations require a doctor's prescription. The drug is available in two formulations, the pamoate and the dihydrochloride or hydrochloride salts. Vistaril, Equipose, Masmoran, and Paxistil are preparations of the pamoate salt, while Atarax, Alamon, Aterax, Durrax, Tran-Q, Orgatrax, Quiess, and Tranquizine are of the hydrochloride salt.

Other drugs related to hydroxyzine are cyclizine, buclizine, and meclizine, and they share all or most of the benefits, indications, contraindications, cautions, and side effects of hydroxyzine. The second-generation antihistamine cetirizine is in fact one of the metabolites of hydroxyzine produced in the human body. Unlike hydroxyzine, cetirizine is not reported to appreciably cross the blood-brain barrier, but it has been reported to be associated with dystonic reactions as well as sedation. Therefore, it has a narrower spectrum of effects, making it an effective antihistamine but removing some or all of the anxiolytic and other psychoactive properties, but it may cause dystonic reactions and drowsiness in some patients.

Pharmacology[edit]

Hydroxyzine's predominant mechanism of action is as a potent H1 receptor inverse agonist (Ki = 2 nM).[6][7][8][9] Unlike many other first-generation antihistamines, it has very low affinity for the mACh receptors (Ki = >10,000 nM),[7][8][9][10][11] and in accordance, has a low propensity for producing anticholinergic side effects.[9][12][13] In addition to its antihistamine activity, hydroxyzine has also been shown to act as a 5-HT2A (Ki = ~50 nM), D2 (Ki = 378 nM), and α1-adrenergic (Ki = ~300 nM) receptor antagonist.[7][8][10] The antiserotonergic effects of hydroxyzine likely underlie its usefulness as an anxiolytic,[14] as other antihistamines without such properties have not been found to be effective in the treatment of anxiety.[15]

Prescription and use[edit]

Hydroxyzine is classified as an antihistamine and anxiolytic and is also used as a tranquilizer; especially common in dentistry and less so in medicine, where for many years it has been preferred in combination with opioids due to its ability to counteract the side effects of opioid pain medications, namely itchiness and nausea, and the fact that its sedative properties complement the pain relieving effects of opioids.[citation needed][citation needed]

Hydroxyzine is prescribed when the onset of an organic disease state manifests through anxiety, as generalized anxiety disorder, or in other more serious cases as psychoneurosis, and is therefore prescribed as a means of regulating normal function. Hydroxyzine has shown to be as effective as the benzodiazepine drug bromazepam in the treatment of generalised anxiety disorder.[16] However, a systematic review concluded that compared with other anxiolytic agents (benzodiazepines and buspirone), hydroxyzine was equivalent in efficacy, acceptability and tolerability, however there is insufficient evidence to recommend it as a treatment for generalised anxiety disorder due to bias in the reviewed studies.[17]

Hydroxyzine can also be used for the treatment of allergic conditions, such as chronic urticaria, atopic or contact dermatoses, and histamine-mediated pruritus. These have also been confirmed in both recent and past studies to have no adverse effects on the liver, blood, nervous system or urinary tract.[18][citation needed]

Use of hydroxyzine for premedication as a sedative has no effects on tropane alkaloids, such as atropine, but may, following general anesthesia, potentiate meperidine and barbiturates, and use in pre-anesthetic adjunctive therapy should be modified depending upon the state of the individual.[18][citation needed]

In other cases, the usage of hydroxyzine is as a form of non-barbiturate tranquilizer[19] used in the pre-operative sedation and treatment of neurological disorders, such as psychoneurosis and other forms of anxiety or tension states.[19]

For dentistry and obstetrics as well as other surgeries and procedures and acute pain situations like accidents, hydroxyzine is useful as a first line anxiolytic and opioid adjunct because it lacks both antagonism and synergy with benzodiazepines and scopolamine, allowing either of these agents to be used simultaneously or later in the procedure if need be.[citation needed]

Animal behavioral research[edit]

Hydroxyzine reduced escape failures in a learned helplessness paradigm in rats.[20]

Clinical description[edit]

Metabolism and pharmacokinetics[edit]

Hydroxyzine can be administered orally or via intramuscular injection. When given orally, hydroxyzine is rapidly absorbed from the gastro-intestinal tract. The effect of hydroxyzine is notable in 30 minutes.

Pharmacokinetically, hydroxyzine is rapidly absorbed and distributed in oral and intramuscular administration, and is metabolized in the liver; the main metabolite (45%), cetirizine, is formed through oxidation of the alcohol moiety to a carboxylic acid by alcohol dehydrogenase, and overall effects are observed within one hour of administration. It has a half-life observed on average of around 3 hours in adults, with higher concentrations found in the skin than in the plasma. Cetirizine, although less sedating, is non-dialyzable and possesses similar anti-histaminergic properties. The other metabolites identified include a N-dealkylated metabolite, and an O-dealkylated 1/16 metabolite with a plasma half-life of 59 hours. These pathways are mediated principally by CYP3A4 and CYP3A5.[21] "In animals, hydroxyzine and its metabolites are excreted in feces via biliary elimination."[22]

Administration in geriatrics differs from the administration of hydroxyzine in younger patients; according to the FDA, there have not been significant studies made (2004), which include population groups over 65, which provide a distinction between elderly aged patients and other younger groups. Hydroxyzine should be administered carefully in the elderly with consideration given to possible reduced elimination.[23]

Similarly, the use of sedating drugs alongside hydroxyzine can cause over-sedation and confusion if administered in large amounts—any form of treatment alongside sedatives should be done under supervision of a doctor.[19][23]

Contraindications[edit]

The administration of hydroxyzine in large amounts by ingestion or intramuscular administration during the onset of pregnancy can cause fetal abnormalities—when administered to pregnant rats, mice and rabbits, hydroxyzine caused abnormalities such as hypogonadism with doses significantly above that of the human therapeutic range.[24] In humans, a significant dose has not yet been established in studies, and by default, the FDA has introduced contraindication guidelines in regard to hydroxyzine.[24] Similarly the use in those at risk from or showing previous signs of hypersensitivity is also contraindicated.[24] Hydroxyzine is contraindicated for intravenous (IV) injection, as it has shown to cause hemolysis.

Other contraindications include the administration of hydroxyzine alongside depressants and other compounds which affect the central nervous system.[24] and if absolutely necessary, it should only be administered concomitantly in small doses.[24] If administered in small doses with other substances, such as mentioned, then patients should refrain from using dangerous machinery, motor vehicles or any other practice requiring absolute concentration, in accordance with safety law.[24]

Studies have also been conducted which show that long-term prescription of hydroxyzine can lead to tardive dyskinesia after years of use, but effects related to dyskinesia have also anecdotally been reported after periods of 7.5 months,[25] such as continual head rolling, lip licking and other forms of athetoid movement. In certain cases, elderly patients' previous interactions with phenothiazine derivatives or pre-existing neuroleptic treatment may have had some contribution towards dyskinesia at the administration of hydroxyzine due to hypersensitivity caused due to the prolonged treatment,[25] and therefore some contraindication is given to the short-term administration of hydroxyzine to those with previous phenothiazine use.[25]

Adverse reactions[edit]

Several reactions have been noted in manufacturer guidelines — deep sleep, incoordination, sedation, calmness, and dizziness have been reported in children and adults, as well as others such as hypotension, tinnitus, and headaches.[26] Gastro-intestinal effects have also been observed, as well as less serious effects such as dryness of the mouth and constipation caused by the mild antimuscarinic properties of hydroxyzine.[26]

Central nervous system problems such as hallucinations or confusion have been observed in rare cases, attributed mostly to overdosage.[23][26] Such properties have been attributed to hydroxyzine in several cases, particularly in patients treated for neuropsychological disorders, as well as in cases where overdoses have been observed. While there are reports of the "hallucinogenic" or "hypnotic" properties of hydroxyzine, several clinical data trials have not reported such side effects from the sole consumption of hydroxyzine, but rather, have described its overall calming effect described through the stimulation of areas within the formatio reticularis. The hallucinogenic or hypnotic properties have been described as being an additional effect from overall central nervous system suppression by other CNS agents, such as lithium or ethanol.[27]

The effect of hydroxyzine has also been tested on the ability of humans in the registration and storage of memory, and was used in comparison with relatively safe drugs, such as lorazepam, to illustrate the effects of benzodiazepines, which are thought to have adverse effects on the capacity of memory storage. Hydroxyzine was found to have no adverse effects on memory in relation to lorazepam, which caused several deficiencies in the capacity of memory storage.[28]

In a comparative study with lorazepam on memory effects, patients who had taken hydroxyzine experienced sedative effects like drowsiness, but recalled that they felt capable, attentive and able to continue with a memory test under these conditions.[29] Conversely, those under the effects of lorazepam felt unable to continue due to the fact they felt out of control with its effects; 8 out of 10 patients describing tendencies of problems with balance and control of simple motor functions.[29]

Somnolence with or without vivid dreams or nightmares may occur in users with antihistamine sensitivities in combination with other CNS depressants. Hydroxyzine exhibits anxiolytic and sedative properties in many psychiatric patients. Other studies have suggested that hydroxyzine acts as an acute hypnotic, reducing sleep onset latency and increasing sleep duration — also showing that some drowsiness did occur. This was observed more in female patients, who also had greater hypnotic response.[30]

Because of potential for more severe side effects, this drug is on the list to avoid in the elderly.[31]

Chemistry[edit]

Hydroxyzine is synthesized by the alkylation of 1-(4-chlorobenzohydril)piperazine with 2-(2-hydroxyethoxy)ethylchloride:[32]

Hydroxyzine synthesis.png

See also[edit]

References[edit]

  1. ^ Simons FE, Simons KJ, Frith EM (January 1984). "The pharmacokinetics and antihistaminic of the H1 receptor antagonist hydroxyzine". The Journal of Allergy and Clinical Immunology. 73 (1 Pt 1): 69–75. doi:10.1016/0091-6749(84)90486-x. PMID 6141198. 
  2. ^ Shorter, Edward (2009). Before Prozac: the troubled history of mood disorders in psychiatry. Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-536874-6. 
  3. ^ SCHRAM, WS (March 1959). "Use of hydroxyzine in psychosis.". Diseases of the Nervous System. 20 (3): 126–9. PMID 13639831. 
  4. ^ FDA DrugInfo: http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=51459
  5. ^ "Hydroxyzine Facts and Comparisons at Drugs.com". 
  6. ^ Gillard M, Van Der Perren C, Moguilevsky N, Massingham R, Chatelain P (February 2002). "Binding characteristics of cetirizine and levocetirizine to human H(1) histamine receptors: contribution of Lys(191) and Thr(194)". Molecular Pharmacology. 61 (2): 391–9. doi:10.1124/mol.61.2.391. PMID 11809864. 
  7. ^ a b c Snowman AM, Snyder SH (December 1990). "Cetirizine: actions on neurotransmitter receptors". The Journal of Allergy and Clinical Immunology. 86 (6 Pt 2): 1025–8. doi:10.1016/S0091-6749(05)80248-9. PMID 1979798. 
  8. ^ a b c Kubo N, Shirakawa O, Kuno T, Tanaka C (March 1987). "Antimuscarinic effects of antihistamines: quantitative evaluation by receptor-binding assay". Japanese Journal of Pharmacology. 43 (3): 277–82. doi:10.1254/jjp.43.277. PMID 2884340. 
  9. ^ a b c WHITE RP, BOYAJY LD (September 1960). "Neuropharmacological comparison of atropine, scopolamine, banactyzine, diphenhydramine and hydroxyzine". Archives Internationales de Pharmacodynamie et de Thérapie. 127: 260–73. PMID 13784865. 
  10. ^ a b Haraguchi K, Ito K, Kotaki H, Sawada Y, Iga T (June 1997). "Prediction of drug-induced catalepsy based on dopamine D1, D2, and muscarinic acetylcholine receptor occupancies". Drug Metabolism and Disposition: the Biological Fate of Chemicals. 25 (6): 675–84. PMID 9193868. 
  11. ^ Orzechowski RF, Currie DS, Valancius CA (January 2005). "Comparative anticholinergic activities of 10 histamine H1 receptor antagonists in two functional models". European Journal of Pharmacology. 506 (3): 257–64. doi:10.1016/j.ejphar.2004.11.006. PMID 15627436. 
  12. ^ Berger, F. M. (1957). "THE CHEMISTRY AND MODE OF ACTION OF TRANQUILIZING DRUGS". Annals of the New York Academy of Sciences. 67 (10): 685–700. doi:10.1111/j.1749-6632.1957.tb46006.x. ISSN 0077-8923. 
  13. ^ K. D. Tripathi (2013). Essentials of Medical Pharmacology. JP Medical Ltd. p. 165. ISBN 978-93-5025-937-5. 
  14. ^ Barbara Olasov Rothbaum; Stein, Dan J.; Hollander, Eric (2009). Textbook of Anxiety Disorders. American Psychiatric Publishing, Inc. ISBN 1-58562-254-0. 
  15. ^ Lamberty Y, Gower AJ (September 2004). "Hydroxyzine prevents isolation-induced vocalization in guinea pig pups: comparison with chlorpheniramine and immepip". Pharmacology, Biochemistry, and Behavior. 79 (1): 119–24. doi:10.1016/j.pbb.2004.06.015. PMID 15388291. 
  16. ^ Llorca PM, Spadone C, Sol O, et al. (November 2002). "Efficacy and safety of hydroxyzine in the treatment of generalized anxiety disorder: a 3-month double-blind study" (PDF). J Clin Psychiatry. 63 (11): 1020–7. doi:10.4088/JCP.v63n1112. PMID 12444816. 
  17. ^ Giuseppe Guaiana1, Corrado Barbui, Andrea Cipriani (8 December 2010). "Hydroxyzine for generalised anxiety disorder". The Cochrane Library. Cochrane Depression, Anxiety and Neurosis Group. doi:10.1002/14651858.CD006815.pub2. 
  18. ^ a b United States Food & Drug Administration, (2004), p1
  19. ^ a b c Dolan, C. M., (1958)
  20. ^ Porsolt, Roger D.; P. Martin; A.Lenégre; S. Fromage; C. E. Giurgea (1989). "Prevention of "learned helplessness" in the rat by hydroxyzine". Drug Development Research. 17 (3): 227–236. doi:10.1002/ddr.430170306. 
  21. ^ "Ucerax (hydroxyzine hydrochloride) 25 mg film-coated tablets. Summary of product characteristics" (PDF). Irish Medicines Board. Retrieved 9 February 2014. 
  22. ^ [1] "The extent of renal excretion of VISTARIL has not been determined"[2]
  23. ^ a b c United States Food & Drug Administration, (2004), p3
  24. ^ a b c d e f United States Food & Drug Administration, (2004), p2
  25. ^ a b c Clark, B. G., Araki, M., et al. (1976)
  26. ^ a b c UCB South-Africa, et al., (2004)
  27. ^ Anderson, P. O., Knoben, J. E., et al. (2002), p794-796
  28. ^ Brabander, A. DE, Debert, W., (1990), p1
  29. ^ a b Brabander, A. DE, Debert, W., (1990), p3
  30. ^ Alford, C.; N. Rombautt, J. Jones, S. Foley, C. Idzikowskit and I. Hindmarch (1992).
  31. ^ NCQA’s HEDIS Measure: Use of High Risk Medications in the Elderly, http://www.ncqa.org/Portals/0/Newsroom/SOHC/Drugs_Avoided_Elderly.pdf
  32. ^ H. Morren, U.S. Patent 2,899,436 (1959); H. Morren, DE 1049383  (1954); H. Morren, DE 1061786  (1954); H. Morren, DE 1068262  (1954); H. Morren, DE 1072624  (1954); H. Morren, DE 1075116  (1954).

External links[edit]

Print sources[edit]

Internet-based[edit]

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