Hydroxyzine

Hydroxyzine

Systematic (IUPAC) name
(±)-2-(2-{4-[(4-chlorophenyl)-phenylmethyl]piperazin-1-yl}ethoxy)ethanol
Clinical data
Trade names	Vistaril
AHFS/Drugs.com	monograph
MedlinePlus	a682866
Pregnancy cat.	A(AU) C(US)
Legal status	℞ Prescription only
Routes	Oral, IM
Pharmacokinetic data
Bioavailability	High in-vivo
Protein binding	93%
Metabolism	Renal
Half-life	20-25 hours
Excretion	Urine, Feces
Identifiers
CAS number	68-88-2 Y
ATC code	N05BB01
PubChem	CID 3658
DrugBank	APRD00688
ChemSpider	3531 Y
UNII	30S50YM8OG Y
KEGG	D08054 Y
ChEBI	CHEBI:5818 Y
ChEMBL	CHEMBL896 Y
Chemical data
Formula	C21H27ClN2O2
Mol. mass	374.904 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C21H27ClN2O2/c22-20-8-6-19(7-9-20)21(18-4-2-1-3-5-18)24-12-10-23(11-13-24)14-16-26-17-15-25/h1-9,21,25H,10-17H2 Y Key:ZQDWXGKKHFNSQK-UHFFFAOYSA-N Y
Y(what is this?)  (verify)

Hydroxyzine ( /haɪˈdrɒksɨziːn/; sold as Vistaril, Atarax) is a first-generation antihistamine of the diphenylmethane and piperazine classes. It was first synthesized by Union Chimique Belge in 1956 and was marketed by Pfizer in the United States later the same year,^[1] and is still in widespread use today.

Hydroxyzine is used primarily as an antihistamine for the treatment of itching, allergies, hyperalgesia, motion sickness-induced nausea, and insomnia, as well as notably for the treatment of mild anxiety.^[2] Even though it is an effective sedative, hypnotic, analgesic, and tranquilizer, it shares almost none of the abuse, dependence, addiction, and toxicity potential of other drugs used for the same range of therapeutic reasons.^{[citation needed]}

Hydroxyzine is used with opioid analgesics to increase the pain-killing ability of a given dose of opioid, reduce the quantity needed to stop a given level of pain, and/or preempt some side effects of opioids like itching, nausea, and vomiting.

Hydroxyzine preparations usually require a doctor's prescription as do other potent antihistamines in many countries whereas some countries allow hydroxyzine and all or most other antihistamines to be sold over-the-counter. 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, therefore having a narrower spectrum of effects, making it an effective antihistamine but removing some or all of the anxiolytic and analgesic-sparing properties.

Prescription and use

Hydroxyzine is both an antihistamine and anxiolytic (see below) and its use as a mild tranquilizer is especially common in dentistry and it retains some popularity in obstetrics, where for many years it was especially preferred for its ability to boost the effectiveness of opioids as well as permit later use of scopolamine or benzodiazepines better than other drugs might.

Hydroxyzine is prescribed when the onset of an organic disease state manifests through anxiety, as general 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.^[3] 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.^{[4][citation needed]}

Use of hydroxyzine for premedication as a sedative has no effects on belladonna 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.^{[4][citation needed]}

In other cases, the usage of hydroxyzine is as a form of non-barbiturate tranquilizer^[5] used in the pre-operative sedation and treatment of neurological disorders, such as psychoneurosis and other forms of anxiety or tension states.^[5]

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.

Hydroxyzine is not thought to be an effective treatment for anxiety if used for a period of over 4 months, and it is therefore a prerequisite of any medical professional prescribing such drugs, to re-assess the usefulness for the individual patient. Rather than its use as an anxiety-reducing agent, hydroxyzine should be reconsidered if the patient has more intense anxiety or other psychoneurosis; then other compounds specifically designed for such conditions should be considered.^[6]

Animal behavioral research

Hydroxyzine reduced escape failures in a learned helplessness paradigm in rats.^[7]

Clinical description

Metabolism and pharmacokinetics

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 metabolised in the liver; the main metabolite (45%) through oxidation of the alcohol moiety to a carboxylic acid, is cetirizine and overall effects are observed within one hour of administration. It has a half-life observed on average of around 7–10 hours in adults, 6–7 hours in children, and 18–21 hours in the elderly, or those with renal insufficiency, with higher concentrations found in the skin than in the plasma. Cetirizine, although less sedating, is non-dialyzable and possesses similar anti-histaminergic properties. "In animals, hydroxyzine and its metabolites are excreted in feces via biliary elimination."^[8]

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.^{[9][citation needed]}

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 the patient.^{[5][9][citation needed]}

Contraindications

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 with doses significantly above that of the human therapeutic range.^{[6][citation needed]} 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.^[6] Similarly the use in those at risk from or showing previous signs of hypersensitivity is also contraindicated.^{[6][citation needed]} Hydroxyzine is contraindicated for intraveneous (IV) injection, as IV injection of hydroxyzine has shown to cause hemolysis.

Other contraindications include the administration of hydroxyzine alongside depressants and other compounds which affect the central nervous system.^[6] and if absolutely necessary, it should only be administered concomitantly in small doses.^[6] 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.^[6]

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,^[10] 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,^[10] and therefore some contraindication is given to the short-term administration of hydroxyzine to those with previous phenothiazine use.^[10]

Adverse reactions

For a full list of side effects, consult the full technical specification of hydroxyzine.

Several reactions have been noted in manufacturer guidelines — deep sleep, incoordination and dizziness have been reported in children and adults, as well as others such as hypotension, tinnitus, and headaches.^[11] Gastro-intestinal effects have also been observed, as well as less serious effects such as dryness of the mouth and constipation caused by antimuscarinic properties of hydroxyzine.^[11]

Central nervous system problems such as hallucinations or confusion have been observed in rare cases, attributed mostly to overdosage.^[9][11] 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 description of 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 alcohol.^[12]

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 hydroxyzine, 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.^[13]

In a comparative study with lorazepam on memory effects, patients who had taken hydroxyzine experienced sedative effects similar to drowsiness, but recalled that they felt capable, attentive and able to continue with a memory test under these conditions.^[14] 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.^[14]

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.^[15]

In contrast to drugs in the benzodiazepine class, (i.e. alprazolam, diazepam) which carry a potential for abuse and dependence, hydroxyzine is very unlikely to cause any dependence due to its relative strength compared to other substances.^{[citation needed]}

Because of potential for more severe side effects, this drug is on the list to avoid in the elderly.^[16]

Pharmacology

Hydroxyzine's predominant mechanism of action is as a potent H₁ receptor inverse agonist (K_i = 2 nM).^{[17][18][19][20]} Unlike most other first-generation antihistamines, it has very low affinity for the mACh receptors (K_i = >10,000 nM) and therefore does not produce any clinically significant anticholinergic effects.^{[18][19][20][21][22]} In addition to its antihistamine activity, hydroxyzine has also been shown to act as a 5-HT_2A (K_i = ~50 nM), D₂ (K_i = 378 nM), and α₁-adrenergic (K_i = ~300 nM ) receptor antagonist.^[18][19][21] It may act on the 5-HT_2C receptor as well.^{[citation needed]} Hydroxyzine's antiserotonergic effects likely underlie its usefulness as an anxiolytic,^[23][24] as other antihistamines without such properties are not effective in the treatment of anxiety.^[24]

Chemistry

Hydroxyzine is synthesized by the alkylation of 1-(4-chlorobenzohydril)piperazine with 2-(2-hydroxyotoxy)ethylchloride:^[25]

References

1. ^ Shorter, Edward (2009). Before Prozac: the troubled history of mood disorders in psychiatry. Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-536874-6. http://books.google.com/?id=8VaYF8pIPxgC&lpg=PR13&dq=hydroxyzine%201956&pg=PR13#v=onepage&q. 
2. ^ "Hydroxyzine Facts and Comparisons at Drugs.com". http://www.drugs.com/cdi/hydroxyzine.html. 
3. ^ 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". J Clin Psychiatry 63 (11): 1020–7. doi:10.4088/JCP.v63n1112. PMID 12444816. http://www.psychiatrist.com/privatepdf/2002/v63n11/v63n1112.pdf. 
4. ^ ^{a b} United States Food & Drug Administration, (2004), p1
5. ^ ^{a b c} Dolan, C. M., (1958)
6. ^ ^{a b c d e f g} United States Food & Drug Administration, (2004), p2
7. ^ 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. 
8. ^ [1] "The extent of renal excretion of VISTARIL has not been determined"[2]
9. ^ ^{a b c} United States Food & Drug Administration, (2004), p3
10. ^ ^{a b c} Clark, B. G., Araki, M., et al. (1976)
11. ^ ^{a b c} UCB South-Africa, et al., (2004)
12. ^ Anderson, P. O., Knoben, J. E., et al. (2002), p794-796
13. ^ Brabander, A. DE, Debert, W., (1990), p1
14. ^ ^{a b} Brabander, A. DE, Debert, W., (1990), p3
15. ^ Alford, C.; N. Rombautt, J. Jones, S. Foley, C. Idzikowskit and I. Hindmarch (1992).
16. ^ NCQA’s HEDIS Measure: Use of High Risk Medications in the Elderly, http://www.ncqa.org/Portals/0/Newsroom/SOHC/Drugs_Avoided_Elderly.pdf
17. ^ 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. http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11809864. 
18. ^ ^{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. 
19. ^ ^{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. 
20. ^ ^{a b} 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. 
21. ^ ^{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. http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=9193868. 
22. ^ 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. http://linkinghub.elsevier.com/retrieve/pii/S0014-2999(04)01262-2. 
23. ^ Barbara Olasov Rothbaum; Stein, Dan J.; Hollander, Eric (2009). Textbook of Anxiety Disorders. American Psychiatric Publishing, Inc. ISBN 1-58562-254-0. http://books.google.com/?id=quQY1R8vsZcC&lpg=PA196&dq=hydroxyzine%20serotonin&pg=PA196#v=onepage&q. 
24. ^ ^{a b} 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. http://linkinghub.elsevier.com/retrieve/pii/S0091-3057(04)00224-2. 
25. ^ 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

Print sources

• Hutcheon, D. E.; D.L. Morris, A. Scriabine (December 1956). "Cardiovascular action of hydroxyzine (Atarax)". J Pharmacol Exp Ther. 118 (4): 451–460. PMID 13385806. 
• Dolan, C. M. (June 1958). "MANAGEMENT OF EMOTIONAL DISTURBANCES—Use of Hydroxyzine (Atarax®) in General Practice". Calif Med. 88 (6): 443–444. PMC 1512309. PMID 13536863. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1512309. 
• Pfizer Labs, Division of Pfizer Inc, NY, NY 10017 (2004) (pdf). Vistaril (hydroxyzine pamoate) Capsules and Oral Suspension. United States Food and Drug Administration. http://www.fda.gov/cder/ogd/rld/11795s16.pdf. Retrieved 2007-03-09. 
• Anderson, Philip O.; James E. Knoben, William G. Troutman (2002). Handbook of Clinical Drug Data. McGraw-Hill Medical. ISBN 0071363629. 
• de Brabander, A.; W. Deberdt (1990). "Effect of Hydroxyzine on Attention and Memory". Human Psychopharmacology (John Wiley & Sons) 5 (4): 357–362. doi:10.1002/hup.470050408. http://www3.interscience.wiley.com/cgi-bin/abstract/109710652/ABSTRACT?CRETRY=1&SRETRY=0. Retrieved 2007-03-09. 
• Clark, B. G.; M. Araki, H. W. Brown (1982). "Hydroxyzine-Associated Tardive Dyskinesia". Ann Neurol. 11 (4): 435. doi:10.1002/ana.410110423. PMID 7103423. 
• Porsolt, R. D.; P. Martin, A. Lenegre, S. Frornage, and C.E. Giurgea (1989). "Prevention of "Learned Helplessness" in the Rat by Hydroxyzine". Drug Dev. Res. 17 (3): 227–236. doi:10.1002/ddr.430170306. http://www3.interscience.wiley.com/cgi-bin/abstract/109670961/ABSTRACT?SRETRY=0. Retrieved 2007-03-10. 
• Alford, C.; N. Rombautt, J. Jones, S. Foley, C. Idzikowskit and I. Hindmarch (1992). "Acute Effects of Hydroxyzine on Nocturnal Sleep and Sleep Tendency the Following Day: a C-EEG Study". Human Psychopharmacology 7 (1): 25–35. doi:10.1002/hup.470070104. http://www3.interscience.wiley.com/cgi-bin/abstract/109711163/ABSTRACT. Retrieved 2007-03-10. 

Internet-based

• RxList , et al. (2004). "Atarax Indications, Dosage, Storage, Stability". RxList - The internet drug index. http://www.rxlist.com/cgi/generic/hydrox_ids.htm. Retrieved 2007-03-09. 
• Medscape (2004). "Vistaril Oral: Monograph - Hydroxyzine Hydrochloride, Hydroxyzine Pamoate". medscape.com. http://www.medscape.com/druginfo/monograph?cid=med&drugid=6144&drugname=Vistaril+Oral&monotype=monograph&print=1. Retrieved 2007-03-09. 
• pfizer (2004). "Non-print version of vistaril fact sheet." (PDF). http://www.pfizer.com/pfizer/download/uspi_vistaril.pdf. Retrieved 2007-07-03. 
• U.S. National Library of Medicine: Drug Information Portal - Hydroxyzine