H₁ Receptor

Hydroxyzine dihydrochloride, when applied to pretreated bladder slices for 60 minutes, reduces serotonin release induced by carbachol (10 μM) by 34% at 10 μM, 25% at 1 μM, and 17% at 0.1 μM[1].

Hydroxyzine dihydrochloride (12.5 mg/kg, 25 mg/kg, and 50 mg/kg intraperitoneally) only significantly increases the effect of morphine on the vocalization after-discharge, which in rats is thought to be the affective component of pain. It has minimal direct analgesic activity. In the tail-flick test, hydroxyzine dihydrochloride (50 mg/kg i.p.) amplifies morphine, whereas hydroxyzine (12.5 mg/kg i.p.) reduces morphine antinociception in rats[3].

Absorption, Distribution and Excretion
The absolute bioavailability of hydroxyzine has not been ascertained, as intravenous formulations are unavailable due to a risk of hemolysis. Hydroxyzine is rapidly absorbed from the gastrointestinal tract upon oral administration, reaching its maximum plasma concentration (Tmax) approximately 2 hours following administration.
Approximately 70% of hydroxyzine's active metabolite, cetirizine, is excreted unchanged in the urine. The precise extent of renal and fecal excretion in humans has not been determined.
The mean volume of distribution is 16.0 ± 3.0 L/kg. Higher concentrations are found in the skin than in the plasma.
Clearance of hydroxyzine has been reported to be 31.1 ± 11.1 mL/min/kg in children and 9.8 ± 3.3 mL/min/kg in adults.
It is not known if hydroxyzine crosses the placenta or is distributed into milk.
Distribution of hydroxyzine into human body tissues and fluids has not been fully characterized. Following administration of hydroxyzine in animals, the drug is widely distributed into most body tissues and fluids with highest concentrations in the liver, lungs, spleen, kidneys, and adipose tissue. The drug is also distributed into bile in animals.
Hydroxyzine is rapidly absorbed from the GI tract following oral administration.
The distribution into cerebrospinal fluid of 4 structurally similar antihistamines, chlorcyclizine hydrochloride, chlorpheniramine maleate, hydroxyzine hydrochloride (hydroxyzine dihydrochloride), and triprolidine hydrochloride, was studied in Sprague-Dawley rats after the administration of intranasal solutions or intra-arterial injections of solutions of each of the antihistamines; drug concentrations were measured in plasma and cerebrospinal fluid (CSF). Doses of 15.4, 13.3, 8.7, and 16.5 mumol/kg of chlorcyclizine, chlorpheniramine, hydroxyzine, and triprolidine, respectively, were administered. Hydroxyzine plasma and CSF concentrations were significantly greater than most of the other antihistamines. Also, hydroxyzine showed the most rapid absorption into plasma following intranasal administration, and its CSF Cmax values were significantly higher after intranasal administration compared to intra-arterial administration. The ratios of AUC (0-180 min) values for intranasal:intra-arterial administration in CSF and plasma for hydroxyzine were 4 and 0.42 and for triprolidine, the only other antihistamine with measurable CSF concentrations, were 0.54 and 0.66, respectively.
For more Absorption, Distribution and Excretion (Complete) data for HYDROXYZINE (8 total), please visit the HSDB record page.

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Metabolism / Metabolites
Hydroxyzine is metabolized in the liver by CYP3A4 and CYP3A5. While the precise metabolic fate of hydroxyzine is unclear, its main and active metabolite (~45 to 60% of an orally administered dose), generated by oxidation of its alcohol moiety to a carboxylic acid, is the second-generation antihistamine [cetirizine]. Hydroxyzine is likely broken down into several other metabolites, though specific structures and pathways have not been elucidated in humans.
Pharmacokinetic parameters of hydroxyzine and its active metabolite cetirizine were determined after oral and intravenous administration of 2 mg kg(-1) of hydroxyzine to six healthy dogs. Plasma drug levels were determined with high-pressure liquid chromatography. Pharmacodynamic studies evaluated the suppressive effect on histamine and anticanine IgE-mediated cutaneous wheal formation. Pharmacokinetic and pharmacodynamic correlations were determined with computer modelling. The mean systemic availability of oral hydroxyzine was 72%. Hydroxyzine was rapidly converted to cetirizine regardless of the route of administration. The mean area-under-the-curve was eight and ten times higher for cetirizine than hydroxyzine after intravenous and oral dosing, respectively. After oral administration of hydroxyzine, the mean peak concentration of cetirizine was approximately 2.2 ug mL(-1) and that of hydroxyzine 0.16 ug mL(-1). The terminal half-life for cetirizine varied between 10 and 11 hr after intravenous and oral administration of hydroxyzine. A sigmoidal relationship was fit to the data comparing cetirizine plasma concentration to wheal suppression. Maximum inhibition (82% and 69% for histamine and anticanine IgE-mediated skin reactions, respectively) was observed during the first 8 hr, which correlated with a plasma concentration of cetirizine greater than 1.5 ug mL(-1). Pharmacological modelling suggested that increasing either hydroxyzine dosages or frequencies of administration would not result in histamine inhibition superior to that obtained with twice daily hydroxyzine at 2 mg kg(-1). In conclusion, there was rapid conversion of hydroxyzine to cetirizine. The reduction of wheal formation appeared almost entirely due to cetirizine. Pharmacodynamic modelling predicted that maximal antihistamine effect would occur with twice daily oral administration of hydroxyzine at 2 mg kg(-1).
Although the exact metabolic fate of hydroxyzine is not clearly established, it appears that the drug is completely metabolized, principally in the liver. In animals, hydroxyzine and its metabolites are excreted in feces via biliary elimination. The carboxylic acid metabolite of hydroxyzine, cetirizine, is a long-acting antihistamine.
Hepatic
Half Life: 20 to 25 hours

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Biological Half-Life
The half-life of hydroxyzine is reportedly 14-25 hours, and appears to be, on average, shorter in children (~7.1 hours) than in adults (~20 hours). Elimination half-life is prolonged in the elderly, averaging approximately 29 hours, and is likely to be similarly prolonged in patients with renal or hepatic impairment.
Hydroxyzine, a potent H1-receptor antagonist often used for relief of pruritus in patients with hepatic dysfunction, was studied in eight patients, mean age 53.4 +/- SD 11.2 years, with primary biliary cirrhosis. The patients ingested a single dose of hydroxyzine, 0.7 mg/kg (mean dose 43.9 +/- 6.6 mg). Before the dose, then hourly for 6 hours, every 2 hours from 6-12 hours, at 24 hours, and every 24 hours for 6 days, serum hydroxyzine and cetirizine were measured and an intradermal injection of 0.01 mL of a 0.1 mg/mL solution of histamine phosphate was performed. ... The mean serum elimination half-life of hydroxyzine was 36.6 +/- 13.1 hours, and the mean serum elimination half-life of cetirizine was 25.0 +/- 8.2 hours. ...
... The pharmacokinetics and antipruritic effects of hydroxyzine hydrochloride in 12 children, mean age 6.1 +/- 4.6 years, with severe atopic dermatitis /were examined/. After a single 0.7 mg/kg orally administered dose of the drug, ... . The mean elimination half-life was 7.1 +/- 2.3 hours, ... .
... The changes in serum half-life values and clearance rates in dogs who were administered hydroxyzine, 0.7 mg/kg, intramuscularly, daily, for 150 days /were studied/. Pharmacokinetic studies were performed on the first day of drug administration, and on days 30, 60, 90, 120, and 150. The mean serum half-life value on day 30, 60, and 120 was significantly longer (p less than 0.05) than that of 2.4 +/- 0.3 hours obtained on day 1. ...
... The pharmacokinetics and the suppression of histamine-induced wheals, flares, and pruritus in the skin after administration of the histamine H1 antagonist hydroxyzine to seven healthy adults /were studied/. After a single oral dose of hydroxyzine, 0.7 mg/kg (mean dose 39.0 +/- 5.4 mg), ... The mean elimination half-life calculated from the terminal linear portion of the serum hydroxyzine concentration vs. time curve was 20.0 +/- 4.1 hr. ...

Toxicity Summary
Hydroxyzine competes with histamine for binding at H₁-receptor sites on the effector cell surface, resulting in suppression of histaminic edema, flare, and pruritus. The sedative properties of hydroxyzine occur at the subcortical level of the CNS. Secondary to its central anticholinergic actions, hydroxyzine may be effective as an antiemetic.

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Hepatotoxicity
Despite widespread use, hydroxyzine has not been linked to liver test abnormalities or to clinically apparent liver injury. Indeed, hydroxyzine is commonly used for the pruritus associated with liver disease. The reason for its safety may relate to low daily dose and limited duration of use.
Likelihood score: E (unlikely to be a cause of clinically apparent liver injury).
References on the safety and potential hepatotoxicity of antihistamines are given together after the Overview section on Antihistamines.
Drug Class: Antihistamines

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Small occasional doses of hydroxyzine would not be expected to cause any adverse effects in breastfed infants. Larger doses or more prolonged use may cause drowsiness and other effects in the infant or decrease the milk supply, particularly in combination with a sympathomimetic such as pseudoephedrine or before lactation is well established. Other agents are preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
In one telephone follow-up study, mothers reported irritability and colicky symptoms 10% of infants exposed to various antihistamines and drowsiness was reported in 1.6% of infants. None of the reactions required medical attention.
All adverse reactions in breastfed infants reported in France between January 1985 and June 2011 were compiled by a French pharmacovigilance center. Of 174 reports, hydroxyzine was reported to cause adverse reactions in 8 infants and to be one of the drugs most often suspected in serious adverse reactions, primarily sedation.
◉ Effects on Lactation and Breastmilk
Antihistamines in relatively high doses given by injection can decrease basal serum prolactin in nonlactating women and in early postpartum women However, suckling-induced prolactin secretion is not affected by antihistamine pretreatment of postpartum mothers. Whether lower oral doses of antihistamines have the same effect on serum prolactin or whether the effects on prolactin have any consequences on breastfeeding success have not been studied. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
The breastfeeding mother of a 5-week-old infant was diagnosed with bipolar disorder, panic attacks and anxiety disorder. She was started on hydroxyzine 50 mg at an unspecified interval and took it for 3 to 5 days with no effect on milk production. She then started aripiprazole 5 mg at an unspecified interval. After 5 days, she reported a decrease in milk production that required supplementation with formula. Nine days after stopping both drugs, her milk supply returned to normal. The decreased milk supply was possibly caused by the medications, with aripiprazole most likely.

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Protein Binding
Hydroxyzine has been shown to bind to human albumin _in vitro_, but the extent of protein binding in plasma has not been evaluated.

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Toxicity Data
Oral, rat LD₅₀: 950 mg/kg.

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Interactions
Hydroxyzine has been shown to inhibit and reverse the vasopressor effect of epinephrine. If a vasopressor agent is required in patients receiving hydroxyzine, norepinephrine or metaraminol should be used; epinephrine should not be used.
Additive anticholinergic effects may occur when hydroxyzine is administered concomitantly with other anticholinergic agents.
Hydroxyzine may be additive with, or may potentiate the action of, other CNS depressants such as opiates or other analgesics, barbiturates or other sedatives, anesthetics, or alcohol. When hydroxyzine is used concomitantly with other CNS depressants, caution should be used to avoid excessive sedation, and the manufacturers recommend that dosage of the CNS depressant be reduced by up to 50%.
Mechanism of a rise of blood hydroxyzine concentrations due to ethanol administration was investigated used rabbits. When 10 mg/kg hydroxyzine dihydrochloride were orally administered together with 10 mL/kg of 1 to 15% ethanol solution, blood hydroxyzine concentrations rised in all rabbits given ethanol solution more than 10%. When 10 mL/kg of 15% ethanol solution were orally administered at 1, 2 or 3 hours before oral administration of hydroxyzine, blood hydroxyzine concentrations rised markedly in all cases. Blood hydroxyzine concentrations rised little or a little when hydroxyzine were orally administered immediately after intravenous administration of 5 mL/kg of 20% ethanol solution. It was considered that the main mechanism of a rise of blood hydroxyzine concentration was not metabolic interaction between hydroxyzine and ethanol, but an enhancement of intestinal absorption of hydroxyzine due to ethanol. It was also found that hydroxyzine in blood distributed rapidly into bodily tissues.

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Non-Human Toxicity Values
LD50 Rat oral 840 mg/kg
LD50 Rat ip 160 mg/kg
LD50 Rat iv 45 mg/kg
LD50 Mouse oral 480 mg/kg
For more Non-Human Toxicity Values (Complete) data for HYDROXYZINE (6 total), please visit the HSDB record page.

[1]. Hydroxyzine inhibits neurogenic bladder mast cell activation. Int J Immunopharmacol, 1998. 20(10): p. 553-63.

[2]. A study of the influence of hydroxyzine and diazepam on morphine antinociceptoion in the rat. Pain, 1979. 7(2): p. 173-80.

[3]. J Basic Clin Pharm . 2016 Sep;7(4):97-104.

Therapeutic Uses
Anti-Anxiety Agents; Antiemetics; Antipruritics; Histamine H1 Antagonists; Sedatives, Nonbarbiturate
MEDICATION (VET): The efficacy of antihistamines for the treatment of pruritus is highly variable. The most commonly used antihistamines include hydroxyzine hydrochloride ...
MEDICATION (VET): In chronic urticaria, antihistamines such as hydroxyzine may be useful ... in horses ... .
Hydroxyzine has also been used for the management of agitation caused by acute alcohol withdrawal; to reduce opiate analgesic dosage; to control motion sickness; and to control nausea and vomiting of various etiologies (e.g., postoperative). /Included in US product label/
Hydroxyzine is used for the symptomatic management of anxiety and tension associated with psychoneuroses and as an adjunct in patients with organic disease states who have associated anxiety; for the management of pruritus caused by allergic conditions such as chronic urticaria or atopic or contact dermatoses, and in histamine-mediated pruritus; and for its sedative effects before and after general anesthesia. The efficacy of hydroxyzine as an anxiolytic agent during long-term administration (i.e., longer than 4 months) has not been established; most clinicians believe that benzodiazepines, barbiturates, and meprobamate are more effective than hydroxyzine for anxiety. Patients with a history of long-term therapy with hydroxyzine should be evaluated periodically to determine the efficacy and need for further treatment. Hydroxyzine should not be used as the sole agent for the treatment of depression or psychoses. /Included in US product label/

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Drug Warnings
Marked local discomfort, sterile abcesses, erythema, local irritation, and tissue necrosis may occur at the site of IM injection, and marked localized subcutaneous tissue induration has been reported as a result of extravasation of the drug.
The most frequent adverse effects of hydroxyzine are drowsiness and dry mouth. Drowsiness usually diminishes with continued therapy or reduction in dosage. Other less frequent adverse nervous system effects of hydroxyzine include dizziness, ataxia, weakness, slurred speech, headache, agitation, and increased anxiety. Involuntary motor activity, including tremor and seizures, has occurred rarely, usually in patients receiving higher than recommended dosages of the drug.
Patients should be warned that hydroxyzine may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle).
Because of the risk of adverse local effects, which may be severe (e.g., gangrene, thrombosis), IM administration of hydroxyzine should be performed with caution to avoid extravasation or inadvertent subcutaneous, IV, or intra-arterial injection.
For more Drug Warnings (Complete) data for HYDROXYZINE (11 total), please visit the HSDB record page.

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Pharmacodynamics
Hydroxyzine blocks the activity of histamine to relieve allergic symptoms such as pruritus. Activity at off-targets also allows for its use as a sedative anxiolytic and an antiemetic in certain disease states. Hydroxyzine is relatively fast-acting, with an onset of effect that occurs between 15 and 60 minutes and a duration of action between 4-6 hours. Hydroxyzine may potentiate the effects of central nervous system (CNS) depressants following general anesthesia - patients maintained on hydroxyzine should receive reduced doses of any CNS depressants required. Hydroxyzine is reported to prolong the QT/QTc interval based on postmarketing reports of rare events of Torsade de Pointes, cardiac arrest, and sudden death, and should be used with caution in patients with an increased baseline risk for QTc prolongation.

C21H27CLN2O2

374.91

374.176

C, 67.28; H, 7.26; Cl, 9.46; N, 7.47; O, 8.53

68-88-2

Hydroxyzine dihydrochloride; 2192-20-3; Hydroxyzine-d4 dihydrochloride; 1219805-91-0; Hydroxyzine-d8; 1189480-47-4; Hydroxyzine pamoate; 10246-75-0; Hydroxyzine-d4 dihydrochloride; 1244-76-4 (HCl); 5978-92-7 (pamoate ester)

3658

Colorless to light yellow solid powder

220 (0.5 torr)

190°C

2.931

1

4

8

26

376

0

ClC1=CC=C(C(N2CCN(CCOCCO)CC2)C3=CC=CC=C3)C=C1

ZQDWXGKKHFNSQK-UHFFFAOYSA-N

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

2-[2-[4-[(4-chlorophenyl)-phenylmethyl]piperazin-1-yl]ethoxy]ethanol

NSC-169188; NSC169188; Hydroxyzine; NSC 169188; U.C.B 4492

2933.59.9500

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)