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
Due to the risk of hemolysis, there is currently no intravenous formulation available; therefore, the absolute bioavailability of hydroxyzine has not been determined. Following oral administration, hydroxyzine is rapidly absorbed from the gastrointestinal tract, reaching peak plasma concentration (Tmax) approximately 2 hours after administration. Approximately 70% of the active metabolite of hydroxyzine, cetirizine, is excreted unchanged in the urine. Its renal and fecal excretion in humans has not been determined. The mean volume of distribution is 16.0 ± 3.0 L/kg. Drug concentrations in the skin are higher than in plasma. The reported clearance of hydroxyzine is 31.1 ± 11.1 mL/min/kg in children and 9.8 ± 3.3 mL/min/kg in adults. It is currently unknown whether hydroxyzine crosses the placenta or is secreted into breast milk. The distribution of hydroxyzine in human tissues and fluids is not fully understood. Animal studies have shown that hydroxyzine is widely distributed in most body fluids and tissues, with the highest concentrations found in the liver, lungs, spleen, kidneys, and adipose tissue. The drug is also distributed into the bile in animals. After oral administration, hydroxyzine is rapidly absorbed from the gastrointestinal tract. This study investigated the distribution of four structurally similar antihistamines—chlorcyclorhizine hydrochloride, chlorpheniramine maleate, hydroxyzine hydrochloride (dihydroxyzine), and triprolidine hydrochloride—in the cerebrospinal fluid of Sprague-Dawley rats via intranasal or intra-arterial administration; and measured drug concentrations in plasma and cerebrospinal fluid. Chlorcyclorhizine, chlorpheniramine, hydroxyzine, and triprolidine were administered at doses of 15.4, 13.3, 8.7, and 16.5 μmol/kg, respectively. The plasma and cerebrospinal fluid concentrations of hydroxyzine were significantly higher than those of most other antihistamines. Furthermore, hydroxyzine is absorbed most rapidly into plasma after intranasal administration, and its cerebrospinal fluid (CSF) Cmax value is significantly higher after intranasal administration than after intra-arterial administration. The ratios of AUC (0–180 min) in CSF and plasma after intranasal and intra-arterial administration of hydroxyzine are 4 and 0.42, respectively, while the corresponding ratios for triprolidine (the only other antihistamine whose CSF concentration can be measured) are 0.54 and 0.66, respectively. For more complete data on the absorption, distribution, and excretion of hydroxyzine (a total of 8 types), please visit the HSDB record page. Hydroxyzine is metabolized in the liver via CYP3A4 and CYP3A5. The exact metabolic pathway of hydroxyzine is not fully understood; its major active metabolite (approximately 45% to 60% of the oral dose) is the second-generation antihistamine [cetirizine], produced by the oxidation of its alcohol group to a carboxylic acid. Hydroxyzine may also be broken down into several other metabolites, but their specific structures and metabolic pathways in the human body have not been elucidated. This study determined the pharmacokinetic parameters of hydroxyzine and its active metabolite cetirizine after oral and intravenous administration of 2 mg/kg hydroxyzine to six healthy dogs. Plasma drug concentrations were determined using high-performance liquid chromatography (HPLC). Pharmacodynamic studies evaluated the inhibitory effects of hydroxyzine on histamine and anti-canine IgE-mediated skin wheal formation. Computer modeling was used to determine the correlation between pharmacokinetic and pharmacodynamic parameters. The mean systemic bioavailability of orally administered hydroxyzine was 72%. Regardless of the route of administration, hydroxyzine was rapidly converted to cetirizine. The mean area under the curve (AUC) of cetirizine after intravenous and oral administration was 8 and 10 times that of hydroxyzine, respectively. After oral administration of hydroxyzine, the mean peak concentration of cetirizine was approximately 2.2 μg/mL, while that of hydroxyzine was approximately 0.16 μg/mL. The terminal half-life of cetirizine was 10 to 11 hours after both intravenous and oral administration of hydroxyzine. The relationship between cetirizine plasma concentration and wheal inhibition rate exhibited an S-shaped curve. The maximum inhibition rate (82% and 69% inhibition rates of histamine and anti-canine IgE-mediated skin responses, respectively) was observed within the first 8 hours after administration, which was associated with cetirizine plasma concentrations above 1.5 μg/mL. Pharmacological models indicated that increasing the dose or frequency of hydroxyzine did not inhibit histamine more effectively than twice-daily administration of 2 mg/kg hydroxyzine. In summary, hydroxyzine is rapidly converted to cetirizine. The reduction in wheal formation was almost entirely attributed to cetirizine. Pharmacodynamic models predicted that twice-daily oral administration of 2 mg/kg hydroxyzine would achieve the maximum antihistamine effect.
Although the exact metabolic pathway of hydroxyzine is not fully understood, the drug appears to be entirely metabolized in the liver. In animals, hydroxyzine and its metabolites are excreted via bile and ultimately excreted in feces. Cetirizine, the carboxylic acid metabolite of hydroxyzine, is a long-acting antihistamine.
Liver
Half-life: 20 to 25 hours

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Biological Half-life
The half-life of hydroxyzine has been reported to be 14-25 hours, with the average half-life in children (approximately 7.1 hours) appearing to be shorter than in adults (approximately 20 hours). The elimination half-life is prolonged in the elderly, averaging approximately 29 hours, and may also be prolonged in patients with impaired renal or hepatic function.
Hydrazine is a potent H1 receptor antagonist commonly used to relieve pruritus symptoms in patients with hepatic impairment. This study included 8 patients with primary biliary cirrhosis, with a mean age of 53.4 ± 11.2 years. Patients received a single dose of hydroxyzine at a dose of 0.7 mg/kg (mean dose 43.9 ± 6.6 mg). Serum hydroxyzine and cetirizine concentrations were measured before administration, followed by hourly administration (for 6 hours), then every 2 hours from 6 to 12 hours, then every 2 hours after 24 hours, and then every 24 hours thereafter (for 6 days). Intradermal injection of 0.01 mL of 0.1 mg/mL histamine phosphate solution was also administered. …The mean serum elimination half-life of hydroxyzine was 36.6 ± 13.1 hours, and that of cetirizine was 25.0 ± 8.2 hours. … The pharmacokinetics and antipruritic effect of hydroxyzine hydrochloride were studied in 12 children with severe atopic dermatitis of mean age 6.1 ± 4.6 years. After a single oral dose of 0.7 mg/kg, … The mean elimination half-life was 7.1 +/- 2.3 hours, … … The changes in serum half-life and clearance in dogs after daily intramuscular injection of 0.7 mg/kg hydroxyzine for 150 days were studied. Pharmacokinetic studies were performed on day 1 and on days 30, 60, 90, 120, and 150. The mean serum half-life values on days 30, 60, and 120 were significantly longer than the 2.4 ± 0.3 hours obtained on day 1 (p < 0.05). …The pharmacokinetics and inhibitory effects on histamine-induced skin wheals, erythema, and pruritus following administration of the histamine H1 receptor antagonist hydroxyzine were investigated in seven healthy adults. Following a single oral dose of 0.7 mg/kg hydroxyzine (mean dose 39.0 ± 5.4 mg)…the mean elimination half-life calculated from the linear portion at the end of the serum hydroxyzine concentration-time curve was 20.0 ± 4.1 hours. …

Toxicity Summary
Hydroxyzine competitively binds to H1 receptors on the surface of effector cells with histamine, thereby inhibiting histamine-induced edema, erythema, and pruritus. The sedative effect of hydroxyzine occurs in the subcortical central nervous system. Due to its central anticholinergic effects, hydroxyzine may have an antiemetic effect. Hepatotoxicity
Although hydroxyzine is widely used, it has not been found to be associated with abnormal liver function or clinically significant liver injury. In fact, hydroxyzine is often used to treat pruritus associated with liver disease. Its safety may be related to the low daily dose and limited duration of use. Probability Score: E (Unlikely to cause clinically significant liver injury). References on the safety and potential hepatotoxicity of antihistamines are listed after the "Antihistamine Overview" section. Drug Category: Antihistamines Effects During Pregnancy and Lactation ◉ Summary of Use During Lactation Occasional small doses of hydroxyzine are not expected to have any adverse effects on breastfed infants. Larger doses or prolonged use may cause drowsiness and other adverse reactions in infants, or reduce milk production, especially when used in combination with sympathomimetic drugs (such as pseudoephedrine) or before lactation is fully established. Other medications are preferable, especially when breastfeeding newborns or premature infants.
◉ Effects on breastfed infants
In a telephone follow-up study, mothers reported that 10% of infants exposed to various antihistamines experienced irritability and colic, and 1.6% experienced drowsiness. None of the adverse reactions required medical attention.
The French National Center for Drug Vigilance compiled all reported adverse reactions in breastfed infants in France between January 1985 and June 2011. Of the 174 reports, hydroxyzine was reported to cause adverse reactions in 8 infants and was one of the most frequently suspected drugs for serious adverse reactions (mainly sedation).
◉ Effects on Lactation and Breast Milk
Higher doses of injected antihistamines can lower basal serum prolactin levels in non-lactating women and early postpartum women. However, pre-administration of antihistamines by postpartum mothers does not affect suckling-induced prolactin secretion. Whether lower oral doses of antihistamines have the same effect on serum prolactin, and whether this effect on prolactin has any impact on breastfeeding success, is currently unknown. Prolactin levels in established lactating mothers may not affect their breastfeeding ability.
A breastfeeding mother of a 5-week-old infant was diagnosed with bipolar disorder, panic attacks, and anxiety. She started taking hydroxyzine 50 mg for an unknown period of 3 to 5 days, but it had no effect on milk production. She then started taking aripiprazole 5 mg for an unknown period. After 5 days, she reported a decrease in milk production and the need for formula supplementation. Her milk production returned to normal 9 days after discontinuing both medications. Reduced milk production may be drug-induced, with aripiprazole being the most likely culprit. Protein Binding: In vitro studies have shown that hydroxyzine binds to human serum albumin, but its plasma protein binding has not been assessed. Toxicity Data: Oral LD50 in rats: 950 mg/kg. Interactions: Hydroxyzine has been shown to inhibit and reverse the vasoconstrictive effects of epinephrine. If a patient taking hydroxyzine requires vasoconstriction, norepinephrine or metaraminol should be used; epinephrine should not be used. Anticholinergic Effects: When used in combination with other anticholinergic drugs, hydroxyzine may have additive anticholinergic effects. Hydrazine may have additive or synergistic effects with other central nervous system depressants (such as opioids or other analgesics, barbiturates or other sedatives, anesthetics, or alcohol). When hydroxyzine is used in combination with other central nervous system depressants, excessive sedation should be avoided. Manufacturers recommend reducing the dose of central nervous system depressants by up to 50%. A study using rabbits investigated the mechanism of increased blood hydroxyzine concentrations after ethanol administration. When 10 mg/kg hydroxyzine hydrochloride and 10 mL/kg of a 1%–15% ethanol solution were administered orally simultaneously, blood hydroxyzine concentrations increased in all rabbits given ethanol concentrations exceeding 10%. When 10 mL/kg of a 15% ethanol solution was administered orally 1, 2, or 3 hours before oral administration of hydroxyzine, blood hydroxyzine concentrations increased significantly in all rabbits. When hydroxyzine was administered orally immediately after an intravenous injection of a 5 mL/kg 20% ethanol solution, the increase in blood hydroxyzine concentration was small or only slight. The study suggests that the main mechanism of increased blood hydroxyzine concentration is not the metabolic interaction between hydroxyzine and ethanol, but rather that ethanol enhances the intestinal absorption of hydroxyzine. The study also found that hydroxyzine in the blood can be rapidly distributed to body tissues.

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Non-human toxicity values
Oral LD50 in rats: 840 mg/kg
Intraperitoneal LD50 in rats: 160 mg/kg
Intravenous LD50 in rats: 45 mg/kg
Oral LD50 in mice: 480 mg/kg
For more complete non-human toxicity data for hydroxyzines (6 in 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 medication; antiemetic; antipruritic; histamine H1 receptor antagonist; non-barbiturate sedative. Veterinary drugs: The efficacy of antihistamines in treating pruritus varies greatly. The most commonly used antihistamines include hydroxyzine hydrochloride… Veterinary drugs: In chronic urticaria, antihistamines such as hydroxyzine may be effective in horses… Hydroxyzine is also used to treat agitation caused by acute alcohol withdrawal; to reduce the dosage of opioid analgesics; to control motion sickness; and to control nausea and vomiting from various causes (e.g., postoperative). /US product label includes/ Hydroxyzine is used to relieve anxiety and tension symptoms associated with neurosis and as adjunctive therapy for patients with organic diseases accompanied by anxiety; to treat pruritus caused by allergic diseases (such as chronic urticaria, atopic dermatitis, or contact dermatitis), as well as histamine-mediated pruritus; and for sedation before and after general anesthesia. The long-term efficacy (i.e., more than 4 months) of hydroxyzine as an anti-anxiety medication has not been established; most clinicians believe that benzodiazepines, barbiturates, and meprobamate are more effective than hydroxyzine in treating anxiety. Patients with a history of long-term hydroxyzine use should be regularly evaluated for efficacy and whether further treatment is needed. Hydroxyzine should not be used as the sole medication for treating depression or psychosis. /US product label contains/

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Drug Warnings
After intramuscular injection, significant local discomfort, sterile abscess, erythema, local irritation, and tissue necrosis may occur at the injection site; extravasation has been reported to cause significant local subcutaneous induration.
The most common adverse reactions to hydroxyzine are drowsiness and dry mouth. Drowsiness usually decreases with continued treatment or dose reduction. Other less common neurological adverse reactions to hydroxyzine include dizziness, ataxia, weakness, slurred speech, headache, agitation, and increased anxiety. Rarely, involuntary movements, including tremors and seizures, may occur, usually in patients taking doses higher than recommended. Patients should be informed that hydroxyzine may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle). Due to the risk of local adverse reactions, which can be serious (e.g., gangrene, thrombosis), hydroxyzine should be administered intramuscularly with caution to avoid extravasation or accidental subcutaneous, intravenous, or intra-arterial injection. For more complete data on hydroxyzine (11 in total), please visit the HSDB record page.

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Pharmacodynamics
Hydroxine relieves allergic symptoms such as itching by blocking the activity of histamine. Due to its non-target activity, hydroxyzine may also be used as a sedative, anti-anxiety, and antiemetic in certain disease states. Hydroxine has a relatively rapid onset of action, ranging from 15 to 60 minutes, and a duration of action of 4 to 6 hours. After general anesthesia, hydroxyzine may enhance the effects of central nervous system (CNS) depressants—therefore, patients taking hydroxyzine should reduce the required dose of CNS depressants. Post-marketing reports indicate that hydroxyzine can prolong the QT/QTc interval and has been associated with rare events such as torsades de pointes, cardiac arrest, and sudden death. Therefore, hydroxyzine should be used with caution in patients at high risk of QTc interval 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.)