Collated from TripSit, Pharmacology, DrugCentral. Where sources differ (e.g. dosing), Compare shows them side by side.
Also known as vistaril, ataraxTS
An antihistamine drug commonly prescribed for anxiety, itchiness, nausea, and insomnia. Hydroxyzine has also been used to potentiate the analgesia of opioids as well as diminishing the negative effects of opioids, such as itchiness.TS
Oral
Route dataTripSit
| Threshold | Light | Common | Strong | Heavy |
|---|---|---|---|---|
| — | — | 25–100 mg | — | —+ |
| Onset | 20–60 minutes |
|---|---|
| Total | 3–5 hours |
| After-effects | 1–8 hours |
🧬 Receptor activityDC
| Target | Action | Affinity | Source | |
|---|---|---|---|---|
| Histamine H1 receptor (HRH1) | Antagonist | 8.699 Ki | DRUGCENTRAL | TargetHistamine H1 receptor (HRH1) ActionAntagonist Affinity8.699 Ki SourceDRUGCENTRAL |
| 5-hydroxytryptamine receptor 2A (HTR2A) | — | 7.3 Ki | DRUGCENTRAL | Target5-hydroxytryptamine receptor 2A (HTR2A) Action— Affinity7.3 Ki SourceDRUGCENTRAL |
| Cytochrome P450 2D6 (CYP2D6) | — | 5.409 Ki | DRUGCENTRAL | TargetCytochrome P450 2D6 (CYP2D6) Action— Affinity5.409 Ki SourceDRUGCENTRAL |
| D(2) dopamine receptor (DRD2) | — | 6.42 Ki | DRUGCENTRAL | TargetD(2) dopamine receptor (DRD2) Action— Affinity6.42 Ki SourceDRUGCENTRAL |
| Envelope glycoprotein gp160 (env) | — | 5.2 IC50 | DRUGCENTRAL | TargetEnvelope glycoprotein gp160 (env) Action— Affinity5.2 IC50 SourceDRUGCENTRAL |
Mechanism of actionPH
The H<sub>1</sub> histamine receptor is responsible for mediating hypersensitivity and allergic reactions. Exposure to an allergen results in degranulation of mast cells and basophils, which then release histamine and other inflammatory mediators. Histamine binds to, and activates, H<sub>1</sub> receptors, which results in the further release of pro-inflammatory cytokines, such as interleukins, from basophils and mast cells. These downstream effects of histamine binding are responsible for a wide variety of allergic symptoms, such as pruritus, rhinorrhea, and watery eyes. Hydroxyzine is a potent inverse agonist of histamine H<sub>1</sub>-receptors - inverse agonists are agents that are considered to have a "negative efficacy", so rather than simply blocking activity at a receptor they actively dampen its activity. Inverse agonism at these receptors is responsible for hydroxyzine's efficacy in the treatment of histaminic edema, flare, and pruritus. Hydroxyzine is not a cortical depressant, so its sedative properties likely occur at the subcortical level of the CNS. These sedative properties allow activity as an anxiolytic. Antiemetic efficacy is likely secondary to activity at off-targets.
Hydroxyzine does not appear to increase gastric secretions or acidity, and usually has mild antisecretory effects. The antispasmodic activity of hydroxyzine is apparently mediated through interference with the mechanism that responds to spasmogenic agents such as acetylcholine, histamine, and serotonin.
Hydroxyzine has CNS depressant, anticholinergic, antispasmodic, and local anesthetic activity, in addition to antihistaminic effects. The drug also has sedative and antiemetic activity. The sedative and tranquilizing effects of hydroxyzine are thought to result principally from suppression of activity at subcortical levels of the CNS; the drug does not have cortical depressant activity. The precise mechanism of antiemetic and antimotion sickness actions of hydroxyzine are unclear, but appear to result, at least in part, from its central anticholinergic and CNS depressant properties.
The effects of the drug hydroxyzine on the activities of the rat liver monoamine oxidases (EC 1.4.3.6; MAO) and the membrane-bound and soluble forms of bovine semicarbazide-sensitive amine oxidase (EC 1.4.3.6; SSAO) were studied. Hydroxyzine was found to be a competitive inhibitor of MAO-B (Ki - 38 microM), whereas it had a low potency towards MAO-A (IC50 > 630 microM). Although it was a relatively potent competitive inhibitor of bovine plasma SSAO (Ki approximately 1.5 microM), it was a weak inhibitor of the membrane-bound form of the enzyme from bovine lung (IC50 approximately 1 mM). These findings extend our knowledge of the drug binding capabilities of the amine oxidases and suggest that these interactions may contribute to the complex actions of this drug.
PharmacodynamicsPH
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.
Pharmacokinetics
Half-lifePH
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. ...
AbsorptionPH
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.
MetabolismPH
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
Protein bindingPH
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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External links
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.