Hydroxyzine Pharmacology

Background: – Hydroxyzine Pharmacology Hydroxyzine, common brands Atarax, and Vistaril, is a first-generation antihistamine. It is a part of the piperazine drug class[1], sharing structural similarities to other antihistamines like Cetirizine, but also drugs of other classes like ranolazine, buspirone, clozapine. Being an H1 blocker, hydroxyzine is commonly used for itching, anxiety, analgesia, urticaria, and insomnia. The main adverse drug reactions associated with hydroxyzine are the anticholinergic effects common with most antihistamines, dry mouth, headache, urinary retention, QTC prolongation, drowsiness[2].

Interactions: Due to hydroxyzine’s pharmacology and mechanism of action, it can exacerbate or worsen gastroparesis by decreasing smooth muscle contraction in the GI tract, and has similar effects on benign prostatic hyperplasia by worsening urinary retention. Hydroxyzine is metabolized into its active drug, cetirizine, by CYP3A4 and CYP3A5[3]. As such, hydroxyzine’s efficacy can be increased with concomitant use of rifampin, carbamazepine, St. John’s Wort; and its efficacy can be decreased with concomitant use of certain azole antifungals, verapamil or diltiazem, or grapefruit juice. The anticholinergic effects can also be compounded when taken with other anticholinergic drugs and can decrease the efficacy of certain dementia medications, like clonidine. Although uncommon, the risk of QTC prolongation, and Torsades de Pointes, can be increased when taken with potassium channel blocking agents like amiodarone or sotalol, or other agents like certain antibiotics and antipsychotics[4][5].

PK/PD & toxicity: Hydroxyzine has an onset of action between 15-60 minutes and a duration of action between 4-6 hours[3]. The half-life of hydroxyzine varies with age. On average, it is 7.1 hours in children, 20 hours in adults[6], and 29 hours in the elderly, and should be dosed appropriately[7]. Its volume of distribution is 16±3 L/kg with high concentrations found in the skin than in plasma[3]. Its clearance is 31.1±11.1 mL/min/kg in children and 9.8±3.3 mL/min/kg in adults. The active drug of hydroxyzine is excreted around 70% unchanged in the urine[6]. Overdoses can be characterized by sedation, but can also cause nausea, vomiting, and seizures. General supportive care of the symptoms is needed for treatment. Vomiting should be induced if it has not occurred. Immediate gastric lavage is also recommended[8].

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[1] Fifer EK. Drugs Used to Treat Ocular and Nasal Congestion Disorders. In: Roche VF, Zito SW, Lemke TL, Williams DA. Eds. Foye’s Principles of Medicinal Chemistry 8e. Lippincott Williams & Wilkins; Accessed May 15, 2021.

[2] Katzung BG. Histamine, Serotonin, & the Ergot Alkaloids. In: Katzung BG, Vanderah TW. eds. Basic & Clinical Pharmacology, 15e. McGraw-Hill; Accessed May 15, 2021.

[3] Altamura AC, Moliterno D, Paletta S, Maffini M, Mauri MC, Bareggi S: Understanding the pharmacokinetics of anxiolytic drugs. Expert Opin Drug Metab Toxicol. 2013 Apr;9(4):423-40. doi: 10.1517/17425255.2013.759209. Epub 2013 Jan 21.

[4] Schlit AF, Delaunois A, Colomar A, Claudio B, Cariolato L, Boev R, Valentin JP, Peters C, Sloan VS, Bentz JWG: Risk of QT prolongation and torsade de pointes associated with exposure to hydroxyzine: re-evaluation of an established drug. Pharmacol Res Perspect. 2017 Apr 21;5(3):e00309. doi: 10.1002/prp2.309. eCollection 2017 Jun.

[5] Nachimuthu S, Assar MD, Schussler JM. Drug-induced QT interval prolongation: mechanisms and clinical management. Ther Adv Drug Saf. 2012;3(5):241-253. doi:10.1177/2042098612454283

[6] Paton DM, Webster DR: Clinical pharmacokinetics of H1-receptor antagonists (the antihistamines). Clin Pharmacokinet. 1985 Nov-Dec;10(6):477-97.

[7] Simons KJ, Watson WT, Chen XY, Simons FE: Pharmacokinetic and pharmacodynamic studies of the H1-receptor antagonist hydroxyzine in the elderly. Clin Pharmacol Ther. 1989 Jan;45(1):9-14. doi: 10.1038/clpt.1989.2.

[8] FDA Approved Drug Products: Vistaril (hydroxyzine pamoate)

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