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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Show notes written by Chong Yol G Kim, PharmD Student

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References

[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)

Diazepam Pharmacology

Diazepam has numerous dosage forms. There are rectal, injectable, and oral formulations of the drug that are commonly used in clinical practice.

Diazepam has 2 major metabolic pathways. It is broken down primarily by CYP3A4 and CYP2C19, leaving open the potential for numerous drug interactions. I discuss this further in the podcast.

Diazepam is on the Beers list because it has a tendency to accumulate in the geriatric patient population and cause adverse effects like sedation, confusion, and falls.

Respiratory depression, coma, and death are significantly more likely in overdose situations where opioids are used in combination with benzodiazepines like diazepam.

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Buspirone Pharmacology

Buspirone is an anti-anxiety medication that has the potential of having some serotonin agonist activity.

Buspirone has a very high first-pass metabolism. This means that the body breaks much of the medication down prior to it getting into the systemic circulation.

Buspirone is broken down by CYP3A4, so concomitant use with inhibitors or inducers can alter its concentrations

Buspirone should not be used as needed as this medication takes a while to start to show benefit.

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