Hydroxyzine

Hydroxyzine is a first-generation antihistaminic belonging to the Antihistamine class.

Hydroxyzine is used in the treatment of Anxiety, Pruritus, Urticaria, and Peripartum management

Hydroxyzine is Rapidly absorbed from the gastrointestinal tract. Bioavailability: Approx 80% (oral). Time to peak plasma concentration: Approx 2 hours and get Widely distributed into most tissues including the bile with the highest concentration in the liver, lungs, spleen, kidneys, and adipose tissue. Crosses the blood-brain barrier and placenta. The volume of distribution: Approx 16±3 L/kg.It is mainly metabolized in the liver via oxidation by alcohol dehydrogenase, CYP3A4, and CYP3A5 to cetirizine as the major active metabolite and gets excreted Via urine (as cetirizine: 25% oral; 16% IM). Elimination half-life: Approx 20 hours (cetirizine).

Onset: Sedative action: 15-30 minutes (oral); rapid (IM).

Duration: Sedative action: 4-6 hours (oral). Decreased histamine-induced wheal and flare areas: 2 to ≥36 hours. Suppression of pruritus: 1-12 hours.

For Oral hydroxyzine,  Tmax is typically reached in 2 to 4 hours after ingestion and for Intramuscular and intravenous Tmax is typically reached within 30 minutes after injection.

Cmax is typically reached at about 1-2 hours after ingestion

Hydroxyzine shows common side effects like insomnia, confusion, hallucination, nervousness, disorientation, depression, anxiety, and mood changes. Renal and urinary disorders: Crystalluria (high doses).

Hydroxyzine is available in tablets, capsules, suspension, and injection

Hydroxyzine is available in India, Germany, Canada, and France.

Hydroxyzine is an antihistamine medication that works by blocking the effects of histamine, a natural substance in the body that is involved in the inflammatory and allergic response. It works by binding to histamine receptors, specifically the H1 receptors, and preventing the activation of these receptors.

Hydroxyzine is available in the form of tablets , capsules, suspension,s and injection

IM:  For IM use only. Aspirate before injection to avoid inadvertent injection into a blood vessel. Do NOT administer IV, Subcutaneously, or intra-arterially (contraindicated). Administer IM deep in large muscles. The preferred site is the upper outer quadrant of the buttock or mid-lateral thigh. The upper outer quadrant of the gluteal region should be used only when necessary to minimize potential damage to the sciatic nerve. The deltoid region should be only used with caution to avoid radial nerve injury. Injections should not be made in the lower or mid-third of the upper arm.

Oral:  Administer without regard to food. Shake the suspension vigorously prior to use.

Hydroxyzine is used in the treatment of Anxiety, Pruritus, Urticaria, and Peripartum management.

Hydroxyzine, a piperazine derivative, competitively blocks histamine H1-receptors on effector cells of the gastrointestinal tract, blood vessels and respiratory tract, thereby inhibiting H1-receptor-mediated reactions such as vasodilation, flare and itch reactions, and sneezing. It is a sedating antihistamine with antimuscarinic and sedative effects, skeletal muscle relaxing, bronchodilator, antiemetic and analgesic properties.

Hydroxyzine is approved for use in the following clinical indications

• Anxiety: Symptomatic relief of anxiety.
• Pruritus: Management of pruritus due to allergic conditions (eg, atopic and contact dermatoses) and histamine-mediated pruritus.
• Peripartum management, adjunct to opioids: As prepartum and postpartum adjunctive medication to permit a reduction in opioid dosage, allay anxiety, and control emesis.
• Urticaria, new onset and chronic spontaneous: Management of urticaria.

• Anxiety, monotherapy, or adjunctive therapy (alternative agent):

Note: May be useful for insomnia associated with anxiety or for short-term immediate control of symptoms until maintenance therapy is effective.

Oral: Usual dosage range: 25 to 50 mg up to 4 times daily, as needed; may increase based on response and tolerability up to 400 mg/day; maximum single dose: 100 mg. For insomnia associated with anxiety, administer at bedtime

• Peripartum management, adjunct to opioids:

Note: May be used to potentiate opioid analgesia and decrease side effects (eg, nausea and vomiting).

IM: 25 to 50 mg as a single dose; may repeat after 4 hours if needed

Pruritus: Oral: 10 to 25 mg 3 to 4 times daily as needed. Some experts may use single doses up to 50 mg.

• Urticaria, new onset and chronic spontaneous (alternative agent):

Note: Second-generation H1-antihistamines are preferred due to less sedating and anticholinergic effects (Ref). May consider use in combination with a second-generation H1-antihistamine in patients in whom bedtime sedating effects may be beneficial, or as initial parenteral therapy in patients with new-onset urticaria in whom more rapid onset of action is desired; avoid use in patients with high-risk occupations (eg, pilots, bus drivers) or who may be more prone to anticholinergic effects (eg, older adults) .

Oral: Initial: 10 to 25 mg at bedtime. May increase in 10 to 25 mg increments at weekly intervals if needed based on response and tolerability; daily dose may be administered at bedtime or in 3 to 4 divided doses . Some experts administer daily doses >100 mg in divided doses; do not exceed 200 mg/day

IM (off label; new onset only): 25 to 50 mg 3 to 4 times per day as needed

Hydroxyzine is available in the dosage strength of

Tablets: 10 mg, 25 mg, and 50 mg

Capsules: 25 mg, 50 mg, and 100 mg

Oral suspension: 10 mg per 5 mL

Injection: 25 mg/mL

Hydroxyzine is available in the form of tablets, capsules, suspension, and injection.

• Dosage Adjustment in Kidney Patient

Altered kidney function:

Oral, IM:

CrCl ≥50 mL/minute: No dosage adjustment necessary.

CrCl 10 to <50 mL/minute: Administer ~50% of usual dose.

CrCl <10 mL/minute: Administer ~25% to 50% of usual dose.

Hemodialysis, intermittent (thrice weekly): Hydroxyzine is unlikely to be significantly dialyzed (large V_d)and its metabolite (cetirizine) is <10% dialyzable.

Oral, IM: Administer 25 to 50% of usual dose.

Peritoneal dialysis: Unlikely to be significantly dialyzed (large V_d):

Oral, IM: Administer 25 to 50% of usual dose.

CRRT: Oral, IM: Administer 50% of usual dose.

PIRRT (eg, sustained, low-efficiency diafiltration): Oral, IM: Administer 50% of usual dose.

Dosage Adjustment for Pediatric Patients:

• Antiemetic:

Note: Expert recommendations for postoperative nausea and vomiting (PONV) management do not suggest hydroxyzine as a therapeutic option; use has typically been replaced by newer agents with an improved safety profile (Ref). Infants, Children, and Adolescents: IM: 1.1 mg/kg/dose; maximum dose: 100 mg/dose.

• Anxiety:

Note: Although FDA approved for use in anxiety, data in pediatric patients are sparse; expert recommendations for pediatric patients do not consider hydroxyzine a therapeutic option for the management of anxiety disorders (eg, generalized anxiety disorder, separation anxiety, specific phobias, panic disorder, PTSD); use has generally been replaced by newer, more effective agents.

• Pruritus:

associated with allergic conditions or chronic urticaria: Children and Adolescents:

Age-directed dosing:

Children <6 years: Oral: 12.5 mg 3 to 4 times daily.

Children ≥6 years and Adolescents: Oral: 12.5 to 25 mg 3 to 4 times daily (Ref). Note: Based on pharmacokinetic studies, dosing once daily (at bedtime) or twice daily may be adequate due to the long half-life .

Weight-directed dosing:

Patient weight ≤40 kg: Oral: 2 mg/kg/day divided every 6 to 8 hours as needed; maximum dose: 25 mg/dose. Note: Based on pharmacokinetic studies, dosing once daily (at bedtime) or twice daily may be adequate due to the long half-life.

Patient weight >40 kg: Oral: 25 to 50 mg once daily at bedtime or twice daily.

Children and Adolescents: Oral: 0.5 mg/kg/dose every 6 hours; maximum dose is age-dependent: Age <6 years: 12.5 mg/dose; age ≥6 years: 25 mg/dose .

Note: In pediatric patients, some experts have recommended lower initial doses, although reported experience is lacking. In adults, experts suggest a lower daily dosing regimen of 37.5 to 75 mg/day in divided doses.

• Pruritus;

associated with opioid use: Limited data available: Children and Adolescents: IM, Oral: 0.5 mg/kg/dose every 6 hours as needed; usual maximum dose: 50 mg/dose.

• Sedation; pre-/postoperative, adjunctive therapy:

Note: Although FDA approved, pre-/postoperative hydroxyzine use has largely been replaced by other agents.

Oral: Children and Adolescents: 0.6 mg/kg/dose; maximum dose: 100 mg/dose.

IM: Infants, Children, and Adolescents: 1.1 mg/kg/dose; maximum dose: 100 mg/dose.

• Sedation; procedural, adjunctive therapy (eg, dental, echocardiography):

Limited data available: Children 2 to 12 years: Oral: 1 mg/kg/dose as a single dose 30 to 45 minutes prior to procedure in combination with other sedatives (eg, midazolam, chloral hydrate) has been used in children prior to dental procedures or echocardiograms; maximum dose: 100 mg/dose

Take after eating and with a full glass of water to decrease gastric upset.

Hydroxyzine is an antihistamine medication used to relieve symptoms of allergies and anxiety. While generally considered safe, there are some contraindications that should be taken into consideration before using hydroxyzine. These include:

• Hypersensitivity: Hydroxyzine should not be used in patients who have a known hypersensitivity to the drug.
• Narrow-angle glaucoma: Hydroxyzine can increase the pressure inside the eye, and should not be used in patients with narrow-angle glaucoma.
• Severe liver disease: Hydroxyzine is metabolized in the liver, and patients with severe liver disease may not be able to effectively metabolize the drug.
• Pregnancy and breastfeeding: Hydroxyzine should be used with caution in pregnant and breastfeeding women, as its safety in these populations has not been fully established.
• Elderly patients: Hydroxyzine should be used with caution in elderly patients, as they may be more sensitive to the sedative effects of the drug.

Concerns related to adverse effects:

• QT prolongation/torsades de pointes: Oral hydroxyzine is contraindicated in patients with a prolonged QT interval.

Disease-related concerns:

• Glaucoma: Use with caution in patients with narrow-angle glaucoma; the condition may be exacerbated by the cholinergic blockade. Screening is recommended.

• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.

• Respiratory disease: Use with caution in patients with asthma or chronic obstructive pulmonary disease (COPD).

Special populations:

Older adult: May cause over-sedation in older adults; avoid use.

Hydroxyzine may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

Hydroxyzine is an antihistamine medication that is commonly used to treat allergies and allergic reactions. While there is limited information on the safety of Hydroxyzine use during breastfeeding, the drug is generally considered to be compatible with breastfeeding.

Oral formulations should be administered on an empty stomach with water (at least 1 hour before or 2 hours after meals, milk, or other dairy products). Maintain fluid intake to ensure adequate hydration and urinary output.

• Common Adverse effects

Irritation in the nose or throat (with nasal spray) Hoarseness or changes in voice (with inhalation) Headache Nausea Cough Sore throat Runny or stuffy nose Sinus pain Dry mouth or throat Skin rash or itching (with topical use)

• Less Common Adverse effects:

Allergic reactions, including hives, itching, or difficulty breathing Eye problems, such as cataracts or glaucoma (with long-term use) Growth suppression in children (with long-term use) High blood sugar levels Increased risk of infections, including fungal infections of the mouth or throat (thrush) Mood changes or behavioral changes, such as agitation or aggression Osteoporosis or bone fractures (with long-term use) Slow wound healing

• Rare Adverse effects

Adrenal suppression (with long-term use) Anaphylaxis (a severe and life-threatening allergic reaction) Cushing's syndrome (with long-term use) Decreased immune system function (with long-term use) Hyperglycemia (high blood sugar levels) Hypokalemia (low levels of potassium in the blood) Hypersensitivity reactions (such as rash or angioedema) Ocular toxicity (such as increased intraocular pressure, cataracts, or glaucoma with long-term use) Psychiatric effects (such as mood changes or suicidal thoughts)

May potentiate the CNS depressant effects of opiates (e.g. meperidine) and other analgesics; barbiturates, benzodiazepines, hypnotics, anxiolytics, antiemetics, antiepileptics, other antihistamines, skeletal muscle relaxants, sedatives, anaesthetics. Potentiate antimuscarinic effects of TCAs, MAOIs, and other anticholinergics (e.g. atropine). Increased plasma concentrations with cimetidine, potent CYP3A4, CYP3A5 and alcohol dehydrogenase inhibitors. Inhibits and reverses the vasopressor effect of epinephrine. May antagonise the effects of betahistine and anticholinesterase drugs. May mask the signs of damage caused by ototoxic agents (e.g. aminoglycosides).

Potentially Fatal: Increases the risk of cardiac arrhythmia with drugs known to prolong QT interval or induce torsade de pointes such as class IA (e.g. quinidine, disopyramide) and class III antiarrhythmics (e.g. amiodarone, sotalol), some antipsychotics (e.g. haloperidol), some antidepressants (e.g. escitalopram, citalopram), some antimalarials (e.g. mefloquine), some antibiotics (e.g. erythromycin, levofloxacin), some gastrointestinal agents (e.g. prucalopride), some anti-cancer drugs (e.g. toremifene, vandetanib), and methadone.

The common side effects of Hydroxyzine include the following :

Irritation in the nose or throat (with nasal spray) Hoarseness or changes in voice (with inhalation) Headache Nausea Cough Sore throat Runny or stuffy nose Sinus pain Dry mouth or throat Skin rash or itching (with topical use).

Symptoms: Excessive sedation, stupor, somnolence, nausea, vomiting, tachycardia, pyrexia, impaired pupillary reflex, tremor, delirium, hallucination. Followed by decreased level of consciousness, respiratory depression, hypotension, convulsion, coma, cardiorespiratory collapse.

Management: Symptomatic and supportive treatment. May consider activated charcoal within 1 hour of ingestion. May employ gastric lavage only if life-threatening amount has been ingested within the previous hour and when airway can be protected following acute ingestion. If hypotension occurs, may administer IV fluids, norepinephrine, dopamine or metaraminol, depending on severity and on the cause of hypotension. Dialysis may be indicated if other agents (e.g. barbiturates) have been ingested concomitantly.

Pharmacodynamic

Hydroxyzine, a piperazine derivative, competitively blocks histamine H1-receptors on effector cells of the gastrointestinal tract, blood vessels and respiratory tract, thereby inhibiting H1-receptor-mediated reactions such as vasodilation, flare and itch reactions, and sneezing. It is a sedating antihistamine with antimuscarinic and sedative effects, skeletal muscle relaxing, bronchodilator, antiemetic and analgesic properties.

Pharmacokinetics

• Absorption: Hydroxyzine is well absorbed after oral administration, with peak plasma concentrations reached within 2-3 hours. The oral bioavailability of hydroxyzine is approximately 80%.

• Distribution: Hydroxyzine is widely distributed throughout the body, including the central nervous system. It has a volume of distribution of approximately 10 L/kg, indicating that it is extensively distributed in body tissues.

• Metabolism: Hydroxyzine is metabolized in the liver by the cytochrome P450 system, primarily by the CYP3A4 and CYP2D6 enzymes. The major metabolite of hydroxyzine is cetirizine, which also has antihistamine activity.

• Excretion: Hydroxyzine and its metabolites are primarily excreted in the urine, with approximately 70% of the dose excreted within 24 hours. The elimination half-life of hydroxyzine is approximately 20 hours.

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
2. https://reference.medscape.com/drug/colestid-Hydroxyzine -342452
3. https://go.drugbank.com/drugs/DB00375
4. https://www.sciencedirect.com/topics/medicine-and-dentistry/Hydroxyzine
5. https://europepmc.org/article/med/6988203