Hydroxyzine

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Hydroxyzine
Systematic (IUPAC) name
Hydroxyzine:

2-(2-{4-[(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethoxy)ethanol

Hydroxyzine pamoate:
1-(p-chlorobenzhydryl) 4- [2-(2-hydroxyethoxy) ethyl] diethylenediamine salt of 1,1'-methylene bis(2-hydroxy-3-naphthalene carboxylic acid)

Identifiers
CAS number 68-88-2
(hydroxyzine)
ATC code N05BB01
PubChem 3658
DrugBank APRD00688
Chemical data
Formula C21H27ClN2O2 
Mol. mass 374.904 g/mol
SMILES eMolecules & PubChem
Synonyms Hydroxyzine pamoate:
Vistaril

Hydroxyzine hydrochloride:
Atarax

[1], Ucerax [2], Serecid [3], ANX
Pharmacokinetic data
Bioavailability High in-vivo
Protein binding 93%
Metabolism Renal
Half life 20 to 25 hours
Excretion Urine, Feces
Therapeutic considerations
Pregnancy cat.

A(AU) C(US)

Legal status

Prescription only

Routes Oral, intramuscular injection

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Overview

Hydroxyzine (pronounced /haɪˈdrɒksɨziːn/) is a first-generation antihistamine, of the piperazine class that is an H1 receptor antagonist. It was synthesised in the early 1950s and the medicinal formulation of this drug was announced in the 04 August 1956 issue of Chemistry Week. It is used primarily as an antihistamine for the treatment of itches and irritations, an antiemetic for the reduction of nausea, as a weak analgesic by itself and as an opioid potentiator, and as an anxiolytic '''for the treatment of anxiety'''.[1]

Its most common formulation is 25 mg small white, capsule-shaped and scored tablets of the hydrochloride salt made by UCB in the Netherlands. In the United States, a nearly-spherical dark green tablet is the most-commonly encountered version of it, with 25 and 100 mg capsules being available as well as a series of colour-coded round tablets from Mallinkrodt (25 mg white, 50 mg orange, 100 mg blue). Hydroxyzine preparations usually require a doctor's prescription as do other potent antihistamines in many countries whereas some countries allow hydroxyzine and all or most other antihistamines to be sold over the counter.

Even though it is an effective sedative, hypnotic, and tranquilizer, it shares almost none of the abuse, dependence, addiction, and toxicity potential of other drugs used for the same range of therapeutic reasons. The drug is available in two formulations, the pamoate and the dihydrochloride or hydrochloride salts. Vistaril, Equipose, Masmoran, Paxistil, and Vistaril Pamoate are preparations of the pamoate salt. Atarax, Alamon, Aterax, Durrax, Tran-Q, Orgatrax, Quiess, Vistaril Parenteral, and Tranquizine are hydroxyzine hydrochloride.

Other drugs related to hydroxyzine are cyclizine (Marezine), buclizine, and meclizine (Dramamine II) and they share all or most of the benefits, indications, contraindications, cautions, and side effects of hydroxyzine. The second-generation antihistamine cetirizine is in fact one of the metabolites of hydroxyzine produced in the human body, therefore having a narrower spectrum of effects, making it an effective antihistamine but removing some or all of the anxiolytic and analgesic-sparing properties.

Prescription and use

Hydroxyzine is both an antihistamine and anxiolytic (see below) and its use as a mild tranquilizer is especially common in dentistry and it retains some popularity in obstetrics, where for many years it was especially preferred for its ability to boost the effectiveness of alphaprodine (Nisentil), a narcotic analgesic related to pethidine as well as permit later use of scopolamine or benzodiazepines better than other drugs might.

Hydroxyzine hydrochloride is distributed by several manufacturers as tablets with strengths of 10, 25, 50, and 100 mg and hydroxyzine pamoate is distributed as capsules with strengths of 25, 50, and 100 mg. Oral liquids and ampules and multi-dose vials for injection are also available. Less commonly manufactured are tablet strengths of 5, 10, 20, and 30 mg , as are 25 mg suppositories. The latter four tablet strengths are used both in human medical and veterinary settings.

Hydroxyzine is prescribed when the onset of an organic disease state manifests through anxiety, as general anxiety disorder, or in other more serious cases as psychoneurosis, and is therefore prescribed as a means of regulating normal function. Hydroxyzine has shown to be as effective as the benzodiazepine drug bromazepam in the treatment of generalised anxiety disorder.[2] Hydroxyzine can also be used for the treatment of allergic conditions, such as chronic urticaria, atopic or contact dermatoses, and histamine-mediated pruritus.[1] These have also been confirmed in both recent and past studies to have no adverse effects on the liver, blood, nervous system or urinary tract.[3]

In the case of both the pamoate and hydrochloride salts, use of hydroxyzine for premedication as a sedative has no effects on belladonna alkaloids, such as atropine, but may, following general anesthesia, potentiate meperidine and barbiturates, and use in pre-anesthetic adjunctive therapy should be modified depending upon the state of the individual.[3] Hydroxyzine is also safe to use alongside other medications or cardiac agents derived from the digitalis plant, as it does not yield any side-effects, due to its effects on the sympathetic, rather than the central nervous system.[3]

Whilst the analgesic-sparing (potentiating) effect is most marked with pethidine and relatives in certain cases such as post-operative pain, the effect can be noticed and used with most or all opioid analgesics and other centrally-acting analgesics which are not opioids such as orphenadrine and nefopam and may also help reduce muscle spasm and set the stage for ibuprofen, naproxen, other NSAIDs, aspirin and paracetamol to work better for the patient, especially if used in conjunction with diphenhydramine (Tylenol PM, Percogesic Extra-Strength and its aspirin, naproxen, diclofenac, and ibuprofen analogues) or phenyltoloxamine (Percogesic original forumla, some extra-strength backache remedies like Momentum and Doan's Pills)

One of the more common regimens for moderate to moderately-severe pain -- be it acute, recurring acute or chronic -- prescribed in the United States and Canada and some European and Asian countries is a prescription for plain codeine tablets or combination products containing paracetamol, aspirin, ibuprofen, or similar drug with codeine (Tylenol With Codeine No. 1, 2, 3 & 4, the Emprin With Codeine and 222-292-293-294 series, and many other trade names) and instructions to combine an anti-inflammatory pain reliever like ibuprofen or naproxen with it and to combine this with a prescription for hydroxyzine to be taken in dosages of 12.5 to 100 mg either along with the codeine or at a fixed schedule of its own. In the case of sports injuries, other injuries, severe sinus infections and others, another part is added to the regimen in the form of a centrally-acting non-benzodiazepine muscle relaxant such as orphenadrine (Norflex), cyclobenzaprine (Flexeril), chlorzoxazone (Parafon), baclofen (Lioresal) and others. Of course, the narcotic can be changed to hydrocodone, dihydrocodeine, ethylmorphine, tramadol, pentazocine, nicodicodeine, propiram, oxycodone, benzylmorphine, thebacon, nicocodeine, dextropropoxyphene, tilidine, meptazinol or others; they can be found alone or in preparations which contain the narcotic along with aspirin, ibuprofen, or other similar drugs with or without paracetamol. The selection of carisoprodol (Soma) as the muscle relaxant often yields a particularly powerful combination and the doses of the narcotic as well as the hydroxyzine must be cut down substantially to start the careful titration of the dose. Such cases may produce enough somnolence to require the elimination of the hydroxyzine or replacement of it with cyclizine and/or addition of caffeine to the regimen by itself or as an ingredient in the narcotic combination product.

In other cases, the usage of hydroxyzine is as a form of non-barbiturate tranquilliser[4] used in the pre-operative sedation and treatment of neurological disorders, such as psychoneurosis and other forms of anxiety or tension states.[4] The trade name Atarax for the hydrochloride points to this ataractic (anti-anxiety) effect and Tranquizine and Tran-Q are trade names which point to a similar spectrum of actions. Physicians and patients both often prefer hydroxyzine to benzodiazepines, babiturates, and meprobamate-glutethemide type depressants as first-line treatments for insomnia and daytime anxiety as hydroxyzine is safer, clears out of the system more quickly than many depressants like diazepam, phenobarbital, chloral hydrate and others, and does not cause physical dependence nor does it generate a morbid seek orientation for the drug in the patient.

It has been suggested through pharmacological trials that the usage of hydroxyzine on dogs reduced the incidence and duration of ventricular arrythmias,[5] and that it is able to block the spasmogenic actions associated with other substances such as serotonin, reserpine, histamine, acetylcholine and the effect of pituitary extract on the duodenum.[4] Similarly, in experiments conducted on the ileum of small rabbits, hydroxyzine was found to inhibit hypermotility caused by the presence of barium chloride.[4]

For dentistry and obstetrics as well as other surgeries and procedures and acute pain situations like accidents, hydroxyzine is useful as a first line anxiolytic and opioid adjunct because it lacks both antagonism and synergy with benzodiazepines and scopolamine, allowing either of these agents to be used simultanteously or later in the procedure if need be.

Hydroxyzine is one of the least anticholinergic first-generation antihistamines at about 8-10 per cent of the antimuscarinic power of atropine. It is also, along with its relatives cyclizine, buclizine, meclizine, and others as well as phenindamine (Thephorin, Nolahist) and cyproheptadine (Periactin) (the prototype of the piperidine chemical class of first-generation antihistamines), and the phenothiazines, part of a small number of antihistamines to have clinically significant antiserotonergic effects as well.

Hydroxyzine has beneficial effects listed in this article but stands out in this pharmacotherapeutic category for its virtually non-existent addiction liability. The piperazine class of antihistamines is the fourth or even lower of the seven categories of first-generation antihistamines in the generation of euphoria in patients. The euphoria, which is mild (certainly not at the same level as morphine &c.) and tends to be either transient or long-lasting, appears to be part of the impact either direct or indirect on dopamine, acetylcholine, and possibly serotonin, norepinephrine, and even endorphin levels and ratios and possible activation of parts of the NMDA systems. Therefore, it would also stand to reason that it is reinforced by the alleviation of discomfort, much in the same way as some people experiencing transient euphoria after taking ibuprofen or naproxen. The ethanolamines (diphenhydramine, orphenadrine, dimenhydrinate, carbinoxamine and others) and alkylamines (triprolidine, pheniramine, brompheniramine, chlorpheniramine and others) are the strongest euphoriants amongst antihistamines and some ethylenediamines like pyrilamine and tripelennamine are on the list as well.

Hydroxyzine is not thought to be an effective treatment for anxiety if used for a period of over 4 months, and it is therefore a prerequisite of any medical professional prescribing such drugs, to re-assess the usefulness for the individual patient. Reasoning for this decision stems from the fact that hydroxyzine is mainly used as an antihistamine and has a somewhat short shelf-life in its common form. Rather than its use as an anxiety-reducing agent, hydroxyzine should be reconsidered if the patient has more intense anxiety or other psychoneurosis; then other compounds specifically designed for such conditions should be considered.[6]

Treatment of learned helplessness

Aside from its prescription as an antihistamine, hydroxyzine has also shown slight possibilities for use in other species, such as dogs, from results and effects observed in rats with "learned helplessness" induced through the use of random inescapable shocks (max 0.8 mA) administered in 1 minute intervals for a period of 15 seconds for an hour.[7] After the condition was induced, rats were then given a conditioned stimulus of a light, and shocked if unable to move to safety from the area producing the current within 3 seconds.[8] Those unable to move were determined as having a conditioned stimulus of expecting shocks from the initial random condition.[7][8]

In the initial treatment to this condition, rats were given hydroxyzine as a curative treatment for the shocks received and as a treatment for the prevention of learned helplessness by injection beforehand; results indicating that hydroxyzine decreased the overall amount of escape failures by a similar amount to those observed in diazepam, which achieved similar results, however, with side effects of amnesia.[9][8] Despite the fact that hydroxyzine clearly increased the ability of the rats to avoid stimuli, it had almost no effect on the rats' ability to respond to the shocks nor remove "stress" after exposure to shocks.[9]

Clinical description

Metabolisation and pharmacokinetics

Hydroxyzine can be administered orally as hydroxyzine hydrochloride or hydroxyzine embonate, or via intramuscular injection as hydroxyzine hydrochloride. When given orally, hydroxyzine is rapidly absorbed from the gastro-intestinal tract. The effect of hydroxyzine is notable in 30 minutes.

Pharmacokinetically, hydroxyzine is rapidly diffused in the body and absorbed in oral and intramuscular administration, and is metabolised in the liver; the main metabolite (45%) through oxidation of the alcohol moiety to a carboxylic acid, is cetirizine and overall effects are observed within one hour of administration. It has a half-life observed on average for around 7-10 hours in adults, 6-7 hours in children, and 18-21 hours in the elderly, or those with renal insufficiency, with higher concentrations found in the skin than in the plasma. Cetirizine, although less sedating, is non-dialyzable and possesses similar anti-histaminergic properties. "In animals, hydroxyzine and its metabolites are excreted in feces via biliary elimination."[4] "The extent of renal excretion of VISTARIL has not been determined"[5] Administration in geriatrics differs from the administration of hydroxyzine (pamoate or Vistaril) in younger patients; according to the FDA, there have not been significant studies made (2004), which include population groups over 65, and therefore have not provided a distinction between elderly aged patients and other younger groups:[10] any hydroxyzine administered should be done with doses at the small end of the dosing range, and be carried out with the knowledge that any existing concomitant disease, or decrease in the function, or lessened excretion, such as the case may be with hepatic, renal or cardiac states.[10]

Similarly, the use of sedating drugs alongside hydroxyzine can cause over-sedation and confusion if administered in large amounts—any form of treatment alongside sedatives should be done under supervision of the patient.[10][4]

Contraindications

The administration of hydroxyzine in large amounts by ingestion or intramuscular administration during the onset of pregnancy can cause fetal abnormalities—when administered to pregnant rats, mice and rabbits, hydroxyzine caused abnormalities with doses significantly above that of the human therapeutic range.[6] In terms of humans, a significant dose has not yet been established in studies, and by default, the FDA has introduced contraindication guidelines in regard to hydroxyzine.[6] Similarly, those at risk from, or showing previous signs of hypersensitivity are also contraindicated.[6]

Other contraindications include the administration of hydroxyzine alongside depressants and other compounds which affect the central nervous system, such as narcotics, non-narcotic analgesics and barbiturates, as well as alcohol,[6] and if absolutely necessary, should only administered concomitantly in small doses[6] as any pre-existing grogginess from these substances may be enhanced. If administered in small doses with other substances, such as mentioned, then patients should refrain from using dangerous machinery, motor vehicles or any other practice requiring absolute concentration, in accordance with safety law.[6]

Studies have also been conducted which show that long-term prescription of hydroxyzine can lead to tardive dyskinesia after years of use, but has also been reported after periods of 7.5 months showed effects related to dyskinesia,[11] such as continual head rolling, lip licking and other forms of athetoid movement. In certain cases, elderly patients' previous interactions with phenothiazine derivatives or pre-existing neuroleptic treatment may have had some contribution towards dyskinesia at the administration of hydroxyzine due to hypersensitivity caused due to the prolonged treatment,[11] and therefore some contraindication is given to the short-term administration of hydroxyzine to those with previous phenothiazine use.[11]

Adverse reactions

For a full list of side effects, consult the full technical specification of hydroxyzine.

Several reactions have been noted in manufacturer guidelines for two forms of hydroxyzine: Atarax and Vistaril. In Atarax, symptoms are similar to those of Vistaril -- deep sleep, incoordination and dizziness have been reported, as in children and adults, as well as others such as hypotension, tinnitus and headaches.[12] Gastro-intestinal effects have also been observed in both Vistaril and Atarax, as well as less serious effects such as dryness of the mouth, constipation caused by antimuscarinic properties of hydroxyzine.[12]

Central nervous system problems such as hallucinations or confusion have been observed in rare cases, attributed mostly to overdosage.[12][10] Such properties have been attributed to hydroxyzine in several cases, particularly in patients treated for neuropsychological disorders, as well as in cases where overdoses have been observed. While there are reports of the "hallucinogenic" or "hypnotic" properties of hydroxyzine, several clinical data trials have not reported such side effects from the sole consumption of hydroxyzine, but rather, have described its overall calming effect described through the stimulation of areas within the formatio reticularis. The description of hallucinogenic or hypnotic properties have been described as being an additional effect from overall central nervous system suppression by other CNS agents, such as lithium or alcohol.[13]

The effect of hydroxyzine has also been tested on the ability of humans in the registration and storage of memory, and was used in comparison with relatively safe drugs, such as hydroxyzine, to illustrate the effects of benzodiazepines, which are thought to have adverse effects on the capacity of memory storage. Hydroxyzine was found to have no adverse effects on memory in relation to lorazepam, which caused several deficiencies in the capacity of memory storage.[14]

In a comparative study with lorazepam on memory effects, patients who had taken hydroxyzine experienced sedative effects similar to drowsiness, but recalled that they felt capable, attentive and able to continue with a memory test under these conditions.[15] Conversely, those under the effects of lorazepam felt unable to continue due to the fact they felt out of control with its effects; 8 out of 10 patients describing tendencies of problems with balance and control of simple motor functions.[15]

Severe somnolence with or without vivid dreams or nightmares may occur in users with antihistamine sensitivities or other CNS depressants available in their systems. Hydroxyzine exhibits very potent anxiolytic and sedative properties in many psychiatric patients. Other studies have suggested that hydroxyzine acts as an acute hypnotic, reducing sleep onset latency and reciprocal increases in sleep duration -- also showing that some drowsiness did occur, but in female patients who also had greater hypnotic response. It did not, however, show any significant or noticeable effect of drowsiness, other than in female patients' subjective responses.[16]

Some users may report shortness of breath or wheezing, a result of a mild allergic reaction to the medication itself.

In contrast to drugs in the benzodiazepine class, (i.e. alprazolam, diazepam) which carry a potential for abuse and dependence, hydroxyzine is very unlikely to cause any dependence due to its relative strength compared to other substances.

References

Notes

  1. 1.0 1.1 RxList, et al. (2004)
  2. Llorca PM, Spadone C, Sol O, et al (November 2002). "Efficacy and safety of hydroxyzine in the treatment of generalized anxiety disorder: a 3-month double-blind study". J Clin Psychiatry 63 (11): 1020–7. PMID 12444816.
  3. 3.0 3.1 3.2 United States Food & Drug Administration, (2004), p1
  4. 4.0 4.1 4.2 4.3 4.4 Dolan, C. M., (1958)
  5. Hutcheon, D. E., Scriabine, A., et al. (1956)
  6. 6.0 6.1 6.2 6.3 6.4 6.5 6.6 United States Food & Drug Administration, (2004), p2
  7. 7.0 7.1 Porsolt, R. D.; P. Martin, A. Lenegre, S. Frornage, and C.E. Giurgea (1989), p229
  8. 8.0 8.1 8.2 Porsolt, R. D.; P. Martin, A. Lenegre, S. Frornage, and C.E. Giurgea (1989), p228
  9. 9.0 9.1 Porsolt, R. D.; P. Martin, A. Lenegre, S. Frornage, and C.E. Giurgea (1989), p230
  10. 10.0 10.1 10.2 10.3 United States Food & Drug Administration, (2004), p3
  11. 11.0 11.1 11.2 Clark, B. G., Araki, M., et al. (1976)
  12. 12.0 12.1 12.2 UCB South-Africa, et al., (2004)
  13. Anderson, P. O., Knoben, J. E., et al. (2002), p794-796
  14. Brabander, A. DE, Debert, W., (1990), p1
  15. 15.0 15.1 Brabander, A. DE, Debert, W., (1990), p3
  16. Alford, C.; N. Rombautt, J. Jones, S. Foley, C. Idzikowskit and I. Hindmarch (1992).

Print sources

Internet-based

Drug information pamphlets

  • UCB South-Africa, et al., (2004). ATERAX 25 mg TABLETS; ATERAX 100 mg TABLETS; ATERAX SYRUP (Manufacturing guidance package insert) Pharmacare Ltd, (a division of Aspen Pharmacare Ltd)
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