1.HYDROXYZINE HISTORY
(How was Hydroxyzine discovered?)

Hydroxyzine is a piperazine derivative that is used as an antihistamine (especially for itches), anti-emetic (nausea reducing), and anxiolytic (anxiety reducing) drug.

The US FDA approved Hydroxyzine in 1957.

2.HYDROXYZINE FACTS

Hydroxyzine is also used to relieve symptoms of certain allergic reactions.

Histamine is a chemical produced by the body. It is stored in cells (mast cells) in almost all tissues of the body. When the body reacts to a foreign substance (an allergen e.g. flower pollen), the mast cells release their stores of Histamine.

Histamine may then bind to receptors (H-1 receptors) in many areas of the body causing an increase in blood flow to the area of the allergy and the release of other chemicals that add to the allergic response. This stimulates the symptoms of an allergic reaction such as inflammation of the skin, airways or tissues, rashes, itching of the skin, eyes or nose, nasal congestion or narrowing of the airways.

Hydroxyzine acts by blocking the binding of Histamine to receptors in the body and so preventing or relieving the typical symptoms of an allergic reaction.

Histamine may be released from and act in a small (localised) area of the body e.g the nose. Alternatively, Histamine can result in a serious or complete body reaction e.g. anaphylactic reaction. Hydroxyzine is only useful for the prevention or relief of localised or less serious allergies such as an itchy rash (rather than very serious allergic reactions). 

Hydroxyzine is called a sedating antihistamine as it enters the brain in significant quantities and is therefore more likely to cause drowsiness than the newer group of non-sedating antihistamines

3.ABOUT HYDROXYZINE MEDICATION

Antihistamines

Pharmacology

In allergic reactions an allergen (a type of antigen) interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors

Histamine, acting on H1-receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, bronchoconstriction, increases vascular permeability, potentiates pain, and more.

While H1-antihistamines ameliorate these effects, it is only efficacious if administered prior to the allergen-challenge. In severe allergies, such as anaphylaxis or angioedema, these effects may be so severe as to be life threatening.

Clinical use of antihistamines

Indications

H1-antihistamines are clinically used in the treatment of histamine-mediated allergic conditions. Specifically, these indications may include:

• allergic rhinitis
• allergic conjunctivitis
• allergic dermatological conditions (contact dermatitis)
• urticaria
• pruritus (atopic dermatitis, insect bites)
• anaphylactic or anaphylactoid reactions - adjunct only
• nausea and vomiting (first-generation H1-antihistamines)
• sedation (first-generation H1-antihistamines)

Antihistamines can be administered topically (through the skin, nose, or eyes) or systemically, based on the nature of the allergic condition. 

Adverse drug reactions
Adverse drug reactions are most commonly associated with the first-generation H1-Antihistamines. This is due to their relative lack of selectivity for the H1-receptor.

The most common adverse effect is sedation - this "side effect" being utilised in many OTC sleeping-aid preparations. Other common adverse effects in first-generation H1-Antihistamines include: dizziness, tinnitus, blurred vision, euphoria, uncoordination, anxiety, insomnia, tremor, nausea and vomiting, constipation, diarrhoea, dry mouth, and dry cough. Infrequent adverse effects include: urinary retention, palpitations, hypotension, headache, hallucination, and psychosis.

The newer second-generation H1-Antihistamines are far more selective for peripheral Histamine H1-receptors and, correspondingly, have a far improved tolerability profile compared to the first-generation agents. The most common adverse effects noted for second-generation agents include: drowsiness, fatigue, headache, nausea and dry mouth.

First-generation H1-receptor antagonists

These are the oldest antihistaminergic drugs and are relatively inexpensive and widely available. They are effective in the relief of allergic symptoms, but are typically moderately to highly potent muscarinic acetylcholine receptor-antagonists (anticholinergic) agents as well. These agents also commonly have action at a-adrenergic receptors and/or 5-HT receptors. This lack of receptor-selectivity is the basis of the poor tolerability-profile of some of these agents, especially compared with the second-generation H1-Antihistamines. Patient response and occurrence of adverse drug reactions vary greatly between classes and between agents within classes.

The first H1-Antihistamine discovered was piperoxan, by Forneau and Daniel Bovet (1933) in their efforts to develop a guinea pig animal-model for anaphylaxis. Bovet went on to win the 1957 Nobel Prize in Physiology or Medicine for his contribution. Following their discovery, the first-generation H1-Antihistamines were developed in the following decades. They can be classified on the basis of chemical structure, and agents within these groups have similar properties.

Ethylenediamines

Ethylenediamines were the first group of clinically-effective H1-Antihistamines developed.

• mepyramine (pyrilamine)
• antazoline
• Ethanolamines

Diphenhydramine was the prototypical agent in this group. Significant anticholinergic adverse effects, including sedation, are observed in this group but the incidence of gastrointestnal adverse effects is relatively low.

• diphenhydramine
• carbinoxamine
• doxylamine
• clemastine
• dimenhydrinate

Alkylamines
The isomerism is a significant factor in the activity of the agents in this group. E-triprolidine, for example, is 1000-fold more potent than Z-triprolidine. This difference relates to the positioning and fit of the molecules in the Histamine H1-receptor binding site. Alkylamines are considered to have relatively fewer sedative and gastrointestinal adverse effects, but relatively greater incidence of paradoxical CNS stimulation.

• pheniramine
• chlorphenamine (chlorpheniramine)
• dexchlorphenamine
• brompheniramine
• triprolidine

Piperazines
These compounds are structurally-related to the ethylenediamines and the ethanolamines; and produce significant anticholinergic adverse effects. Compounds from this group are often used for motion sickness, vertigo, nausea and vomiting. The second-generation H1-Antihistamine cetirizine also belongs to this chemical group.

• hydroxyzine
• meclizine

Tricyclics
These compounds differ from the phenothiazine antipsychotics in the ring-substitution and chain characteristics. (Nelson, 2002) They are also structurally related to the tricyclic antidepressants, explaining the antihistaminergic adverse effects of those two drug classes and also the poor tolerability profile of tricyclic H1-Antihistamines. The second-generation H1-Antihistamine loratadine was derived from compounds in this group.

• promethazine
• alimemazine (trimeprazine)
• cyproheptadine
• azatadine

Second-generation H1-receptor antagonists

These are newer drugs that are much more selective for peripheral H1 receptors in preference to the central nervous system histaminergic and cholinergic receptors. This selectivity significantly reduces the occurrence of adverse drug reactions compared with first-generation agents, while still providing effective relief of allergic conditions.

Systemic

• acrivastine
• astemizole
• cetirizine
• levocetirizine
• fexofenadine
• loratadine
• desloratadine
• mizolastine
• terfenadine (withdrawn from most markets due to risk of cardiac arrhythmias and replaced with fexofenadine)

• azelastine
• levocabastine
• olopatadine

Other agents

Inhibitors of histamine release

These agents appear to stabilise the mast cells to prevent degranulation and mediator release.

• cromoglicate (cromolyn)
• nedocromil

H2-receptor antagonists

Clinically-relevant Histamine H2-receptors are found principally in the parietal cells of the gastric mucosa. H2-receptor "antagonists" are also inverse agonists, rather than true antagonists; and are used to reduce the secretion of gastric acid. Examples include cimetidine, ranitidine, and famotidine.

H3- and H4-receptor antagonists

These are experimental agents and do not yet have defined clinical uses.

Other agents with antihistaminergic activity

Many drugs, used for other indications, possess unwanted antihistaminergic activity. These include tricyclic antidepressants, antipsychotics, etc. 

4.HYDROXYZINE EFFECTIVENESS
(When is Hydroxyzine best taken?)

Hydroxyzine dosage can be administered orally as hydroxyzine hydrochloride or hydroxyzine embonate or as an intramuscular injection as hydroxyzine hydrochloride. When given orally, Hydroxyzine dosage is rapidly absorbed from the gastro-intestinal tract. The effect of Hydroxyzine is notable in 30 minutes. Hydroxyzine is diffused throughout the body, but higher concentrations can be found in the skin than in the plasma. It is metabolised in the liver, and the main metabolite (45%), through oxidation of the alcohol moiety to a carboxylic acid, is cetirizine. Hydroxyzine half-life is on average 14 hours for adults, but it can be as low as 5 hours for small children and over 30 hours for elderly people. Hydroxyzine is excreted into the urine almost wholly as metabolites.

5.HYDROXYZINE EFFECTS ON SPECIAL POPULATION
(How do different people react to Hydroxyzine?)

Nursing Mothers

It is not known whether Hydroxyzine is excreted in human milk. Since many drugs are so excreted, Hydroxyzine should not be given to nursing mothers.

Geriatric Use

A determination has not been made whether controlled clinical studies of Hydroxyzine included sufficient numbers of subjects aged 65 and over to define a difference in response from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

The extent of renal excretion of Hydroxyzine has not been determined. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selections.

Sedating drugs may cause confusion and over sedation in the elderly; elderly patients generally should be started on low doses of Hydroxyzine and observed closely.

6.HYDROXYZINE EFFECTS ON MEDICAL CONDITIONS
(How does Hydroxyzine affect your existing condition/ailment?)

Hydroxyzine should not be used if you suffer from decreased kidney function or diabetes mellitus.

7.OTHER/ALTERNATE USES OF HYDROXYZINE
(What else does Hydroxyzine treat?)

Hydroxyzine can also be used as an adjunct to pre- and post-operative medication and it also possesses a weak analgesic effect.

8.ADVERSE/SIDE EFFECTS of HYDROXYZINE
(What are the side effects of Hydroxyzine?)

Side effects reported with the administration of Hydroxyzine are usually mild and transitory in nature.

Anticholinergic : Dry mouth. 

Central Nervous System : Drowsiness is usually transitory and may disappear in a few days of continued therapy or upon reduction of the dose. Involuntary motor activity including rare instances of tremor and convulsions have been reported, usually with doses considerably higher than those recommended. Clinically significant respiratory depression has not been reported at recommended doses.