ANTIHISTAMINES

Introduction

Histamine is a potent vasodilator, bronchial smooth muscle constrictor, and stimulant of nociceptive itch nerves. In addition to histamine, multiple chemical itch mediators can act as pruritogens on C-fibers, including neuropeptides, prostaglandins, serotonin, acetylcholine, and bradykinin.

Histamine receptors

Human skin mast cells express H1, H2, and H4 receptors but not H3 receptors.

H1 and H2 receptors are involved in wheal formation and erythema,

Only H1 receptor agonists cause pruritus

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Complete blockade of H1 receptors does not totally relieve itching, and combinations of H1 and H2 blockers may be superior to H1 blockers alone.

1^st generation  antihistamines

Oral antihistamines, particularly H1-receptor antagonists, have some anticholinergic activity and are sedating, making them useful for the control of pruritus.

First-generation sedating H1 receptor antagonists include:

Hydroxyzine  hydrochloride

Diphenhydramine  

Promethazine 

Cyproheptadine.

2^nd generation antihistamines

These are nonsedating H1-receptor blockers

They are as effective as the first-generation H1 blockers,

They  are metabolized by CYP3A4 and, to a lesser extent, by CYP2D6 and should not be coadministered with medications that inhibit these enzymes (e.g., imidazole antifungals and macrolide antibiotics).

Doxepin

Antipruritic effects of doxepin are attributed to its H1 and H2- histamine receptor antagonism

It is a  tricyclic antidepressant and sedative anticholinergic effects

It is used as an alternative for severe pruritus.

A topical formulation of doxepin also is available as a 5% cream, which can be used in conjunction with low-to-moderate potency topical glucocorticoids.

 The systemic effect from topical doxepin is comparable with that of low-dose oral therapy.

Topical application of the cream should be performed four times daily for up to 8 days of therapy.

Doxepin: Pharmacokinetics

Percutaneous absorption is variable and may result in significant drowsiness in some patients.

Plasma levels of doxepin similar to those achieved during oral therapy may be obtained with topical application

Doxepin: Pharmacokinetics

Due to the high plasma levels, the usual drug interactions associated with tricyclic antidepressants may occur.

Therefore, monoamine oxidase inhibitors must be discontinued at least 2 weeks prior to the initiation of doxepin cream.

Doxepin:Adverse effects

Adverse local effects include marked burning and stinging of the treatment site which may necessitate discontinuation of the cream in some patients.

Allergic contact dermatitis appears to be frequent, and patients should be monitored for symptoms of hypersensitivity.

In view of the anticholinergic effect of doxepin, topical use is contraindicated in patients with untreated narrow-angle glaucoma or a tendency to urinary retention.

H2 Receptor antagonists

H2-receptor blockers include cimetidine, ranitidine, famotidine, and nizatidine.

Besides their use in combination with H1-receptor blockers for pruritus, the H2-receptor blockers have immunomodulating effects

This  property has been exploited in children to treat warts.

Treatment of pruritus

The term pruritus is derived from the Latin prurire, which means “to itch.”

Pruritus is a symptom unique to skin that occurs in a multitude of dermatologic disorders, including dry skin or xerosis, atopic eczema, urticaria, and infestations.

 Itching also may be a sign of internal disorders, including malignant neoplasms, chronic renal failure, and hepatobiliary disease.

The treatment of pruritus  depends on the underlying disorder.

Treatment of pruritus

General measures employing copious application of emollients usually are sufficient for xerosis.

Inflammatory disorders such as atopic dermatitis and contact dermatitis may respond better to potent topical glucocorticoids and oral doses of sedating antihistamines.

Treatment of pruritus

Antihistamines are useful in histamine-induced pruritus and in other pruritic disorders.

In these conditions, the sedating effects of these drugs facilitate sleep and reduce scratching at night, when most pruritic disorders are more symptomatic.

Treatment of pruritus

Cholestasis-associated pruritus may respond to cholestyramine, ursodeoxycholic acid, ondansetron, or rifampicin.

The pruritus of uraemia is treated most effectively with UVB radiation.

Prurigo, a disorder associated with itchy nodules of the skin, is difficult to treat.

In addition to topical and intralesional steroids, prurigo may respond to the opioid antagonist naltrexone at a dose of 50 mg/day or to the proton pump inhibitor omeprazole.

Pramoxine

Pramoxine hydrochloride is a topical anesthetic that can provide temporary relief from pruritus associated with mild eczematous dermatoses.

 Pramoxine is available as a 1% cream, lotion, or gel and in combination with hydrocortisone acetate.

Application to the affected area two to four times daily may provide short-term relief of pruritus.

Local adverse effects include transient burning and stinging.

Care should be exercised to avoid contact with the eyes.