Antihistamines: Histamine-1 receptor antagonists

Antihistamines

Antihistamines primarily act to block histamine effects that oc-cur in an immediate (type I) hypersensitivity reaction, commonly called an allergic reaction. They’re available alone or in combina-tion products by prescription or over-the-counter.

Histamine-1 receptor antagonists

The term antihistamine refers to drugs that act as histamine-1 (H₁) receptor antagonists; that is, they compete with histamine for binding to H₁-receptor sites throughout the body. However, they don’t displace histamine already bound to the receptor.

It’s all about chemistry

Based on chemical structure, antihistamines are categorized into five major classes:

§    Ethanolamines include clemastine fumarate, dimenhydrinate, and diphenhydramine hydrochloride.

§    Alkylamines include brompheniramine maleate, chlorphenir-amine maleate, and dexchlorpheniramine maleate.

§    Phenothiazines include promethazine hydrochloride.

§    Piperidines include azatadine maleate, cetirizine hydrochloride, cyproheptadine hydrochloride, desloratadine, fexofenadine hy-drochloride, loratadine, and meclizine hydrochloride.

§    Miscellaneous drugs, such as hydroxyzine hydrochloride and hydroxyzine pamoate, also act as antihistamines.

Pharmacokinetics (how drugs circulate)

H₁-receptor antagonists are well absorbed after oral or parenteral administration. Some can also be given rectally.

Distribution

With the exception of loratadine and desloratadine, antihistamines are distributed widely throughout the body and central nervous system (CNS).

Less penetration, fewer effects

Fexofenadine, desloratadine, and loratadine, which are nonsedat-ing antihistamines, minimally penetrate the blood-brain barrier so that little of the drug is distributed in the CNS, producing fewer ef-fects there than other antihistamines.

Metabolism and excretion

Antihistamines are metabolized by liver enzymes and excreted in urine; small amounts appear in breast milk. Fexofenadine, mainly excreted in stool, is an exception. Cetirizine undergoes limited he-patic metabolism.

Pharmacodynamics (how drugs act)

H₁-receptor antagonists compete with histamine for H₁ receptors on effector cells (the cells that cause allergic symptoms), blocking histamine from producing its effects. (See How chlorpheniraminestops an allergic response)

Antagonizing tactics

H₁-receptor antagonists produce their effects by:

§    blocking the action of histamine on the small blood vessels

§    decreasing dilation of arterioles and engorgement of tissues

§    reducing the leakage of plasma proteins and fluids out of the capillaries (capillary permeability), thereby lessening edema

§    inhibiting most smooth-muscle responses to histamine (in par-ticular, blocking the constriction of bronchial, GI, and vascular smooth muscle)

§    relieving symptoms by acting on the terminal nerve endings in the skin that flare and itch when stimulated by histamine

§    suppressing adrenal medulla stimulation, autonomic ganglia stimulation, and exocrine gland secretion, such as lacrimal and salivary secretion.

Straight to the head

Several antihistamines have a high affinity for H₁ receptors in the brain and are used for their CNS effects. These drugs include diphenhydramine, dimenhydrinate, promethazine, and various piperidine derivatives.

No stomach for this

H₁-receptor antagonists don’t affect parietal cell secretion in the stomach because their receptors are H₂ receptors, not H₁.

Pharmacotherapeutics (how drugs are used)

Antihistamines are used to treat the symptoms of type I hypersen-sitivity reactions, such as:

§    allergic rhinitis (runny nose and itchy eyes caused by a local sensitivity reaction)

§    vasomotor rhinitis (rhinitis not caused by allergy or infection)

§    allergic conjunctivitis (inflammation of the membranes of the eye)

§    urticaria (hives)

§    angioedema (submucosal swelling in the hands, face, and feet).

Not just for allergies

Antihistamines can have other therapeutic uses:

• Many are used primarily as antiemetics (to control nausea and vomiting).

• They can also be used as adjunctive therapy to treat an anaphylactic reaction after the serious symptoms are controlled.

• Diphenhydramine can help treat Parkinson’s disease and druginduced extrapyramidal reactions (abnormal involuntary movements).

• Because of its antiserotonin qualities, cyproheptadine may be used to treat Cushing’s disease, serotonin-associated diarrhea, vascular cluster headaches, and anorexia nervosa.

Drug interactions

Antihistamines may interact with many drugs, sometimes with life-threatening consequences:

• They may block or reverse the vasopressor effects of epinephrine, producing vasodilation, increased heart rate, and very low blood pressure.

• They may mask the toxic signs and symptoms of ototoxicity (adetrimental effect on hearing) associated with aminoglycosides or large dosages of salicylates.

• They may increase the sedative and respiratory depressant effects of CNS depressants, such as tranquilizers or alcohol.

• Loratadine may cause serious cardiac effects when taken with macrolide antibiotics (such as erythromycin), fluconazole, ketoconazole, itraconazole, miconazole, cimetidine, ciprofloxacin, and clarithromycin. (See Adverse reactions to antihistamines.)