Antihistamine Side Effects, Actions, Allergies, Motion, Sleeping

What are antihistamines?

Antihistamines are those drugs that block the H1 histamine receptors and not the other histamine receptors like H2, H3 and H4. It is also known as a H1-receptor blocker. These drugs act by block the histamine-induced responses in allergic reactions. It is the most widely used allergy medicine for most of the common allergic diseases.

Several H1-blockers are currently available many of which are over-the-counter drugs. Antihistamines are generally divided into first-generation and second-generation drugs. A strong sedative effect of the older first generation antihistamines is one of the most distinguishing features between the two groups.

First Generation Antihistamines

The first generation antihistamines are the older group of antihistamines and are often used as ‘sleeping aids’ because of its strong sedative actions. Although the sedative effect of antihistamines are sometimes desired, like in a patient with allergic rhinitis who is having difficulty sleeping, generally the use of these drugs should be limited in a person who is driving or operating heavy machinery.

Some of the first generation antihistamines also block other receptors like cholinergic (muscarinic) receptors and alpha adrenergic receptors. The anticholinergic effect also helps with nasal and bronchial secretions, in preventing nausea and vomiting (including motion sickness and vomiting associated with pregnancy), vestibular disturbances and in treatment of drug-induced movement disorders.

Doxepin is an antihistamine with additional antidepressant actions. Most of the first-generation antihistamines exert its actions for about 6 hours, but a few like chlorpheniraminecan act for about 24 hours.

The first-generation antihistamines include :

  • diphenhydramine
  • dimenhydrinate
  • chlorpheniramine
  • brompheniramine
  • promethazine
  • doxepin
  • hydroxyzine
  • cyclizine
  • buclizine
  • tripelennamine clemastine
  • pyrilamine

Some of the first-generation antihistamines (like promethazine, dimenhydrinate, diphenhydramine) which are available for parenteral use, may be used intravenously in emergency indications.

Second Generation Antihistamines

The newer antihistamines are called second-generation antihistamines. These drugs have significantly less sedative effects compared to older generation antihistamines. The limited distribution of these drugs to the brain due to low lipid solubility is one of the main reasons for its reduced sedative effects. Many physicians prefer the non-sedative second-generation antihistamine for out-patient use.

Most of the second-generation antihistamines are given once daily as it has a long duration of action, but are relatively more expensive than first generation drugs.

The second-generation antihistamines available for oral use include :

  • cetrizine
  • levocetrizine
  • loratadine
  • desloratadine
  • acrivastine
  • ebastine
  • mizolastine
  • fexofenadine

Azelastine (nasal spray and eye drops) and levocabastine (eye drops) are available for topical use alone.

Actions of Antihistamines

All antihistamines competitively block histamine H1 receptors and this action is primarily responsible for the benefits of antihistamines in allergy treatment. In allergic diseases, the H1 receptor blockage is instrumental in control of the histamine-induced symptoms like itching, swelling and redness.

In addition, the first generation antihistamines also have anti-cholinergic effects which may be beneficial for other symptoms like bronchial and nasal secretions, even if it not due to an allergic reaction. The second-generation antihistamines like cetrizine inhibit the release of histamine from mast cells by an unknown mechanism and may contribute to the beneficial effects in treatment of allergic diseases.

Uses of Antihistamines (Indications)

Allergic Reactions

Antihistamines have been considered as highly valued agents for prevention or treatment of a wide variety of allergic disorders. Antihistamines are most useful in acute types of allergies that present with symptoms of rhinitis, urticaria, and conjunctivitis in which histamine is considered to be the primary immune mediator involved.

The non-sedating second generation antihistamines are preferred drugs in hay fever, but drugs like chlorpheniramine may be used. Some patients prefer slightly sedative antihistamines in order to have a peaceful sleep while suffering from allergic diseases with symptoms of sneezing, rhinitis, conjunctivitis or itching of skin, nose or throat. At times these sedative actions help to ease the symptoms like an itching sensation in chronic urticaria or atopic dermatitis.

Antihistamines are only of limited use in treating angioedema that has already developed, but may be of use in preventing angioedema if treated prior to the exposure to allergen. In life threatening angioedema, adrenaline is the drug of choice and intravenous antihistamines have only an adjuvant role.

Treatment of anaphylaxis is primarily with adrenaline and antihistamines may play an adjuvant role. Pretreatment with antihistamines can prevent or minimize anaphylactic reactions but after onset of anaphylaxis, antihistamines can only be of use in controlling itching or urticaria. Antihistamines have a minimal role in allergic asthma in which several immune mediators in addition to histamine are involved.

Insect bites, food allergy and drug allergy which are characterized by itch, urticaria and angioedema benefit from antihistamines. Pretreatment with antihistamines prevent such allergic responses to a great extent.

Motion Sickness and Vertigo

The anticholinergic actions of first-generation H1 blockers make them one of the most important agents available for the prevention of motion sickness. The useful antihistamine drugs in motion sickness are promethazine, dimenhydrinate, diphenhydramine, cyclizine and meclizine, the last two having a milder sedative effect. Effectiveness of H1 blockers in preventing motion sickness is increased when combined with ephedrine. Treatment with antihistamines after the onset of motion sickness is seldom useful.

Dimenhydrinate and meclizine are also found to be useful in vertigo and other vestibular disturbances like Meniere’s disease.

Nausea and Vomiting

Doxylamine in combination with pyridoxine was available in the United States  for morning sickness (nausea and vomiting associated with pregnancy), but was withdrawn from markets owing to a controversy regarding possible abnormalities in fetus. Hydroxyzine, cyclizine and promethazine are other antihistamines that have been used in pregnancy-induced vomiting (vomiting during pregnancy).

Promethazine may also be of use in post-operative or chemotherapy-induced nausea and vomiting, but less preferred now due to availability of better drugs.

Sleeping Aid

Antihistamines are available over-the-counter and have strong sedative actions. This has led to the use of some of the first-generation antihistamines as sleeping aids. Diphenhydramine is also present in some of the proprietary remedies for sleeplessness that are available over-the-counter. The sedative antihistamines may also be used as mild anxiolytic (anti-anxiety medication).

Common Cold and Flu

Antihistamines are popular drugs used in the common cold and flu despite the fact that it can do more harm than good. The nasal discharge in common cold may be relieved by the drying effect due to the anticholinergic actions of the older antihistamines. The excessive drying of nasal secretions in common cold can result in stagnation of the secretions and subsequent bacterial infection.

Side Effects of Antihistamines

The most important undesirable effect of antihistamines is sedation although some patients may consider it a desirable effect and make use of the drug as a sleeping aid. The sedative effect of antihistamines is addictive with alcohol or other CNS (central nervous system) depressants and can lead to dangerous depression of the brain. For safety reasons, the sedative antihistamines are contraindicated during driving or while operating machinery.

Anticholinergic effects (like dry mouth, blurred vision, urinary retention) are other common side effects seen with antihistamines. Related side effects can include dizziness, incoordination, fatigue and double vision (diplopia). Occasionally in children, antihistamines can result in CNS stimulation resulting in sleeplessness, excitation, euphoria and convulsions. The sedative effects and anticholinergic effects are mostly seen with the first generation antihistamines.

The digestive tract related adverse effects account for other common side effects. This includes nausea, vomiting, appetite loss, constipation or diarrhea and abdominal discomfort.

Antihistamines itself can occasionally cause a drug allergy and is more frequently seen with topical agents. The drug allergy can be in the form of contact dermatitis or photosensitivity. Very rarely antihistamines can result in reduced white blood cells (leukopenia or agranulocytosis). Some of the antihistamines (like azelastine, hydroxyzine) have been found to produce teratogenic effects in animals and hence its use in pregnant women is not recommended. Infants of nursing mothers taking antihistamines may show drowsiness or irritability.

Patients without co-existing depression may show intolerance to doxepin. Antihistamines like astemizole and terfenadine were linked cardiac arrhythmias, which led to its withdrawal in the United States. Enhanced cardiac arrhythmic potential with these drugs were seen when combined with antifungal drugs like ketoconazole and antibiotics like erythromycin.

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