NCLEX: Antihistamines

Histamine is a chemical messenger mostly generated in mast cells. Histamine, via multiple receptor systems, mediates a wide range of cellular responses, including allergic and inflammatory reactions, gastric acid secretion, and neurotransmission in parts of the brain. Histamine has no clinical applications, but agents that inhibit the action of histamine (antihistamines or histamine receptor blockers) have important therapeutic applications.

Antihistamines

A. Location, synthesis, and release of histamine

Focus topic: Antihistamines

  • Location: Histamine is present in practically all tissues, with significant amounts in the lungs, skin, blood vessels, and GI tract. It is found at high concentration in mast cells and basophils. Histamine functions as a neurotransmitter in the brain. It also occurs as a component of venoms and in secretions from insect stings.
  • Synthesis: Histamine is an amine formed by the decarboxylation of the amino acid histidine by the enzyme histidine decarboxylase, which is expressed in cells throughout the body, including neurons, gastric parietal cells, mast cells, and basophils. In mast cells, histamine is stored in granules. If histamine is not stored, it is rapidly inactivated by the enzyme amine oxidase.
  • Release of histamine: Most often, histamine is just one of several chemical mediators released in response to stimuli. The stimuli for release of histamine from tissues may include destruction of cells as a result of cold, toxins from organisms, venoms from insects and spiders, and trauma. Allergies and anaphylaxis can also trigger significant release of histamine.

Antihistamines

B. Mechanism of action

Focus topic: Antihistamines

Histamine released in response to certain stimuli exerts its effects by binding to various types of histamine receptors (H1, H2, H3, and H4). H1 and H2 receptors are widely expressed and are the targets of clinically useful drugs. Histamine has a wide range of pharmacologic effects that are mediated by both H1 and H2 receptors. For example, the H1 receptors are important in producing smooth muscle contraction and increasing capillary permeability. Histamine promotes vasodilation of small blood vessels by causing the vascular endothelium to release nitric oxide. In addition, histamine can enhance the secretion of proinflammatory cytokines in several cell types and in local tissues. Histamine H1 receptors mediate many pathological processes, including allergic rhinitis, atopic dermatitis, conjunctivitis, urticaria, bronchoconstriction, asthma, and anaphylaxis. Moreover, histamine stimulates the parietal cells in the stomach, causing an increase in acid secretion via the activation of H2 receptors.

Antihistamines

C. Role in allergy and anaphylaxis

Focus topic: Antihistamines

The symptoms resulting from intravenous injection of histamine are similar to those associated with anaphylactic shock and allergic reactions. These include contraction of airway smooth muscle, stimulation of secretions, dilation and increased permeability of the capillaries, and stimulation of sensory nerve endings. Symptoms associated with allergy and anaphylactic shock result from the release of certain mediators from their storage sites. Such mediators include histamine, serotonin, leukotrienes, and the eosinophil chemotactic factor of anaphylaxis. In some cases, these mediators cause a localized allergic reaction, producing, for example, actions on the skin or respiratory tract. Under other conditions, these mediators may cause a full-blown anaphylactic response. It is thought that the difference between these two situations results from differences in the sites from which mediators are released and in their rates of release. For example, if the release of histamine is slow enough to permit its inactivation before it enters the bloodstream, a local allergic reaction results. However, if histamine release is too fast for efficient inactivation, a full-blown anaphylactic reaction occurs.

Antihistamines: H1 ANTIHISTAMINES

Focus topic: Antihistamines

The term antihistamine refers primarily to the classic H1-receptor blockers. The H1-receptor blockers can be divided into first- and second generation drugs. The older first-generation drugs are still widely used because they are effective and inexpensive. However, most of these drugs penetrate the CNS and cause sedation. Furthermore, they tend to interact with other receptors, producing a variety of unwanted adverse effects. In contrast, the second-generation agents are specific for peripheral H1 receptors. Because they are made polar mainly by adding carboxyl groups (for example, cetirizine is the carboxylated derivative of hydroxyzine), the second-generation agents do not penetrate the blood–brain barrier, causing less CNS depression than the first generation drugs. Among the second-generation agents, desloratadine [des-lor-AH-tah-deen], fexofenadine [fex-oh-FEN-a-deen], and loratadine [lor-AT-a-deen] show the least sedation (Figure 30.5). Cetirizine [seh-TEER-ih-zeen] and levocetirizine [lee-voe-seh-TEER-ih-zeen] are partially sedating second-generation agents.

Antihistamines

Antihistamines

A. Actions

Focus topic: Antihistamines

The action of all the H1-receptor blockers is qualitatively similar. Most of these compounds do not influence the formation or release of histamine. Rather, they block the receptor-mediated response of a target tissue. They are much more effective in preventing symptoms than reversing them once they have occurred. However, most of these agents have additional effects unrelated to their ability to block H1 receptors. These effects reflect binding of the H1-receptor antagonists to cholinergic, adrenergic, or serotonin receptors. For example, cyproheptadine [SYE-proe-HEP-ta-deen] also acts as a serotonin antagonist on the appetite center and is sometimes used offlabel as an appetite stimulant and in treating anorgasmy associated with the use of selective serotonin reuptake inhibitors. Antihistamines such as azelastine and ketotifen also have mast cell–stabilizing effects in addition to their histamine receptor–blocking effects.

B. Therapeutic uses

Focus topic: Antihistamines

1. Allergic and inflammatory conditions: H1-receptor blockers are useful in treating and preventing allergic reactions caused by antigens acting on immunoglobulin E antibody. For example, oral antihistamines are the drugs of choice in controlling the symptoms of allergic rhinitis and urticaria because histamine is the principal mediator released by mast cells. Ophthalmic antihistamines, such as azelastine [a-ZEL-uh-steen], olopatadine [oh-loe-PAT-a-deen], ketotifen [kee-toe-TYE-fen], and others, are useful for the treatment of allergic conjunctivitis. However, the H1-receptor blockers are not indicated in treating bronchial asthma, because histamine is only one of several mediators that are responsible for causing bronchial reactions. [Note: Epinephrine has actions on smooth muscle that are opposite to those of histamine. It acts via β2 receptors on smooth muscle, causing cAMP-mediated relaxation. Therefore, epinephrine is the drug of choice in treating systemic anaphylaxis and other conditions that involve massive release of histamine.]

2. Motion sickness and nausea: Along with the antimuscarinic agent scopolamine, certain H1-receptor blockers, such as diphenhydramine [dye-fen-HYE-dra-meen], dimenhydrinate [dye-men-HYE-dri-nate] (a chemical combination of diphenhydramine and a chlorinated theophylline derivative), cyclizine [SYE-kli-zeen], meclizine [MEK-lizeen], and promethazine [proe-METH-a-zeen], are the most effective agents for prevention of the symptoms of motion sickness. They are usually not effective if symptoms are already present and, thus, should be taken prior to expected travel. The antihistamines prevent or diminish nausea and vomiting mediated by both the chemoreceptor and vestibular pathways. The antiemetic action of these medications seems to be due to their blockade of central H1 and M1 muscarinic receptors. Meclizine is also useful for the treatment of vertigo associated with vestibular disorders.

3. Somnifacients: Although they are not the medications of choice, many first-generation antihistamines, such as diphenhydramine and doxylamine [dox-IL-a-meen], have strong sedative properties and are used in the treatment of insomnia. These agents are available over-the-counter (OTC), or without a prescription. The use of first-generation H1 antihistamines is contraindicated in the treatment of individuals working in jobs in which wakefulness is critical. The second-generation antihistamines have no value as somnifacients.

C. Pharmacokinetics

Focus topic: Antihistamines

H1-receptor blockers are well absorbed after oral administration, with maximum serum levels occurring at 1 to 2 hours. The average plasma half-life is 4 to 6 hours, except for that of meclizine and the second generation agents, which is 12 to 24 hours. First-generation H1- receptor blockers are distributed in all tissues, including the CNS. All first-generation H1 antihistamines and some second-generation H1 antihistamines, such as desloratadine and loratadine, are metabolized by the hepatic cytochrome P450 system. Levocetirizine is the active enantiomer of cetirizine. Cetirizine and levocetirizine are excreted largely unchanged in urine, and fexofenadine is excreted largely unchanged in feces. After a single oral dose, the onset of action occurs within 1 to 3 hours. The duration of action for many oral antihistamines is 24 hours, allowing once-daily dosing. Azelastine, olopatadine, ketotifen, alcaftadine [al-KAF-ta-deen], bepotastine [bep-oh-TAS-teen], and emedastine [em-e-DAS-teen] are available in ophthalmic formulations that allow for more targeted tissue delivery. Azelastine and olopatadine have intranasal formulations, as well.

D. Adverse effects

Focus topic: Antihistamines

First-generation H1-receptor blockers have a low specificity, interacting not only with histamine receptors but also with muscarinic cholinergic receptors, α-adrenergic receptors, and serotonin receptors. The extent of interaction with these receptors and, as a result, the nature of the side effects varies with the structure of the drug. Some side effects may be undesirable, and others may be of therapeutic value. Furthermore, the incidence and severity of adverse reactions for a given drug varies between individual subjects.

Antihistamines

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1. Sedation: First-generation H1 antihistamines, such as chlorpheniramine [klor-fen-IR-a-meen], diphenhydramine, hydroxyzine [hye- DROX-ee-zeen], and promethazine, bind to H1 receptors and block the neurotransmitter effect of histamine in the CNS. The most frequently observed adverse reaction is sedation. Diphenhydramine may cause paradoxical hyperactivity in young children. Other central actions include fatigue, dizziness, lack of coordination, and tremors. Sedation is less common with the second-generation drugs, since they do not readily enter the CNS. Second-generation H1 antihistamines are specific for peripheral H1 receptors.

2. Other effects: First-generation antihistamines exert anticholinergic effects, leading not only to dryness in the nasal passage but also to a tendency to dry out the oral cavity. They also may cause blurred vision and retention of urine. The most common adverse reaction associated with second-generation antihistamines is headache. Topical formulations of diphenhydramine can cause hypersensitivity reactions such as contact dermatitis when applied to the skin.

3. Drug interactions: Interaction of H1-receptor blockers with other drugs can cause serious consequences, such as potentiation of effects of other CNS depressants, including alcohol. Patients taking Nmonoamine oxidase inhibitors (MAOIs) should not take antihistamines because the MAOIs can exacerbate the anticholinergic effects of the antihistamines. In addition, the first-generation antihistamines (diphenhydramine and others) with anticholinergic (antimuscarinic) actions may decrease the effectiveness of cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) in the treatment of Alzheimer’s disease.

4. Overdoses: Although the margin of safety of H1-receptor blockers is relatively high, and chronic toxicity is rare, acute poisoning is relatively common, especially in young children. The most common and dangerous effects of acute poisoning are those on the CNS, including hallucinations, excitement, ataxia, and convulsions. If untreated, the patient may experience a deepening coma and collapse of the cardiorespiratory system.

Antihistamines

Antihistamines: HISTAMINE H2-RECEPTOR BLOCKERS

Focus topic: Antihistamines

Histamine H2-receptor blockers have little, if any, affinity for H1 receptors. Although antagonists of the histamine H2 receptor (H2 antagonists or H2-receptor blockers) block the actions of histamine at all H2 receptors, their chief clinical use is as inhibitors of gastric acid secretion in the treatment of ulcers and heartburn.

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