Antihistamines

Histamine is a small molecule produced in specialized cells throughout the body. The compound plays an important role in allergic reactions and regulation of gastric acid secretion. The antihistamines, a widely used family of drugs, block histamine actions.

In order to understand the antihistamines, we must first understand histamine itself. Accordingly, the chapter begins with a discussion of histamine, emphasizing its contribution to allergic responses. Discussion of the antihistamines follows.

Histamine

Histamine is a locally acting compound with prominent and varied effects. In the vascular system, histamine dilates small blood vessels and increases capillary permeability. In the bronchi, histamine produces constriction of smooth muscle. In the stomach, histamine stimulates secretion of acid. In the central nervous system (CNS), histamine acts as a neurotransmitter. Despite this impressive spectrum of actions, clinical use of histamine is limited to diagnostic procedures. However, although its clinical utility is minimal, histamine is still of great interest owing to its involvement in two common pathologic states: allergic disorders and peptic ulcer disease.

Distribution, synthesis, storage, and release

The initial requirement for allergic release is production of antibodies of the immunoglobulin E class. These antibodies are generated following exposure to specific allergens (eg, pollens, insect venoms, certain drugs). Once made, the antibodies become attached to the outer surface of mast cells and basophils (Fig. 70–1). When the individual is re-exposed to the allergen, the allergen becomes bound by the antibodies. As indicated in Figure 70–1, binding of allergen to adjacent antibodies creates a bridge between those antibodies. By a mechanism that is not fully understood, this bridging process mobilizes intracellular calcium. The calcium, in turn, causes the histamine-containing storage granules to fuse with the cell membrane and disgorge their contents into the extracellular space. Note that allergic release of histamine requires prior exposure to the allergen; an allergic reaction cannot occur during initial allergen exposure.

Figure 70–1 Release of histamine by allergen-antibody interaction.
(IgE = immunoglobulin E.)

Nonallergic release.

Several agents (certain drugs, radiocontrast media, plasma expanders) can act directly on mast cells to trigger histamine release. With these agents, no prior sensitization is needed. Cell injury can also cause direct release.

Physiologic and pharmacologic effects

Histamine acts primarily through two types of receptors, named H₁ and H₂. The response produced depends on which of these receptors is involved.

Effects of H₁ stimulation

Vasodilation.

Activation of H₁ receptors causes dilation of small blood vessels (arterioles and venules). Vasodilation is prominent in the skin of the face and upper body, causing the area to become warm and flushed. If extensive vasodilation occurs, total peripheral resistance declines and blood pressure falls.

Increased capillary permeability.

Activation of H₁ receptors increases capillary permeability. How? Receptor activation causes capillary endothelial cells to contract, creating openings between these cells through which fluid, protein, and platelets can escape. Escape of fluid and protein into the interstitial space produces edema. If loss of intravascular fluid is substantial, blood pressure may fall.

Bronchoconstriction.

Histamine₁ activation causes constriction of the bronchi. If histamine is administered to an individual with asthma, severe bronchoconstriction will follow. However, although exogenous histamine can induce bronchial constriction, histamine is not the cause of bronchoconstriction that occurs during a spontaneous asthma attack. Consequently, antihistamines are of no use for treating asthma.

CNS effects.

In the CNS, H₁ receptors have a role in cognition, memory, and the cycle of sleeping and waking. In addition, H₁ receptors appear to have a role in seizure suppression, modulation of neurotransmitter release, and regulation of energy and endocrine homeostasis.

Other effects.

Activation of H₁ receptors on sensory nerves produces itching and pain. Histamine₁ activation also promotes secretion of mucus.

Effects of H₂ stimulation

The major response to activation of H₂ receptors is secretion of gastric acid. Histamine acts directly on parietal cells of the stomach to promote acid release. Although acetylcholine and gastrin also help regulate acid release, histamine has a dominant role. We know this because, in the presence of H₂ blockade, acetylcholine and gastrin are unable to elicit acid secretion.

Role of histamine in allergic responses

Allergic reactions are mediated by histamine and other compounds (eg, prostaglandins, leukotrienes, tryptase). The intensity of an allergic reaction is determined by which mediator is involved.

Mild allergy.

The symptoms of mild allergy (eg, rhinitis, itching, localized edema) are caused largely by histamine, acting at H₁ receptors. As a result, mild allergic conditions (eg, hay fever, acute urticaria, mild transfusion reactions) are generally responsive to antihistamine therapy.

Severe allergic reactions (anaphylaxis).

Severe allergic reactions manifest as anaphylactic shock, a syndrome characterized by bronchoconstriction, hypotension, and edema of the glottis. Although histamine is involved in anaphylaxis, it plays a minor role; other substances (eg, leukotrienes) are the principal mediators. Since histamine has little to do with producing anaphylaxis, it follows that antihistamines are of little help as treatment. The drug of choice for anaphylaxis is epinephrine. The rationale for using epinephrine is discussed in Chapter 17.

The two types of antihistamines: h₁ antagonists and h₂ antagonists

Antihistamines fall into two basic categories: H₁ receptor antagonists and H₂ receptor antagonists. The H₁ antagonists produce selective blockade of H₁ receptors. The H₂ antagonists produce selective blockade of H₂ receptors. The principal use of H₁ blockers is treatment of mild allergic disorders. The principal use of H₂ blockers is treatment of gastric and duodenal ulcers. Because H₂ antagonists do not block H₁ receptors, these drugs are of no use for treating allergies. In this chapter, we focus on H₁ antagonists. The H₂ blockers, which are important and widely used, are discussed in Chapter 78 (Drugs for Peptic Ulcer Disease).

H₁ antagonists i: basic pharmacology

The H₁ antagonists are the classic antihistamines. These agents were in use long before H₂ blockers came along. In fact, before H₂ blockers became available, the term H₁ antagonist did not exist; the drugs that we now call H₁ antagonists or H₁ blockers were simply referred to as antihistamines. Because of its historic use, the term antihistamines is still employed as a synonym for the subgroup of histamine antagonists that produce selective H₁ blockade. In this chapter, we respect tradition and continue to use the term antihistamine interchangeably with H₁ blocker and H₁ antagonist.

Although all H₁ antagonists available have similar antihistaminic actions, these drugs differ significantly in side effects. Because of these differences, selection of a prototype to represent the group is not feasible. Hence, rather than structuring discussion around one prototypic drug, we discuss the H₁ antagonists collectively. Differences among individual antihistamines are addressed as appropriate.

Classification of h₁ antagonists

The H₁ antagonists fall into two major groups: first-generation H₁ antagonists and second-generation H₁ antagonists. The principal difference between the groups is that first-generation antihistamines are highly sedating, whereas second-generation antihistamines are not.

Mechanism of action

Histamine₁ blockers bind selectively to H₁-histaminic receptors, thereby blocking the actions of histamine at these sites. H₁ antagonists do not block H₂ receptors. Also, they do not block release of histamine from mast cells or basophils.

It should be noted that, although interaction of the classic antihistamines with histaminic receptors is limited to the H₁ receptor subtype, these drugs can also bind to nonhistaminic receptors. Most notably, certain antihistamines can bind to and block muscarinic receptors. This action underlies several important side effects.

Pharmacologic effects

Peripheral effects.

The major therapeutic effects of the H₁ antagonists can be attributed to preventing the actions of histamine at H₁ receptors. In arterioles and venules of the skin, H₁ blockers inhibit the dilator actions of histamine, and thereby reduce localized flushing. In capillary beds, the antihistamines prevent histamine-induced increases in permeability, and thereby reduce edema. By blocking histamine at sensory nerves, H₁ antagonists reduce itching and pain. Blockade of H₁ receptors in mucous membranes suppresses secretion of mucus.

Effects on the CNS.

Antihistamines can cause both excitation and depression of the CNS. At therapeutic doses, antihistamines produce CNS depression: reaction time is slowed, alertness is diminished, and drowsiness is likely. These effects are more pronounced with some antihistamines than with others. With most second-generation antihistamines (eg, fexofenadine), CNS depression is negligible.

Overdose with antihistamines can produce CNS stimulation. Convulsions frequently result. Very young children are especially sensitive to CNS stimulation by these drugs.

Other pharmacologic effects.

Blockade of muscarinic cholinergic receptors by antihistamines can produce typical anticholinergic responses. These are discussed below under Adverse Effects. Several antihistamines can suppress nausea and vomiting, as discussed below under Motion Sickness.

Therapeutic uses

All of the H₁ antagonists are useful in treating allergic disorders. Some are also indicated for other conditions (eg, motion sickness, insomnia).

Mild allergy.

Antihistamines can reduce symptoms of mild allergies. In people with seasonal allergic rhinitis (also known as hay fever or rose fever), H₁ blockers can reduce sneezing, rhinorrhea, and itching of the eyes, nose, and throat (although they can’t reduce nasal congestion). In patients with acute urticaria, these drugs can reduce redness, itching, and edema. The antihistamines can also reduce symptoms of allergic conjunctivitis and urticaria associated with mild transfusion reactions. In all of these conditions, benefits result from H₁ receptor blockade—not from preventing allergen-induced release of histamine from mast cells and basophils. Because mild allergic reactions may be mediated by substances in addition to histamine, antihistamines often fail to produce complete relief.

Severe allergy.

As noted, the major symptoms of anaphylaxis (hypotension, laryngeal edema, bronchospasm) are caused by mediators other than histamine. Hence, although antihistamines may be employed as adjuncts in patients with anaphylaxis, their benefits are limited.

Motion sickness.

Some antihistamines, such as promethazine [Phenergan] and dimenhydrinate [Dramamine], are labeled for use in motion sickness. Benefits derive from blocking H₁ receptors and muscarinic receptors in the neuronal pathway leading from the vestibular apparatus of the inner ear to the vomiting center of the medulla. Motion sickness and its treatment are discussed in Chapter 80. The antihistamines employed for motion sickness, along with their dosages, are listed in Table 80–1.

Insomnia.

The ability of antihistamines to cause drowsiness has been exploited in the treatment of insomnia. Practically every over-the-counter (OTC) sleep aid contains an H₁ antagonist—diphenhydramine or pyrilamine—as its active ingredient. However, although antihistamines can induce sleep when used in sufficient dosage, the doses recommended for OTC preparations are usually too low to be effective.

Common cold.

Despite their widespread presence in cold remedies, antihistamines are of practically no value against the common cold. These drugs neither prevent colds nor shorten their duration. Moreover, since histamine does not mediate symptoms of colds, H₁ blockade cannot even provide symptomatic relief. The only benefit these drugs may offer is a moderate reduction in rhinorrhea, an effect that derives from their anticholinergic properties, not from H₁ blockade.

Adverse effects

All of the H₁ blockers can produce undesired effects. As a rule, these responses are more of a nuisance than a source of serious discomfort or danger. Frequently, side effects subside with continued drug use. Because individual antihistamines differ in their abilities to produce particular side effects (Table 70–1), adverse responses can be minimized by judicious drug selection.

TABLE 70–1

Pharmacologic Effects of H₁ Antagonists Used for Parenteral Therapy

Drug	H₁-Blocking Activity*	Sedative Effects*	Anticholinergic Effects*
First-Generation Agents
Alkylamines
Brompheniramine	+ + +	+	+ +
Chlorpheniramine	+ +	+	+ +
Dexchlorpheniramine	+ + +	+	+ +
Ethanolamines
Clemastine	+ to + +	+ +	+ + +
Diphenhydramine	+ to + +	+ + +	+ + +
Phenothiazines
Promethazine^†	+ + +	+ + +	+ + +
Piperazines
Hydroxyzine	+ + to + + +	+ + +	+ +
Piperidines
Cyproheptadine	+ +	+	+ +
Second-Generation (Nonsedating) Agents
Cetirizine^‡	+ + +	+	±
Levocetirizine^‡	+ + +	+	±
Fexofenadine	+ + +	±	±
Loratadine	+ + to + + +	±	±
Desloratadine	+ + to + + +	±	±

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Tags: Pharmacology for Nursing Care

Jul 24, 2016 | Posted by admin in NURSING | Comments Off

Histamine

Distribution, synthesis, storage, and release

Distribution.

Synthesis and storage.

Release.

Physiologic and pharmacologic effects

Effects of H₁ stimulation

Vasodilation.

Increased capillary permeability.

Bronchoconstriction.

CNS effects.

Other effects.

Effects of H₂ stimulation

Role of histamine in allergic responses

Mild allergy.

Severe allergic reactions (anaphylaxis).

Classification of h₁ antagonists

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Antihistamines

Antihistamines

The two types of antihistamines: h₁ antagonists and h₂ antagonists

H₁ antagonists i: basic pharmacology

Mechanism of action

Pharmacologic effects

Peripheral effects.

Effects on the CNS.

Other pharmacologic effects.

Therapeutic uses

Mild allergy.

Severe allergy.

Motion sickness.

Insomnia.

Common cold.

Adverse effects

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Antihistamines

Antihistamines

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