Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 14 Histamine and Antihistamines

MAJOR DRUG CLASSES

First-generation H1 receptor antagonists (sedating)

Second-generation H1 receptor antagonists (non-sedating)

Therapeutic Overview

Histamine is synthesized, stored, and released primarily by mast cells and has profound effects on many organs. It is an important mediator of immediate hypersensitivity reactions and acuteinflammatory responses and is a primary stimulator of gastric acid secretion. It is also an important neurotransmitter in the central nervous system (CNS) (see Chapter 27).

The many undesirable effects of histamine preclude its use as a drug. However, drugs that block histamine receptors or prevent its release from mast cells have important clinical uses. The effects of histamine on the heart, vascular, and nonvascular smooth muscle and on the secretion of gastric acid are mediated by at least three distinct receptors: H1, H2, and H3. A fourth histamine receptor (H4) was identified following the sequencing of the human genome, and it is thought to have a role in chemotaxis and mediator release in various types of immune cells. H4 receptor antagonists have antiinflammatory properties and efficacy in models of allergy and in autoimmune disorders.

H1 and H2 receptors have been most widely characterized and mediate well-defined responses in humans, as summarized in Table 14-1. Most responses are mediated by H1 receptors, such as bronchoconstriction, and are selectively antagonized by classical antihistamines, more accurately described as selective H1 receptor blocking drugs such as diphenhydramine. Antihistamines are widely used to treat allergic reactions, motion sickness, and emesis and as over-the-counter sleeping aids. H2-mediated responses such as gastric acid secretion are selectively antagonized by specific H2 receptor blocking drugs such as cimetidine. The H2 receptor antagonists are discussed extensively in Chapter 18; this chapter focuses on histamine and H1 receptor antagonists.

TABLE 14–1 Histamine Receptor Subtypes Mediating Selected Responses in Humans

Subtype

Responses

H1 receptor only

Basilar, pulmonary, coronary artery constriction; increased permeability of postcapillary venules; contraction of bronchiolar smooth muscle; stimulation of vagal sensory nerve endings promoting bronchospasm and coughing; gastrointestinal smooth muscle relaxation and contraction; Epi release from adrenal medulla

H2 receptor only

Acid and pepsin secretion from oxyntic mucosa; facial cutaneous vasodilation; pulmonary and carotid artery relaxation; increased rate and force of cardiac contraction; relaxation of bronchial smooth muscle; inhibition of IgE-dependent degranulation of basophils

H1 and H2 (?) receptors

Decreased total peripheral resistance; increased forearm blood flow; increased cardiac atrial and ventricular automaticity; stimulation of cutaneous nerve endings causing pain and itching

H3 receptors have been studied primarily in experimental animals, where they are located on nerve endings and mediate the inhibition of release of histamine and several other transmitters. This receptor remains an attractive target for drug development.

Abbreviations

CNS

Central nervous system

Epi

Epinephrine

IgE

Immunoglobulin E

Clinical uses of histamine antagonists are summarized in the Therapeutic Overview Box.

Therapeutic Overview

Histamine and Histamine Receptor Agonists

No significant clinical use

Antihistamines (H1 Receptor Antagonists)

Allergic reactions

Motion sickness

Insomnia

Nausea and vomiting

H2 Receptor Antagonists

Peptic ulcers and gastroesophageal reflux disease (see Chapter 18)

Mechanisms of Action

Synthesis and Metabolism of Histamine

The synthesis and catabolism of histamine are depicted in Figure 14-1. Histamine is synthesized by decarboxylation of the amino acid L-histidine by histidine decarboxylase. Most histamine is stored in an inert form at its site of synthesis, and very little is freely diffusible. After synthesis and release from its storage sites, histamine acts at its targets and is rapidly metabolized through two primary pathways. Oxidative deamination leads to formation of imidazole acetic acid, while methylation, which predominates in the brain, leads to the formation of N-methylimidazole acetic acid. Both metabolites are inactive and subject to further biotransformation.

image

FIGURE 14–1 Synthesis and metabolism of histamine.

Storage and Release of Histamine by Mast Cells and Basophils

Histamine is stored and released primarily by mast cells. Although basophils and central neurons also use histamine, their role is not fully understood. Histamine is widely distributed, with the highest concentrations in the skin, lungs, and gastrointestinal tract mucosa, consistent with mast cell densities in these tissues.

Mast cells and basophils have high-affinity immunoglobulin E (IgEbinding sites on their surface membranes and store histamine in secretory granules. Different types of mast cells can be classified by their staining properties, anatomical locations, or susceptibility to degranulation by polyamines. Anatomically, mast cells are classified as being of mucosal or connective tissue origin. However, there are mixed populations in both tissues and additional heterogeneity within these two classes. Human mast cells differ with respect to their proteoglycan structure and content, the types of serine proteases in their storage granules, the eicosanoids synthesized and released on degranulation, and the extent to which degranulation is inhibited by cromolyn Na+.

In mast cell granules, histamine exists as an ionic complex with a proteoglycan, chiefly heparin sulfate, but also chondroitin sulfate E. In basophils, histamine is also stored in granules as an ionic complex, predominantly with proteoglycans. The release of histamine and other mediators from mast cells and basophils is common during allergic reactions but also can be induced by drugs and endogenous compounds to produce pseudoallergic, anaphylactoid reactions as shown in Figure 14-2. The role of mast cells in immediate and delayed hypersensitivity reactions and nonallergic disorders explains the therapeutic utility of antihistamines and degranulation inhibitors.

image

FIGURE 14–2 Summary of mast cell release of histamine. Some stimuli act indirectly through receptors for immunoglobulins (indentations in the membrane), whereas others act directly by causing an increase in intracellular Ca++, which triggers the release of histamine from mast cells.

*The gastrointestinal effects of histamine at H2 receptors are discussed in Chapter 18.

Histamine is released by noncytolytic or cytolytic degranulation. Cytolytic release occurs when the membrane is damaged, does not require energy or intracellular Ca++, and is accompanied by leakage of cytoplasmic contents. Cytolytic release can be induced by drugs such as phenothiazines, H1 receptor antagonists, and opioids, but the concentrations required are usually greater than therapeutic concentrations.

Noncytolytic release is evoked by binding of a specific ligand to a receptor in the plasma membrane, resulting in exocytosis of secretory granules. Noncytolytic release requires energy, depends on intracellular Ca++, and is not accompanied by leakage of cytoplasmic contents. A classic example is degranulation of sensitized mast cells or basophils induced by cross-bridging of adjacent IgE molecules on the cell surface. This involves activation of various phospholipases, fusion of secretory granules with the plasma membrane, and extrusion of their contents. Such exocytosis results in the release of histamine, heparin, eosinophil, and neutrophil chemotactic factors; neutral proteases; and other enzymes. The release of other mediators, such as eicosanoids and platelet-activating factor, can also occur.

Noncytolytic release can also be produced by other mechanisms, often by highly basic substances. These include the polyamine compound 48/80, polypeptides such as bradykinin, substance P, formylmethionylleucinylphenylalanine, protamine, anaphylatoxins, and a protein present in bee venom. With the exception of protamine, a heparin antagonist, none of these agents has any therapeutic use, but they are likely important in pathological responses.

Noncytolytic degranulation can also be induced by several drugs including d-tubocurarine, succinylcholine, morphine, codeine (in therapeutic doses), doxorubicin, and vancomycin. The mechanism may involve activation of protein kinase A and NF-κB. Histamine release in vivo may also be produced by some plasma expanders, notably those based on cross-linked gelatin, and by radiocontrast media, especially those of high osmotic strength. Intravenous administration of these compounds is most likely to result in histamine release. Life-threatening reactions are rare but occur occasionally.

The most acute and potentially severe allergic reaction is anaphylaxis. In both animals and humans, parenterally administered histamine triggers responses that mimic the early responses of anaphylaxis, including hypotension, vasodilation, myocardial depression, dysrhythmias, urticaria, angioedema, and bronchospasm. These can be partially reversed by H1 and H2 receptor antagonists; however, they are most effective when administered prophylactically rather than after an acute reaction has begun. Histamine is only one of many anaphylactic mediators, but it has important effects on the production and effectiveness of others.

Noncytolytic degranulation of mast cells results in both anaphylactic and anaphylactoid reactions. Many substances can release histamine independently of IgE. However, the clinical signs and symptoms are indistinguishable from those of true anaphylaxis, because the same mediators are involved. The term anaphylactoid is used to refer to a clinical syndrome indistinguishable from anaphylaxis but caused by something other than an immune response.

Many of the solutions and drugs used in general anesthesia can produce mast cell degranulation, especially if administered intravenously. However, skeletal muscle paralysis, the effects of other drugs, and mechanical ventilation can mask signs of histamine release. Cardiac dysrhythmias or hypotension without flush, rashes, or angioedema may be seen. Indeed, most patients undergoing general anesthesia have elevated histamine levels but are relatively asymptomatic. Preoperative prophylaxis with H1 and H2 receptor antagonists remains controversial but is used for certain patients at risk (atopic patients and patients with previous reactions).

A summary of agents that release histamine is presented in Table 14-2. Histamine concentrations of 0.2 to 1.0 ng/mL in humans produce mild signs and symptoms, including metallic taste, headache, and nasal congestion. Concentrations exceeding 1 ng/mL produce moderate effects, including skin reactions, cramping, diarrhea, flushing, tachycardia, cardiac dysrhythmias, and hypotension. Life-threatening hypotension, ventricular fibrillation, and bronchospasm leading to cardiopulmonary arrest can occur when concentrations approach 12 ng/mL.

TABLE 14–2 Common Causal Factors Involved in Anaphylactic and Anaphylactoid Reactions

IgE-Mediated Anaphylaxis

Non–IgE-Mediated Anaphylactoid Reactions

Food

Drugs

Peanuts, seafood, eggs, milk products, grains

Anesthesia related: neuromuscular blocking agents, opioids, plasma expanders

Drugs

 

Antibiotics: penicillins, cephalosporins, sulfonamides

Antibiotics: vancomycin

Others: protamine

 

Dyes

Venoms

Radiocontrast media, fluorescein

Hymenoptera, fire ants, snakes

 
 

Other Idiopathic Reactions

 

Some cases of exercise-induced bronchospasm

Urticaria related to cold, heat, sunlight, and other physical factors

Foreign Proteins

Nonhuman insulin, corticotropin, serum proteins, seminal proteins, vaccines, antivenoms

Enzymes

 

Chymopapain

 

Other

 

Some cases of exercise-induced bronchospasm

 

Inhibitors of Degranulation and Histamine Release

Because many mediators are released from mast cells and basophils during noncytolytic degranulation, agents that can prevent this reaction are of therapeutic value. Cromolyn sodium is used to treat asthma and bronchospastic diseases and is discussed in Chapter 16.

H1 Receptor Antagonists

The classic antihistamines are selective H1 receptor antagonists. Histamine was originally thought to be the dominant mediator of immediate hypersensitivity reactions. However, H1 receptors antagonists could reverse only histamine-induced hypotension and bronchoconstriction, and they were not very effective in the management of global anaphylaxis because of the release of other mediators during anaphylaxis. The inability of H1 receptor antagonists to block the effects of histamine on cardiovascular H2 receptors also limited their effectiveness.

H1 antagonists have little structural resemblance to histamine (Figs. 14-1 and 14-3). A common feature, however, is a substituted ethylamine containing a nitrogen atom in an alkyl chain or ring. H1antagonists are classified by the chemical group containing the substituted ethylamine.

image

FIGURE 14–3 Structures of selected H1 receptor antagonists.

All currently available antihistamines share the common property of competitively blocking H1 receptors. Terfenadine and astemizole are exceptions but were withdrawn from the U.S. market because of serious adverse effects. Differences between the many available compounds are due to their pharmacokinetic properties and specific adverse reactions. Because a major clinical problem with the use of early antihistamines was their marked sedative effects, many compounds were subsequently developed that did not cross the blood-brain barrier. Differences in their abilities to cross the blood-brain barrier are the basis for classification as first-generation (sedating) or second-generation (non-sedating) drugs.

Other Antiallergic Properties of Antihistamines

Antihistamines also have important actions at receptors other than H1 receptors. Many first-generation antihistamines also block muscarinic cholinergic, dopamine, α1 adrenergic, and serotonin receptors. For example, azatadine is a fairly potent antagonist of serotonin, and promethazine exhibits weak α1 adrenergic and moderate dopamine (D2) receptor blocking activity. H1 receptor antagonists also inhibit mediator release, basophil migration, and eosinophil recruitment, which can contribute to their antiallergy effects through poorly understood mechanisms.

Other effects have also been observed for second-generation antihistamines, including inhibition of allergen-induced migration of eosinophils, basophils, and neutrophils and an inhibition of platelet-activating factor-induced eosinophil accumulation in skin. The clinical significance of these effects remains to be established.

Pharmacokinetics

The pharmacokinetic parameters of selected H1 receptor antagonists are given in Table 14-3. Those of cromolyn are presented in Chapter 16, and those of H2 receptor antagonists are presented in Chapter 18.

TABLE 14–3 Pharmacokinetic Parameters of Selected H1 Receptor Antagonists

Drug

t1/2 (hrs)

Disposition

Cetirizine

7–9

R, N

Chlorpheniramine

~20

M

Desloratadine

~27

M, N

Diphenhydramine

–8

M

Fexofenadine

14

R, N

Loratadine

2–15

M, A, N

Promethazine

7–15

M

M, Metabolism; A, active metabolite that contributes to therapeutic effect; N, non-sedating; R, renal elimination.

All H1 antagonists are well absorbed after oral administration, have good bioavailability, and have onsets of action of approximately 30 to 60 minutes; they vary in duration of action. In terms of distribution, first-generation antihistamines distribute throughout the body and readily penetrate the CNS. By design, second-generation antihistamines such as fexofenadine, loratadine, and desloratadine do not readily penetrate the CNS and are much less sedative.

All antihistamines are metabolized extensively by the liver, and metabolites are eliminated by renal excretion. Some are substrates for monoamine oxidase. The antihistamines often induce hepatic cytochrome P450 enzymes and may facilitate their own metabolism or that of other drugs. Their actions and toxicities can be enhanced in patients with hepatic failure.

Relationship of Mechanisms of Action to Clinical Response

Actions of Histamine

Vascular System

The effects of histamine on the systemic vasculature are complex, and different vascular beds show different responses (see Table 14-1). The predominant action is vasodilation resulting from relaxation of arteriolar smooth muscle, precapillary sphincters, and muscular venules mediated by H1 and H2 receptors. Vasodilation produced by H1 receptors occurs at lower doses and is transient, whereas that caused by H2 receptors occurs at higher doses and is sustained. Both H1 and H2 antagonists are required to completely block the hypotensive response.

Histamine also acts at H1 receptors on endothelial cells in postcapillary venules to cause endothelial cells to contract and expose permeable basement membranes. This results in edema from the buildup of fluid and plasma protein in the surrounding tissue.

A summary of the actions of histamine on the vasculature is seen in the triple response of Lewis that occurs after intradermal injection. Initially a small red spot is produced at the site of injection and is then slowly surrounded by a flushed area. In a few minutes a wheal appears at the site of the original red spot. The red spot and the erythema are caused by vasodilation, with the red spot resulting from the direct actions of histamine on the cutaneous vasculature and the erythema from axon reflexes that produce vasodilation. These responses are mediated by H1 and H2 receptors, with H1 receptors predominating. The wheal results from edema. Intradermal histamine also stimulates nerve endings to produce pain and itching. These local reactions represent a microcosm of the systemic effects of large doses of histamine that cause cardiovascular shock.

Heart

Histamine exerts direct and indirect actions on the human heart. Indirectly it accelerates rate and increases force of contraction because of a baroreceptor-mediated increase in sympathetic tone in response to systemic vasodilation. Direct actions on the heart are mediated primarily by H2 receptors and include increases in rate, atrial and ventricular automaticity, and contractile force. Modest tachycardia occurs at doses of histamine that produce little change in systemic pressure, whereas low doses cause primarily indirect actions that are due to systemic vasodilation.

Respiratory System

Histamine causes bronchoconstriction in humans after inhalation or intravenous injection through activation of H1 receptors. Normally, histamine is not especially potent; however, patients with asthma are often hyper-reactive, and therefore aerosolized histamine has been used as a provocative test for bronchial reactivity.

Histamine may also produce a modest relaxation of contracted bronchial smooth muscle through H2 receptors, although this is not usually clinically significant. Histamine also acts on H1 receptors to increase secretion of airway fluid and electrolytes, which may produce pulmonary edema and contribute to bronchial obstruction in patients with extrinsic asthma (see Chapter 16).

Gastrointestinal System

An important physiological function of histamine is its role as a primary mediator in the secretion of gastric acid, discussed in Chapter 18.

Other Actions

Headaches, nausea, and vomiting have also been observed in human volunteers receiving histamine. In high doses histamine stimulates catecholamine release from the adrenal medulla, an effect particularly pronounced in patients with pheochromocytoma, a catecholamine-secreting tumor of the adrenal medulla.

Central Nervous System

The role of histamine in the brain is largely inferred from results of studies in experimental animals. Postulated roles include the regulation of temperature, H2O balance, nociception, blood pressure, and arousal. The role of individual receptor subtypes remains unclear, although considerable interest has been generated in drugs that act on H3 receptors.

Anaphylaxis and Anaphylactoid Reactions

Histamine is an early mediator in anaphylactoid reactions and probably has a permissive effect on the release of other mediators, because antihistamines are far more effective prophylactically than after an inflammatory reaction has begun. Anaphylaxis can result in death from cardiovascular collapse or respiratory obstruction and must be treated immediately.

When possible, the causative agent in anaphylaxis should be identified and histamine concentrations monitored. Serum histamine concentrations begin to rise 5 to 10 minutes after exposure to the causative agent and may remain elevated for up to 60 minutes. Urinary histamine and its metabolites may stay elevated longer and can be valuable in diagnosis. Serum tryptase is released almost exclusively from mast cells in parallel with histamine release. Its concentrations increase 1 to 1.5 hours after the onset of symptoms, may stay elevated for 4 to 5 hours, and have been used to diagnose anaphylaxis postmortem. The clinical severity of rechallenge with Hymenoptera (e.g. wasp) venom correlates with the extent to which serum histamine and tryptase concentrations increase, but the nature of the triggering agent or individual variations may alter this relationship.

Histamine Agonists

Several histamine agonists are available but are rarely used clinically. The selective H2 receptor agonist betazole is used occasionally as a gastric secretagogue in diagnostic tests for acid secretion. However, pentagastrin is preferred because it produces fewer systemic effects.

Inhibitors of Mast Cell Degranulation

Cromolyn Na+ inhibits the degranulation of mast cells and activation of inflammatory cells. It is used in the treatment of asthma and bronchospastic disorders (see Chapter 16).

H1 Receptor Antagonists

All H1 receptor antagonists are useful in treating allergic reactions. They also have varying degrees of sedative, antiemetic, antimotion sickness, antiparkinsonian, antitussive, and local anesthetic actions. Certain antihistamines are used exclusively for one or another of these properties rather than in treatment of allergic reactions.

The effectiveness of H1 receptor antagonists in the treatment of motion sickness and extrapyramidal symptoms may result from their antimuscarinic actions. They may promote sleep by blocking central H1 receptors and muscarinic receptors. The drugs with antiemetic activity are largely those in the phenothiazine class, and they may work primarily by acting as dopamine D2 receptor antagonists. Local anesthetic actions result from the blockade of Na+ channels. Thus the actions of antihistamines at sites other than H1 receptors are the source of both therapeutic and adverse effects. Pharmacological properties of representative H1 antagonists are summarized in Table 14-4.

TABLE 14–4 Properties of H1 Receptor Antagonist Classes

Chemical Class/Agents

Comments

Alkylamines

Brompheniramine

Chlorpheniramine

Triprolidine

Moderately sedating in usual doses, moderate antimuscarinic activity, no antiemetic or antimotion sickness actions

Ethanolamines

Clemastine

Carbinoxamine

Dimenhydrinate

Diphenhydramine

Significant sedative actions, marked antimuscarinic and antimotion sickness actions; diphenhydramine is in many over-the-counter preparations; dimenhydrinate contains diphenhydramine as the 8-chlorotheophyllinate salt

Ethylenediamines

Pyrilamine

Tripelennamine

Low to moderate sedative actions, very little antimuscarinic actions, no antimotion sickness activity in usual doses

Piperizines

Cetirizine

Hydroxyzine

Meclizine

Cyclizine

Varying degrees of antimuscarinic, antimotion sickness, and sedative actions; meclizine is less sedating than hydroxyzine, used primarily in treatment of motion sickness and vertigo; hydroxyzine has marked sedative and antimuscarinic actions, used as an antiemetic, sedative, and mild anxiolytic agent; cetirizine, a carboxy metabolite of hydroxyzine, is non-sedating

Piperidines

Azatadine

Fexofenadine

Desloratadine

Loratadine

Phenindamine

Fexofenadine, loratadine, and desloratadine are non-sedating and have little or no antimuscarinic activity; azatadine has low to moderate sedative and antimuscarinic actions, marked antiserotonin activity; phenindamine is more likely to produce stimulation

Phenothiazines

Methdilazine

Promethazine

Trimeprazine

Marked antimuscarinic, antiemetic, antimotion sickness activities; α1 adrenergic receptor-blocking activity can cause orthostatic hypotension; sedation is common, especially with promethazine

The release of histamine from mast cells and basophils is accompanied by the release of many other mediators of the immediate hypersensitivity response. Drugs that antagonize H1 receptors are useful as monotherapy in mild pseudoallergic or true allergic reactions and as adjunct agents in the treatment of severe reactions. The treatment of severe allergic reactions requires the use of a physiological antagonist such as an adrenergic agonist, commonly Epi (see Chapter 11), which will reverse the hypotension, laryngeal edema, and bronchoconstriction produced by mast cell mediators.

The effectiveness of H1 receptor antagonists in the treatment and prevention of allergic disorders is limited to symptoms resulting mainly from the actions of histamine. Allergic reactions that respond best to treatment with H1 receptor antagonists are seasonal ones, but perennial allergic rhinitis, conjunctivitis, and itching associated with acute and chronic urticaria may also respond. H1 receptor antagonists are also of some value in the treatment of atopic and contact dermatitis. The choice of a non-sedating or sedating compound depends on whether sedation is desirable. These agents are also the main active ingredient of over-the-counter sedatives. Tolerance to sedative properties may develop within a few days.

H1 receptor antagonists are not primary drugs for treating bronchial asthma (see Chapter 16) but may be useful in patients with asthma who require therapy for allergic rhinitis, allergic dermatoses, or urticaria.

Tolerance to antihistamines often occurs. Frequently the desired therapeutic effects can be restored by switching a patient to a drug from a different chemical class. The mechanisms involved are not well understood.

H1 receptor antagonists that enter the CNS are used in prophylaxis of motion sickness. Promethazine and diphenhydramine are most potent but are also associated with a high incidence of sedation. Promethazine is an effective antiemetic that can reduce vomiting stemming from a variety of causes. Meclizine, cyclizine, and dimenhydrinate (a salt of diphenhydramine) are used in over-the-counter preparations for the prevention of motion sickness. However, none is as effective as the antimuscarinic agent scopolamine (see Chapter 10). These agents also are used in symptomatic treatment of vertigo.

H2 Receptor Antagonists

The H2 receptor antagonists are discussed in Chapter 18.

Combination of H1 and H2 Receptor Antagonists

Combinations of H1 and H2 receptor antagonists are used in the prophylaxis and treatment of severe allergic reactions. Such a combination is more effective than either antagonist alone in reducing histamine-induced vasodilatation, hypotension, mucus secretion, decrease in diastolic blood pressure, and widening of pulse pressure that occur in this setting. Because many mediators are involved, other antiallergic agents are often required, including corticosteroids (see Chapter 39).

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

Clinical problems with the H1 receptor antagonists are listed in the Clinical Problems Box. Problems associated with H2 receptor antagonists are covered in Chapter 18, and those with cromolyn are covered in Chapter 16.

H1 Receptor Antagonists

Most adverse effects of H1 receptor antagonists stem from their antimuscarinic and sedative actions. CNS depression is common with the older agents and occurs in 25% to 50% of patients. Antihistamines with antimuscarinic activity may cause dry mouth, blurred vision, urinary retention, constipation, and other symptoms typical of muscarinic receptor blockade (see Chapter 10). Additional effects include insomnia, nervousness, tremors, and euphoria. Appetite stimulation and weight gain have been reported for some drugs. Paradoxical excitation can occur in children; nausea, vomiting, diarrhea, and epigastric distress are also reported. Over-the-counter cough and cold medicines containing H1 receptor antihistamines in pediatric formulations have raised significant concerns about lack of efficacy and excessive adverse effects in children.

The main signs of acute overdose of most first-generation antihistamines are similar to those of antimuscarinic drugs and in high doses include convulsive seizures. Overdose can result in a rare but potentially hazardous quinidine-like effect, resulting in prolongation of the QT interval, which represents the time for ventricular depolarization and repolarization and is an estimate of the duration of the average ventricular action potential. The antihistamines, like several other classes of drugs that prolong the QT interval, can produce torsades de pointes, a prefibrillatory ventricular dysrhythmia. Such dysrhythmias are reported for both first- and second-generation antihistamines. The possibility of serious adverse effects is increased if hepatic metabolism is reduced, when adverse effects can occur at usual therapeutic doses. No such effects have been reported for cetirizine, fexofenadine, loratadine, or desloratadine.

The incidence of CNS depression and antimuscarinic effects is less in patients receiving second-generation agents and is comparable to those produced by placebo. The incidence of true allergic responses is low for drugs administered systemically. However, allergic responses are relatively common after repeated topical use; therefore such use is discouraged. Teratogenic effects of piperazine derivatives are observed in experimental animals, and although there is no evidence of this in humans, antihistamines are not recommended during pregnancy.

CLINICAL PROBLEMS

H1 Receptor Antagonists

Antimuscarinic actions

Sedative effects

CNS depression

Paradoxical excitation in children

Topical use leading to allergic reactions

Antimuscarinic and CNS effects are minimal for second-generation agents

The centrally acting H1 receptor antagonists can potentiate the actions of other CNS depressants, including sedative hypnotics, narcotic analgesics, general anesthetics, and alcohol.

New Horizons

Several drugs are under development, including drugs that act on H3 receptors. H3 agonists, which inhibit transmitter release, may be useful in the treatment of asthma by virtue of their ability to inhibit neurogenically evoked bronchospasm. Similarly, such agents may provide a novel means of reducing gastric acid secretion and reducing intestinal hypermotility. Actions of drugs acting on H3 receptors may prove useful for potential treatment of attention-deficit hyperactivity disorder, dementias, schizophrenia, and obesity and sleep disorders.

Genetic variants of histamine receptors have been observed, but the clinical implications of these variants have not yet been identified.

TRADE NAMES

(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)

First-Generation H1 Receptor Antagonists (sedating)

Brompheniramine (Atrohist, Bromarest, Bromfed, Dimetane)

Chlorpheniramine (Chlortrimeton, Teldrin)

Clemastine (Tavist)

Cyclizine (Marezine)

Dexchlorpheniramine (Dexchlor, Polaramine)

Dimenhydrinate (Dimetabs, Dramamine, Marmine)

Diphenhydramine (Benadryl)

Meclizine (Antivert, Bonikraft, Medivert)

Phenindamine (Nolahist)

Promethazine (Phenameth, Phenergan)

Tripelennamine (PBZ, Vaginex)

Triprolidine (Zymine)

Second-Generation H1 Receptor Antagonists (non-sedating)

Azelastine (Atelin,Optivar)

Cetirizine (Zyrtec)

Desloratadine (Clarinex)

Fexofenadine (Allegra)

Loratadine (Claritin)

FURTHER READING

Anonymous. Drugs for allergic disorders. Treat Guidel Med Lett. 2007;60:71-80.

Esbenshade TA, Fox GB, Cowart MD. Histamine H3 receptor antagonists: Preclinical promise for treating obesity and cognitive disorders. Mol Interv. 2006;6:77-88.

Miyoshi K, Das AK, Fujimoto K, et al. Recent advances in molecular pharmacology of the histamine systems: Regulation of histamine H1 receptor signaling by changing its expression level. J Pharmacol Sci. 2006;101:3-6.

SELF-ASSESSMENT QUESTIONS

1. First-generation antihistamines differ from second-generation antihistamines in that the first-generation agents generally show:

A. Greater affinities for H1 receptors.

B. Partial agonist activity.

C. Greater antimuscarinic activity.

D. Greater sedative effects.

E. Greater affinity for H3 receptors

2. Synthesis of histamine by the body involves which one of the following enzymes?

A. Histamine-N-methyltransferase

B. Diamine oxidase

C. N-methylhistamine oxidase

D. L-Histidine reductase

E. L-Histidine decarboxylase

3. Responses mediated by H2 receptors include:

A. Bronchoconstriction.

B. Gastric acid secretion.

C. Decreased force of ventricular contraction.

D. Stimulation of basophil degranulation.

E. Inhibition of norepinephrine release.

4. Histamine release from mast cells:

A. Is often induced by antibodies.

B. Is seldom induced by antibodies.

C. Is often induced by antihistamines.

D. Often results in bronchodilation.

E. Often results in reduced gastric secretion.