18 – Histamine and Histamine Antagonists*










276
CASE STUDY
Mr. H. is your 67-year-old dental patient. He needs to have tooth #19
extracted and an immediate implant placed. He tells you he is extremely
anxious and would like moderate sedation for the procedure. You review
his medical history and find a past medical history significant for benign
prostatic hyperplasia (BPH) and hypertension (HTN). His HTN is well con-
trolled with lisinopril, and he takes no medicines for his BPH. His surgical
history is significant for a hernia repair 3 years ago. He does note a history
of severe postoperative nausea and vomiting in recovery. You evaluate
the patient, discuss risks versus benefits, and decide to use moderate IV
sedation for treatment. Would you include a first-generation antihista-
mine, promethazine, in your sedation regimen to help with the patient’s
sedation and possible postoperative nausea and vomiting?
AUTACOIDS
Autacoids from the Greek autos (“self”) and akos (“cure”) are endog-
enous organic molecules with potent pharmacologic effects, that are
not part of traditional immune or autonomic groups. Histamine and
serotonin (5-hydroxytryptamine) are two important amine autacoids.
Other autacoids, which produce paracrine type effects, include poly-
peptides (angiotensin, bradykinin, and kallidin), lipid-derived sub-
stances (prostaglandins, leukotrienes, and platelet-activating factor),
and nitric oxide. This chapter will focus on histamine and histamine
antagonists.
HISTAMINE
Histamine, formed from the amino acid histidine (Fig. 18-1), is a ubiq-
uitous amine that modulates local immune responses and regulates
physiologic function including gastric secretion, neurotransmission
in the central nervous system (CNS), and local control of the micro-
circulation. Pharmacologic properties of histamine suggest that this
substance is involved in inflammatory and anaphylactic reactions.
18
KEY INFORMATION
Autacoids are potent endogenous substances with complex
physiologic and pathophysiologic functions with non-
autonomic pharmacologic effects. They include histamine,
serotonin, prostaglandin, vasoactive peptides, and nitric
oxide.
Histamine, formed from the amino acid histidine, is a
ubiquitous amine, that modulates local immune responses
and regulates physiologic function including gastric secretion,
neurotransmission in the central nervous system, and local control
of the microcirculation.
Most histamine is produced and stored within granules
in mast cells, leukocytes (basophils and eosinophils), and
enterochromaffin cells of the stomach.
Physical or chemical agents that nonspecifically cause injury to
tissue can cause the immediate release of histamine from mast
cells in the affected area.
Histamine release can occur as a consequence of the binding of
specific antigens to allergen-specific antibodies via reaginic (IgE)
antibodies. These are attached to the plasma membranes of mast
cells and basophils.
Histamine exerts its effects by binding G protein–coupled
histamine receptors, (see chapter 1), designated H
1
through H
4
.
Histamine antagonists do not alter the formation, release, or
degradation of histamine but competitively antagonize it at the
receptor sites.
H
1
blockers are clinically used for allergies of the immediate type
(e.g., hay fever, allergic rhinitis, urticaria), such as those caused by
antigens, which act on IgE antibody-sensitized mast cells.
Older H
1
antihistamines, first generation, are highly sedating
agents with significant autonomic receptor blockade.
Second-generation H
1
blockers, typified by cetirizine,
fexofenadine, and loratidine, have less lipid solubility than
first-generation agents and do not cross the blood–brain barrier,
therefore greatly reducing their sedative and autonomic effects.
Side effects of first-generation H
1
blockers may be the desired
therapeutic (sedation and dry mouth) outcome.
Four H
2
blockers are available: cimetidine, ranitidine, famotidine,
and nizatidine. They are potent competitive antagonists of the H
2
receptors, therapeutically reducing gastric acid secretion.
Cimetidine is a competitive inhibitor of the hepatic mixed-
function oxidase enzymes responsible for the metabolism of some
drugs.
Cimetidine has been shown to increase blood concentrations of
numerous drugs, including anticoagulants of the warfarin type,
tricyclic antidepressants, various benzodiazepines, phenobarbital,
theophylline, propranolol and other β-adrenoceptor blockers,
Ca
2+
channel blockers, lidocaine, estradiol, and phenytoin.
Ranitidine, famotidine, and nizatidine have fewer adverse effects
than cimetidine because binding of these agents to cytochrome
P450 enzymes is much less firm than that of cimetidine.
Histamine and Histamine Antagonists*
Matthew R. Cooke and Joseph A. Giovannitti Jr.
*The authors wish to recognize Clarence L. Trummel for his past contributions
to this chapter.

277
CHAPTER 18 Histamine and Histamine Antagonists
Local application of histamine causes redness, swelling, and edema,
mimicking a mild inflammatory reaction. Large doses of systemically
administered histamine have the potential to produce profound vascu-
lar changes similar to those seen in shock of traumatic or anaphylactic
origin.
Formation, Distribution, and Release
The histamine content of different tissues varies greatly. The highest
concentrations are found in lung, skin, and intestinal mucosa. Organs
such as the pancreas, spleen, liver, and kidney have low histamine
content. The physiologic significance of this pattern of distribution is
unknown. Histamine may be derived from dietary sources or synthe-
sized by bacteria in the gastrointestinal tract. However, most is formed
in situ.
High concentrations of histamine are found in vesicles within mast
cells, leukocytes (basophils and eosinophils), enterochromaffin cells
of the gastrointestinal tract, some neurons, and other cells. Mast cells
synthesize histamine and store it as a proteinaceous complex with
heparin or chondroitin sulfate in membrane-bound secretory granules
where it can be discharged from the cell by a process called exocytosis,
or degranulation (Fig. 18-2).
Histamine outside the mast cell or basophil is found within neurons
of the hypothalamus. The function of these histaminergic neurons is
unknown. Another site of non–mast cell histamine is the entero-
chromaffin cell in the gastric mucosa. Here histamine stimulates gastric
acid secretion by mucosal parietal cells. Certain neoplasms, collectively
known as carcinoids, also secrete various autacoids, including hista-
mine, which likely contribute to the so-called carcinoid syndrome.
Various conditions (or stimuli) trigger the release of histamine:
Tissue injury
Physical or chemical agents that nonspecifically cause injury to tissue,
particularly skin or mucosa, cause the immediate release of histamine
from mast cells in the affected area. Depending on the severity of injury,
histamine continues to be released for several minutes and seems to be
largely responsible for the initial sharp increase in vascular permeability
that is characteristic of acute inflammation. This histamine-dependent
change in permeability is transient (30 minutes) but is followed in
2 to 4 hours by a more prolonged increase in permeability lasting up
to 4 hours. Although inhibitors of histamine release, or inhibitors of
the subsequent action of histamine, can block the initial phase of vas-
cular permeability after injury, they have little effect on the second-
ary or delayed phase, suggesting that autacoids or factors other than
histamine mediate the secondary phase. The mechanism by which a
nonspecific injury triggers mast cell degranulation is unclear. Proposed
mechanisms include direct physical damage to mast cells or alterna-
tively via initial production of factors such as activated complement
components or vasoactive polypeptides, which stimulate histamine
release.
Allergic reactions
Presentation of a specific antigen to a previously sensitized subject can
trigger immediate allergic reactions, ranging in intensity from mild
(localized edema, erythema, and itching) to severe (marked decrease
in blood pressure and bronchospasm). The pathophysiologic manifes-
tations of such reactions are caused largely by the release of histamine
(Fig. 18-3). Release occurs as a consequence of the binding of specific
antigens to allergen-specific reaginic (IgE) antibodies that are attached
to the plasma membranes of mast cells and basophils; these are trans-
membrane high-affinity receptors termed FcεRI. Antigen–antibody
interaction is an appropriate stimulus for the series of events leading to
degranulation of these cells (see Fig. 18-3).
Drugs and other foreign compounds
Large groups of drugs and other chemicals can trigger histamine release
directly without a requirement for previous sensitization through an
immune response. For convenience, these agents can be classified as
basic histamine releasers, macromolecular compounds, and enzymes.
The basic histamine releasers include aliphatic and arylalkyl amines,
amides, amidines, diamidines, quaternary ammonium compounds,
FIG 18-2 Summary of mast cell release of histamine. Some stimuli act through receptors for immunoglobu-
lins (indentations in the membrane), whereas others act directly by causing an increase in intracellular Ca
2+
,
which triggers the release of histamine from mast cells. (From Wecker L, Crespo L, et al: Brody’s human
pharmacology, ed 5, Philadelphia, 2010, Mosby.)
HC
HN
C
H
N
C
HC
HN
C
H
N
C
CH
2
CH
COOH
NH
2
Histidine
decarboxylase
CH
2
CH
2
NH
2
CO
2
+
Histidine Histamine
FIG 18-1 Conversion of histidine to histamine.

278 CHAPTER 18 Histamine and Histamine Antagonists
alkaloids, piperidine derivatives, pyridinium compounds, opioids,
antimalarial drugs, dyes, and basic polypeptides.
Metabolism
Histamine of either exogenous or endogenous origin is rapidly inacti-
vated by two routes. The more important of these is methylation of the
imidazole ring by the enzyme histamine-N-methyltransferase, which
is widely distributed throughout the body. The other route involves
the oxidative deamination of histamine by diamine oxidase to produce
imidazole acetic acid, much of which is subsequently conjugated with
ribose. All metabolites are inactive and, along with a small amount of
free histamine, are excreted by the kidney.
Mechanism of Action
Histamine exerts its effects by binding to G protein–coupled histamine
receptors, (Chapter 1) designated H
1
through H
4
(Table 18-1). Most of the
important effects of histamine can be attributed to its actions on smooth
muscle and glands. The existence of compounds that can selectively
block the actions of histamine strongly supports the existence of four
histamine receptors: H
1
, H
2
, H
3
, and H
4
. Although the first two seem to
be unique (i.e., have selective agonists and antagonists), the H
3
and H
4
receptors share a degree of homology and are more difficult to distin-
guish pharmacologically from one another (see Table 18-1).
General Therapeutic Uses
Although no valid therapeutic applications exist for histamine, it is of
limited use as a diagnostic tool in the assessment of gastric acid pro-
duction and in testing for nonallergic bronchial hyperreactivity in
asthmatics.
Adverse Effects
The toxic effects of histamine are predictable based on its pharmaco-
logic actions and include cutaneous flushing, hypotension, headache,
visual disturbances, dyspnea, and gastrointestinal disturbances such
FIG 18-3 General mechanism underlying an allergic reaction. Exposure to an antigen activates B cells to form
IgE-secreting plasma cells. The secreted IgE molecules bind to IgE-specific Fc receptors on mast cells. After
a second exposure to the allergen, the bound IgE is cross-linked, which triggers the release of active medi-
ators (e.g., histamine) from mast cells. The mediators cause smooth muscle contraction, increased vascular
permeability, and vasodilation. (From Koeppen B, Stanton B: Berne and Levy physiology, ed 6, Philadelphia,
2010, Mosby.)

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276CASE STUDYMr. H. is your 67-year-old dental patient. He needs to have tooth #19 extracted and an immediate implant placed. He tells you he is extremely anxious and would like moderate sedation for the procedure. You review his medical history and find a past medical history significant for benign prostatic hyperplasia (BPH) and hypertension (HTN). His HTN is well con-trolled with lisinopril, and he takes no medicines for his BPH. His surgical history is significant for a hernia repair 3 years ago. He does note a history of severe postoperative nausea and vomiting in recovery. You evaluate the patient, discuss risks versus benefits, and decide to use moderate IV sedation for treatment. Would you include a first-generation antihista-mine, promethazine, in your sedation regimen to help with the patient’s sedation and possible postoperative nausea and vomiting?AUTACOIDSAutacoids from the Greek autos (“self”) and akos (“cure”) are endog-enous organic molecules with potent pharmacologic effects, that are not part of traditional immune or autonomic groups. Histamine and serotonin (5-hydroxytryptamine) are two important amine autacoids. Other autacoids, which produce paracrine type effects, include poly-peptides (angiotensin, bradykinin, and kallidin), lipid-derived sub-stances (prostaglandins, leukotrienes, and platelet-activating factor), and nitric oxide. This chapter will focus on histamine and histamine antagonists.HISTAMINEHistamine, formed from the amino acid histidine (Fig. 18-1), is a ubiq-uitous amine that modulates local immune responses and regulates physiologic function including gastric secretion, neurotransmission in the central nervous system (CNS), and local control of the micro-circulation. Pharmacologic properties of histamine suggest that this substance is involved in inflammatory and anaphylactic reactions. 18KEY INFORMATION • Autacoids are potent endogenous substances with complex physiologic and pathophysiologic functions with non-autonomic pharmacologic effects. They include histamine, serotonin, prostaglandin, vasoactive peptides, and nitric oxide. • Histamine, formed from the amino acid histidine, is a ubiquitous amine, that modulates local immune responses and regulates physiologic function including gastric secretion, neurotransmission in the central nervous system, and local control of the microcirculation. • Most histamine is produced and stored within granules in mast cells, leukocytes (basophils and eosinophils), and enterochromaffin cells of the stomach. • Physical or chemical agents that nonspecifically cause injury to tissue can cause the immediate release of histamine from mast cells in the affected area. • Histamine release can occur as a consequence of the binding of specific antigens to allergen-specific antibodies via reaginic (IgE) antibodies. These are attached to the plasma membranes of mast cells and basophils. • Histamine exerts its effects by binding G protein–coupled histamine receptors, (see chapter 1), designated H1 through H4. • Histamine antagonists do not alter the formation, release, or degradation of histamine but competitively antagonize it at the receptor sites. • H1 blockers are clinically used for allergies of the immediate type (e.g., hay fever, allergic rhinitis, urticaria), such as those caused by antigens, which act on IgE antibody-sensitized mast cells. • Older H1 antihistamines, first generation, are highly sedating agents with significant autonomic receptor blockade. • Second-generation H1 blockers, typified by cetirizine, fexofenadine, and loratidine, have less lipid solubility than first-generation agents and do not cross the blood–brain barrier, therefore greatly reducing their sedative and autonomic effects. • Side effects of first-generation H1 blockers may be the desired therapeutic (sedation and dry mouth) outcome. • Four H2 blockers are available: cimetidine, ranitidine, famotidine, and nizatidine. They are potent competitive antagonists of the H2 receptors, therapeutically reducing gastric acid secretion. • Cimetidine is a competitive inhibitor of the hepatic mixed-function oxidase enzymes responsible for the metabolism of some drugs. • Cimetidine has been shown to increase blood concentrations of numerous drugs, including anticoagulants of the warfarin type, tricyclic antidepressants, various benzodiazepines, phenobarbital, theophylline, propranolol and other β-adrenoceptor blockers, Ca2+ channel blockers, lidocaine, estradiol, and phenytoin. • Ranitidine, famotidine, and nizatidine have fewer adverse effects than cimetidine because binding of these agents to cytochrome P450 enzymes is much less firm than that of cimetidine.Histamine and Histamine Antagonists*Matthew R. Cooke and Joseph A. Giovannitti Jr.*The authors wish to recognize Clarence L. Trummel for his past contributions to this chapter. 277CHAPTER 18 Histamine and Histamine AntagonistsLocal application of histamine causes redness, swelling, and edema, mimicking a mild inflammatory reaction. Large doses of systemically administered histamine have the potential to produce profound vascu-lar changes similar to those seen in shock of traumatic or anaphylactic origin.Formation, Distribution, and ReleaseThe histamine content of different tissues varies greatly. The highest concentrations are found in lung, skin, and intestinal mucosa. Organs such as the pancreas, spleen, liver, and kidney have low histamine content. The physiologic significance of this pattern of distribution is unknown. Histamine may be derived from dietary sources or synthe-sized by bacteria in the gastrointestinal tract. However, most is formed in situ.High concentrations of histamine are found in vesicles within mast cells, leukocytes (basophils and eosinophils), enterochromaffin cells of the gastrointestinal tract, some neurons, and other cells. Mast cells synthesize histamine and store it as a proteinaceous complex with heparin or chondroitin sulfate in membrane-bound secretory granules where it can be discharged from the cell by a process called exocytosis, or degranulation (Fig. 18-2).Histamine outside the mast cell or basophil is found within neurons of the hypothalamus. The function of these histaminergic neurons is unknown. Another site of non–mast cell histamine is the entero-chromaffin cell in the gastric mucosa. Here histamine stimulates gastric acid secretion by mucosal parietal cells. Certain neoplasms, collectively known as carcinoids, also secrete various autacoids, including hista-mine, which likely contribute to the so-called carcinoid syndrome.Various conditions (or stimuli) trigger the release of histamine:Tissue injuryPhysical or chemical agents that nonspecifically cause injury to tissue, particularly skin or mucosa, cause the immediate release of histamine from mast cells in the affected area. Depending on the severity of injury, histamine continues to be released for several minutes and seems to be largely responsible for the initial sharp increase in vascular permeability that is characteristic of acute inflammation. This histamine-dependent change in permeability is transient (≤30 minutes) but is followed in 2 to 4 hours by a more prolonged increase in permeability lasting up to 4 hours. Although inhibitors of histamine release, or inhibitors of the subsequent action of histamine, can block the initial phase of vas-cular permeability after injury, they have little effect on the second-ary or delayed phase, suggesting that autacoids or factors other than histamine mediate the secondary phase. The mechanism by which a nonspecific injury triggers mast cell degranulation is unclear. Proposed mechanisms include direct physical damage to mast cells or alterna-tively via initial production of factors such as activated complement components or vasoactive polypeptides, which stimulate histamine release.Allergic reactionsPresentation of a specific antigen to a previously sensitized subject can trigger immediate allergic reactions, ranging in intensity from mild (localized edema, erythema, and itching) to severe (marked decrease in blood pressure and bronchospasm). The pathophysiologic manifes-tations of such reactions are caused largely by the release of histamine (Fig. 18-3). Release occurs as a consequence of the binding of specific antigens to allergen-specific reaginic (IgE) antibodies that are attached to the plasma membranes of mast cells and basophils; these are trans-membrane high-affinity receptors termed FcεRI. Antigen–antibody interaction is an appropriate stimulus for the series of events leading to degranulation of these cells (see Fig. 18-3).Drugs and other foreign compoundsLarge groups of drugs and other chemicals can trigger histamine release directly without a requirement for previous sensitization through an immune response. For convenience, these agents can be classified as basic histamine releasers, macromolecular compounds, and enzymes. The basic histamine releasers include aliphatic and arylalkyl amines, amides, amidines, diamidines, quaternary ammonium compounds, FIG 18-2 Summary of mast cell release of histamine. Some stimuli act through receptors for immunoglobu-lins (indentations in the membrane), whereas others act directly by causing an increase in intracellular Ca2+, which triggers the release of histamine from mast cells. (From Wecker L, Crespo L, et al: Brody’s human pharmacology, ed 5, Philadelphia, 2010, Mosby.)HCHNCHNCHCHNCHNCCH2CHCOOHNH2HistidinedecarboxylaseCH2CH2NH2CO2+Histidine HistamineFIG 18-1 Conversion of histidine to histamine. 278 CHAPTER 18 Histamine and Histamine Antagonistsalkaloids, piperidine derivatives, pyridinium compounds, opioids, antimalarial drugs, dyes, and basic polypeptides.MetabolismHistamine of either exogenous or endogenous origin is rapidly inacti-vated by two routes. The more important of these is methylation of the imidazole ring by the enzyme histamine-N-methyltransferase, which is widely distributed throughout the body. The other route involves the oxidative deamination of histamine by diamine oxidase to produce imidazole acetic acid, much of which is subsequently conjugated with ribose. All metabolites are inactive and, along with a small amount of free histamine, are excreted by the kidney.Mechanism of ActionHistamine exerts its effects by binding to G protein–coupled histamine receptors, (Chapter 1) designated H1 through H4 (Table 18-1). Most of the important effects of histamine can be attributed to its actions on smooth muscle and glands. The existence of compounds that can selectively block the actions of histamine strongly supports the existence of four histamine receptors: H1, H2, H3, and H4. Although the first two seem to be unique (i.e., have selective agonists and antagonists), the H3 and H4 receptors share a degree of homology and are more difficult to distin-guish pharmacologically from one another (see Table 18-1).General Therapeutic UsesAlthough no valid therapeutic applications exist for histamine, it is of limited use as a diagnostic tool in the assessment of gastric acid pro-duction and in testing for nonallergic bronchial hyperreactivity in asthmatics.Adverse EffectsThe toxic effects of histamine are predictable based on its pharmaco-logic actions and include cutaneous flushing, hypotension, headache, visual disturbances, dyspnea, and gastrointestinal disturbances such FIG 18-3 General mechanism underlying an allergic reaction. Exposure to an antigen activates B cells to form IgE-secreting plasma cells. The secreted IgE molecules bind to IgE-specific Fc receptors on mast cells. After a second exposure to the allergen, the bound IgE is cross-linked, which triggers the release of active medi-ators (e.g., histamine) from mast cells. The mediators cause smooth muscle contraction, increased vascular permeability, and vasodilation. (From Koeppen B, Stanton B: Berne and Levy physiology, ed 6, Philadelphia, 2010, Mosby.) 279CHAPTER 18 Histamine and Histamine Antagonistsas nausea, vomiting, and diarrhea. Massive doses may lead to shock and circulatory failure. Histamine, even in low doses, may have serious adverse consequences in elderly individuals or patients with cardiovas-cular disease, asthma, or recent gastrointestinal bleeding.HISTAMINE ANTAGONISTSHistamine antagonists, or antihistamines, encompass a group of com-pounds with the characteristic ability to block the actions of histamine. These compounds do not alter the formation, release, or degradation of histamine but competitively antagonize it at receptor sites. Four groups of antihistamines are now known by their ability to selectively block effects of histamine mediated by the various receptors. These groups of antihistamines are appropriately termed H1, H2, H3, and H4 receptor antagonists. The generic term antihistamine is often used to refer to the “classic” antihistamines, or H1 antagonists.H1 Receptor AntagonistsMost antihistamines with the ability to block H1 receptors contain a side chain that resembles the ethylamino group in histamine. These H1 receptor antagonists, or H1 antihistamines, can be represented by the following general formula:Aryl1R1R2Aryl2XCCNA general conclusion from examination of structure–activity relation-ships is that a basic nitrogen atom is essential, whether it exists in an aliphatic side chain, as in diphenhydramine, or in a ring structure, as in meclizine (Table 18-2).By using the general formula just presented, most H1 antihistamines can be grouped according to the substitution made at the X position (see earlier). Levocabastine is a piperidine, but it does not fit the struc-tural chemistry in the six aforementioned categories. Azelastine, used only topically on the nasal mucosa, is a phthalazinone and is structur-ally unrelated to these other categories.The chemical structures of representative compounds of each of the major classes of H1 antihistamines are shown in Table 18-2. Despite their structural heterogeneity, the older antihistamines have only minor differences in pharmacologic properties, and these are mainly in potency, duration of action, and intensity of effects on other systems. In the last few decades, several H1 antihistamines have been developed that differ from older antihistamines in that they are largely devoid of effects on the CNS. Because of this difference, this group of agents, which are predominantly piperidine derivatives and include fexofenadine, levocabastine, and loratadine, is often termed second-generation antihistamines to distinguish them from the older, or first-generation, antihistamines. Other second-generation H1 anti-histamines include acrivastine (an alkylamine), cetirizine (a pipera-zine), and azelastine (a phthalazinone).Pharmacologic effectsH1 antihistamines exert various effects. Although the basis of some of these effects is obscure, many clearly result from histamine antagonism. These agents inhibit the contraction of gastrointestinal and bronchial smooth muscle and decrease capillary permeability and the flare and itch components of the “triple response.” H1 antihistamines do not block histamine-induced gastric secretion. However, they do antago-nize the increased secretions of the salivary and lacrimal glands and the increased release of epinephrine from the adrenal medulla stimulated by histamine. Xerostomia is a common side effect of H1 antihistamines. As with many other pharmacologic inhibitors, the basic mechanism of action can be explained in terms of a competitive blockade of recep-tors. Antihistamines interact with the H1 receptors on the target cell, resulting in a decreased availability of these receptors for histamine. This interaction is reversible, or competitive, because the inhibition produced by a given concentration of antihistamine can be overcome by increasing the concentration of histamine.No evidence indicates that antihistamines interfere with the syn-thesis, release, or biotransformation of histamine. Cetirizine seems to be unique among antihistamines because it has been reported to have antieosinophilic activity, so it inhibits the late phase of inflammation in addition to the more immediate histaminic effects.The action of H1 antihistamines in antagonizing histamine is spe-cific. H1 antihistamines “reverse” the effects of histamine by inhibiting further action, but they have no directly opposing actions of their own. In contrast, epinephrine nonspecifically antagonizes histamine by exert-ing its own distinct effects, such as vasoconstriction, bronchodilation, and decreased gastrointestinal motility. The distinction is important in TABLE 18-1 G Protein–Coupled Histamine ReceptorsType Location Post-Receptor Mechanism FunctionHistamine H1 receptor • CNS: Produced in the tuberomammillary nucleus, projecting to the dorsal raphe, locus coeruleus, and either to and/or through the hippocampal formation, amygdala, basal gan-glia, thalamus, superior colliculus, cerebellum, and additional structures. • PNS: Smooth muscle and endotheliumGq ↑ IP3 DAG • CNS: Sleep–wake cycle, body temperature, nociception, endocrine homeostasis, appetite, mood, learning, and memory • PNS: Causes bronchoconstriction, bronchial smooth muscle contraction, vasodilation, separation of endothelial cells (responsible for hives), and pain and itching due to insect stings; the primary receptors involved in aller-gic rhinitis symptoms and motion sicknessHistamine H2 receptor Located on parietal cells and vascular smooth muscle cellsGs ↑ CAMP Primarily stimulates gastric acid secretion; also involved in vasodilationHistamine H3 receptor Central nervous system and to a lesser extent peripheral nervous system tissue/nerve endingsGi ↓ CAMP Decreased neurotransmitter release: histamine, acetylcholine, norepinephrine, serotoninHistamine H4 receptor Leukocytes, primarily in the basophils; also found on thymus, small intestine, spleen, and colonGi ↓ CAMP Plays a role in mast cell chemotaxisCAMP, Cyclic adenosine phosphate; CNS, central nervous system; DAG, diacylglycerol; IP3, inositol triphosphate; PNS, peripheral nervous system. 280 CHAPTER 18 Histamine and Histamine AntagonistsTABLE 18-2 Chemical Classification, Representative Structures, and Dosages of Major H1 AntihistaminesClassRepresentative Compound* (Proprietary Name)Usual Adult Dose (Oral)Duration of ActionSome Other Compounds in the Same ClassAlkylaminesClNCH2CH2CH3CH3HC NChlorpheniramine maleate (Chlor-Trimeton, others)4 mg 4-6 hr Acrivastine (in Semprex-D): 8 mg, 6-8 hrBrompheniramine maleate (Dimetane): 4 mg, 4-6 hrDexchlorpheniramine maleate (Polaramine): 2 mg, 4-6 hrTriprolidine hydrochloride (Actidil): 2.5 mg, 4-6 hrEthanolaminesCH2CH2CH3CH3HC NODiphenhydramine hydrochloride (Benadryl, others)25-50 mg 6-8 hr Carbinoxamine maleate (in Carbiset): 4-8 mg, 6-8 hrClemastine fumarate (Tavist): 1.34-2.68 mg, 8-12 hrDimenhydrinate (Dramamine): 50-100 mg, 4-6 hrDoxylamine succinate (Unisom): 12.5-25 mg, 4-6 hrEthylenediaminesCH2CH2CH3CH3CH2NNNTripelennamine citrate (PBZ, others)25-50 mg 4-6 hr Pyrilamine maleate (Nisaval): 25-50 mg, 6-8 hrPiperazinesCH2NNClCH3HCMeclizine hydrochloride (Bonine, others)25-50 mg 24 hr Buclizine hydrochloride (Bucladin-S): 50 mg, 4-12 hrCetirizine hydrochloride (Zyrtec): 5-10 mg, 24 hrCyclizine hydrochloride (Marezine): 50 mg, 4-6 hrHydroxyzine hydrochloride (Atarax, others): 50-100 mg, 6-24 hrHydroxyzine pamoate (Vistaril): 50-100 mg, 6-24 hrPhenothiazinesCH3CH3CH2CH2CH3NSNPromethazine hydrochloride (Phenergan)12.5-25 mg 4-12 hr Methdilazine hydrochloride (Tacaryl): 8 mg, 6-12 hrTrimeprazine tartrate (Temaril): 2.5 mg, 6 hrPiperidinesClNN COCH2CH3OLoratadine hydrochloride (Claritin)10 mg 24 hr Azatadine maleate (Optimine): 1-2 mg, 8-12 hrCyproheptadine hydrochloride (Periactin)†: 4 mg, 6-8 hrFexofenadine hydrochloride (Allegra): 60 mg, 12 hrLevocabastine hydrochloride (Livostin): topicalPhenindamine tartrate (Nolahist): 25 mg, 4-6 hr 281CHAPTER 18 Histamine and Histamine Antagonistsunderstanding why a physiologic antagonist such as epinephrine is a more effective agent than an antihistamine for relieving bronchospasm associ-ated with asthma, anaphylaxis, and other allergic reactions. The ineffec-tiveness of H1 antihistamines in relieving these physiologic effects is partly the result of involvement of autacoids other than histamine in mediating allergic bronchospasm in humans. These substances include leukotrienes and kinins, against which classic antihistamines show little antagonism.The older H1 antihistamines, typified by diphenhydramine, are sed-ative agents with significant autonomic receptor blockade (Table 18-2). Second-generation H1 blockers, typified by cetirizine, fexofenadine, and loratidine, have less lipid solubility than first-generation agents and do not cross the blood–brain barrier, therefore greatly reducing their sedative and autonomic effects. Sedation is mediated by the inhibition of H1 receptors in the brain. The ability to cause sedation varies widely among the available first-generation H1 antihistamines. The agents with the most sedation are the ethanolamines and phenothiazines, whereas the alkylamines have a low incidence of drowsiness. Tolerance to the sedative effects of H1 antihistamines may develop with long-term use. However, concomitant decreases in peripheral antihistaminic effects have not been observed.Another clinically useful CNS effect of first-generation H1 antihista-mines is inhibition of nausea and vomiting, associated with motion sick-ness. These agents also possess mild anti-Parkinson activity. They work via a central cholinergic receptor–blocking action. Because H1 agents possess antimuscarinic activity, there is a decrease in salivary secretion. Second-generation H1 antihistamines have little or no antimuscarinic activity.Antihistamines have some degree of local anesthetic activity. This property is most notable in diphenhydramine, promethazine, pyril-amine, and tripelennamine. Antihistamines have occasionally been used clinically in dentistry when conventional local anesthetics are contraindicated.Large doses of first-generation H1 antihistamines can cause CNS stimulation that may result in convulsions. Paradoxical excitement, restlessness, or insomnia may occasionally be encountered even at therapeutic doses.Absorption, rate, and excretionH1 antihistamines are well absorbed after either oral or parenteral administration. The onset of action occurs 15 to 60 minutes after an oral dose. Effects are typically maximal in 1 to 2 hours, with a duration of 4 to 6 hours, although the duration is longer for some agents (see Table 18-2). In contrast, most second-generation H1 antihistamines have a considerably longer duration of action. Loratadine is trans-formed to an active metabolite with an average elimination half-time of greater than 24 hours, which allows once-daily dosing.Biotransformation of first-generation H1 antihistamines is termi-nated by conversion to inactive metabolites through hydroxylation in the liver. Second-generation antihistamines are extensively metabo-lized in the liver by the CYP3A4 microsomal enzyme. In some cases, such as with loratadine, these result in active metabolites. Concurrent administration of other agents metabolized by this same enzyme can reduce the biotransformation of these particular antihistamines. Other second-generation H1 antihistamines (e.g., acrivastine and cet-irizine) are not metabolized to an active form and are largely excreted unchanged in the urine. Cetirizine is a metabolite of the first-genera-tion agent hydroxyzine.General therapeutic usesThe introduction of antihistamines into clinical medicine stimulated great interest regarding application in histamine-mediated patho-logic states. The early enthusiasm for antihistamines often led to their irrational use in various clinical situations. Although subsequent expe-rience has brought about a better appreciation of the therapeutic indi-cations and limitations of antihistamines, they are often still used when their clinical efficacy is doubtful or when other agents might be more appropriate.The most prominent use of H1 antihistamines is in countering the manifestations of various allergic conditions, that is, reactions TABLE 18-2 Chemical Classification, Representative Structures, and Dosages of Major H1 Antihistamines—cont’dClassRepresentative Compound* (Proprietary Name)Usual Adult Dose (Oral)Duration of ActionSome Other Compounds in the Same ClassPhthalazinonesCH3NNOCH2ClNAzelastine hydrochloride (Astelin)274 μg (topical nasal application; per nostril)8-12 hrSecond-generation H1 antihistamines are acrivastine, azelastine, cetirizine, desloratadine, fexofenadine, levocabastine, levocetirizine, and loratadine.H1 histamine receptor blockers used in ophthalmology are emedastine, epinastine, ketotifen, and olopatadine.*Each structural formula is of the free base form.†Also a serotonin-receptor antagonist.TABLE 18-3 Classification of H1 Receptor BlockersH1 Receptor ClassX Substitution on Antihistamine MoleculeAlkylamines CarbonEthanolamines OxygenEthylenediamines NitrogenPiperazines Piperazine ringPhenothiazines Phenothiazine nucleusPiperidines Piperidine ring 282 CHAPTER 18 Histamine and Histamine Antagonistsresulting from antigen–antibody combination in which histamine release occurs. Remember, antihistamines have no effect on the inter-action of antigens and antibodies or on the release of histamine that may be triggered by this interaction. Antihistamines act by competi-tively antagonizing the binding of liberated histamine to its receptor. They cannot alter the allergic basis of a given disease, but they may only provide relief from some of the symptoms. Antihistamines are most effective when given before the release of histamine. After histamine release has occurred, an antihistamine can only reduce further unde-sirable effects.The clinical applications and efficacy of H1 antihistamines (Table 18-4) can be summarized as follows: 1. H1 antihistamines are generally useful in the treatment of nasal allergies of either a seasonal (e.g., hay fever) or perennial (non-seasonal) nature because they relieve rhinorrhea, sneezing, lacrimation, and itching of the eyes and nasal mucosa. Azelas-tine is effective for 12 hours when applied topically to the nasal mucosa. This route of administration minimizes unwanted systemic effects such as drowsiness. Antihistamines are often combined with decongestants such as pseudoephedrine for the management of allergic symptoms in the upper respiratory tract. H1 antihistamines are less effective in treating chronic or vasomo-tor (nonallergic) rhinitis. 2. Allergic dermatoses are treated with H1 antihistamines. Acute and chronic urticarias respond favorably to these agents. Angioedema also responds to antihistamine therapy; however, a severe attack involving the larynx almost certainly requires epinephrine for proper management of this serious complication. H1 antihista-mines may, also, be useful in controlling the itching associated with eczematous pruritus, atopic or contact dermatitis, and insect bites. In some situations (e.g., atopic dermatitis), topical corticosteroids are usually more effective. Although antihistamines are topically effective in treating pruritus and urticaria, topical application can also cause an allergic dermatitis. 3. H1 antihistamines have minimal effect on the acute manifesta-tions of bronchial asthma. The pathogenesis of bronchial asthma is complex, and mediators of bronchial muscle constriction other than histamine are involved. β-Adrenergic receptor agonists and corticosteroids are the primary drugs used to alleviate an acute asthmatic episode. Antihistamines have been used in an attempt to decrease pre-asthmatic cough in children, although the efficacy of this therapy is not established. 4. H1 antihistamines, particularly chlorpheniramine, combined with nasal decongestants and analgesics, are widely used for symptom-atic relief of the common cold. There are dozens of such prepa-rations on the market, which indicates the popularity of these nostrums. Unless the cold is superimposed on an allergic rhinitis, any relief obtained from this combination stems largely from the drying of the mucosa caused by the anticholinergic action of the antihistamine and the actions of the vasoconstrictor and analgesic. Antihistamines alone are of no proven value in either preventing or shortening the duration of the common cold. 5. A CNS action of first-generation H1 antihistamines can be used to prevent or treat nausea and vomiting induced by motion. In general, these agents exert less anti–motion sickness activity than do anticholinergics such as scopolamine. H1 antihistamines may also be useful in counteracting nausea and vomiting in vestibular disturbances such as Meniere disease and other forms of vertigo. The effectiveness of individual antihistamines varies widely; pro-methazine, diphenhydramine, dimenhydrinate, and cyclizine are probably the most effective of all. The more effective agents also tend to have greater sedative effects. 6. Various over-the-counter (OTC) preparations sold as hypnotics include H1 antihistamines, especially diphenhydramine. These agents are added because of their ability to cross the blood–brain barrier and induce sleep. Antihistamines are less effective sedatives than benzodiazepines and sedative-hypnotics, even at higher doses. 7. Some miscellaneous uses of H1 antihistamines include reduction of tremors and muscle rigidity in Parkinson disease, treatment of headaches of unknown cause, and control of nonhemolytic, non-pyrogenic reactions to blood transfusion. They are also useful in relieving acute dystonias caused by phenothiazines and other neu-roleptics. Promethazine is used as an adjunct to general anesthesia to produce drowsiness and to prevent or control nausea and vom-iting induced by anesthetic agents and opioid analgesics.Adverse effectsAt therapeutic doses, H1 antihistamines are relatively free of serious adverse reactions. The most common side effects result from CNS depression, which is generally manifested as drowsiness, diminished alertness, lethargy, and decreased motor coordination. The incidence of sedation varies with individual agents, but in general the ethanolamines and the phenothiazines are the most sedating, the ethylenediamines are intermediate, and the alkylamines and piperazines are the least sedating. As previously mentioned, loratadine and other second-generation H1 antihistamines are essentially devoid of sedative or other CNS effects. Sedation caused by antihistamines may be a serious liability in a patient whose daily activities require mental alertness and coordination. In such cases, a reduction of dosage or substitution of agents may be necessary. If antihistamines are to be used as part of balanced sedation/anesthesia (i.e., preop promethazine), the patient should be monitored closely.The anticholinergic properties of antihistamines occasionally cause insomnia, tremors, nervousness and irritability, palpitations, tachy-cardia, dry mouth, blurred vision, urinary retention, and constipation. Gastrointestinal disturbances—nausea, vomiting, and epigastric distress—also occur but are uncommon. The incidence of these effects is dose-related.Serious disturbances of cardiac rhythm have occurred in patients receiving astemizole or terfenadine, second-generation H1 antihista-mines of the piperidine class. These drugs have been off the market for several years. Newer second-generation H1 antihistamines are not associated with these adverse effects.Large doses of a first-generation H1 antihistamine can cause marked stimulation of the CNS manifested by hallucinations, excite-ment, and motor disturbances such as tremors and convulsions. Deaths from overdosage almost invariably occur outside a therapeutic setting (e.g., accidental poisoning in the home).TABLE 18-4 Efficacy of H1 AntihistaminesClinical Applications of H1 Antihistamines EfficacyNasal allergies +++Allergic dermatitis +++Bronchial asthma ++Severe anaphylactic reaction* 0Symptom relief of colds +++Prevent and/or treat nausea +++Hypnotics +Local anesthetics +0, No effect; +, modest effect; ++, moderate effect; +++, significant effect.*H1 antihistamines have no primary therapeutic role because they cannot control either the marked hypotension or the bronchospasm associated with a severe anaphylactic reaction. 283CHAPTER 18 Histamine and Histamine AntagonistsAllergic reactions to H1 antihistamines can occur; they are more frequent after topical application than after oral administration and can complicate the treatment of allergic lesions of the skin or oral mucosa. Allergic reactions can take the form of urticarial, eczema-tous, bullous, or petechial rashes; fixed drug eruptions; or, more rarely, anaphylaxis.As with most drugs, various blood dyscrasias (hemolytic anemia, agranulocytosis, pancytopenia, and thrombocytopenia) have been reported after the use of antihistamines. Patients receiving long-term antihistamine therapy should be periodically monitored. Although cer-tain piperazine H1 antihistamines have been shown to be teratogenic in some laboratory animal models, there is no clinical evidence to indicate that antihistamines cause birth defects in humans. More specifically, meta-analysis of human pregnancy outcomes following first semester exposure to antihistamines has shown no increase in birth defects.Antihistamines are variably excreted in breast milk. Because infants, especially newborns and premature infants, are at higher risk of adverse effects, the use of antihistamines in nursing women should be avoided. Antihistamines, similar to other anticholinergic drugs, may inhibit lactation.Table 18-5 shows a comparison between the two generations of H1 antihistamines.Uses in dentistryH1 antihistamines are used in dentistry primarily for their CNS actions, rather than for their specific antihistaminic effects. Promethazine, hydroxyzine, and diphenhydramine may be used in minimal–moderate sedation procedures and as premedication for deep sedation and general anesthesia. The sedative effect is increased by the concomitant administration of an opioid analgesic and a ben-zodiazepine; fentanyl and midazolam are commonly used for this purpose. The preoperative administration of these agents may also cause some inhibition of salivary and bronchial secretions, although more effective anticholinergic drugs should be used if control of secretions is essential. Another particular benefit of antihistamines is their ability to reduce postoperative nausea and vomiting in the outpatient setting.H1 antihistamines have some local anesthetic activity, and their feasibility as local anesthetic agents for dental procedures has been shown. They have not been used much for this purpose because far more effective agents (e.g., lidocaine) are available. However, the local anesthetic activity of antihistamines may be useful in the exceedingly rare case of allergy to conventional amide local anesthetics.H1 antihistamines can be used as secondary agents in the manage-ment of systemic anaphylactic reactions that may occur in the course of dental therapy. They can also be valuable in the treatment of aller-gic lesions of the oral mucosa and as adjuncts in treating angioneu-rotic edema of the orofacial region.H2 Receptor AntagonistsChemistry and classificationH2 receptor antagonists, or H2 antihistamines, are basically structural analogues of histamine (Fig. 18-4). Two changes in the histamine mol-ecule are necessary to achieve H2 receptor–blocking activity. One is modification of the imidazole ring or its substitution by a furan or thi-azole ring. A second modification is the presence of a flexible connect-ing chain linked to a polar substituent capable of hydrogen binding.The four available drugs in this group are cimetidine, ranitidine, famotidine, and nizatidine. Ranitidine is a modification of cimeti-dine, in that it does not contain an imidazole ring but rather contains a furan ring. Famotidine and nizatidine are based on a thiazole ring structure (see Fig. 18-4).Pharmacologic effectsThe H2 blockers are relatively selective and potent competitive antago-nists of the H2 receptors, with the main therapeutic effect being reduc-tion of gastric acid secretion. H2 antagonists cause a marked reduction in H+ output, pepsin activity, and the total volume of gastric secretions (Fig. 18-5). Blockade of cardiovascular and mast cell H2 receptor–mediated effects have been demonstrated but with minimal clinical significance.Absorption, fate, and excretionH2 antihistamines are rapidly and completely absorbed after oral administration, except for famotidine. All undergo a variable degree of first-pass metabolic degradation in the liver, resulting in an oral bioavailability of approximately 50% for cimetidine, ranitidine, and famotidine and more than 90% for nizatidine. Therapeutic concen-trations are reached in approximately 1 to 2 hours. The elimination half-life is 2 to 3.5 hours, except for nizatidine, which has a half-life of 1 to 1.5 hours. Urinary excretion of the parent compound accounts for 60% to 70% of the dose of each drug. The remainder is oxidized with sulfoxide being a major metabolite excreted in the urine and feces. Cimetidine (300 mg), the least potent agent, reduces basal gastric acid secretion by at least 80% for 4 to 5 hours, whereas famotidine (20 mg), the most potent, lasts for 10 to 12 hours. Because of the relative safety of these drugs, increased doses can be used to extend the duration of effect.General therapeutic usesH2 antihistamines are used clinically for their marked ability to inhibit basal and stimulated secretion of gastric acid. They are approved for use in a wide variety of gastrointestinal disorders in which reduction of acid secretion may relieve symptoms, lead to healing, and prevent recurrence of previously resolved disease. Specifically approved indications include duodenal ulcer disease (active or in maintenance), active gastric ulcer disease, gastro-esophageal reflux disease (GERD), and pathologic hypersecretory conditions (e.g., systemic mast cell disease and Zollinger-Ellison disease). H2 antihistamines are generally given orally, but parenteral forms for famotidine and ranitidine are also available for acute sup-pression of gastric acid secretion. Oral dosage may be divided into once- or twice-daily administration; if once daily, the dose is best given at bedtime to block nocturnal gastric acid secretion.A major use of H2 antihistamines is treatment of active benign gastric ulcers and prophylaxis or treatment of active duodenal ulcers. All the currently available agents (cimetidine, ranitidine, famotidine, TABLE 18-5 Comparison of First and Second-Generation Antihistamines (H1 Blockers)First Generation Second GenerationUseful against allergies Yes YesPass the blood–brain barrierYes NoCause sedation Yes NoAntimuscarinic effect Yes LittleLocal anesthetic effect Yes NoUseful vs Parkinsonism* Yes NoUseful vs nausea Yes No*As an adjunct. 284 CHAPTER 18 Histamine and Histamine Antagonistsand nizatidine) have been shown to be equally effective in appropri-ate doses in suppressing gastric acid secretion (by up to 90%) and accelerating the healing of duodenal and, to a lesser extent, gastric ulcers. Healing of ulcers generally occurs within 2 to 4 months of therapy; if healing is not achieved in this period, further therapy is unlikely to be successful. Although cimetidine and other H2 anti-histamines have been used to treat upper gastrointestinal bleeding caused by liver disease, such as cirrhosis, little evidence supports their effectiveness in these conditions. Finally, H2 antihistamines may be used before general anesthesia, particularly in patients with gastroin-testinal obstruction, to elevate gastric pH and reduce the danger of aseptic pneumonia if gastric contents are aspirated during induction.After their introduction, H2 receptor antagonists became one of the most widely prescribed groups of drugs in the world. Their use has declined considerably in recent years because of the introduction of proton pump inhibitors. The U.S. Food and Drug Administration now allows OTC marketing of all four currently available H2 antihis-tamines for symptomatic relief of occasional heartburn, GERD, acid indigestion (hyperchlorhydria), or “sour” stomach. This decision reflected the extensive use of H2 antihistamines previously dispensed by prescription for unapproved conditions, while acknowledging the relative safety of these agents in unsupervised use. Such OTC use may risk delaying diagnosis of more serious disease, such as peptic ulcer or gastric cancer.Adverse effectsThe initial impression that H2 antagonists are generally free of serious adverse effects has been validated by the passage of time and extensive clin-ical use. However, cimetidine and, to a lesser extent, other H2 antihista-mines can cause various toxic reactions and side effects. Perhaps untoward responses are a result of an incomplete understanding of the presence and function of H2 receptors in tissues other than the gastric mucosa.Adverse effects of cimetidine are manifested in the CNS. These are highly variable and range from minor symptoms (dizziness, lethargy, and fatigue) to more serious disturbances (mental confusion, delir-ium, focal twitching, hallucinations, and seizures). The CNS effects often seem to be dose-related and are most commonly seen in elderly patients or patients with impaired liver or kidney function.Cimetidine exerts many effects on endocrine function that are gen-erally minor and reversible on cessation of therapy. The most notable of these is gynecomastia. Other complications include elevation of serum prolactin concentrations, galactorrhea, loss of libido, impotence, and reduction in sperm counts. Small but definite increases in serum creati-nine concentrations occur in most patients treated with cimetidine. This effect is not associated with other changes in renal function and ceases when the drug is withdrawn. With cimetidine there is a transient leuko-penia, granulocytopenia, and thrombocytopenia reported. It is difficult to implicate cimetidine as a direct bone marrow suppressant because the cases reported almost always involve the concomitant use of other drugs or the existence of other serious systemic diseases. Although cimetidine enhances cell-mediated immune reactions, no evidence suggests that this phenomenon is related to any of the observed clinical responses.Although cimetidine initially seemed to have no significant drug interactions, subsequent clinical reports and laboratory studies indi-cate that this is not the case. Cimetidine has been shown to increase blood concentrations of numerous drugs, including anticoagulants of the warfarin type, tricyclic antidepressants, various benzodiazepines, phenobarbital, theophylline, propranolol and other β-adrenoceptor blockers, Ca2+ channel blockers, lidocaine, estradiol, and phenytoin, creating a risk of toxicity. The basis of these interactions is compet-itive inhibition by cimetidine of the hepatic mixed-function oxidase enzymes responsible for the metabolism of these drugs. Several cyto-chrome enzymes are inhibited. Also, a cimetidine-induced decrease in hepatic blood flow may depress the entry of drugs into the liver and slow metabolism. Patients receiving cimetidine together with any from a long list of drugs should be carefully monitored; if appro-priate, reduction of dosages or use of alternative agents should be considered.SMetiamideCH2(CH2)2CH3NHNNHCNHCH3SSCimetidineCH2(CH2)2CH3NHNNHCNHCH3NCNSRanitidineCH2(CH2)2CH2ONHCNHCH3HCNO2NH3CCH3SFamotidineCH2(CH2)2SNCNH2NSONH2NCNH2ONH2SNizatidineCH2(CH2)2CH2NNHCNHCH3HCNO2NH3CCH3SFIG 18-4 Structural formulas of four H2 receptor antagonists. 285CHAPTER 18 Histamine and Histamine AntagonistsRanitidine, famotidine, and nizatidine have fewer adverse effects than cimetidine. These drugs have little if any antiandrogenic effects. Serum prolactin concentrations, impotence, and gynecomastia are of minimal concern. Mental disturbances are less likely with these drugs, and they have not been reported to elevate serum creatinine concentrations. Because the binding of these agents to cytochrome P450 enzymes is much less firm than that of cimetidine, they do not significantly inhibit the microsomal metabolism of other drugs.H3 and H4 Receptor AntagonistsDiscovery of the histamine H3 and H4 receptor some years ago has opened the door to potential new therapeutic agents. H3 receptors are located mainly in the CNS, while H4 receptors are primarily expressed on leukocytes. Structural similarities and differences between H3 and H4 receptors and species differences are causes of limitations in the evaluation of their biologic profile. Drugs that target the H3 receptor will likely focus on neurotransmission, improving neuronal diseases, such as cognitive impairment, schizo-phrenia, sleep/wake disorders, epilepsy, and neuropathic pain. The H4 receptor, the newest identified members of the histamine recep-tor family, will likely target immunomodulation. Research suggests it may have therapeutic indications in allergy, inflammation, auto-immune disorders, and possibly cancer.504030201001.6 6.4 25.6 51.21.6 6.4 25.651.2504030201001.6 6.4 25.6 51.21.6 6.4 25.651.2Acid output (mmol H/hr)Histamine dihydrochloride (µg/kg/hr)IIIIVIIIHistamine aloneHistamine  cimetidine 0.6 mg/kg/hrFIG 18-5 Inhibition of histamine-stimulated gastric acid production by cimetidine in humans. Histamine dihydrochloride in doses of 1.6 to 51.2 μg/kg/hr was infused intravenously with or without cimetidine at a dose of 0.6 mg/kg/hr for 105 minutes. When cimetidine was given, its administration was begun 15 minutes before the histamine infusion was started. Gastric juice was collected at 15-minute intervals and analyzed for acid concentration; the last four 15-minute intervals were used to establish the dose–response curves. Data shown are individual results from four normal adult subjects (I-IV ). (From Aadland E, Berstad A: Inhibition of histamine- and pentagastrin-stimulated gastric secretion by cimetidine in man. In Creutzfeldt W, editor: Cimetidine, Amsterdam, 1978, Excerpta Medica Foundation.) 286 CHAPTER 18 Histamine and Histamine AntagonistsNonproprietary (Generic) Name Proprietary (Trade) NameH1 RECEPTOR ANTAGONISTS: FIRST-GENERATIONAlkylaminesBrompheniramine In Dimetane, BromphenChlorpheniramine Chlor-Trimeton, in TeldrinDexbrompheniramine In Disobrom, in DrixoralDexchlorpheniramine PolaraminePheniramine In Dristan, in TriaminicTriprolidine Actidil, TripohistEthanolaminesClemastine TavistDimenhydrinate* Dramamine, MarmineDiphenhydramine Benadryl, SominexDoxylamine UnisomCarbinoxamine Karbinal, in RondecPhenyltoloxamine In Comhist LA, in PhenylgesicEthylenediaminesPyrilamine In Midol CompleteTripelennamine PBZPiperazinesBuclizine Bucladin-SCyclizine MarezineHydroxyzine Atarax, VistarilMeclizine Antivert, BoninePhenothiazinesMethdilazine TacarylPromethazine PhenerganPiperidinesAzatadine OptimineCyproheptadine PeriactinNonproprietary (Generic) Name Proprietary (Trade) NameH1 RECEPTOR ANTAGONISTS: FIRST-GENERATIONKetotifen†ZaditorPhenindamine NolahistOthersEmedastine†EmadineEpinastine†ElestatOlopatadine†PatanolH1 RECEPTOR ANTAGONISTS: SECOND-GENERATION (NONSEDATING)AlkylamineAcrivastine In Semprex-DPiperazinesCetirizine ZyrtecLevocetirizine XyzalPiperidinesDesloratadine ClarinexFexofenadine AllegraLevocabastine†LivostinLoratadine ClaritinPhthalazinoneAzelastine‡Astelin, AzelexH2 RECEPTOR ANTAGONISTSCimetidine TagametFamotidine PepcidNizatidine AxidRanitidine Zantac ANTIHISTAMINESCASE DISCUSSIONPromethazine may effectively alleviate anxiety, facilitating the surgery and preventing postoperative nausea and vomiting. Older antihistamines readily enter the CNS causing sedation and preventing motion sickness. However, promethazine and several other first-generation H1 antihistamines are also effective alpha blockers. Thus, when the patient attempts to get out of the dental chair after the procedure, he may experience severe orthostatic hypo-tension and faint. When sudden changes are made (supine to standing) the blood pressure may rapidly drop, causing syncope. Replacing the patient in the horizontal position will allow him to regain consciousness. Also, patients with BPH may have difficulty with micturition due to increased urinary reten-tion, a possible side effect of promethazine. If this patient had narrow-angle glaucoma, he could be at risk for increased ocular pressure due to the anticho-linergic properties of the older first-generation antihistamine.GENERAL REFERENCES 1. Church MK, Church DS: Pharmacology of antihistamines, Indian J Derma-tol 58(3):219–224, May 2013, http://dx.doi.org/10.4103/0019-5154.110832. http://www.ncbi.nlm.nih.gov/pubmed/23831018-comments. 2. Monczor F, Fernandez N, Fitzsimons CP, Shayo C, Davio C: Antihista-minergics and inverse agonism: potential therapeutic applications, Eur J Pharmacol 715(1–3):26–32, September 5, 2013. http://dx.doi.org/10.1016/j .ejphar.2013.06.027. Epub July 4, 2013. 3. Tabarean IV: Histamine receptor signaling in energy homeosta-sis, Neuropharmacology, June 21, 2015. http://dx.doi.org/10.1016/j. neuropharm.2015.04.011. pii:S0028-3908(15)00140-9; Epub ahead of print. 4. Thurmond RL: The histamine H4 receptor: from orphan to the clin-ic, Front Pharmacol 6:65, March 31, 2015. http://dx.doi.org/10.3389/fphar.2015.00065.*The chlorotheophylline salt of diphenhydramine.†For topical ophthalmic use.‡For topical use.

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