60 mg

HCl, hydrochloride.

*For a discussion of phenothiazines, see Chapter 18.

^Preparations are designated as follows: O, oral solids; L, oral liquids; I, Injection; S, suppository; T, topical. Many ^-receptor antagonists also are available in preparations 4 that contain multiple drugs.

9 *Has mild sedating effects.

'Trade name drug also contains other medications. §Also has antiserotonin properties.

Dibenzoxepin Tricyclics (Doxepin) Doxepin, the only drug in this class, is marketed as a tricyclic antidepressant (see Chapter 17). It also is a remarkably potent Hj antagonist. Doxepin is much better tolerated by patients who have depression than by those who do not. In nondepressed patients, sometimes even very small doses, e.g., 20 mg may be poorly tolerated because of disorientation and confusion.

Ethanolamines (Prototype: Diphenhydramine) These drugs possess significant antimus-carinic activity and have a pronounced tendency to induce sedation. About half of those treated with conventional doses experience somnolence. The incidence of GI side effects is low.

Ethylenediamines (Prototype: Pyrilamine) These include some of the most specific Hj antagonists. Although their central effects are relatively feeble, somnolence occurs in a fair proportion of patients. GI side effects are quite common.

Alkylamines (Prototype: Chlorpheniramine) These are among the most potent H1 antagonists. The drugs are less prone than some H1 antagonists to produce drowsiness and are more suitable agents for daytime use, but again, a significant proportion of patients do experience sedation. Side effects involving CNS stimulation are more common than with other groups.

First-Generation Piperazines The oldest member of this group, chlorcyclizine, has a more prolonged action and produces a comparatively low incidence of drowsiness. Hydroxyzine is a long-acting compound that is used widely for skin allergies; its considerable CNS-depressant activity may contribute to its prominent antipruritic action. Cyclizine and meclizine have been used primarily to counter motion sickness, although promethazine and diphenhydramine (dimenhydrinate) are more effective (as is scopolamine; see below).

Second-Generation Piperazines (Cetirizine) Cetirizine is the only drug in this class. It has minimal anticholinergic effects. It also has negligible penetration into the brain but is associated with a somewhat higher incidence of drowsiness than the other second-generation H1 antagonists.

Phenothiazines (Prototype: Promethazine) Most drugs of this class are H1 antagonists and also possess considerable anticholinergic activity. Promethazine, which has prominent sedative effects, and its many congeners are used primarily for their antiemetic effects (see Chapter 37).

First-Generation Piperidines (Cyproheptadine, Phenindamine) Cyproheptadine uniquely has both antihistamine and antiserotonin activity. Cyproheptadine and phenindamine cause drowsiness and also have significant anticholinergic effects.

Second-Generation Piperidines (Prototype: Loratadine) Current drugs in this class include loratadine, desloratadine, and fexofenadine. These agents are highly selective for H1 receptors, lack significant anticholinergic actions, and penetrate poorly into the CNS. Taken together, these properties appear to account for the low incidence of side effects of piperidine antihistamines.

Therapeutic Uses

H1 antagonists have an established and valued place in the symptomatic treatment of various immediate hypersensitivity reactions. In addition, the central properties of some of the series are of therapeutic value for suppressing motion sickness or for sedation.

Allergic Diseases

Hj antagonists are most useful in acute types of allergy that present with symptoms of rhinitis, urticaria, and conjunctivitis. Their effect is confined to the suppression of symptoms attributable to the histamine released by the antigen-antibody reaction. In bronchial asthma, systemic anaphylaxis and angioedema, histamine antagonists have limited efficacy and are not used as sole therapy.

Other allergies are more amenable to therapy with H1 antagonists. The best results are obtained in seasonal rhinitis and conjunctivitis (hay fever, pollinosis), in which these drugs relieve the sneezing, rhinorrhea, and itching of eyes, nose, and throat. A gratifying response is obtained in most patients, especially at the beginning of the season when pollen counts are low; however, the drugs are less effective when the allergens are most abundant, when exposure to them is prolonged, and when nasal congestion is prominent. Topical preparations, nasal sprays, or topical ophthalmic preparations of antihistamines have been shown to be effective in allergic conjunctivitis and rhinitis.

Certain allergic dermatoses respond favorably to H1 antagonists. Benefit is most striking in acute urticaria, although the itching in this condition is perhaps better controlled than are the edema and the erythema. Chronic urticaria is less responsive, but some benefit may occur in a fair proportion of patients. Furthermore, the combined use of H1 and H2 antagonists sometimes is effective when therapy with an H1 antagonist alone has failed. Doxepin may be effective in the treatment of chronic urticaria that is refractory to other antihistamines.

H1 antagonists have a place in the treatment of pruritus. Some relief may be obtained in many patients suffering atopic dermatitis and contact dermatitis (although topical glucocorticoids are more effective) and in such diverse conditions as insect bites and poison ivy. Again, doxepin may be more effective in suppressing pruritus than are other antihistamines. Many drug reactions attributable to allergic phenomena respond to therapy with H1 antagonists, particularly those characterized by itch, urticaria, and angioedema; serum-sickness reactions also respond to intensive treatment.

Common Cold

Despite persistent popular belief, H1 antagonists are without value in combating the common cold.

Motion Sickness, Vertigo, and Sedation

Scopolamine, given orally, parenterally, or transdermally, is the most effective of all drugs for the prophylaxis and treatment of motion sickness. Whenever possible, scopolamine should be administered an hour or so before the anticipated motion. Treatment after the onset of nausea and vomiting rarely is beneficial.

Some H1 antagonists, notably dimenhydrinate and meclizine, often are of benefit in vestibular disturbances such as Meniere's disease and in other types of true vertigo. Only promethazine has usefulness in treating the nausea and vomiting subsequent to chemotherapy or radiation therapy for malignancies; however, other effective antiemetic drugs are available (see Chapter 37).

H2-RECEPTOR ANTAGONISTS The pharmacology and clinical utility of H2 antagonists to inhibit gastric acid secretion are described in Chapter 36.

H3 Receptor and Ligands

The H3 receptors are localized on terminals as well as on cell bodies/dendrites in the hypothalamic tuberomammillary nucleus on histaminergic neurons. By inhibiting Ca2+ conductance, the activated H3 receptor depresses neuronal firing at the level of cell bodies/dendrites and decreases histamine release from depolarized terminals. Thus, H3-receptor ligands are unique agents to modify histaminergic neurotransmission in brain; the agonists decrease it, and the antagonists increase it. H3-receptor ligands currently are research tools to delineate the functional role of cerebral histamine and are drug candidates in neuropsychiatry.

H4 Receptor and Ligands

The H4 receptor has considerable sequence similarity with the H3 receptor and binds many H3 agonists, although with lower affinity. The H3 antagonist thioperamide also has significant H4 antagonistic activity, whereas H3 antagonists clobenpropit and burimamide are partial agonists of the H4 receptor. Because the H4 receptor is expressed primarily on cells of hematopoietic origin (notably mast cells, basophils, and eosinophils) and to a lesser extent in the intestine, there is great interest in the possible role of H4 receptors in inflammatory processes. H4 antagonists are promising drug candidates to treat inflammatory conditions involving mast cells and eosinophils, such as allergic rhinitis, asthma, and rheumatoid arthritis.


A number of factors, including tissue damage, allergic reactions, viral infections, and other inflammatory events, activate a series of proteolytic reactions that generate bradykinin and kallidin in tissues. These peptides contribute to inflammatory responses as autacoids that act locally to produce pain, vasodilation, and increased vascular permeability. Much of their activity is due to stimulation of the release of potent mediators such as prostaglandins, NO, or endothelium-derived hyperpolarizing factor (EDHF).

The Endogenous Kallikrein-Kininogen-Kinin System SYNTHESIS AND METABOLISM OF KININS

Bradykinin is a nonapeptide (Table 24-3). Kallidin has an additional lysine residue at the N-terminal position and is sometimes referred to as lysyl-bradykinin. The two peptides are cleaved from a2 globulins termed kininogens (Figure 24-2). There are two kininogens, high-molecular-weight (HMW) and low-molecular-weight (LMW) kininogen. A number of serine proteases will generate

Table 24-3

Structure of Kinin Agonists and Antagonists




Bradykinin Kallidin

[des-Arg9]-bradykinin [des-Arg10]-kallidin des-Arg9-[Leu8]-bradykinin HOE 140 CP 0127

Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg

Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe Arg-Pro-Pro-Gly-Phe-Ser-Pro-Leu



Agonist, B2 Agonist, B2 Agonist, Bj Agonist, Bj Antagonist, Bj

Antagonist, B2 Antagonist, B2

abbreviations: Hyp, fra«s-4-hydroxy-Pro; Thi, ß-(2-thienyl)-Ala; Tic, [d]-1,2,3,4-tetrahydroisoquinolin-3-yl-carbonyl; Oic, (3as,7as)-octahydroindol-2-yl-carbonyl. B, bissuccimidohexane.

Kinin Bradikini Dan Kalikrein

FIGURE 24-2 Synthesis and receptor interactions of active peptMes generated by the kallikrein-kinin and renin-angiotensin systems. Bradykinin (BK) is generated by the action of plasma kallikrein on high-molecular-weight (HMW) kininogen, whereas kallidin (Lys-bradykinin) is synthesized by the hydrolysis of low-molecular-weight (LMW) kinino-gen by tissue kallikrein. Kallidin and BK are natural ligands of the B2 receptor but can be converted to corresponding agonists of the Bj receptor by removal of the C-terminal Arg by the action of kininase I-type enzymes: the plasma membrane-bound carboxypeptidase M (CPM) or soluble plasma carboxypeptidase N (CPN). Kallidin or [des-Arg10] kallidin can be converted to the active peptides BK or [des-Arg9] BK by aminopeptidase removal of the ^-terminal Lys residue. In a parallel fashion, the inactive decapeptide angiotensin I (Ang I) is generated by the action of renin on the plasma substrate angiotensinogen. By removal of the C-terminal His-Leu dipeptide, angiotensin-converting enzyme (ACE) generates the active peptide Ang II. These two systems have opposing effects. Whereas Ang II is a potent vasoconstrictor that also causes aldosterone release and Na+ retention via activation of the ATj receptor, BK is a vasodilator that stimulates Na+ excretion by activating the B2 receptor. ACE generates active Ang II and at the same time inactivates BK and kallidin; thus, its effects are prohypertensive, and ACE inhibitors are effective antihypertensive agents. The B2 receptor mediates most of BK's effects under normal circumstances, whereas synthesis of the Bj receptor is induced by inflammatory mediators and plays a major role in chronic inflammatory conditions. Both the Bj and B2 receptors couple through Gq to activate PLC and increase intracellular Ca2+; the physiological response depends on receptor distribution on particular cell types and occupancy by agonist peptides. For instance, on endothelial cells, activation of B2 receptors results in Ca2+-calmodulin-dependent activation of eNOS and generation of NO, which causes cGMP accumulation and relaxation in neighboring smooth muscle cells. On smooth muscle cells, activation of kinin receptor coupling through the same pathway results in an increased [Ca2+]i and contraction. Bj and B2 receptors also can couple through Gi to activate PLA2, causing the release of arachidonic acid and the local generation of prostanoids and other metabolites.

kinins, but the highly specific proteases that release bradykinin and kallidin from the kininogens are termed kallikreins (see below).

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