The effects of histamine released in the body can be reduced in several ways. Physiologic antagonists, especially epinephrine, have smooth muscle actions opposite to those of histamine, but they act at different receptors. This is important clinically because injection of epinephrine can be lifesaving in systemic anaphylaxis and in other conditions in which massive release of histamine— and other more important mediators—occurs.
Release inhibitors reduce the degranulation of mast cells that results from immunologic triggering by antigen-IgE interaction. Cromolyn and nedocromil appear to have this effect (see Chapter 20) and have been used in the treatment of asthma. Beta2-adrenoceptor agonists also appear capable of reducing histamine release.
Histamine receptor antagonists represent a third approach to the reduction of histamine-mediated responses. For over 70 years, compounds have been available that competitively antagonize many of the actions of histamine on smooth muscle. However, not until the H2-receptor antagonist burimamide was described in 1972 was it possible to antagonize the gastric acid-stimulating activity of histamine. The development of selective H2-receptor antagonists has led to more effective therapy for peptic disease (see Chapter 62). Selective H3 and H4 antagonists are not yet available for clinical use. However, potent and partially selective experimental H3-receptor antagonists, thioperamide and clobenpropit, have been developed.
Compounds that competitively block histamine or act as inverse agonists at H1 receptors have been used in the treatment of allergic conditions for many years, and in the discussion that follows are referred to as antagonists. Many H1 antagonists are currently marketed in the USA. A large number are available without prescription, both alone and in combination formulations such as “cold pills” and “sleep aids” (see Chapter 63).
The H1 antagonists are conveniently divided into first-generation and second-generation agents. These groups are distinguished by the relatively strong sedative effects of most of the first-generation drugs. The first-generation agents are also more likely to block autonomic receptors. Second-generation H1 blockers are less sedating, owing in part to reduced distribution into the central nervous system. All the H1 antagonists are stable amines with the general structure illustrated in Figure 16–1. Doses of some of these drugs are given in Table 16–2.
These agents are rapidly absorbed after oral administration, with peak blood concentrations occurring in 1–2 hours. They are widely distributed throughout the body, and the first-generation H1 blockers enter the central nervous system readily. Some of them are extensively metabolized, primarily by microsomal systems in the liver. Several of the second-generation agents are metabolized by the CYP3A4 system and thus are subject to important interactions when other drugs (such as ketoconazole) inhibit this subtype of P450 enzymes. Most of the drugs have an effective duration of action of 4–6 hours following a single dose, but meclizine and several second-generation agents are longer-acting, with a duration of action of 12–24 hours. The newer agents are considerably less lipid-soluble than the first-generation drugs and are substrates of the P-glycoprotein transporter in the blood-brain barrier; as a result, they enter the central nervous system with difficulty or not at all. Many H1 antagonists have active metabolites. The active metabolites of hydroxyzine, terfenadine, and loratadine are available as drugs (cetirizine, fexofenadine, and desloratadine, respectively).