Page 295 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 16 Histamine, Serotonin, & the Ergot Alkaloids 281

Other Histamine Agonists ■ HISTAMINE RECEPTOR
Small substitutions on the imidazole ring of histamine signifi- ANTAGONISTS
cantly modify the selectivity of the compounds for the histamine
receptor subtypes. Some of these are listed in Table 16–1. H -RECEPTOR ANTAGONISTS
1
Compounds that competitively block histamine or act as inverse
CLINICAL PHARMACOLOGY OF agonists at H receptors have been used in the treatment of allergic
1
HISTAMINE conditions for many years, and in the discussion that follows are
referred to as antagonists. Many H antagonists are currently
1
Clinical Uses marketed in the USA. A large number are available without
prescription, both alone and in combination formulations such as
In pulmonary function laboratories, histamine aerosol has rarely “cold pills” and “sleep aids” (see Chapter 63).
been used as a provocative test of bronchial hyperreactivity.
Histamine has no other current clinical applications.
BASIC PHARMACOLOGY OF
Toxicity & Contraindications H -RECEPTOR ANTAGONISTS
1
Adverse effects of histamine release, like those following admin-
istration of histamine, are dose related. Flushing, hypotension, Chemistry & Pharmacokinetics
tachycardia, headache, urticaria, bronchoconstriction, and The H antagonists are conveniently divided into first-generation
1
gastrointestinal upset are noted. These effects are also observed after and second-generation agents. These groups are distinguished by
the ingestion of spoiled fish (scombroid fish poisoning), and the relatively strong sedative effects of most of the first-generation
histamine produced by bacterial action in the flesh of improperly drugs. The first-generation agents are also more likely to block
stored fish is the major causative agent. autonomic receptors. Second-generation H blockers are less
1
Histamine should not be given to patients with asthma (except sedating, owing in part to reduced distribution into the central
as part of a carefully monitored test of pulmonary function) or to nervous system. All the H antagonists are stable amines with
1
patients with active ulcer disease or gastrointestinal bleeding. 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,
HISTAMINE ANTAGONISTS with peak blood concentrations occurring in 1–2 hours. They are
widely distributed throughout the body, and the first-generation
The effects of histamine released in the body can be reduced in H blockers enter the central nervous system readily. Some of them
1
several ways. Physiologic antagonists, especially epinephrine, are extensively metabolized, primarily by microsomal systems in
have smooth muscle actions opposite to those of histamine, but the liver. Several of the second-generation agents are metabolized
they act at different receptors. This is important clinically because by the CYP3A4 system and thus are subject to important interac-
injection of epinephrine can be lifesaving in systemic anaphylaxis tions when other drugs (such as ketoconazole) inhibit this subtype
and in other conditions in which massive release of histamine— of P450 enzymes. Most of the drugs have an effective duration
and other more important mediators—occurs. of action of 4–6 hours following a single dose, but meclizine and
Release inhibitors reduce the degranulation of mast cells that several second-generation agents are longer-acting, with a dura-
results from immunologic triggering by antigen-IgE interaction. tion of action of 12–24 hours. The newer agents are considerably
Cromolyn and nedocromil appear to have this effect (see less lipid-soluble than the first-generation drugs and are substrates
Chapter 20) and have been used in the treatment of asthma. of the P-glycoprotein transporter in the blood-brain barrier; as a
-adrenoceptor agonists also appear capable of reducing
Beta 2 result, they enter the central nervous system with difficulty or not
histamine release. at all. Many H antagonists have active metabolites. The active
1
Histamine receptor antagonists represent a third approach to metabolites of hydroxyzine, terfenadine, and loratadine are available
the reduction of histamine-mediated responses. For over 70 years, as drugs (cetirizine, fexofenadine, and desloratadine, respectively).
compounds have been available that competitively antagonize
many of the actions of histamine on smooth muscle. However,
not until the H -receptor antagonist burimamide was described Pharmacodynamics
2
in 1972 was it possible to antagonize the gastric acid-stimulating Both neutral H antagonists and inverse H agonists reduce or
1
1
activity of histamine. The development of selective H -receptor block the actions of histamine by reversible competitive binding to
2
antagonists has led to more effective therapy for peptic disease (see the H receptor. Several have been clearly shown to be inverse ago-
1
Chapter 62). Selective H and H antagonists are not yet available nists, and it is possible that all act by this mechanism. They have
4
3
for clinical use. However, potent and partially selective experimental negligible potency at the H 2 receptor and little at the H receptor.
3
H -receptor antagonists, thioperamide and clobenpropit, For example, histamine-induced contraction of bronchiolar or
3
have been developed. gastrointestinal smooth muscle can be completely blocked by