AUTACOID	EFFECTS ON VSM	EFFECTS ON NVSM	OTHER EFFECTS
Histamine	Vasodilation and edema	Contraction of bronchial and other NVSMs	Itching, increase in gastric acid secretion
Serotonin	Vasoconstriction in most vascular beds	Contraction of gastrointestinal and other NVSMs	Central nervous system neurotransmission, stimulation of platelet aggregation
Eicosanoids
Leukotrienes	Vasoconstriction or vasodilation	Contraction of bronchial and other NVSMs	Inflammatory effects, increase in vascular permeability
Prostaglandin E	Vasodilation	Relaxation of bronchial muscle and contraction of uterine muscle	Inhibition of gastric acid secretion
Prostaglandin F	Vasoconstriction in most vascular beds	Contraction of bronchial and uterine muscle	Increase in aqueous humor outflow
Prostaglandin I	Vasodilation	Contraction	Inhibition of platelet aggregation
Thromboxane A₂	Vasoconstriction	Contraction	Stimulation of platelet aggregation

NVSM, Nonvascular smooth muscle; VSM, vascular smooth muscle.

Autacoids regulate certain aspects of gastrointestinal, uterine, and renal function, and they are involved in pain, fever, inflammation, allergic reactions, asthma, thromboembolic disorders, and other pathologic conditions. Drugs that inhibit autacoid synthesis or block autacoid receptors are helpful in treating these conditions, whereas drugs that activate autacoid receptors are useful for inducing labor, alleviating migraine headaches, counteracting drug-induced peptic ulcers, and other purposes.

Autacoids include monoamines, such as histamine and serotonin, as well as fatty acid derivatives, including prostaglandins and leukotrienes. Autacoids activate specific membrane receptors in target tissues, mostly of the G protein–coupled receptor (GPCR) type. Their effects are usually restricted to the tissue in which they are formed, but under pathologic conditions, extraordinarily large amounts of autacoids can be released into the systemic circulation. These disorders include carcinoid tumor and anaphylactic shock, which cause the release of copious amounts of serotonin and histamine, respectively, and exert systemic effects including CNS effects. Most autacoids are rapidly metabolized to inactive compounds, as seen with prostaglandins, and some autacoids undergo tissue reuptake, as evidenced by 5-hydroxytryptamine (5-HT) reuptake transporter proteins in neurons and peripheral cells.

This chapter provides basic information about autacoids and reviews the many types of drugs that influence their effects. Some autacoid drugs are covered completely here, whereas other chapters provide more details on other agents.

Histamine and Related Drugs

Histamine Biosynthesis and Release

Histamine is a biogenic amine produced primarily by mast cells and basophils, which are particularly abundant in the skin, gastrointestinal tract, and respiratory tract. Histamine is also produced by paracrine cells in the gastric fundus, where it stimulates acid secretion by parietal cells. Histamine also functions as a neurotransmitter in the CNS (see Chapter 18).

Histamine is formed when the amino acid histidine is decarboxylated in a reaction catalyzed by the enzyme L–histidine decarboxylase. Histamine is stored in granules (vesicles) in mast cells and basophils until it is released. It is released from mast cells when membrane-bound immunoglobulin E (IgE) interacts with an IgE antigen to cause mast cell degranulation. This process can be blocked by cromolyn sodium and related respiratory drugs, as described in Chapter 27. A number of other stimuli can also cause the release of histamine from mast cells (Fig. 26-1). Stimuli that increase cyclic guanosine monophosphate increase histamine release, whereas those that increase cyclic adenosine monophosphate oppose this action.

FIGURE 26-1 Release of histamine from mast cells. Numerous chemical and physical stimuli activate histamine release from mast cells. Complement activation from serum sickness or bacterial endotoxins produces the anaphylactic peptides C3a and C5a, allergic antigens bind to immunoglobulin E *(IgE)* antibodies, and chemicals and other substances increase guanosine triphosphate *(GTP)* and cyclic guanosine monophosphate *(cGMP)* to activate enzymes causing increased intracellular calcium and release of histamine granules. β-Adrenoceptor agents and some prostaglandins increase adenosine triphosphate *(ATP)* and cyclic adenosine monophosphate *(cAMP)* and reduce activated enzymes.

Mast cell degranulation can also be triggered by bacterial toxins and by drugs such as morphine and tubocurarine. Some of these stimuli result in the formation of inositol triphosphate (IP₃) and diacylglycerol (DAG). As with neurons, this causes the release of intracellular calcium and the fusion of granule membranes with the plasma membrane, thereby releasing histamine and other compounds. The release of histamine that can occur with morphine administration does not appear to be mediated by opioid receptors because the opioid antagonist naloxone does not inhibit morphine-induced histamine release from mast cells.

Histamine is inactivated by methylation and oxidation reactions that are catalyzed by a methyltransferase enzyme and diamine oxidase, respectively.

Histamine Receptors and Effects

Histamine receptors have been classified as H₁, H₂, and H₃. All three types are typical, seven-transmembrane GPCR proteins.

H₁ receptors are involved in allergic reactions that cause dermatitis, rhinitis, conjunctivitis, and other forms of allergy. Activation of H₁ receptors in the skin and mucous membranes causes vasodilation; increases vascular permeability; and leads to erythema (heat and redness), congestion, edema, and inflammation. Stimulation of H₁ receptors on mucocutaneous nerve endings can cause pruritus (itching), and in the lungs it initiates the cough reflex. If sufficient histamine is released into the circulation, total peripheral resistance and blood pressure fall and the individual may progress to anaphylactic shock. Activation of H₁ receptors also causes bronchoconstriction and contraction of most gastrointestinal smooth muscles.

H₂ receptors are most noted for increasing gastric acid secretion, but they are also involved in allergic reactions. For this reason, H₂ receptor antagonists are sometimes used in combination with H₁ receptor antagonists in the treatment of allergies. Activation of H₂ receptors in the heart increases the heart rate and contractility, but the cardiac effects of histamine are not prominent under most conditions.

H₃ receptors are located in various tissues in the periphery and on nerve terminals. Activation of these presynaptic receptors in the brain inhibits the release of histamine and other neurotransmitters.

Antihistamine Drugs

Antihistamines, or histamine receptor antagonists, have been categorized on the basis of their receptor selectivity as H₁ receptor antagonists or H₂ receptor antagonists. Chapter 28 outlines the properties of H₂ receptor antagonists, which are used primarily to treat peptic ulcer disease. There are presently no approved H₃ receptor agents, although clinical trials are underway.

Histamine H₁ Receptor Antagonists

Classification

The following discussion focuses on the properties and uses of four groups of H₁ receptor antagonists. Chlorpheniramine, clemastine, dimenhydrinate, diphenhydramine, hydroxyzine, meclizine, and promethazine are examples of first-generation drugs. Cetirizine, fexofenadine, loratadine, and desloratadine are examples of second-generation drugs. Drugs in these two groups are administered orally or parenterally. A major difference in the two groups is that the first-generation antihistamines are distributed to the CNS and can cause sedation, whereas the second-generation antihistamines do not cross the blood-brain barrier significantly. Azelastine is an example of an intranasal antihistamine, and levocabastine, ketotifen, epinastine, and olopatadine are used for ophthalmic treatment.

Mechanisms and Pharmacokinetics

The H₁ antihistamines contain an alkylamine group that resembles the side chain of histamine and permits them to bind to the H₁ receptor and act as competitive receptor antagonists. The drugs can block most of the effects of histamine on vascular smooth muscles and nerves and thereby prevent or counteract allergic reactions.

When antihistamines are administered orally, they are rapidly absorbed and are widely distributed to tissues. Many of them are extensively metabolized in the liver by cytochrome P450 enzymes. Hydroxyzine has an active metabolite that is also available as the drug cetirizine, and this drug is excreted unchanged in the urine and feces.

Azelastine is an H₁ antihistamine that is marketed as a nasal spray for the treatment of allergic rhinitis. It blocks H₁ receptors and inhibits the release of histamine from mast cells, and it is much more potent than either sodium cromoglycate or theophylline in its inhibition. The systemic bioavailability of azelastine after intranasal administration is about 40%, and the plasma half-life is about 22 hours. Azelastine is metabolized by cytochrome P450 enzymes to an active metabolite, desmethylazelastine, a substance whose plasma concentrations are 20% to 30% of azelastine concentrations. Azelastine and its principal metabolite are both H₁ receptor antagonists. The unchanged drug and its active metabolite are excreted primarily in the feces.

Pharmacologic Effects and Indications

The H₁ antihistamines are all equally effective in treating allergies, but they differ markedly in their sedative, antiemetic, and anticholinergic properties (Table 26-2). The second-generation antihistamines cause little or no sedation, so they are often preferred for the treatment of allergies. Antihistamines are usually more effective when administered before exposure to an allergen than afterward. Hence persons with seasonal allergies, such as allergic rhinitis (see Chapter 27), should take them on a regular basis throughout the allergy season.

TABLE 26-2

Pharmacologic Properties of Selected Histamine H₁ Receptor Antagonists

DRUG	DURATION OF ACTION (HOURS)	SEDATIVE EFFECTS	ANTIEMETIC EFFECTS	ANTICHOLINERGIC EFFECTS
First-Generation Antihistamines
Chlorpheniramine	6	Medium	None	Medium
Dimenhydrinate	8	High	Medium	High
Diphenhydramine	8	High	Medium	High
Hydroxyzine	6	High	High	Medium
Meclizine	12	Medium	High	Medium
Promethazine	12	High	High	High
Second-Generation Antihistamines
Cetirizine	24	Low	None	Very low
Fexofenadine	12	Very low	None	Very low
Loratadine	24	Very low	None	Very low
Intranasal Antihistamines
Azelastine	12	Low	None	Very low