Autacoid Drugs

Autacoid Drugs

Classification of Autacoid Drugs

aAlso epinastine (ELESTAT) and olopatadine (PATANOL).

bAlso zolmitriptan (ZOMIG), rizatriptan (MAXALT), naratriptan (AMERGE), frovatriptan (FROVA), almotriptan (AXERT), and eletriptan (RELPAX).

cRecently withdrawn from the market in the United States.

dAlso granisetron (KYTRIL), palonosetron (ALOXI), alosetron (LOTRONEX), and dolasetron (ANZEMET).

eAlso bimatoprost (LUMIGAN) and travoprost (TRAVATAN).


Autacoids (also spelled autocoids) are substances produced by neural and nonneural tissues throughout the body that act locally to modulate the activity of smooth muscles, nerves, glands, platelets, and other tissues (Table 26-1). Several autacoids also serve as neurotransmitters in the central nervous system (CNS) or enteric nervous system.

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.

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


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.

First-Generation Antihistamines

Because the first-generation antihistamines have sedative effects, they are occasionally used to produce sedation. They are also used to treat nausea and vomiting, to prevent motion sickness in persons traveling by plane or boat, and to treat vertigo (an illusory sense that the environment or one’s own body is revolving).

The most sedating antihistamines are diphenhydramine, hydroxyzine, and promethazine. Doxepin has antidepressant and anxiolytic effects, but because of its high affinity for blocking central H1 receptors, it was recently approved at low doses for the treatment of insomnia. These drugs have been used to induce sleep or for preoperative sedation. Their sedating properties can also be useful in relieving distress caused by the severe pruritus associated with some allergic reactions. Persons taking these drugs should be cautioned against driving or operating machinery.

Pheniramine drugs, such as chlorpheniramine, are less sedating than other first-generation drugs and are used primarily in the treatment of allergic reactions to pollen, mold spores, and other environmental allergens.

Meclizine, diphenhydramine, hydroxyzine, and promethazine have higher antiemetic activity than other antihistamines. Meclizine is less sedating than diphenhydramine, hydroxyzine, and promethazine, so it is frequently used to prevent motion sickness or treat vertigo. Dimenhydrinate is a mixture of diphenhydramine and 8-chlorotheophylline and is also used for these purposes. Promethazine suppositories are often used to relieve nausea and vomiting associated with various conditions (see Chapter 28).

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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Autacoid Drugs

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