Autacoids and Their Pharmacological Modulators


A. Definitions
1. Autacoids are chemical mediators that are synthesized and function in a localized tissue or area and participate in physiologic or pathophysiologic responses to injury. They act only locally and therefore also termed “local hormone.” Autacoids normally do not function as the classical blood-borne hormones. Typically, autacoids are short-lived and rapidly degraded.

2. Autacoid modulators interfere with the synthesis, inhibit the release or the receptors upon which they act.

B. Physiologic function
1. Autacoids modulate blood flow in specific tissues.

2. Some autacoids modulate secretory processes, for example, histamine on gastric acid formation.

3. Autacoids modulate smooth muscle function.

4. Autacoids play a key role in allergy, inflammation, smooth muscle function, pain, and certain types of drug reactions (Anaphylaxis).

C. Major classes. The autacoids to be discussed in this chapter can be divided into three categories based on their chemical structure. Not all known autacoids will be discussed and the reader should consult a standard pharmacology text for information on vasoactive intestinal polypeptide, substance P, and the cytokines.
1. Biogenic amines: Histamine, serotonin (5-hydroxytryptamine)

2. Polypeptides: Bradykinin, angiotensin

3. Lipid-derived autacoids
a. Eicosanoids. Prostaglandins, leukotrienes, thromboxane

b. Platelet activating factor


A. Histamine

2. Metabolism. Two pathways are involved in the degradation of histamine. The major degradation pathway (>50% histamine degradation) involves conversion of histamine to an inactive metabolite 1-methylhistamine by imidazole-N-methyltransferase. The minor pathway (25% histamine degradation) involves breakdown of histamine by diamine oxidase (histaminase) to form imidazoleacetic acid.

3. Distribution and storage sites. Histamine is widely distributed in tissues and its concentration and rate of synthesis varies greatly from tissue to tissue.
a. The primary tissue sites storing histamine are the lungs, skin, mucosal layer of the stomach and basophils.
(1) Food and vagal stimulation can release histamine from the stomach mucosal enterochromaffin-like (ECL) cells. The released histamine then initiates gastric acid secretion (see Chapter 11, Figure 11-2).

(2) Allergic responses in the skin and lungs are due in part to histamine release from mast cells.

b. Mast cells are the primary cells that store histamine where it exists in a complex with heparin sulfate and chondroitin sulfate E in storage granules. The rate of histamine synthesis and turnover in mast cells is low.

c. Histamine is also found in CNS where it may act as a neurotransmitter.

d. Many venoms and insect stings contain histamine, as well as other biologically active substances.

e. Histamine is found in the digesta where it is formed in large part by bacterial action. This histamine normally does not reach the systemic circulation since it is metabolized by enzymes in the gut wall and liver.

4. Release
a. Immune release. When sensitized mast cells or basophils are coupled to IgE antibodies and then exposed to the proper antigen; the mast cell degranulates, thereby releasing histamine and other autacoids. This is also referred to type I IgE-mediated hypersensitivity reaction.

b. Drug-induced release. Drugs, usually strong bases (morphine, polymyxin, tubocurarine, codeine, lidocaine, penicillin), and/or their vehicles are capable of releasing histamine but this release does not involve degranulation or mast cell injury. These drugs displace or compete with histamine for the binding sites with heparin.

c. Plant and animal stings are capable of releasing histamine, which is an important component of the physiologic reaction (erythema, pain, itch) to these stings.

d. Physical injury such as heat, cold, or trauma can disrupt the mast cells thereby releasing histamine.

5. Receptor pharmacology (see Table 3-1 for overview of histamine receptor pharmacology).

Four classes of receptors (H1, H2, H3, and H4) mediate the action of histamine.

a. H1-receptors are coupled to Gq protein–phospholipase C and mediate the following effects:
(1) Contraction of smooth muscle and neuronal actions are due to increases in [Ca2+]i and activation of protein kinase C (see Chapter 1 for detailed information).

(2) Relaxation of vascular smooth muscle involves Ca2+-induced formation of nitric oxide (NO).

(3) H1-receptors mediate contraction of bronchiolar and intestinal smooth muscle, vasodilation of small arteries and veins, increased capillary permeability and pruritus. There are considerable species variations in their sensitivity of bronchial smooth muscle to contraction by histamine. The guinea pig bronchi are the most sensitive but the bronchi of rabbit, dog, goat, calf, pig, horse, and human also contract. In contrast, histamine relaxes respiratory smooth muscle in cats (via H1 and H2) and sheep (via H2). The mechanisms by which H1-receptors mediate brochodilation in cats are not known. H2-receptors mediate bronchodilation via an increase in cAMP levels (see below). H1-agonists and H1-antihistamines are listed in Table 3-1.

b. H2-receptors are coupled to Gs protein-adenylyl cyclase
Stimulation of Gs-coupled H2 receptors activate adenylyl cyclase and increase tissue cAMP levels. This is the mechanism by which vascular smooth muscle relaxes, and gastric acid secretion is stimulated.

H2-receptor primarily mediates gastric acid secretion and vasodilatation.

(1) Agonists include 4-methylhistamine and dimaprit.

(2) H2-Antihistaminec include: cimetidine, ranitidine, famotidine, and nizatidine. Recent evidence suggests, just like H1-antihistamines, these drugs are inverse agonists. (Table 3-1).

c. H3-receptors are coupled to Gi/o protein. Inhibition of the release of histamine and other neurotransmitters involves inhibition of cAMP synthesis, opening of K+ channels to increase K+ efflux, and closure of Ca2+ channels to block Ca2+ entry into the nerve.

H3-receptors are located presynaptically on neurons and inhibit neurotransmitter release. There are no drugs used in veterinary medicine that specifically activate or block these receptors.

d. H4-receptors are coupled to Gi/o protein and activate phospholipase C-β by Gβγ (see Chapter 1 for detailed information). These receptors are selectively expressed in mast cells, basophils, and eosinophils. Activation of H4-receptors mediates histamine-induced mast cell chemotaxis and leukotriene B4 production via activation of phospholipase C-β. Thus, H4-receptors may play a role in early events of inflammation, edema, and thermal hyperalgesia.

H4-receptor antagonists are being developed as anti-inflammatory drugs that involve mast cells and eosinophils.

6. Physiologic and pathologic roles
a. Gastric acid secretion. Histamine is the most important regulator of gastric acid secretion and it stimulates secretion via H2 receptors (see below under pharmacological effects).

b. Allergic reactions and anaphylactic shock. The binding of antigenic substances to IgE molecules on mast cells causes the release of histamine. Other biologically active substances such as prostaglandin D2 and leukotrines (LTC4 and LTD4) are also released.

c. Inflammation. Histamine may be involved in the vasodilation observed in the inflammatory process.

d. Neurotransmission. Histamine is a neurotransmitter in various brain areas and is involved in activating sensory nerves resulting in pain and itch sensations.

e. Microcirculation. Histamine relaxes arterioles and increases capillary permeability.

7. Pharmacologic effects (summarized in Table 3-1).
a. Cardiovascular system
(1) Histamine dilates arterioles, capillaries, and venules, increases cardiac contractility and heart rate by activating both H1– and H2-receptors. The cardiovascular effects are complex. There is a decrease in peripheral resistance (vasodilatation), resulting in hypotension. The stimulation of cardiac activity involves a direct action and reflex activation of the sympathetic nervous system, which is activated by the low blood pressure.

(2) There is an increase in capillary permeability brought about by contracting the endothelial cells, which exposes the basement membrane. Fluid and protein pass across the basement membrane to produce edema.

b. Respiratory system. Respiratory smooth muscle is contracted in most species via H1-receptors (see II A 5 a). There is also stimulation of glandular secretion and prostaglandin formation. Asthmatics are generally more sensitive to histamine than normal animals.

c. Glandular tissue. Histamine can stimulate glandular tissues to increase secretion. A most important action of histamine is its ability to increase gastric acid and pepsin secretion from the gastric mucosa via H2-receptors (see Chapter 11, Figure 11-2).
(1) Regulation of gastric acid production is quite complex. Acid secretion by parietal cells is regulated by histamine, acetylcholine (ACh), gastrin, and prostaglandin E2 (PGE2).

(2) Sight and smell of food activate the vagus via the CNS to release ACh on parietal cells (M3-muscarinic receptor) and on enterochromaffin-like (ECL) paracrine cells (M1-muscarinic receptor).

(3) The presence of food and an increase in antral pH initiate the release of gastrin. Gastrin acts on CCK2 receptors of the parietal and ECL cells. Histamine is released from ECL cells that are close by, and activate parietal H2-receptors.

(4) ACh has both a direct and indirect action on gastric acid production. Activation of M3-receptors directly activates the parietal cell, whereas activation of the M1-receptor on the ECL cells releases histamine which in turn activates H2-receptors on the parietal cell.

(5) Gastrin has both a direct and indirect action. Gastrin directly activates CCK2-receptors on parietal cells to increase gastric acid secretion and indirectly increases gastric acid secretion by activating the release of histamine from ECL cells, which again in turn activates H2-receptors on the parietal cells. Thus, histamine release is a major factor in the stimulation of acid production by both ACh and gastrin.

(6) Activation of H2-receptors enhances the gastric acid secretion by ACh and gastrin on parietal cells. Upon H2-receptor stimulation, intracellular cAMP is increased. Activation of PKA by cAMP translocates H+, K+-ATPase in tuberovesicles to canalicular membrane, which subsequently releases H+ into the lumen. Upon stimulation of M3-receptors and gastrin (CCK2) receptors, calmodulin kinase is activated to translocate the H+, K+-ATPase to canalicular membrane as well. Chloride is released into lumen by K+ and Cl carrier, evoking next increase in HCl level in the lumen (see Figure 11-2).

(7) H2-antihistamines inhibit not only HCl secretion by histamine but secretion stimulated by gastrin, ACh (vagus), and food. This explains why H2-antihistamines are effective therapy for peptic ulcers. Proton pump inhibitors (e.g., omeprazole) block the H+, K+-ATPase in canalicular membrane. PGE2 act as a negative regulator of gastric acid secretion as PGE2 activates Gi/o-coupled EP3 receptors on parietal cells.

(8) Histamine can increase the release of catecholamines from the adrenal medulla and stimulate salivary secretion.

d. Intradermal tissue. Intradermal injection of histamine produces a triple response (of Lewis). Insect and plant stings mimic many of these responses.
(1) A reddening at the site of injection is due to dilation of the small arterioles.

(2) Dilation of arterioles extends beyond injection site (Flare). The flare involves an axon reflex since cutting the cholinergic nerves abolishes the reflex.

(3) Swelling (Wheal) occurs at the injection site due to separation of the endothelial cells and edema caused by the increased capillary permeability, which is due to H1-receptor-mediated contraction of endothelial cells.

(4) The intradermal injection of histamine causes pain and itching by stimulation of H1-receptors on sensory nerve endings.

8. Therapeutic uses of histamine agonists
a. Histamine phosphate can be used for diagnostic purposes for testing of gastric acid secretion and pheochromocytoma. However, its profound side effects limit its use.

b. Betazole is an analog of histamine, which is an H2-receptor agonist. Betazole has a 10-fold selectivity for stimulation of gastric acid production over vasodilation. Pentagastrin is also used for this purpose.

FIGURE 3-1. Synthesis and catabolism of histamine. Note: The conversion of imidazole acetaldehyde to imidazoleacetic acid is catalyzed by acetaldehyde dehydrogenase.


TABLE 3-1. Histamine Pharmacology—An Overview


B. Antihistamines. Therapeutically useful antihistamine drugs are H1-antihistamines and H2-antihistamines. At present there are no clinically useful H3 or H4-antihistamines.
1. H1-antihistamines were the first type of antihistaminic drugs discovered and are sometimes referred to as the classical antihistaminics. See Table 3-1 for examples of drugs in this class.
a. Mechanism of action. Traditionally, it was thought that H1-antihistamines act as competitive antagonists of histamine receptors. However, recently it has been demonstrated that most, if not all, of H1-antihistamines act as inverse agonists rather than the receptor antagonists. (See Chapter 1 for detailed information on inverse agonists.)

b. Classification of H1antihistamines. Histamine can be broadly classified into two groups based on usage: (1) first-generation H1-antihistamines and (2) second generation H1-antihistamines.

Most frequently used first-generation H1-antihistamines are diphenhydramine, dimenhydrinate, hydroxyzyline, chlorpheniramine, meclizine, promethazine, and cyproheptadine. These drugs are unionized drugs at physiological pH and easily cross the blood–brain barrier (BBB). Therefore, they produce CNS side effects, in particular, sedation.

Commonly used second-generation drugs are loratadine (Claritin®), cetirizine (Zyrtec®), and fexofenadine (Allegra®). This class of drugs is ionized at physiological pH and is difficult to cross BBB. See Table 3-2 for chemical classification of H1-antihistamines (Table 3-2).

c. Pharmacologic effects of H1-antihistamines
(1) Relaxation of contracted bronchiolar smooth muscle.

(2) Relaxation of contracted intestinal smooth muscle.

(3) Inhibition of histamine-induced vasodilation and increased capillary permeability and thereby blocking formation of edema and wheals.

(4) Inhibition of itch sensation by prevention of stimulation of sensory nerves. Many H1-antihistamines have a potent local anesthetic action that may contribute to their inhibition of itching and pain.

Note: H1-antihistamines alone are not effective for treatment of systemic anaphylaxis because large amount of other autacoids are released during anaphylaxis.

d. Other pharmacologic effects of H1-antihistamines (Table 3-2).
(1) Sedation is a common effect of first-generation H1 -antihistamines but sedation does not correlate with their potency for inhibiting H1-receptors. Sedation may be a desirable/undesirable effect and can be expected to be additive to other CNS depressants.

(2) Antimuscarinic effects are prominent for some H1-antihistamines, for example, diphenhydramine and promethazine, which decrease secretions and relax smooth muscles.

(3) Antimotion sickness (antiemetic) effects. This effect is due to the inhibition of histaminergic signals from the vestibular nucleus to the vomiting center in the medulla. All H1-antihistamine have this effect, but some of them (diphenhydramine, dimenhydrinate, and meclizine) have more potent antimotion sickness effect than others in the group.

e. Therapeutic uses. H1-antihistamines are administered orally, parenterally, or topically for the following conditions.
(1) Treatment of patients with allergic conditions and to reduce or ameliorate the effects due to histamine. Conditions benefited from

H1-antihistamines include:

(a) Urticaria and pruritus

(b) Allergic reactions to drugs

(c) Anaphylaxis

(2) Prevention of motion sickness. Diphenhydramine, dimenhydrinate, and meclizine are more effective in preventing motion sickness than other H1-antihistamines.

(3) Sedation induction. Promethazine and diphenhydramine are the most potent for inducing sedation.

f. Pharmacokinetics
(1) The pharmacokinetics of vast majority of H1-antihistamines have not been studied in domestic animals. Most information is derived from humans.

(2) All H1-antihistamines are effectively absorbed following oral administration and Tmax = 1–3 hours.

(3) All H1-anithistamines that have been studied for pharmacokinetics are well distributed and are bound by plasma proteins (≥60%).

(4) All H1-antihistamines are metabolized by cytochrome P450 enzymes, and these metabolites further undergo conjugation.

(5) The first-generation antihistamines are excreted primarily by the kidneys as metabolites.

(6) The second-generation antihistamines that cause least or no sedation are excreted more into feces when compared with the first-generation drugs: cetirizine (70% in urine, 30% in feces); loratadine (40% in urine, 40% in feces as metabolites); fexofenadine (11% in urine, 80% in feces).

(7) Elimination t½ : See Table 3-2 for information in humans. The t½ information for animals is mostly not available.

g. Adverse effects (see also Table 3-2)
(1) CNS depression (lethargy, somnolence, ataxia) are the most common but they may diminish with time. The performance of working dogs may be adversely affected.

(2) Antimuscarinic effects (dry mouth, urinary retention) occur with many H1-antihistaqmines. They should be used with caution in patients with angle closure glaucoma.

(3) In high doses CNS stimulation is possible, for example, pyrilamine in the horse.

(4) Some individuals could develop allergy to the use of H1-antihsitamines.

(5) Drug tolerance. The decrease in efficacy and sedation (also called subsensitivity) can develop during the use of H1-antihistamines for days or weeks. The mechanisms underlying this phenomenon are not understood.

2. H2-antihistamines. These drugs are inhibitors of gastric acid secretion. They have little action on H1-receptors.
a. Chemistry. H2-antihistamines contain imidazole ring with uncharged side chains and are smaller than H1-antihistamines. See Figure 3-2 for an example of drugs in this class.

b. Pharmacologic effects. H2-antihistamines competitively inhibits histamine (H2-receptors) in parietal cell and thereby decreases gastric acid production during basal conditions and when stimulated by food, vagal activity, pentagastrin, gastrin, or histamine. H2-antihistamines have been reported to act as inverse agonists, but further validation of this observation is needed.

c. Therapeutic uses. H2-antihistamines are administered orally to treat gastric, abomasal and duodenal ulcers, drug-induced erosive gastritis, duodenal gastric reflux, and esophageal reflux. Cimetidine is least potent among the four H2-antihistamines. Lack of therapeutic effect of cimetidine has been reported in dogs.

d. Pharmacokinetics
(1) All four drugs are well absorbed when administered orally. T max is 2–3 hours for all four drugs. The bioavailability for cimetidine, ranitidine, nizatidine, and famotidine is 95%, 81%, >70%, and 40–50%, respectively.

(2) All four drugs are well distributed in the body, with 10–20% bound by plasma proteins.

(3) Cimetidine, ranitidine, and famotidine are metabolized by cytochrome P450 enzymes. Only < 10% of nizatidine is metabolized by CYP450 enzymes.

(4) All four drugs are excreted by the kidneys as the primary route. The majority of cimetidine, ranitidine, and famotidine is excreted as metabolites and 30– 50% is excreted as the unchanged drug. A total of ≥60% of nizatidine is excreted as the unchanged drug.

(5) Plasma t½ of cimetidine, ranitidine, and famotidine are 2–3 hours for all three drugs. The t½ for cimetidine and ranitidine in dogs are 1.3 hours and 2.2 hours, respectively. Plasma t½ of nizatidine is 1–2 hours in humans; no information is available for animals.

e. Adverse effects are uncommon when recommended dosages are used. Cimetidine possesses weak antiandrogenic activity and can cause gynecomastia and decreased libido in humans. The antiandrogenic effect is, in part, due to decreased testosterone synthesis.

Ranitidine, famotidine, and nizatidine seem to be very well tolerated. Rarely, agranocytosis has been seen with the use of ranitidine and famotidine.

f. Drug interactions. Cimetidine can inhibit the hepatic cytochrome P450 enzymes. It may reduce the metabolism of other drugs, which undergo hepatic metabolism, thereby elevating and prolonging their concentration in the plasma.

3. Inhibitors of histamine release. The one drug in this category, cromolyn sodium, differs in mechanism of action from the H1– and H2-antihistamines discussed above.
a. Cromolyn sodium inhibits the release of histamine and other autacoids from mast cells. It does not inhibit H1– and H2-receptors, but opens chloride channel to hyperpolarize the cells.
(1) It is primarily used to treat pulmonary and nasal allergic reactions.

(2) It is not well absorbed from the gut and has no clinical use when given orally.

(3) It is used in a prophylactic manner.

(4) It has been used in the horse where it is nebulized and delivered via a face mask.

(5) The 4% eye drop is used to control allergic conjunctivitis.

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May 28, 2017 | Posted by in GENERAL | Comments Off on Autacoids and Their Pharmacological Modulators

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