Autacoids and Autacoid Antagonists Flashcards

1
Q

Histamine

A

Histamine is 2-(4-imidazoyl)ethylamine. It occurs in plants as well as in animal tissues; it is a component of some venoms and stinging secretions.

Formed by decarboxylation of the amino acid L-histidine, a reaction catalyzed by histidine decarboxylase. Once formed, histamine is stored or rapidly inactivated.

Very little histamine is excreted unchanged.

Most tissue histamine exists in bound form in granules in mast cells or basophils. Many stimuli can trigger the release of mast cell histamine. Mast cells are rich at sites of potential tissue injury: nose, mouth, feet, internal body surfaces, and blood vessels, particularly at pressure points and bifurcations.

Non-mast cell histamine is found in several tissues, including the brain, where it functions as a neurotransmitter. An important nonneuronal site of histamine storage and release is the enterochromaffin-like cell of the fundus of the stomach. These cells release histamine, one of the primary acid secretagogues, to activate the acid- producing parietal cells of the mucosa.

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2
Q

Storage and Release of Histamine

A

IMMUNOLOGIC RELEASE

Mast cells and basophils, if sensitized by IgE antibodies attached to their surface membranes, degranulate when exposed to the appropriate antigen. This type of release requires energy and Ca2+. Degranulation leads to the simultaneous release of histamine, ATP, and other mediators stored together in secretory granules. Histamine released by this mechanism is a mediator in immediate (type I) allergic reactions.

CHEMICAL AND MECHANICAL RELEASE

Certain amines, including drugs such as morphine and tubocurarine, can displace histamine from the heparin-protein complex within cells. This type of release doesn’t require energy and is not associated with mast cell injury or degranulation.

Chemical and mechanical mast cell injury causes degranulation and histamine release.

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3
Q

Histamine Mechanism of Action

A

Four cell surface histamine receptors have been characterized: H1, H2, H3 & H4.

All belong to the large superfamily of receptors linked to G proteins.

All four receptors have constitutive activity in some systems; thus, some antihistamines previously considered to be antagonists are actually inverse agonists. Furthermore, a single molecule may be an agonist at one receptor and an antagonist at another.

In the brain, H1 and H2 receptors are located on postsynaptic membranes; H3 are predominantly presynaptic.

H1 receptors are present in endothelium, smooth muscle cells and nerve endings. H1 receptors are coupled to PLC; their activation leads to formation of IP3 and DAG; IP3 causes a rapid release of Ca2+ from the ER.

H2 receptors are present in gastric mucosa, cardiac muscle cells and some immune cells. H2 receptors are linked to the stimulation of adenylyl cyclase and thus to activation of cAMP-dependent protein kinase in the target cell.

Activation of H3 receptors reduces transmitter release from histaminergic and other neurons.

H4 receptors are mainly found on leukocytes in the bone marrow and circulating blood. They appear to have important chemotactic effects on eosinophils and mast cells. They may play an important role in inflammation and allergy.

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4
Q

Cardiovascular System Effects of Histamine

A

Vasodilation

By far the most important action of histamine on human beings. Vasodilation involves both H1 and H2 receptors. H1 receptors have the higher affinity for histamine and mediate a dilator response that is rapid and short lived. By contrast, activation of H2 receptors causes dilation that develops slowly and is more sustained. H2 receptors are located on vascular smooth muscle cell, and the vasodilation is mediated by cAMP; H1 receptors reside on endothelial cells and their stimulation leads to formation of NO. The decrease in blood pressure is usually accompanied by reflex tachycardia.

Heart

Direct cardiac effects of histamine include both increased contractility and increased pacemaker rate. These effects are mediated mainly by H2 receptors. In human atrial muscle, histamine can also decrease contractility: this effect is mediated by H1 receptors. If histamine is given IV, its direct cardiac effects are not prominent and are overshadowed by baroreflexes elicited by the reduced blood pressure.

Increased Capillary Permeability

Histamine-induced edema results from the action of histamine on H1 receptors in the vessels of the microcirculation, especially the postcapillary vessels. The effect is associated with separation of the endothelial cells which permits the transudation of fluid and molecules as large as small proteins into the perivascular tissue. This effect is responsible for the urticaria (hives) that signals the release of histamine in the skin. Apparently actin and myosin within these nonmuscle cells contract, resulting in separation of endothelial cells and increased permeability.

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5
Q

GI and Bronchiolar Smooth Muscle, Nervous System, Secretory System, and Anaphylactic Effects of Histamine

A

GI Tract Smooth Muscle

Histamine causes contraction of intestinal smooth muscle (H1 effect) and histamine- induced contraction of guinea pig ileum is a standard bioassay for histamine.

Bronchiolar Smooth Muscle

Histamine causes bronchoconstriction mediated by H1 receptors. Patients with asthma are very sensitive to histamine.

NERVOUS SYSTEM

Histamine is a powerful stimulant of sensory nerve endings, especially those mediating pain and itching. This H1-mediated effect is an important component of urticarial response and reactions to insect and nettle stings.

SECRETORY TISSUE

Histamine is a powerful stimulant of gastric acid secretion and to a lesser extent of gastric pepsin and intrinsic factor production. The effect is caused by activation of H2 receptors in gastric parietal cells, and is associated with increased adenylyl cyclase activity, cAMP concentration and intracellular Ca2+ concentration. Histamine also stimulates secretion in the small and large intestine.

HISTAMINE AND ANAPHYLAXIS

Systemic mast cell degranulation can cause the life-threatening condition known as anaphylaxis. Typically, anaphylactic shock is initiated in a previously sensitized individual by a hypersensitivity reaction to an insect bite, an antibiotic such as penicillin, or ingestion of certain highly allergenic foods (e.g., nuts). Anaphylactic shock can be lethal within minutes if not treated rapidly by the administration of epinephrine.

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6
Q

Clinical Uses and Toxicity of Histamine

A

CLINICAL USES

Pulmonary Function Testing

In pulmonary function laboratories, histamine aerosol is sometimes used as a provocative test of nonspecific bronchial hyperactivity.

TOXICITY

Adverse effects are dose-related. Flushing, hypotension, tachycardia, headache, wheals, bronchoconstriction, GI upset.

Histamine should not be given to asthmatics or to patients with active ulcer disease or GI bleeding.

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7
Q

Physiological Antagonists of Histamine

A

PHYSIOLOGICAL ANTAGONISTS

Physiological antagonists, especially epinephrine, have smooth muscle actions opposite to those of histamine, but they act at different receptors. Important clinically because injection of epinephrine can be life-saving in systemic anaphylaxis and in other conditions in which massive release of histamine –and other mediators- occurs.

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8
Q

Cromolyn and Nedocromil

A

RELEASE INHIBITORS OF HISTAMINE

Reduce the degranulation of mast cells that results from immunologic triggering by antigen-IgE interaction. Cromolyn and nedocromil appear to have this effect and are used in the treatment of asthma, although the molecular mechanism underlying their action is unknown. β2-agonists also appear capable of reducing histamine release.

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9
Q

H1-Receptor Antagonists

A

H1 RECEPTOR ANTAGONISTS

Can be divided into first-generation and second-generation. First-generation have sedative effects and are more likely to block autonomic receptors. Second-generation are less sedating because of their less complete distribution into the CNS (they are less liposoluble). Additionally, they are substrates of the P-glycoprotein transporter, which further limits their brain penetration.

First generation:

Chlorpheniramine, Cyclizine, Dimenhydrinate, Diphenhydramine

Second-generation:

Fexofenadine, Loratadine, Cetirizine, Hydroxyzine, Meclizine, Promethazine, Astemizole, Terfenadine

Note: astemizole and terfenadine have been withdrawn from the US market because they induced the potentially fatal arrhythmia, torsades de pointes (see below).

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10
Q

Actions and Uses of H1-Antagonists

A

Historically, H1-antihistamines were considered to be H1 receptor antagonists. Recently, however, they have been shown to be inverse agonists.

Histamine-induced contraction of bronchiolar and GI muscle can be completely blocked by these agents.

H2 receptor-mediated actions such as increase in gastric acid secretion are unaffected.

The first-generation H1 antagonists have additional effects unrelated to their blocking of H1 receptors. These effects reflect binding of the H1 antagonists to cholinergic, α- adrenergic, serotonin and local anesthetic receptor sites.

USES

Allergic conditions

H1 blockers are useful in treating allergies caused by antigens acting on IgE-antibody sensitized mast cells. Antihistamines are the drugs of choice in controlling symptoms of allergic rhinitis and urticaria because histamine is the principal mediator.

H1 blockers are ineffective in treating bronchial asthma because histamine is only one of several mediators.

Epinephrine is the drug of choice in treating systemic anaphylaxis and other conditions that involve massive release of histamine.

Motion sickness and nausea

Along with the antimuscarinic agent scopolamine, certain first-generation H1 receptor blockers, such as diphenhydramine, dimenhydrinate and promethazine, are the most effective agents for prevention of symptoms of motion sickness. The antihistamines prevent or diminish vomiting and nausea mediated by both the chemoreceptor and vestibular pathways.

Somnifacients

Some first-generation H1 blockers, such as diphenhydramine, have strong sedative properties and are used in the treatment of insomnia. The use of H1 antihistaminics is contraindicated in individuals working in jobs where wakefulness is critical.

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11
Q

Adverse and Drug Interactions of H1-Antagonists

A

ADVERSE

Sedation: less common with second generation agents.

Dry mouth: due to anticholinergic effects.

DRUG INTERACTIONS

Significant cardiac toxicity, including potentially lethal ventricular arrhythmias, occurred in several patients taking either of the early second-generation agents, terfenadine or astemizole, in combination with ketoconazole, itraconazole or macrolide antibiotics such as erythromycin. These antimicrobial drugs inhibit the metabolism of many drugs by CYP3A4 and cause significant increases in blood concentrations of the antihistamines. The mechanism of this toxicity involves blockade of the HERG K+ channels in the heart that are responsible for repolarization of the action potential. The result is prolongation of the action potential, and excessive prolongation leads to arrhythmias. Both terfenadine and astemizole were withdrawn from the US market in recognition of these problems.

Grapefruit juice also inhibits CYP3A4 and has been shown to increase terfenadine’s blood levels significantly.

The active metabolite of terfenadine is currently marketed as fexofenadine (carboxylated terfenadine). Fexofenadine lacks the cardiac toxicity of terfenadine.

For those H1 antagonists that cause significant sedation, addition of other drugs that cause central nervous system depression produces additive effects and is contraindicated while driving or operating machinery.

Similarly, the autonomic blocking actions of older antihistaminics are additive with those of muscarinic and α-blocking drugs.

OVERDOSES

The margin of safety of the H1 blockers is relatively high, and chronic toxicity is rare. However, acute poisoning is relatively common, especially in young children. The most common and dangerous effects of acute poisoning are those on the CNS, including hallucinations, excitement, ataxia, and convulsions. If untreated, the patient may experience a deepening coma and collapse of the cardiorespiratory system.

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12
Q

Cimetidine, Ranitidine, Famotidine, Nizatidine

A

H2 RECEPTOR ANTAGONISTS

Main clinical use is to inhibit gastric acid secretion. By competitively blocking the binding of histamine to H2 receptors, these agents reduce intracellular concentration of cAMP and thereby, secretion of gastric acid. They inhibit >90% of basal, food-stimulated and nocturnal secretion of gastric acid after a single dose. Cimetidine is the prototype.

ACTIONS

Competitive, reversible inhibitors of H2 receptors. Completely inhibit gastric acid secretion induced by histamine or gastrin. They only partially inhibit gastric acid secretion induced by muscarinic agonists.

USES

Peptic ulcers: promote healing of duodenal and gastric ulcers. Recurrence is common after treatment is stopped. This can be prevented by eradication of H. pylori and H2 antagonists continue to be widely used in peptic ulcer therapy in combination with antimicrobial drugs.

Acute stress ulcers: useful in managing acute stress ulcers associated with major physical trauma in high-risk patients in intensive care units.

GERD: effective in prevention and treatment of heart-burn (gastroesophageal reflux). About 50% of patients don’t benefit and proton pump inhibitors are now used preferentially in the treatment of GERD. Because H2 blockers act by stopping acid secretion, they may not relieve symptoms for at least 45 minutes. Antacids more efficiently neutralize secreted acid already in the stomach, but their effects are shorter-acting.

ADVERSE EFFECTS

H2 antagonists are extremely safe drugs. Adverse effects occur in less than 3% of patients and include headache, dizziness, diarrhea, muscular pain, constipation.

Mental status changes (confusion, hallucinations, agitation) may occur with administration of IV H2 antagonists, especially in patients in the ICU who are elderly or who have renal or hepatic dysfunction. These adverse effects may be more common with cimetidine.

Cimetidine inhibits cytochrome P450 and can slow metabolism of several drugs.

Cimetidine binds to androgen receptors and has antiandrogenic effects, such as gynecomastia and reduced sperm count in men and galactorrhea in women.

Studies have not shown harmful effects on the fetus when H2-blockers are given to pregnant women. However, they cross the placenta and should be given only when absolutely necessary. They are secreted into breast milk and may affect the nursing infant.

H2 antagonists may rarely cause blood dyscrasias.

Rapid IV infusion may cause bradycardia and hypotension through blockade of cardiac H2 receptors; therefore, IV injection should be given over 30 minutes.

H2 antagonists rarely cause reversible abnormalities in liver chemistry.

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13
Q

Serotonin (5-hydroxytryptamine, 5-HT)

Where is it found?

A

Widely distributed in nature; found in plant and animal tissues, venoms and stings.

Formed from the amino acid L-tryptophan by hydroxylation of the indole ring followed by decarboxylation of the amino acid.

Serotonin is stored or is rapidly inactivated, usually by oxidation catalyzed by MAO.

In mammals, over 90% of the serotonin in the body is found in enterochromaffin cells in the GI tract.

In the blood, serotonin is found in platelets.

Serotonergic neurons are found in the enteric nervous system of the GI tract and around blood vessels.

In the pineal gland, serotonin is a precursor of melatonin.

Serotonin is found in the raphe nuclei of the brain stem, which contain cell bodies of serotonergic neurons that synthesize, store and release serotonin as a transmitter.

Brain serotonergic neurons are involved in various functions such as mood, sleep, appetite, temperature regulation, the perception of pain, the regulation of blood pressure and vomiting.

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14
Q

Pharmocological Effects, and Mechanism of Action of Serotonin

A

MECHANISM OF ACTION

Seven families of 5-HT receptor subtypes have been characterized. Six are G protein- coupled receptors and one is a ligand-gated ion channel.

The 5-HT3 receptor is the only monoamine neurotransmitter receptor known to function as a ligand-gated ion channel.

PHARMACOLOGICAL EFFECTS

GI TRACT

5-HT increases GI motility. Due to activation of 5-HT2 smooth muscle receptors and to action on ganglion cells of the enteric nervous system.

Activation of 5-HT4 receptors of the enteric nervous system causes increased acetylcholine release and mediates the prokinetic effect of serotonin agonists like cisapride. Overproduction of serotonin in carcinoid tumour results in severe diarrhea.

CARDIOVASCULAR SYSTEM

Serotonin constricts large vessels, both arteries and veins. Due to activation of 5-HT2 receptors on vascular smooth muscle cells.

PLATELETS

5-HT causes platelet aggregation via 5-HT2A receptors.

NERVOUS SYSTEM

5-HT excites some neurons and inhibits others, and also acts presynaptically to inhibit transmitter release from nerve terminals.

5-HT3 receptors in the GI tract and in the vomiting center of the medulla participate in the vomiting reflex.

5-HT is a potent stimulant of pain and itch sensory nerve endings, an effect mediated by 5-HT3 receptors. Serotonin is responsible for some of the symptoms caused by insect and plant stings.

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15
Q

Sumatriptan

A

5-HT1D/1B RECEPTOR AGONISTS (TRIPTANS)

Sumatriptan is the prototype. The triptans are selective for the 5-HT1B and 5-HT1D receptor subtypes. Triptans are used almost exclusively in migraine headache.

Migraine involves the trigeminal nerve distribution to intracranial arteries. These nerves release peptide neurotransmitters, especially calcitonin gene-related peptide, a powerful vasodilator. Substance P and neurokinin A may also be involved.

Triptans reduce both sensory activation in the periphery and nociceptive transmission in the brainstem trigeminal nucleus, where they diminish central sensitization. The triptans also cause vasoconstriction, opposing the vasodilation thought to be involved in the pathophysiology of migraine attacks.

Triptans are currently first-line therapy for acute severe migraine attacks.

Due to their vasoconstrictive action they should not be used in patients at risk for coronary heart disease.

Note: Although the triptans are effective in ameliorating the acute symptoms of migraine, other classes of drugs are used for migraine prophylaxis. These include: β-adrenergic blockers, tricyclic antidepressants, valproic acid, topiramate, gabapentin, verapamil, ACE inhibitors, ARBs, and botulinum toxin.

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16
Q

Metoclopramide

A

5-HT4 RECEPTOR AGONISTS

Prokinetic agent. Its administration results in coordinated contractions that enhance transit. The mechanism of action of metoclopramide is as follows:

1. It facilitates acetylcholine release from enteric neurons; this cholinomimetic action may be mediated indirectly by several different mechanisms, including suppression of inhibitory interneurons by antagonism at 5-HT3 receptors and stimulation of excitatory neurons via activation of 5-HT4 receptors.

2. Metoclopramide has both central and peripheral antidopaminergic actions. The central antidopaminegic action is responsible for its antinauseant and antiemetic properties; the peripheral antidopaminergic action contributes to its prokinetic activity by counteracting the inhibitory effects of dopamine, mediated via dopamine D2 receptors on cholinergic enteric neurons.

ADVERSE EFFECTS

The most common side effects of metoclopramide are somnolence, nervousness and dystonic reactions. Extrapyramidal effects and tardive dyskinesia, although rare, may occur. Like domperidone, and other dopamine antagonists, metoclopramide can also cause galactorrhea, but this is infrequent.

17
Q

Cisapride

A

5-HT4 RECEPTOR AGONISTS

Cisapride activates 5-HT4 receptors. Until recently, it was one of the most commonly used prokinetic agents for a variety of disorders, particularly gastroesophageal reflux disease and gastroparesis. Cisapride was found to cause serious cardiac adverse effects; it was shown to extend the action potential and the QT interval; serious cardiac arrhythmias and deaths from ventricular tachycardia, ventricular fibrillation, torsades de pointes and QT prolongation were reported in patients taking cisapride, particularly when used with other drugs that inhibit CYP3A4. As a consequence, cisapride is no longer generally available in the US. The drug is available only on a limited basis.

18
Q

Cyproheptadine

A

5-HT2 RECEPTOR ANTAGONISTS

Resembles the phenothiazine antihistaminic agents in chemical structure and has potent H1 blocking actions. It prevents smooth muscle effects of both serotonin and histamine but has no effect on gastric secretion stimulated by histamine. It has significant antimuscarinic effects and causes sedation.

USES

Perennial and seasonal allergic rhinitis, vasomotor rhinitis, allergic conjunctivitis due to inhalant allergens and foods, cold urticaria, dermatographism. Treatment of smooth muscle manifestations of carcinoid tumor.

Cyproheptadine is used to treat serotonin syndrome. Serotonin syndrome is the result of overstimulation of 5-HT1A and 5-HT2 receptors and includes hyperthermia, muscle rigidity and myoclonus. It may be fatal.

19
Q

Ondansetron

A

5-HT3 RECEPTOR ANTAGONISTS

Used as anti-emetic drugs, particularly for controlling the severe nausea and vomiting that occurs with many forms of cancer chemotherapy.

Causes Torsades de pointes!

20
Q

The Ergot Alkaloids

A

Ergotamine, Dihydroergotamine, Bromocriptine, Cabergoline, Ergonovine, Methylergonovine

Produced by Claviceps purpurea, a fungus that infects grain.

MECHANISM OF ACTION

The ergot alkaloids act on several types of receptors. Their effects include agonist, partial agonist, and antagonist actions at α-adrenoceptors and 5-HT receptors; and agonist or partial agonist actions at CNS dopamine receptors.

Furthemore, some members of the ergot family have a high affinity for presynaptic receptors, whereas others are more selective for postsynaptic receptors.

CLINICAL PHARMACOLOGY

Migraine

Ergot derivatives are highly specific for migraine pain; they are not analgesic for any other condition. The triptan drugs are preferred by most clinicians, but traditional therapy with ergotamine can be quite effective when given during the prodrome of an attack. Ergotamine is available for oral, sublingual, rectal suppository and inhaler use.

Hyperprolactinemia

Bromocriptine and cabergoline are effective in reducing the high levels of prolactin that result from pituitary tumors.

Postpartum Hemorrhage

Oxytocin is the preferred agent for control of postpartum hemorrhage, but if this agent is ineffective, ergonovine or methylergonovine IM can be tried.

Diagnosis Of Variant Angina

Ergonovine is used as a diagnostic agent to provoke coronary artery spasm. A small dose of ergonovine IV given to patients with variant angina usually produces focal spasm caused by segmental abnormalities of the coronary artery.

21
Q

Eicosanoids

A

Principal eicosanoid subgroups are the prostaglandins, prostacyclins, thromboxanes and leukotrienes. Prostacyclin and thromboxane are often considered members of the prostaglandins since they are also cyclized derivatives.

Eicosanoids are not found preformed in tissues; they are generated de novo from phospholipids.

The main source of eicosanoids is arachidonic acid, a 20-carbon unsaturated fatty acid containing four double bonds. Arachidonic acid is found esterified in phospholipids, usually in the 2 position.

Hormones, autacoids, and other substances augment the synthesis of eicosanoids by interacting with (presumably) plasma-membrane receptors coupled to G proteins. This results in the direct activation of phospholipases or in elevated Ca2+ which can also activate these enzymes. Physical stimuli are believed to cause an influx of Ca2+ by perturbing the cell membrane, thereby activating phospholipase A2.

There are two major pathways in the synthesis of eicosanoids from arachidonic acid:

Cyclo-oxygenases: which initiate the biosynthesis of prostaglandins, prostacyclins and thromboxanes

Lipoxygenases: which initiate the synthesis of leukotrienes, and other compounds.

The anti-inflammatory action of the glucocorticoids is due largely to inhibition of induction of cyclooxygenase. These drugs may also stimulate production of the phospholipase A2 inhibitor, lipocortin.

The anti-inflammatory action of the non-steroidal anti-inflammatory drugs (NSAIDs) is due mainly to the fact that they inhibit the action of the fatty acid cyclo- oxygenases.

22
Q

The Cyclo-Oxygenase Pathway

A

Cyclo-oxygenase (COX) exists in 2 forms –COX-1 and COX-2.

COX-1 is found in most cells as a constitutive enzyme and it is thought that the prostaglandins it produces are involved in normal homeostasis (e.g. regulating vascular responses and coordinating the actions of circulating hormones).

COX-2 is found primarily in inflammatory cells. COX-2 is induced by inflammatory stimuli. COX-2 is prominently expressed by growth factors, tumor promoters, and cytokines. Lipopolysaccharide (endotoxin) is particularly potent in this respect. This has relevance for the mechanism of action of NSAIDs.

23
Q

The Lipoxygenase Pathway

A

The metabolism of arachidonic acid by lipoxygenases results in the production of leukotrienes and lipoxins. Leukotrienes produced by 5-lipoxygenase are present in inflammatory cells (PMNs, basophils, mast cells, eosinophils, macrophages). This pathway is associated with asthma, anaphylactic shock and cardiovascular disease. Stimulation of these cells elevates intracellular Ca2+ and releases arachidonate.

The leukotrienes LTC4 and LTD4 are potent bronchoconstrictors and are recognized as the primary components of the slow-reacting substance of anaphylaxis (SRS-A), that is secreted in asthma and anaphylaxis.

24
Q

Mechanism of Action of Eicosanoids

A

Eicosanoids act in autocrine and paracrine fashion.

Bind to receptors in cell surface. All the receptors are G protein-coupled.

Some eicosanoid receptors are coupled to activation of adenylyl cyclase; some are coupled to inhibition of adenylyl cyclase; some are coupled to activation of PLC.

The contractile effects of eicosanoids on smooth muscle are mediated by release of Ca2+, while their relaxing effects are mediated by elevations in cAMP.

25
Q

Dinoprostone, and Misoprostol

A

OBSTETRICS

Dinoprostone (PGE2), and misoprostol (a synthetic derivative of PGE1), can be used to ripen the cervix at or near term.

26
Q

Carboprost tromethamine, and Misoprostol

A

OBSTETRICS

Carboprost tromethamine (15-methyl-PGF2α), and misoprostol can be used for the management of postpartum hemorrhage.

27
Q

Dinoprostone and Carboprost Tromethamine

A

OBSTETRICS

Dinoprostone and carboprost tromethamine can be used as abortifacients in the second trimester of pregnancy.

28
Q

Misoprostol

A

OBSTETRICS

Misoprostol has been used in combination with the progesterone antagonist mifepristone or with methotrexate as an abortifacient combination.

29
Q

Alprostadil

A

PEDIATRICS

Alprostadil (PGE1) is given as an infusion to maintain patency of the ductus arteriosus in infants with transposition of the great vessels until surgical correction can be undertaken.

UROLOGY

Alprostadil (PGE1) is used in the treatment of impotence. Preparations are available for injection into the penis as well as for insertion into the urethra. Alprostadil has been superseded by the use of PDE5 inhibitors such as sildenafil.

30
Q

Epoprostenol

A

PULMONARY HYPERTENSION & DIALYSIS

Prostacyclin (PGI2) lowers peripheral, pulmonary and coronary resistance. A commercial preparation of PGI2 (epoprostenol) is approved for use in severe pulmonary hypertension and to prevent platelet aggregation in dialysis machines.

31
Q

Misoprostol

A

GASTRIC CYTOPROTECTION

Misoprostol is approved for prevention of peptic ulcers in patients who must take high doses of NSAIDs.

32
Q

Latanoprost

A

OPHTALMOLOGY

Latanoprost, a PGF2α derivative, is used for treatment of glaucoma. It increases the outflow of aqueous humour, thus reducing intraocular pressure.

33
Q

Leukotriene Pathway Inhibitors

Zileuton, Zafirlukast, Montelukast

A

Leukotriene B4 is a potent neutrophil chemoattractant, and LTC4 and LTD4 exert many effects known to occur in asthma, including bronchoconstriction, increased bronchial reactivity, mucosal edema, and mucus hypersecretion. Antigen challenge of sensitized human lung tissue results in the generation of leukotrienes.

Two approaches to interrupting the leukotriene pathway have been pursued:

Inhibition of 5-lypoxygenase, thereby preventing leukotriene synthesis (zileuton)

Inhibition of the binding of LTD4 to its receptor in target tissues, thereby preventing its action (zafirlukast, montelukast).

These drugs are used in the treatment of moderate to severe asthma in patients who are poorly controlled by conventional therapy or experience adverse effects with corticoids.

34
Q

Glucocorticoids

A

Glucocorticoids inhibit cytosolic phospholipase A2, thus blocking the release of arachidonic acid from phospholipids, and its subsequent conversion to eicosanoids.

Glucocorticoids inhibit the synthesis of COX-2.

These actions are thought to be the major mechanisms of the important anti- inflammatory action of corticosteroids.

35
Q

NSAIDs

A

The NSAIDs are a group of agents with antipyretic, analgesic and anti- inflammatory activities.

They act primarily by inhibiting the cyclooxygenase enzymes.