Eicosanoids

Serotonin Agonists

Serotonin is an important neurotransmitter, a local hormone in the gut, a component of the platelet clotting process, and is thought to play a role in migraine headache and several other clinical conditions, including carcinoid syndrome.
Serotonin has no clinical applications as a drug. However, several receptor subtype-selective agonists have proved to be of value.
Buspirone, a 5-HT1A agonist, has received attention as an effective nonbenzodiazepine anxiolytic.
Appetite suppression appears to be associated with agonist action at 5-HT2C receptors in the central nervous system, and dexfenfluramine, a selective 5-HT agonist, was widely used as an appetite suppressant but was withdrawn because of cardiac valvulopathy. Lorcaserin, another 5-HT2C agonist, has recently been approved by the FDA for use as a weight-loss medication.
The 5-HT1D/1B agonists (triptans, eg, sumatriptan) are used almost exclusively for migraine headache. Most adverse effects are mild and include altered sensations (tingling, warmth, etc), dizziness, muscle weakness, neck pain, and for parenteral sumatriptan, injection site reactions. Chest discomfort occurs in 1–5% of patients, and chest pain has been reported, probably because of the ability of these drugs to cause coronary vasospasm. They are therefore contraindicated in patients with coronary artery disease and in patients with angina. Another disadvantage is the fact that their duration of effect (especially that of almotriptan, sumatriptan, rizatriptan, and zolmitriptan) is often shorter than the duration of the headache. As a result, several doses may be required during a prolonged migraine attack, but their adverse effects limit the maximum safe daily dosage. Naratriptan and eletriptan are contraindicated in patients with severe hepatic or renal impairment or peripheral vascular syndromes; frovatriptan in patients with peripheral vascular disease; and zolmitriptan in patients with Wolff-Parkinson-White syndrome.
Cisapride, a 5-HT4 agonist, was used in the treatment of gastro-esophageal reflux and motility disorders. Tegaserod, a 5-HT4 partial agonist, is used for irritable bowel syndrome with constipation
SEROTONIN-RECEPTOR ANTAGONISTS

A wide variety of drugs with actions at other receptors (eg, a adrenoceptors, H1-histamine receptors) also have serotonin receptor-blocking effects. Phenoxybenzamine has a long-lasting blocking action at 5-HT2 receptors. Cyproheptadine resembles the phenothiazine antihistaminic agents in chemical structure and has potent H1-receptorblocking as well as 5-HT2-blocking actions.
Ondansetron is the prototypical 5-HT3 antagonist. This drug and its analogs are very important in the prevention of nausea and vomiting associated with surgery and cancer chemotherapy

Ergot alkaloids

Mechanism of Action
The ergot alkaloids act on several types of receptors. Their effects include agonist, partial agonist, and antagonist actions at a adrenoceptors and serotonin receptors
(especially 5-HT1A and 5-HT1D; less for 5-HT2 and 5-HT3); and agonist or partial agonist actions at central nervous system dopamine receptors. Furthermore, some members of the ergot family have a high affinity for presynaptic receptors, whereas others are more selective for postjunctional receptors.

Clinical Uses

In spite of their significant toxicities, ergot alkaloids are still widely used in patients with migraine headache or pituitary dysfunction. They are used only occasionally in the postpartum patient.
Migraine Ergot derivatives are highly specific for migraine pain; they are not analgesic for any other condition. Ergotamine tartrate is available for oral, sublingual, rectal suppository, and inhaler use. It is often combined with caffeine (100 mg caffeine for each 1 mg ergotamine tartrate) to facilitate absorption of the ergot alkaloid. The vasoconstriction induced by ergotamine is long-lasting and cumulative when the drug is taken repeatedly, as in a severe migraine attack. Therefore, patients must be carefully informed that no more than 6 mg of the oral preparation may be taken for each attack and no more than 10 mg per week. Dihydroergotamine, 0.5–1 mg intravenously, is favored by some clinicians for treatment of intractable migraine.
Hyperprolactinemia: Bromocriptine is extremely effective in reducing the high levels of prolactin that result from pituitary tumors and has even been associated with regression of the tumor in some cases. Cabergoline is similar but more potent. Bromocriptine has also been used in the same dosage to suppress physiologic lactation.
Postpartum Hemorrhage: The uterus at term is extremely sensitive to the stimulant action of ergot, and even moderate doses produce a prolonged and powerful spasm of the muscle quite unlike natural labor. Therefore, ergot derivatives should be used only for control of postpartum uterine bleeding and should never be given before delivery. ergonovine maleate, 0.2 mg given intramuscularly, can be tried. It is usually effective within 1–5 minutes and is less toxic than other ergot derivatives for this application.
Toxicity & Contraindications
gastrointestinal disturbances, including diarrhea, nausea, and vomiting. Activation of the medullary vomiting center and of the gastrointestinal serotonin receptors is involved.
A more dangerous toxic effect—usually associated with overdosage—of agents like ergotamine and ergonovine is prolonged vasospasm. This sign of vascular smooth muscle stimulation may result in gangrene and may require amputation.
Bowel infarction has also been reported and may require resection. Vasospasm caused by ergot is refractory to most vasodilators, but infusion of large doses of nitroprusside or nitroglycerin has been successful in some cases.


The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds
The eicosanoids are oxygenation products of polyunsaturated long-chain fatty acids. They are ubiquitous in the animal kingdom and are also found—together with their precursors—in a variety of plants. They constitute a very large family of compounds that are highly potent and display an extraordinarily wide spectrum of biologic activity.

Products of Prostaglandin Endoperoxide Synthases (Cyclooxygenases)

Two unique COX isozymes convert AA into PGH2. PGH synthase-1 (COX-1) is expressed constitutively in most cells. In contrast, PGH synthase-2 (COX-2) is more readily inducible; its expression varies depending on the stimulus. COX-2 is an immediate early-response gene product that is markedly up-regulated by shear stress, growth factors, tumor promoters, and cytokines. The prostaglandins, thromboxane, and prostacyclin, collectively termed the prostanoids, are generated from PGH2 through the action of downstream isomerases and synthases. Several products of the arachidonate series are of current clinical importance.

Clinical Pharmacology Of Eicosanoids

Female Reproductive System
Dinoprostone (PGE2) and PGF2α are used in obstetrics to induce labor. For abortifacient purposes, the recommended dosage is a 20-mg dinoprostone vaginal suppository repeated at 3- to 5- hour intervals depending on the response of the uterus. The mean time to abortion is 17 hours, but in more than 25% of cases, the abortion is incomplete and requires additional intervention.
Antiprogestins (eg, mifepristone) have been combined with an oral oxytocic synthetic analog of PGE1 (misoprostol) to produce early abortion. The major toxicities are cramping pain and diarrhea. The oral and vaginal routes of administration are equally effective, but the vaginal route has been associated with an increased incidence of sepsis, so the oral route is now recommended.
An analog of PGF2α is also used in obstetrics, carboprost tromethamine is used to induce second-trimester abortions and to control postpartum hemorrhage that is not responding to conventional methods of management. Vomiting and diarrhea occur commonly, probably because of gastrointestinal smooth muscle stimulation. In some patients transient bronchoconstriction can occur. Transient elevations in temperature are also may occur.
Numerous studies have shown that PGE2, PGF2α, and their analogs effectively initiate and stimulate labor. For the induction of labor or softening of the cervix, dinoprostone is used either as a gel (0.5 mg PGE2 every 6 hours; maximum 24-hour cumulative dose of 1.5 mg) or as a controlled-release vaginal insert (10 mg PGE2) that releases PGE2 over 12 hours. An advantage of the controlled-release formulation is a lower incidence of gastrointestinal effects (< 1% versus 5.7%).
Male Reproductive System: Intracavernosal injection or transurethral suppository therapy with alprostadil (PGE1) is a second-line treatment for erectile dysfunction. Penile pain is a frequent side effect. Prolonged erection and priapism are side effects that occur in less than 4% of patients and are minimized by careful titration to the minimal effective dose. When given by injection, alprostadil may be used as monotherapy or in combination with either papaverine or phentolamine.
Cardiovascular System
Pulmonary Hypertension: PGI2 lowers peripheral, pulmonary, and coronary vascular resistance. It has been used to treat primary pulmonary hypertension as well as secondary pulmonary hypertension, which sometimes occurs after mitral valve surgery. In addition, prostacyclin has been used successfully to treat portopulmonary hypertension, which arises secondary to liver disease. The first commercial preparation of PGI2 (epoprostenol) approved for treatment of primary pulmonary hypertension improves symptoms, prolongs survival, and delays or prevents the need for lung or lung-heart transplantation. Side effects include flushing, headache, hypotension, nausea, and diarrhea. The extremely short plasma half-life (3–5 minutes) of epoprostenol necessitates continuous intravenous infusion through a central line for long-term treatment, which is its greatest limitation. Iloprost (half-life about 30 minutes) is usually inhaled six to nine times per day (2.5–5 mcg/dose). Treprostinil (half-life about 4 hours) may be delivered by subcutaneous or intravenous infusion or by inhalation.
Patent Ductus Arteriosus: Patency of the fetal ductus arteriosus depends on COX-2-derived PGE2 acting on the EP4 receptor. At birth, reduced PGE2 levels, a consequence of increased PGE2 metabolism, allow ductus arteriosus closure. In certain types of congenital heart disease (eg, transposition of the great arteries, pulmonary atresia, pulmonary artery stenosis), it is important to maintain the patency of the neonate’s ductus arteriosus until corrective surgery can be carried out. This can be achieved with alprostadil (PGE1). Adverse effects include apnea, bradycardia, hypotension, and hyperpyrexia. Because of rapid pulmonary clearance (the half-life is about 5–10 minutes in healthy adults and neonates), the drug must be continuously infused at an initial rate of 0.05–0.1 mcg/kg/min, which may be increased to 0.4 mcg/kg/min. Prolonged treatment has been associated with ductal fragility and rupture.
Respiratory System: PGE2 is a powerful bronchodilator when given in aerosol form. Unfortunately, it also promotes coughing, and an analog that possesses only the bronchodilator properties has been difficult to obtain. However, the cysteinyl leukotrienes—LTC4, LTD4, and LTE4—probably dominate during asthmatic constriction of the airways. leukotriene-receptor inhibitors (eg, zafirlukast, montelukast) are effective in asthma. A lipoxygenase inhibitor (zileuton) has also been used in asthma but is not as popular as the receptor inhibitors. It remains unclear whether leukotrienes are partially responsible for acute respiratory distress syndrome. Corticosteroids and cromolyn are also useful in asthma. Corticosteroids inhibit eicosanoid synthesis and thus limit the amounts of eicosanoid mediator available for release. Cromolyn appears to inhibit the release of eicosanoids and other mediators such as histamine and platelet-activating factor from mast cells.
Gastrointestinal System
The word “cytoprotection” was coined to signify the remarkable protective effect of the E prostaglandins against peptic ulcers in animals at doses that do not reduce acid secretion. Misoprostol is an orally active synthetic analog of PGE1. The drug is administered at a dosage of 200 mcg four times daily with food. This and other PGE analogs (eg, enprostil) are cytoprotective at low doses and inhibit gastric acid secretion at higher doses. Because it is also an abortifacient, misoprostol is a pregnancy category X drug. Misoprostol use is low, probably because of its adverse effects including abdominal discomfort and occasional diarrhea. Dose-dependent bone pain and hyperostosis have been described in patients with liver disease who were given long-term PGE treatment
Glaucoma
Latanoprost, a stable long-acting PGF2α derivative, was the first prostanoid used for glaucoma. The success of latanoprost has stimulated development of similar prostanoids with ocular hypotensive effects, and bimatoprost, and travoprost are now available. These drugs act at the FP receptor and are administered as drops into the conjunctival sac once or twice daily. Adverse effects include irreversible brown pigmentation of the iris and eyelashes, drying of the eyes, and conjunctivitis.