Serotonin Phase II Spring 2014

Serotonin Serotonin (5-hydroxytryptamine, 5-HT) An important neurotransmitter, a local hormone in the gut, a component of the platelet clotting process, is thought to play a role in migraine headache one of the mediators of the signs and symptoms of carcinoid syndrome, (an unusual manifestation of carcinoid tumor, a neoplasm of enterochromaffin cells.)

Serotonin formed in biologic systems from the amino acid L-tryptophan After synthesis, the free amine is stored or is rapidly inactivated by oxidation catalyzed by the enzyme monoamine oxidase (MAO). In the pineal gland, serotonin serves as a precursor of melatonin, a melanocyte-stimulating hormone. In mammals (including humans), over 90% of the serotonin in the body is found in enterochromaffin cells in the gastrointestinal tract.

Serotonin Cont. In the blood, serotonin is found in platelets, which are able to concentrate the amine by means of an active serotonin transporter mechanism (SERT) similar to that in the membrane of serotonergic nerve endings. Once transported into the platelet or nerve ending, 5-HT is concentrated in vesicles by a vesicle-associated transporter (VAT) that is blocked by reserpine.

Serotonin Cont. involved in clinical conditions such as depression, anxiety, and migraine. Serotonergic neurons are also found in the enteric nervous system of the gastrointestinal tract and around blood vessels. In rodents (but not in humans), serotonin is found in mast cells.

Serotonin Cont. Serotonin is also found in the raphe nuclei of the brainstem, which contain cell bodies of serotonergic neurons that synthesize, store, and release serotonin as a transmitter. Brain serotonergic neurons are involved in numerous diffuse functions such as mood, sleep, appetite, and temperature regulation, as well as the perception of pain, the regulation of blood pressure, and vomiting.

Serotonin Serotonin receptor subtypes. 5-HT1A 5-HT1B 5-HT1Da,b 5-HT1E 5-HT1F  5-HT2A 5-HT2B 5-HT2C 5-HT3 5-HT4 5-HT5A 5-HT5B 5-HT6 5-HT7

CLINICAL PHARMACOLOGY OF SEROTONIN 1. Serotonin Agonists 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 wide attention for its usefulness as an effective nonbenzodiazepine anxiolytic. Dexfenfluramine, another selective 5-HT agonist, was widely used as an appetite suppressant but was withdrawn because of toxicity. Appetite suppression appears to be associated with agonist action at 5-HT2C receptors in the central nervous system. Sumatriptan (5-HT1D/1B agonist) and other triptans are agonists effective in the treatment of acute migraine and cluster headache attacks.

Serotonin Agonists Cisapride, a 5-HT4 agonist, was used in the treatment of gastroesophageal reflux and motility disorders. Because of toxicity, it is now available only for compassionate use in the USA. Tegaserod, a newer 5-HT4 partial agonist, is used for irritable bowel syndrome with constipation.

Serotonin SEROTONIN-RECEPTOR ANTAGONISTS A wide variety of drugs with actions at other receptors (a adrenoceptors, H1-histamine receptors, etc) are also serotonin receptor-blocking agents. Phenoxybenzamine has a long-lasting blocking action at 5-HT2 receptors. The ergot alkaloids are partial agonists at serotonin receptors. Cyproheptadine has potent H1-receptor-blocking as well as 5-HT2-blocking actions. The major clinical applications of cyproheptadine are in the treatment of carcinoid tumor and in cold-induced urticaria.

Serotonin Ketanserin blocks 5-HT1c and 5-HT2 receptors. However, this drug potently blocks vascular alpha-1 adrenoceptors. The drug blocks 5-HT2 receptors on platelets and antagonizes platelet aggregation promoted by serotonin. The mechanism involved in ketanserin's hypotensive action is not clear but probably involves alpha-1 adrenoceptors more than 5-HT2 receptor blockade. Ketanserin is available in Europe for the treatment of hypertension and vasospastic conditions but has not been approved in the USA.

Serotonin Ritanserin, another 5-HT2 antagonist, has little or no alpha-blocking action. It has been reported to alter bleeding time and to reduce thromboxane formation, presumably by altering platelet function. 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.

THE ERGOT ALKALOIDS THE ERGOT ALKALOIDS Ergot alkaloids are produced by Claviceps purpurea, a fungus that infects grain under damp growing or storage conditions. This fungus synthesizes histamine, acetylcholine, tyramine, and other biologically active products in addition to a score or more of unique ergot alkaloids. These alkaloids affect a adrenoceptors, dopamine receptors, 5-HT receptors, and perhaps other receptor types. Similar alkaloids are produced by fungi parasitic to a number of other grass-like plants.

THE ERGOT ALKALOIDS THE ERGOT ALKALOIDS (cont.) The accidental ingestion of ergot alkaloids in contaminated grain can be traced back more than 2000 years from descriptions of epidemics of ergot poisoning (ergotism). The most dramatic effects of poisoning are dementia with florid hallucinations; prolonged vasospasm, which may result in gangrene; and stimulation of uterine smooth muscle, which in pregnancy may result in abortion. Detailed structure-activity analysis and appropriate semisynthetic modifications have yielded a large number of agents with documented or potential clinical value.

THE ERGOT ALKALOIDS MECHANISM OF ACTION the ergot alkaloids act on several types of receptors. Their effects include agonist, partial agonist, and antagonist actions at alpha-adrenoceptors and serotonin receptors (especially 5-HT1A and 5-HT1D; less for 5-HT1C, 5-HT2, and 5-HT3); agonist or partial agonist actions at central nervous system dopamine receptors.

THE ERGOT ALKALOIDS Clinical Pharmacology of Ergot Alkaloids MIGRAINE Ergot derivatives are highly specific for migraine pain; ergotamine is effective when given during the acute migraine attack; it becomes progressively less effective if delayed. 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. For very severe attacks, ergotamine tartrate, 0.25-0.5 mg, may be given intravenously or intramuscularly.

THE ERGOT ALKALOIDS Clinical Pharmacology of Ergot Alkaloids MIGRAINE(cont) Dihydroergotamine, 0.5-1 mg intravenously, is favored by some clinicians for treatment of persistant (difficult to manage) migraine. Intranasal dihydroergotamine may also be effective. Methysergide a derivative of ergotamine may be used in the migraine prophylaxis

THE ERGOT ALKALOIDS 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. Therefore, ergot derivatives should be used only for control of late uterine bleeding and should never be given before delivery. Oxytocin is the preferred agent for control of postpartum hemorrhage, but if this peptide agent is ineffective, ergonovine maleate, 0.2 mg usually given intramuscularly, can be tried. It is usually effective within 1-5 minutes and is less toxic than other ergot derivatives for this application. It is given at the time of delivery of the placenta or immediately afterward if bleeding is significant.

THE ERGOT ALKALOIDS HYPERPROLACTINEMIA Increased serum levels of the anterior pituitary hormone prolactin are associated with secreting tumors of the gland and also with the use of centrally acting dopamine antagonists, especially the D2-blocking antipsychotic drugs. Because of negative feedback effects, hyperprolactinemia is associated with amenorrhea and infertility in women as well as galactorrhea in both sexes. 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.