PHARMACOLOGICAL AGENTS AFFECTING EMESIS - A REVIEW .1.

The availability of radiolabelled ligands selective for various putati ve neurotransmitter receptor sites and the development of quantitative autoradiography has led to a greater understanding of the neuronal pa thway and receptor subtypes involved in the vomiting reflex induced by various mechanisms both within the central nervous system and the per iphery. Receptors for acetylcholine, dopamine, histamine and serotonin have been detected in a number of brain regions associated with the v omiting reflex, and provide a rational basis for the antiemetic action of drugs that inhibit receptor subtypes for these neurotransmitters. The basis of the antiemetic action of other drugs such as dexamethason e and the cannabinoids is still obscure. Some drugs act on more than 1 receptor subtype. Metoclopramide may inhibits both dopamine D2- and 5 -HT3 receptors in producing its antiemetic effect. Both metoclopramide and domperidone appear to have additional peripheral actions that con tribute to their effectiveness. The cannabinoids are effective in cyto toxic-induced vomiting, perhaps acting via endorphin receptors or by i nhibiting prostaglandin synthesis. The effectiveness of 5-HT3 receptor antagonists may depend on the block of both central and peripheral ne uronal 5-HT3 receptors.Vomiting constitutes a major disadvantage to th e use of many drugs; vomiting induced by aminoglycoside antibiotics ap pears to be due to ototoxicity and is relieved by histamine H-1-recept or antagonists. The protracted vomiting associated with the use of som e cytotoxics in cancer chemotherapy may involve psychic components, th e chemoreceptor trigger zone and peripheral sensory neurons. Both 5-HT 3 and dopamine D2-receptor antagonists exert some control, the former being more effective with cytotoxics of high emetogenic potential, suc h as cisplatin. Serotonin 5-HT3 receptor antagonists or high doses of metoclopramide in combination with anxiolytics and steroids as well as greater attention to pharmacokinetic profiles of the drugs involved w ould appear to offer improved control. The use of dopamine receptor an tagonists in controlling emesis induced by dopamine agonists used in P arkinson's disease poses theoretical problems which can be overcome by using drugs with selectivity for the chemoreceptor trigger zone, such as domperidone or metoclopramide. However, higher doses of these drug s may produce some impairment of therapeutic responses to the agonists . Muscarinic and nicotinic agonists currently under investigation in A lzheimer's disease pose another therapeutic dilemma as emesis is due t o a central action of these compounds. Several sites may be involved i ncluding the chemoreceptor trigger zone and frontal lobes. Opiates may act through dopamine receptors or mu-receptors on dopaminergic nerves , but serotonergic mechanisms may also be involved in the action of so me opiates. Part II of this article discusses treatment of migraine, m orning sickness, motion sickness, postoperative vomiting, radiation-in duced emesis and nausea from labyrinthine disorders.