Inhibition of different types of serotonin receptors by antagonists has therapeutic applications.
5 HT2 antagonists: antipsychotics
5-HT2A and 5-HT2C receptor antagonists which cross the blood-brain barrier have antipsychotic properties and are called atypical neuroleptic or atypical antipsychotic agents. In addition to their 5HT2A antagonist effect, they inhibit dopaminergic receptors.
Atypical neuroleptic agents with 5-HT2A antagonist effect improve the productive and negative symptoms of psychosis probably better than classical neuroleptic agents but these latter were often prescribed in too large doses.
Clozapine is the reference drug of atypical antipsychotics. In addition to its 5-HT2 antagonist effect, clozapine has several effects: antidopaminergic, antimuscarinic, antihistaminic and alpha-blocking. Its use is limited because it causes in about 1% of treated patients an agranulocytosis. It can moreover induce myocarditis.
Loxapine, 5-HT2 antagonist and D1, D2 and D3 dopaminergic antagonist, is also generally classified among atypical neuroleptic agents.
Olanzapine, has a chemical structure which presents an analogy with that of clozapine, and is an atypical antipsychotic with antiserotonin 5-HT2A, D2 and D1antidopamine, H1 antihistamine and antimuscarinic properties. It often induces weight gain.
Risperidone is a 5-HT2A and a D2 dopamine receptor antagonist classified among atypical antipsychotics, acting particularly on the negative symptoms of schizophrenia and inducing few extrapyramidal side effects. Concerning its pharmacokinetics, risperidone is converted into 9-OH risperidone, active metabolite.
Ziprasidone, 5-HT2 receptors antagonist, and to a lesser extent, D2 dopamine receptors antagonist , is an atypical antipsychotic but it could lengthen the QT interval, particularly in case of pharmacokinetic interactions with other drugs.
Ritanserin is a 5-HT2 antagonist without antidopaminergic effect, which was tested as antipsychotic but was not marketed.
Ketanserin, is a 5-HT2 antagonist with a preferential peripheral action. It has also an alpha-1-adrenergic-blocking action. By these two mechanisms of action and perhaps others not well characterized, it induces a decrease of arterial pressure. It reduces the severity of certain symptoms of the carcinoid syndrome
Amoxapine is an antidepressant, inhibitor of serotonin and noradrenaline reuptake, which has moreover 5-HT2 antagonist and H1 antihistamine effects.
5-HT3 antagonists: antiemetic agents (-setrons)
The principal effect of 5-HT3 receptor antagonists is to inhibit vomiting induced by antineoplastic drugs, such as cisplatin and doxorubicin, which are cytotoxic and release serotonin from the digestive tract. Serotonin released stimulates 5-HT3 receptors localized on vagal terminations in the digestive tract leading to ascending impulses and on Area postrema, both stimulations leadind to hyperemesis. The specific antagonists of 5-HT3 receptors inhibit vomiting and are classified among antiemetic agents.
Drugs used are ondansetron, granisetron, tropisetron and dolasetron. These drugs are generally administered in slow intravenous injection (duration from 15 to 30 minutes) before the beginning of the emetic chemotherapy administered in intravenous infusion. Their oral presentation has the same therapeutic uses but is intended for the treatment of nausea and vomiting of moderate intensity. Studies of other antagonists such as zacopride are ongoing.
Efficacy of 5-HT3 antagonists is better than that of metoclopramide which is a dopaminergic antagonist with a low 5-HT3 antagonist effect.
Their adverse effects are: headache, asthenia, drowsiness, arterial hypertension or hypotension, bradycardia, hiccup, constipation.
Nonspecific antagonists: antimigraine agents
Several drugs, methysergide, cyproheptadine, pizotifen and oxetorone having antagonist properties of serotonin receptors have been used for several years in the preventive treatment of migraine. They inhibit various types of serotonin receptors, in particular 5-HT2, and are generally antihistamines and sedatives.
Methysergide, a semisynthetic ergot alkaloid, because of its adverse effects, particularly vasoconstriction and retroperitoneal fibrosis with possible obstruction of urinary route, is reserved for preventive treatment of migraine resistant to the other drugs for a course not exceeding 3 or 6 months.
Cyproheptadine has 5-HT antagonist and H1 antihistamine effects. It is used in the treatment of allergic disorders and in the management of migraine. It has been used as an appetite stimulant. It has atropinic effets and the counter-indications which result from this effect
Pizotifen and oxetorone are serotonin antagonists and sedating antihistamines used in the prophylaxis of migraine.