5HT Antagonists

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Chapter: Essential pharmacology : 5Hydroxytryptamine, Its Antagonists And Drug Therapy Of Migraine

The ability to antagonize at least some actions of 5HT is found in many classes of drugs, e.g. ergot derivatives (ergotamine, LSD, 2bromo LSD, methysergide), adrenergic α blockers (phenoxybenzamine), antihistaminics (cyproheptadine, cinnarizine), chlorpromazine, morphine, etc.,


5HT ANTAGONISTS

 

The ability to antagonize at least some actions of 5HT is found in many classes of drugs, e.g. ergot derivatives (ergotamine, LSD, 2bromo LSD, methysergide), adrenergic α blockers (phenoxybenzamine), antihistaminics (cyproheptadine, cinnarizine), chlorpromazine, morphine, etc., but these are nonselective and interact with several other receptors as well. Many are partial agonists or antagonize certain actions of 5HT but mimic others. The salient features of drugs which have been used clinically as 5HT antagonists and some newly developed selective antagonists are described below:

 

1.    Cyproheptadine

 

It primarily blocks 5HT2A receptors and has additional H1 antihistaminic, anticholinergic and sedative properties. Like other antihistaminics, it has been used in allergies and is a good antipruritic, but the anti 5HT action has no role in these conditions. It increases appetite and has been recommended in children and poor eaters to promote weight gain. An action on growth hormone secretion has been suggested to account for this.

 

The anti 5HT activity of cyproheptadine has been utilized in controlling intestinal manifestations of carcinoid and postgastrectomy dumping syndromes as well as in antagonizing priapism/orgasmic delay caused by 5HT uptake inhibitors like fluoxetine and trazodone.

 

Side effects drowsiness, dry mouth, confusion, ataxia, weight gain.

 

2.    Methysergide

 

It is chemically related to ergot alkaloids; antagonizes action of 5HT on smooth muscles including that of blood vessels, without producing other ergot like effects: does not interact with α adrenergic or dopamine receptors. Methysergide is a potent 5HT2A/2C antagonist with some tissue specific agonistic actions as well; but is nonselective—acts on 5HT1 receptors also. It has been used for migraine prophylaxis, carcinoid and postgastrectomy dumping syndrome. Prolonged use has caused abdominal, pulmonary and endocardial fibrosis, because of which it has gone into disrepute.

 

3.   Ketanserin

 

It has selective 5HT2 receptor blocking property with negligible action on 5HT1, 5HT3 and 5 HT4 receptors and no partial agonistic activity. Among 5HT2 receptors, blockade of 5HT2A is stronger than 5HT2C blockade. 5HT induced vasoconstriction, platelet aggregation and contraction of airway smooth muscle are antagonized but not contraction of guinea pig ileum or rat stomaArticle No. It has additional weak α1, H1 and dopaminergic blocking activities.

 

Ketanserin is an effective antihypertensive, but α1 adrenergic blockade appears to be causative rather than 5HT2A blockade.

 

Trials of Ketanserin in vasospastic conditions have shown symptomatic improvement only in Raynaud’s disease.

 

Ritanserin is a relatively more 5HT2A selective congener of ketanserin.

 

4.   Clozapine

 

In addition to being a dopaminergic antagonist (weaker than the typical neuroleptics), this atypical antipsychotic is a 5HT2A/2C blocker. Clozapine may also exert inverse agonist activity at cerebral 5HT2A/2C receptors which may account for its efficacy in resistant cases of schizophrenia.

 

5.   Risperidone

 

This atypical antipsychotic is a combined 5HT2A + dopamine D2 antagonist, similar to clozapine. Like the latter, it especially ameliorates negative symptoms of schizophrenia, but produces extrapyramidal side effects at only slightly higher doses.

 

Other atypical antipsychotics like olanzapine and quetiapine are also combined 5HT and DA antagonists, but interact with other neurotransmitter receptors as well.

 

6.   Ondansetron

 

It is the prototype of the new class of selective 5HT3 antagonists that have shown remarkable efficacy in controlling nausea and vomiting following administration of highly emetic anticancer drugs and radiotherapy.

 

Granisetron and Tropisetron are the other selective 5HT3 antagonists.

 

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