Action of neuroleptics on different types of neurotransmitter receptor relevance to side effects

In recent years traditional neuroleptics, as exemplified by chlorpromazine, have been structurally modified to produce drugs with greater affinity for dopamine receptors while retaining some of their activity on other receptor systems (e.g. on alphaj adrenoceptors, 5-HT2 receptors and histamine! receptors). In the non-phenothiazine series, a high degree of specificity for the D2 receptors has been achieved with sulpiride and pimozide, with haloperidol showing antagonistic effects on the 5-HT2 and alpha1 adrenoceptors in addition to its selectivity for D2 receptors. The cis-(Z) isomers of the thioxanthines are potent neuroleptics that, in addition to their selectivity for D2 receptors, also show antagonistic effects on D1, 5-HT2 and alpha! adrenergic receptors; cis(Z)-flupenthixol has a greater effect on Dj receptors than cis-(Z)-clopenthixol. It should be emphasised that the effect of such drugs on 5-HT2 receptors is weak.

In the phenothiazine series of neuroleptics, thioridazine has less antimuscarinic potency than chlorpromazine, but appears to be equally active as an antagonist of 5-HT2 and D2 receptors; like chlorpromazine, however, it is a potent alpha1 adrenoceptor antagonist. In contrast, the potent phenothiazine neuroleptic perphenazine is only slightly less selective in blocking D2 receptors than haloperidol but, unlike the latter, has a greater antagonistic effect on histamine receptors.

With the typical neuroleptics in wide clinical use (e.g. chlorpromazine, thioridazine, haloperidol, pimozide, flupenthixol and clopenthixol), there would appear to be a correlation between their D2 antagonistic potency and their clinical potency; presumably the ability of these drugs to block 5-HT2 receptors to varying extents is also evidence that the serotonergic system is involved in their clinical activity in some way.

The actions of neuroleptics on histamine, muscarinic and alpha1 adrenergic receptors explain the side effects of these drugs, i.e. sedation, anticholinergic effects and hypotensive effects, respectively, which are generally considered to be undesirable and can lead to poor patient compliance. Table 11.9 summarises the main side effects of the typical neuroleptics.

Table 11.9. Main side effects of typical neuroleptics

Side effect

Possible cause

Parkinsonism, dystonias, akathisia

Hypotension

Sedation

Tachycardia and other anticholinergic effects Seizures

Agranulocytosis, skin rashes Skin pigmentation Jaundice

Cardiac conduction defects

Dopamine blockade of basal ganglia

All potent typical neuroleptics Due to a1 receptor blockade All less potent neuroleptics Due to histamine1 blockade All less potent neuroleptics Due to muscarinic receptor blockade

All less potent neuroleptics ?Due to muscarinic receptor blockade

Most neuroleptics Allergic reactions

Many neuroleptics; clozapine Dopamine-melanin conversion

All less potent neuroleptics Bile duct obstruction?

Chlorpromazine Muscarinic blockade, Na+ channel blockade Thioridazine, chlorpromazine, sertindole?

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