Classification of the typical neuroleptics

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In addition to their well-established antipsychotic properties, the neuro-leptics have a number of clinically important properties that include their antiemetic and antinauseant actions, their antihistaminic effects and their ability to potentiate the actions of analgesics and general anaesthetics.

Reserpine is unique among the neuroleptics in that it is a naturally occurring alkaloid obtained from the snake plant Rauwolfia serpentina. The use of aqueous extracts of the root of this plant for the treatment of ''hysteria'' was known to the native practitioners in the Indian subcontinent for centuries before the main active principal, reserpine, was isolated in the early 1950s. The marked antihypertensive effect of the drug, combined with its tranquillizing activity, led to its use in the treatment of schizophrenia. However, as has already been discussed in an earlier chapter, reserpine depletes all transmitters that are contained in storage vesicles in nerve terminals by selectively blocking their uptake by the magnesium-dependent adenosine triphosphatase (ATPase) linked transport site on the vesicle membrane. This renders the transmitter susceptible to intraneuronal catabolism. However, the side effects of long-term reserpine administration in schizophrenic patients were so numerous that its use has been largely discontinued. These side effects, which can be predicted from the action of reserpine on the storage vesicles for noradrenaline, 5-HT, dopamine and acetylcholine, include sedation, Parkinsonism, predisposition to seizures, hypotension and a general impairment of peripheral sympathetic activity associated with parasympathetic hyperactivity (e.g. nausea, diarrhoea, gastric hypersecretion with susceptibility to gastric ulceration, bradycardia and hypersalivation).

Of the phenothiazines, chlorpromazine was the first drug to be introduced for the treatment of schizophrenia and is still the most widely used worldwide. All phenothiazines have antihistaminic, anticholinergic, anti-dopaminergic and adrenolytic properties, the potencies of the drugs for these different types of receptors depending upon the structure of the side chain which is attached to the tricyclic ring system. In general terms, it appears that the substitution of a halogen atom in the tricyclic ring (position "R" in Figure 11.8) is essential for neuroleptic activity. Thus promazine, which lacks a halogen substituent, has weak neuroleptic properties but it is a potent antihistaminic and anticholinergic agent. The side chain (position "B" in Figure 11.8) is important for the neuroleptic potency and also the anticholinergic, antihistaminic and adrenolytic side effects. Of the three main chemical classes of phenothiazines in clinical use, the aliphatic type are the least potent neuroleptics but are the most sedative, with pronounced anticholinergic, antihistaminic and adrenolytic properties. These effects are related to the structure of aliphatic side chain. The piperidine type are slightly more potent as neuroleptics and also have anticholinergic and adrenolytic side effects. The most potent, and least sedative, phenothiazines are in the piperazine group. This type of neuroleptic largely lacks anticholinergic, antihistaminic and adrenolytic activity.

The aliphatic phenothiazine chlorpromazine is the prototype neuroleptic with a wide range of pharmacological effects. Its antipsychotic and antiemetic properties are attributed to its antagonist action at central dopamine receptors in the mesocortical and vomiting centres, respectively, while the hypotensive action of chlorpromazine and related phenothiazines is associated with their alpha1 adrenoceptor antagonist properties combined with their ability to reduce hypothalamic and central vasomotor function. The depression of hypothalamic activity also accounts for the hypothermia which may occur at therapeutic doses, particularly in the elderly patient. The antimuscarinic and antihistaminic activity, which can be predicted from the structure of the aliphatic side chain, accounts for the sedative and peripheral anticholinergic effects of this group of drugs. The aliphatic phenothiazine triflupromazine is a more potent neuroleptic than chlorpromazine due to substitution of — CF3 for the — Cl group in the ring.

The piperidine phenothiazines, as exemplified by the most widely used member of this series thioridazine, are approximately equivalent to the aliphatic phenothiazines but tend to be more sedative. Members of this series are therefore widely used for the more agitated, anxious psychotic patient. As their ability to cause parkinsonism appears to be less than with the other phenothiazines, possibly because of their potent central antic-holinergic effects and slightly greater selectivity for mesocortical dopamine receptors, they are widely used to treat elderly psychotic patients.

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