Phenothiazines antiemetic activity

Replacement of the terminal nitrogen of the piperazine by carbon is said to enhance the antiemetic activity of the phenothiazines at the expense of the other pharmacologic effects. The simplest compound in this series, pipamazine (88), is prepared by alkylation of nipecotamide (87) with the chloropropyl phenothiazine (58). Preparation of the analogous sulfoxide begins with acetylation of the thiomethyl compound, 89 [prepared by a route... 

Vomiting is triggered in the chemoreceptor trigger zone of the medulla, and nearly all dopamine receptor agonists (e.g. bromocriptine), and agents that increase dopamine in the brain (e.g. levodopa), cause vomiting. Conversely, many dopamine receptor antagonists (e.g. metoclopramide, and phenothiazines, e.g. chlorpromazine and prochlorperazine) have antiemetic activity. 

Mechanism of Action A phenothiazine derivative that blocks dopamine at postsynap-tic receptor sites. Possesses strong extrapyramidal and antiemetic effects and weak anticholinergic and sedative effects. Therapeutic Effect Suppresses behavioral response in psychosis reduces locomotor activity and aggressiveness. Pharmacokinetics Readily absorbed following PO administration. Protein binding 90%-99%. Metabolized in liver. Excreted in urine. Half-life 24 hr. 

The pharmacology of all these neuroleptics is extremely complex. Briefly, phenoth-iazines and related drugs have a calming effect on psychotic patients, without producing excessive sedation. Other central effects include the important antiemetic effect in disease-, drug-, or radiation-induced nausea, but not so much in motion sickness. Butyrophenones are more effective antiemetics than phenothiazines and also potentiate the activity of anesthetics. 

Phenothiazines are antipsychotic agents that can be used for their potent antiemetic and sedative properties (see Chapter 29). The antiemetic properties of phenothiazines are mediated through inhibition of dopamine and muscarinic receptors. Sedative properties are due to their antihistamine activity. The agents most commonly used as antiemetics are prochlorperazine, promethazine, and thiethylperazine. 

A number of the antihistamines, particularly the phenothi-azines and aminoalkyl ethers, have antiemetic actions and thus may be u.seful in the treatment of nausea, vomiting, and motion sickness. Also, those agents that produce pronounced. sedation have application as nonpiescription sleeping aids." - "Several of the phenothiazines have limited u.se in Parkinson-like syndromes as a result of their ability to block central muscarinic receptors." -And. a number of antihistamines, including promethazine, pyrilamine. tri-pelennamine and diphenhydramine, display local anesthetic activity that may be therapeutically useful. ... 

In the phenothiazine area, it has been amply demonstrated that structural changes, in addition to producing expected quantitative changes in tranquilizing activity, also produce unexpected qualitative changes in biological activity. As a result antipruritic, antispasmodic, anticonvulsant, antibacterial, antiemetic, antimotion sickness, anthelmintic, and antidepressant compounds have been developed by molecular modification of the phenothiazines. 

Dystonia is characterized by an exaggerated posturing of the head, neck, or jaw by spastic contraction of the muscles of the lips, tongue, face, or throat, which makes drinking, eating, swallowing, and speech difficult by torticollis, retrocollis, opisthotonus, distress, and ultimately anoxia. Neuroleptic-induced dystonia, which may occur in children treated actively with phenothiazine derivatives for their antiemetic properties, disappears in sleep and is treated effectively with diphenhydramine hydrochloride (Benadryl), which possesses both anticholinergic and antihistaminic properties. 

Phenothiazines (Prototype Promethazine) Most drngs of this class are Hj antagonists and also possess considerable anticholinergic activity. Promethazine, which has prominent sedative effects, and its many congeners are nsed primarily for their antiemetic effects. 

Phenothiazines such as prochlorperazine, thiethylperazine, and chlorpromazine see Chapter 18) are among the most commonly used antinauseants and antiemetics. Their principal mechanism of action is dopamine receptor antagonism at the CTZ. Compared to metoclopramide or ondansetron see above), these drugs do not appear to be as uniformly effective in cancer chemotherapy-induced emesis. On the other hand, they also possess antihistaminic and anticholinergic activities, which are of value in other forms of nausea, such as motion sickness. 

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