Extrapyramidal side-effects mechanisms

Because clozapine may block specific DA receptors, its antipsychotic activity could be consistent with an antidopaminergic mechanism of action. Conversely, clozapine does not typically induce extrapyramidal symptoms, which are presumably subserved by the A-9 system. Thus, while clozapine is known to block striatal DA receptors, in positron emission tomography (PET) studies, resolution is not sufficient to clarify effects on other tracts. Furthermore, low doses of metoclopramide, which significantly decrease the number of DA neurons spontaneously active in A-9, do not have antipsychotic effects (except at high doses) but can induce tardive dyskinesia (TD), as well as acute extrapyramidal side effects (EPS). 

SSRIs reduce dopamine cell firing in the substantia nigra through their effects on serotonin input to this nucleus. The net result is that they can cause generally mild extrapyramidal side effects (EPS) (500). The most common are restlessness and tremors. The same mechanism is probably responsible for their interaction with other agents that affect central motor systems. Thus, the SSRIs can potentiate the tremor seen with lithium, as well as EPS caused by antipsychotics, bupropion, and psychostimulants (376, 500). 

Attenuation of brain dopamine (DA) neurotransmission has been widely recognized as a useful mechanism for the treatment of the psychotic symptoms of schizophrenia.1-3 Antagonism of DA receptors is a major component of the mechanism of action of classical antipsychotic agents such as haloperidol and chlorpromazine as well as the newer atypical agents such as clozapine,4,5 risperidone,6 sertindole,7 and olanzapine.8 9 However a significant portion of schizophrenic patients do not respond to DA antagonist therapy and their use is often limited by a variety of severe side effects including extrapyramidal side effects (EPS) and tardive dyskinesia (TD).10-12 While atypical antipsy-... 

In a few cases, marked extrapyramidal side-effects (akathisia, dystonia, and parkinsonism) have been reported with flupbenazine, perphenazine, sulpiride, and thiothixene when fluoxetine is added to the regimen. The mechanism is speculated to be the result of fluoxetine-induced further suppression of dopaminergic activity in the nigrostriatal pathways (serotonergic stimulation leads to decreased dopamine release), in addition to increases in their plasma concentration. Fluoxetine has been shown to increase haloperidol serum levels by about 20%, presumably via inhibition of cytochrome P450 enzymes. Fluoxetine can increase the risk of seizure induction when added to clozapine due to an increase in clozapine serum levels, or by additive effects. Concomitant treatment with fluoxetine and risperidone is associated with a mean 4-fold increase in the plasma concentration of risperidone. ... 

A mutual increase in serum levels of both thioridazine and paroxetine is evident when these agents are combined. Paroxetine has also been shown to increase haloperidol and perphenazine serum levels, with associated extrapyramidal side-effects. The mechanism is presumably via inhibition of hepatic enzymes. With respect to the second-generation antipsychotic drugs (SCAs), paroxetine at a dose of 20 mg/daily produces a 3-9-fold elevation in plasma risperidone. If paroxetine is administered with clozapine, mean plasma concentrations of clozapine and norclozapine may increase significantly (by about 30%). 

Most antipsychotic drugs as well as tricyclic antidepressants (TCAs) are inhibitors of the chytochrome P450 liver catabolic enzymes, thus potentially increasing each other s serum levels. Chlorpromazine increases imipramine serum levels. Levomepromazine can cause a significant increase in clomipramine serum levels. Perphenazine has been reported to increase the serum levels of amitriptyline, desipramine, imipramine, and nortriptyline. Thioridazine has also been shown to increase TCA serum levels (mainly desipramine). Marked extrapyramidal side-effects have been reported in a few cases with fluphenazine or perphenazine when fluoxetine was added to the regimen. The mechanism is not known. A mutual increase in serum levels of both thioridazine and paroxetine is evident when these agents are... 

Ciozapine (Clozaril) Antipsychotic mechanism unclear. Blocks dopamine receptors as well as cholinergic, adrenergic, serotonergic histaminergic neurotransmission. Schizophrenia in those whom traditional antipsychotics have failed or have produced intolerable side effects. Very few extrapyramidal side effects. Potent antimuscarinic effects. Agranulocytosis in 2%. No tardive dyskinesia or increased prolactin release. 

Compounds 13-15 are tertiary aminoalcohol ethers, a type of structure typically associated with the early antihistamines such as diphenhydramine. It is known that one of the most prominent and annoying side effects of such drugs (dryness of the mouth) are effects associated with anticholinergic mechanisms. In fact, this property has led to its use in Parkinsonism and particularly for drug-induced extrapyramidal movement disorders. The o-methyl analog, orphenadrine, was introduced because of its lower antihistaminic activity and higher anticholinergic action. Because it also reduces spasticity in voluntary muscles it is marketed as a skeletal muscle relaxant as well (under a different trade name). 

The purported mechanism of antipsychotic action of the butyrophenones and diphenyl-butylamines is believed to be as that of the phenothiazines, namely, at least in part, antagonism at postsynaptic DA receptors. It is not surprising that the spectrum of side effects is also similar, with extrapyramidal dystonic reactions at the top of the list. 

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