PHARMACODYNAMICS AND PHARMACOKINETICS OF CLOZAPINE(4)

Another group of receptors of significant clinical importance is the muscarinic cholinergic receptors. From a therapeutical perspective, it is well established that there is an inverse relationship between cholinergic receptor affinity and the incidence of EPS . Under normal circumstances, dopamine binding to postsynaptic cholinergic neurons in the ni-grostriatal pathway blocks acetylcholine release. When nigrostriatal D2 receptors are antagonized, the resultant cholinergic overactivity increases the risk of ensuing EPS . Furthermore, muscarinic cholinergic activity may be involved in the pathophysiology of schizophrenia. There is evidence that muscarinic cholinergic modulation effects positive and negative symptoms. Neuroendocrine and polysomnographic data also suggest that there is increased muscarinic cholinergic activity in schizophrenia . It has been suggested that cholinergic blockade is responsible for the atypical actions of clozapine . In light of this information it may be desirable for an antipsychotic combination to have cholinergic receptor blockade activity. Clinicians should remain cognizant of possible side effects such as memory dysfunction, dry mouth and constipation, endeavoring to minimize them while taking advantage of the therapeutic effects of cholinergic blockade. buy ortho tri-cyclen online

The third consideration of combination antipsychotic therapy is that of drug-drug interactions, particularly those that interfere with cytochrome P450 metabolism. Altering the pharmacokinetic characteristics of an antipsychotic with another antipsychotic may result in extreme effects on both antipsychotic action and side effects. Clozapine is metabolized to clozapine N-oxide and N-demethyclozapine via cytochromes P450 3A4 and 1A2 . Neither metabolite has shown more potent receptor affinity than clozapine at any receptor site. Clozapine may have an effect on cytochrome P4501A2,2B1,2C9,2C19 and 3A, although there is conflict in the literature regarding this matter . As a consequence of clozapine’s pharmacokinetic profile, a desirable augmenting agent should not greatly affect cytochrome P450 3A4 or 1A2.