Archive for the ‘Antipsychotic’ Category


Although haloperidol has been chosen as an example of a rational approach to antipsychotic augmentation of clozapine, it would be remiss to suggest that it is the only suitable agent. Although haloperidol certainly fits the desired pharmacodynamic and pharmacokinetic profile for combination with clozapine, it was selected over other possible candidates due to the relative abundance of reliable biochemical information. For example, trifluoperazine has a pharmacodynamic profile similar to that of haloperidol with the exceptions that trifluoperazine shows significant 5-HT2A affinity and much less alphaj-adrenergic affinity . Both of these differences are advantageous from a side effect perspective. Furthermore, because trifluoperazine is a less potent neuroleptic than haloperidol, a more precise low dose titration may be facilitated. Unfortunately, the literature pertaining to the pharmacokinetics of trifluoperazine is limited, especially in the field of metabolism, precluding a discussion of clozapine augmentation with trifluoperazine in the present report. buy asthma inhaler

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AUGMENTATION OF CLOZAPINE WITH HALOPERIDOL(2)

Alpha1-adrenergic receptor blockade resulting from low dose haloperidol is low relative to that of clozapine.

Haloperidol is also an appropriate choice for clozapine augmentation from a pharmacokinetic standpoint. The predominant cytochrome P450 isoform involved in the metabolism of haloperidol to 1,2,3,6-tetrahydropyridine is cytochrome P450 3A4. 1,2,3,6-tetrahydropyridine is further metabolized to haloperidol pyridium by both cytochrome P450 3A4 and cytochrome P450 2D6 . Neither of these haloperidol metabolites shows more potent pharmacodynamic effects at any receptor site than haloperidol. Furthermore, haloperidol influences cytochrome P450 2D6 in a complex fashion that involves both stimulatory and inhibitory effects . However, because clozapine is not metabolized by cytochrome P450 2D6, its metabolism should be unaffected by the presence of haloperidol. It has been suggested that clozapine noncompetitively inhibits cytochrome P450 3A and that clozapine elevates cytochrome P450 3A . Neither claim seems to have corroborating evidence in the literature. Although the effect of clozapine on haloperidol metabolism is uncertain, low dose haloperidol titration should limit potential problems. buy asthma inhalers

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Haloperidol fulfills the desired pharmacodynamic criteria for clozapine augmentation. Its affinity for the D2 receptor is approximately 83 times greater than that of clozapine, while its affinity for the 5-HT2A receptor is less than 5% of that of clozapine and its affinity for the muscarinic and histaminic receptors is less than 1% of that of clozapine . These circumstances are extremely beneficial; low doses of haloperidol may be added to therapeutic doses of clozapine to bolster D2 blockade without exacerbating side effects resulting from his-taminic and cholinergic receptor blockade. At the same time, the benefit of clozapine’s affinity for the 5-HT2a and cholinergic receptors on minimizing the incidence of EPS associated with high D2 blockade is conceivably maintained. Haloperi-dol’s affinity for the alpha1-adrenergic receptor is less than that of clozapine; thus, augmentation with low dose haloperi-dol should not further enhance the alpha1-adrenergic blockade resulting from clozapine. buy flovent inhaler

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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

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Complementary effects of combination therapy are also important at other receptor sites. For example, it is possible that clozapine’s antiadrenergic actions may contribute to its atypical properties . This hypothesis is supported by elec-trophysiological studies showing that alpha1-blockade antagonizes an excitatory noradrenergic input on mesolimbic dopaminergic neurons, thereby reducing excessive dopaminergic firing . However, definitive evidence supporting this theory is lacking . Apart from possible therapeutic effects, alpha1-receptor blockade is associated with side effects such as dizziness, tachycardia and postural hypotension. However, with the consideration that schizophrenia is an etiologically diverse syndrome and that the proposed polypharmacy strategy is meant to augment the treatment of patients who are partially responsive by using a multireceptor binding agent, some alpha1-blockade may be warranted. buy ortho tri-cyclen

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PHARMACODYNAMICS AND PHARMACOKINETICS OF CLOZAPINE(2)

Historically, in vitro binding affinities of antipsychotics to D2 receptors have been used to predict efficacy, dose and possible side effects such as extrapyramidal symptoms (EPS) and endocrine disturbances . Positron emission tomography studies support this premise, indicating neuroleptic therapeutic efficacy and an increased risk of EPS at approximately 70% and 80% D2 receptor blockade, respectively . It has been speculated that the binding of 5-HT2A receptors may reduce the incidence of EPS by antagonizing the inhibitory control of serotonin on the dopaminergic system in the nigrostriatal pathway . The 5-HT2A-dopamine hypothesis of atypical antipsychotic action has become pronounced in the literature to the point that the ratio of 5-HT2A to D2 receptor blockade has been suggested to predict an agent’s potential for atypical antipsychotic properties . Whether the occurrence of EPS is the consequence of a reduced 5-HT2A to D2 ratio, or is dependent solely on increased D2 occupancy is still open for debate. birth control pills

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The question then becomes, ‘what constitutes an appropriate augmenting antipsychotic’? With limited literature focusing on antipsychotic polypharmacy, the best approach to this query involves a rational application of pharmacodynamic and pharmacokinetic principles. Because each antipsychotic displays a unique pharmacodynamic and pharmacokinetic profile, it is necessary to consider the contributions of each agent when two antipsychotics are combined. In the present paper, augmentation of the atypical antipsychotic clozapine with a second antipsychotic is presented as an example and is based on the approach proposed above.

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Rational antipsychotic polypharmacy

Oct 12, 2012 Author: Walter Mcneil | Filed under: Antipsychotic

Rational antipsychotic polypharmacy

In three recent prescription surveys, up to 25% of patients with psychiatric were prescribed two or more antipsychotics concurrently . Despite the prevalence of antipsychotic polypharmacy in clinical practice, clinical evidence in this area is limited . The lack of both evidence-based data and theoretical models of antipsychotic combination therapy implies that physicians rely on clinical experience and anecdotal case reports in the design of polypharmacy treatment protocols. This task is enormous when one recognizes the subtle differences in distinguishing the numerous antipsychotics in addition to the probable heterogeneous etiology of schizophrenia . Rather than have clinicians rely on intuition to discern pathophysiologically distinct illnesses that may have identical syndromal profiles, it is appropriate to design a rational theoretical basis for combination antipsychotic therapy.

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