Adrenergic receptors antipsychotic action

FIGURE 11—7. This figure represents an icon of a conventional antipsychotic drug. Such drugs generally have at least four actions blockade of dopamine 2 receptors (D2) blockade of muscarinic-cholinergic receptors (Ml) blockade of alpha 1 adrenergic receptors (alpha 1) and blockade of histamine receptors (antihistaminic actions [HI ). 

Still other pharmacologic actions are associated with the conventional antipsychotic drugs. These include generally undesired activity at alpha 1 adrenergic receptors as well as at histamine 1 receptors, as already discussed (Fig. 11—7). Thus, conventional antipsychotic drugs have activities at three of the same neurotransmitter receptors... 

The antipsychotic actions of neuroleptic drugs reflect blockade at dopamine and/or serotonin receptors. However, many of these agents also block cholinergic, adrenergic, and histamine receptors, causing a variety of side effects (Figure 13.3). 

Ziprasidone is an atypical antipsychotic in clinical use for both schizophrenia and bipolar disorder (see footnote 1). It has a high affinity for dopamine, serotonin, and alpha-adrenergic receptors and a moderate affinity for histamine receptors. The exact mechanism of action of ziprasidone is unknown. However it has been presumed that its antipsychotic activity is mediated primarily by antagonism at dopamine receptors, specifically D2. Serotonin antagonism may also play a role in the effectiveness of ziprasidone. Antagonism at histaminic and alpha adrenergic receptors are likely responsible for some of the side effects of ziprasidone, such as sedation and orthostasis. The worldwide sales of ziprasidone are expected to be 1 billion in 2009. 

Mechanism of Action An antipsychotic that blocks postsynaptic dopamine receptor sites in brain. Has alpha-adrenergic blocking effects, and depresses the release of hypothalamic and hypophyseal hormones. Therapeutic Effect Suppresses psychotic behavior. 

In pharmacodynamic interactions, the pharmacological effect of a drug is changed by the action of a second drug at a common receptor or bioactive site. For example, low-potency antipsychotics and tertiary amine TCAs have anticholinergic, antihistaminic, a-adrenergic antagonist, and quinidine-Kke effects. Therefore, concurrent administration of chlorpromazine and imipramine results in additive sedation, constipation, postural hypotension, and depression of cardiac conduction. 

Epinephrine stimulates both adrenergic a,and (3, receptors, providing a balance of vasoconstrictor and vasodilator actions. With antipsychotic therapy, the a, receptors are blocked in a dose-dependent manner. Thus, the effects of epinephrine on the vasodilatory P2 receptors would predominate, resulting in hypotension. 

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