Adrenergic effects, antipsychotics

Reserpine, a rauwolfia alkaloid with peripherally acting anti-adrenergic effects (0.5 mg p.o.), is used in mild to moderate essential hypertension. In addition, reserpine (0.1 to 1 mg p.o. daily) has been used as an antipsychotic. 

Risperidone (11) was also included among a a 1-adrenergic receptor antagonists to study a quantitative structure-activity relationship (99BMC2437). A pharmacophore model for atypical antipsychotics, including 11, was established (00MI41). An increased plasma level of 11 and 9-hydroxyrisperidone (12) was observed in combination with paroxetine (01 MI 13). The effect of vanlafaxine on the pharmacokinetics of 11 was reported (99MI13). 

The answer is c. (Hardman, pp 414-4163) Unwanted pharmacologic side effects produced by phenothiazine antipsychotic drugs (e.g., perphenazine) include Parkinson-like syndrome, akathisia, dystonias, galactorrhea, amenorrhea, and infertility. These side effects are due to the ability of these agents to block dopamine receptors. The phenothiazines also block muscarinic and a-adrenergic receptors, which are responsible for other effects. 

Tolerance to this effect usually occurs within 2 to 3 months. Reducing the dose or changing to an antipsychotic with less a-adrenergic blockade may also help. 

The net result is that low potency antipsychotics cause more histamine-blocking, acetylcholine-blocking, and a-1 adrenergic blocking side effects. The high potency antipsychotics are more likely to produce dopamine-blocking side effects. Now, let s take a brief look at each of the specific medications. 

Sedation is common after use of all antipsychotic drugs and is especially notable with the low-potency phenoth-iazines this is a result of their activity at aj-adrenergic and Hi-histaminergic receptors. However, sedation decreases during long-term treatment, and many patients become tolerant to this effect. Single daily doses given at bedtime minimize this problem. 

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. 

Numerous drug-drug interactions have been reported with the antipsychotic agents. These may be mediated through pharmacodynamic effects. For example, antipsychotics that block aj-adrenergic receptors may potentiate the antihypertensive effects of prazosin, labetalol, and some other antihypertensive agents. Conversely, antipsychotics associated with a2-adrenergic receptor blockade may interfere with the antihypertensive effects of clonidine and methyldopa (Richelson, 1999). 

Antipsychotic agents may have several cardiovascular effects. Medication-induced hypotension is generally more problematic with lower-potency neuroleptics than with other antipsychotics and appears to be mediated through tti-adrenergic blockade. Besides increases in heart rate that may be the result of hypotension, antipsychotics with appreciable anticholinergic effects (see Clinical Implications, below) can lead to tachycardia (Gutgesell et ah, 1999). 

The answer is h. (Katzung, p 482.) Haloperidol, a butyrophenone, is by far the most likely antipsychotic to produce extrapyramidal toxicides. Other agents, such as piperazine (an aromatic phenothiazine), thiothixene (a thioxanthene), and pimozide (a diphenylbutyropiperidine) are comparitively less likely to produce extrapyramidal toxicity than haloperidol. The antagonism of dopamine in the nigrostriatal system might explain the Parkinson-like effects. Both haloperidol and pimozide act mainly on D2 receptors, whereas thioridazine and piperazine act on a-adrenergic receptors, and have a less potent but definite effect on D2 receptors. 

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. 

FIGURE 11 — 13- Side effects of conventional antipsycbotics, part 3. In this diagram, the icon of a conventional antipsychotic drug is shown with its alpha 1 (alpha 1 antagonist) portion inserted into alpha 1 adrenergic receptors, causing the side effects of dizziness, decreased blood pressure, and drowsiness. 

Setoguchi, M., Sakamori, M., Takehara, S., Fukuda, T. Effects of iminodibenzyl antipsychotic drugs on cerebral dopamine and alpha-adrenergic receptors. Eur.J. Pharmacol. 1985, 112, 313-322. 

Electroconvulsive therapy has been used as antidepressive, mood-stabilizing and antipsychotic treatments (Eitan and Lerer 2006 Shapira et al., 1991). It is reported that electroconvulsive shocks (ECS), an animal model for the ECT, affect the NE system. Thus, both acute and chronic ECS increase cortical and hippocampal NE release. Chronic ECS also desensitize a2-adrenergic autoreceptors in the PFC (Thomas et al., 1992). Paradoxically, electrophysiological studies report that chronic ECS suppress the firing activity of NE neurons in the ECS (Grant and Weiss 2001). Based on the evidences of ECS-induced increase in brain NE levels, it can be concluded that the benefitial effect of the ECT is mediated, at least in part, via NE system. 

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). 

Thioxanthenes, such as flupenthixol and clopenthixol, are similar in structure to the phenothiazines. The therapeutic effects are similar to those of the piperazine group. Antipsychotic thioxanthenes are thought to benefit psychotic conditions by blocking postsynaptic dopamine receptors in the brain. They also produce an alpha-adrenergic blocking effect and depress the release of most hypothalamic and hypophyseal hormones. However, the concentration of prolactin is increased due to blockade of prolactin inhibitory factor (PIF), which inhibits the release of prolactin from the pituitary gland. 

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