Dopamine receptor antipsychotic effects

Both approaches are effective in therapy and may usefully be combined. It therefore comes as no surprise that drugs which prolong the action of acetylcholine (anticholinesterases) or drugs which deplete dopamine stores (reserpine) or block dopamine receptors (antipsychotics, e.g. chlorpromazine) will exacerbate the symptoms of parkinsonism or induce a parkinson-like state. 

Drug-induced psychosis can occur without activation of brain dopamine receptors All effective antipsychotic dmgs have high affinity for dopamine D2 receptors Fluphenazine has been prescribed for a 20-year-old male patient. His schizophrenic symptoms have improved enough for him to reside in a halfway house in the community. He visits his physician with a list of complaints about his medication. Which one of the following is not likely to be on his list ... 

It has been suggested that high affinity for certain 5-HT receptors is a possible method for reducing extrapyramidal side effects observed with antipsychotics. LiabiUty for extrapyramidal side effects has been hypothesi2ed to be related to the ratio of the affinity between dopamine receptor... 

With respect to other ethnic groups, African Americans may have a differential sensitivity to weight gain on clozapine (de Leon etal, 2007). They may also require lower doses than Caucasians (Kelly et al, 2006) and inter-individual as well as ethnic responsiveness maybe partly explained by differences in dopamine receptor polymorphisms (Hwang et al, 2005). It is conceivable that side effects may also be differentially expressed based on pharmacodynamic differences resulting from polymorphisms in other receptor types (histaminergic, muscarinic, etc.). This area remains largely unexplored with respect to ethnic differences in antipsychotic side effects. 

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. 

Changes in dopamine receptor density may be involved in the side effects of antipsychotic drugs 222... 

Strange, P. G. Antipsychotic drugs importance of dopamine receptors for mechanisms of therapeutic actions and side effects. Pharmacol. Rev. 53 119-133, 2001. 

Whatever the underlying causes may be, neuroleptic medications are the most effective treatment for schizophrenia. All antipsychotic medications have some form of dopamine receptor antagonism and they are distinguished by their chemical class. The phenothiazines include chlorpromazine (Thorazine), thioridazine (Mellaril), mesoridazine (Serentil), trifluoperazine (Stelazine), fluphenazine (Prolixin), and prochlorperazine (Compazine). The thioxanthenes include chlorprohixine (Taractan) and thiothixene (Navane). Butyrophenones are represented by haloperidol (Haldol). Loxapine (Loxitane) is a dibenzoxapine, and molindone (Moban) is a dihydroindolone. 

Some medication side effects also occur only after prolonged administration and, as such, are products of the adaptive response to the continued administration of the medication. For example, taking a so-called conventional or typical antipsychotic for a long period of time can cause involuntary movements called tardive dyskinesias. These dyskinesias are believed to occur after chronic administration of the antipsychotic has caused changes in the density and/or sensitivity of dopamine receptors in brain regions that coordinate movement. 

In admittedly oversimplified terms, it is believed that hyperactivity of dopamine neurons in the mesolimbic pathway contribute to the positive symptoms of schizophrenia. All the typical antipsychotics are believed to work by reducing the activity of the mesolimbic dopamine pathway. More specifically, they do this by blocking dopamine receptors on the nerve cells. Over a period of 1-3 weeks, the dopamineblocking effect of the typical antipsychotic begins to relieve the positive symptoms of schizophrenia. 

As you might anticipate, dopamine receptor-blocking antipsychotics lower the functional dopamine/acetylcholine ratio in the nigrostriatal pathway. As a resnlt, the antipsychotics have the same effect in this pathway as idiopathic PD. This is how antipsychotics produce their so-called extrapyramidal side effects (EPS). EPS can take the form of parkinsonism (e.g., rigidity, tremor) or acnte dystonic reactions. 

These medications cannot be dosed solely based on their dopamine receptor blocking potency, because they also have effects on other receptors that must be factored into their dosing (see Table 4.6). For example, it is not unusual to begin treatment of a psychotic patient with a 5 mg dose of haloperidol. In terms of dopamine receptor blocking potency, 5 mg of haloperidol is more or less equivalent to 500 mg of chlorpromazine. If a patient were immediately treated with 500 mg of chlorpromazine, however, he/she would likely have side effect problems such as dizziness and excessive sedation. This is because the medications with the lowest dopamine receptor blocking potency are the most potent at other receptor systems responsible for these side effects. (See Table 4.7) The evolution of antipsychotics from low to medium to high potency has been driven not only by the desire to find... 

The second theory is that some atypicals work by balancing dopamine blockade with serotonin receptor blockade. We know that one of the roles of serotonin is to attenuate (or lessen) dopamine activity. Blocking serotonin action therefore may release just enough dopamine activity in the nigrostriatal pathway to avoid EPS without interfering with the antipsychotic effects in the mesolimbic area. 

The predominant mechanism by which currently available antipsychotic medications interfere with dopamine activity is by blockade of dopamine receptors on neurons innervated by dopamine nerve terminals. Of the five types of dopamine receptors, all antipsychotics share in common the fact that they block the dopamine type 2 receptor, also known as the D2 receptor, to a varying degree. Some of the atypical antipsychotics also block other dopamine receptors (see Table 13.5). The role of blockade of Dl, D3, D4, and other dopamine receptors in the therapentic effects of antipsychotic drugs remains unclear. Aripiprazole is an exception to this in that it is a partial agonist at the D2 receptor. 

Typical Versus Atypical Antipsychotics. We discussed at length in Chapter 5 just what makes a typical antipsychotic typical and what makes an atypical antipsychotic atypical. We ll spare you a rehash of that lengthy discussion however, it is important to note that all typical antipsychotics are not created equal. Although they all work by blocking the dopamine D2 receptor, their potency at this receptor varies up to 100-fold. In addition, antipsychotic side effects are not due solely to dopamine receptor blockade. In many cases, the most troublesome side effects result from blocking other receptor types including histamine, acetylcholine, and the norepinephrine alpha-1 receptor system. 

Drugs that are successful in treating the disease act as dopamine receptor blockers and are known as antipsychot-ics or neuroleptics (e.g. chlorpromazine, haloperidol). Antipsychotic drags reduce some of the symptoms, especially the delusions and hallucinations. A side-effect of the drugs is that they can result in symptoms similar to those seen in patients with Parkinson s disease. This is not surprising, since the hypothesis to explain Parkinson s disease is too low a concentration of dopamine in a specific area of the brain (see below). 

The antipsychotic effect is probably due to an antagonistic action at dopamine receptors. Aside from their main antipsychotic action, neuroleptics display additional actions owing to their antagonism at... 

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