Dopamine blockers

Domperidone [133], one of the most potent D2-dopamine blockers and antagonists of apomorphine-induced emesis with limited brain-blood barrier permeability, did not establish a position as an antiemetic, especially against cisplatin [134], Recently, the use of domperidone as a parenteral antiemetic has been discontinued because of serious cardiovascular toxicity. 

The hypothetical link between dopamine and schizophrenia was forged by two reciprocally related findings. The first was that potent dopamine agonist stimulants like d-amphetamine and cocaine could cause a psychosis that was schizophrenia-like, in that it had auditory hallucinations and paranoia. The second was that the neuroleptic drugs that were effective in reversing both schizophrenia and stimulant-induced psychosis were dopamine blockers. Moreover, the antipsychotic potency of the neuroleptics was proportional to their binding affinity to the D2 receptor. 

Remington et al. (2006) conducted a similar PET study of the long-acting injectable form of risperidone at doses of 25, 50, or 75 mg every 2 weeks. After reaching stabilization, nine patients with a diagnosis of schizophrenia or schizoaffective disorder were scanned twice, 3 days postinjection and 5 days before the next injection. According to Remington et al. (2006), all three doses of injectable risperidone showed peak D(2) occupancy levels above the 65% threshold associated with optimal clinical response the 75-mg dose approximated the 80% threshold linked to increased risk of extrapyramidal reactions. Clearly, it is all in the dose all of the atypicals are potent dopamine blockers. 

Risperdal was first marketed in 1994 as an atypical neuroleptic. The clinical trials, most of which lasted a few weeks, were too short to determine the rate of tardive dyskinesia and many other adverse effects. Indeed, the brief controlled clinical trials used for the approval of both clozapine and risperidone do not provide sufficient information to determine either efficacy or safety since the drugs would be used for months and years in individual patients, rather than for a few weeks (see chapter 13). Patients taking the medications over the coming years will provide the experimental data. However, since Risperdal is a potent dopamine blocker, it should have been anticipated that it would cause similar adverse reactions as the older neuroleptics. In my own experience, I have evaluated many cases of tardive dyskinesia caused by Risperdal, Zyprexa, and Geodon. Meanwhile, the Food and Drug Administration (FDA) has required the same tardive dyskinesia and neuroleptic malignant syndrome warnings on the labels of clozapine and risperidone as on the labels of the older neuroleptics. 

Regardless of the mechanism, all neuroleptics produce lobotomy-like indifference or deactivation. This is the primary effect of all drugs thus far developed for the control of patients labeled schizophrenic or acutely manic. If the medications failed to produce a deactivation effect, they would not be useful for the control of very difficult or disturbed individuals. We shall find that these drugs are potent dopamine blockers, producing all of the more severe central nervous system impairments caused by other neuroleptics. 

In a 1988 review of tardive dystonia, Burke and Kang found 21 reports describing 131 patients (for reviews, see also Greenberg et al., 1985 Kane et al., 1992). As already emphasized, because all the atypical neuroleptics are potent dopamine blockers (except clozapine), it should have been assumed that all of them could cause TD and tardive dystonia. Case reports confirm that risperidone (Vercueil et al., 1999 Narendran et al., 2000) and olanzapine (Gunal et al., 2001 Dunayevich et al., 1999) can cause tardive dystonia. 

On October 6, 2006, the FDA announced its approval of Risperdal for the treatment of extreme irritability in autistic children. The only way Risperdal can reduce this so-called extreme irritability (anger and temper tantrums) is by deactivating the frontal lobes, limbic system, and reticular activating system, causing a chemical lobotomy with emotional blunting. Since Risperdal is a potent dopamine blocker, it has this capacity. 

All drugs listed in Part IV Antipsychotic Drugs (Neuroleptics) can cause extrapyrami-dal symptoms (EPS) and tardive dyskinesia (TD), although Clozaril and Phenergan are weaker dopamine blockers with less of a tendency to cause these adverse effects. 

Other, chemically distinct dopamine blockers were then developed, such as thiothixene, haloperidol, loxapine, molindone, and pimozide. All of these antipsychotics are potent dopamine blockers and collectively were called neuroleptics because they inadvertently cause certain neurological side effects (discussed below). More recently, atypical antipsychotic medications have been developed (clozapine and risperidone), which are effective antipsychotics yet are weak dopamine blockers and cause minimal neurological side effects. This group is discussed separately below. 

Cocaine is a tropane-type derivative with several chiral centres and only the (lJ ,2f ,3S,5S)-stereoisomer, also called (—)-cocaine, appears to have appreciable psychostimulant properties. Its primary mode of action is based on blockage of the dopamine transporter which is defined as a directly mediated mechanism. Cocaine is therefore classified as a dopamine blocker rather than dopamine releaser, as is the case with some amfetamines. A large number of 2P,3P-cocaine analogues are well tolerated by the dopamine transporter but not necessarily by the noradrenaline or serotonin counterparts. This means that dopamine reuptake blockage alone is not necessarily sufficient to reinforce consumption, and appropriate stmctural modifications could lead to the development of treatment options for cocaine abuse. 

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