Specific Agents

Haloperidol, USP. Haloperidol, 4-[4-(p-chlorophenyl)-4-hydroxypiperidino]-4-fluorobutyrophenone (Haldol), is an odorless white to yellow crystalline powder. Haloperidol is well and rapidly absorbed and has a high bioavailability. It is more than 90% bound to plasma proteins. Haloperidol is excreted slowly in the urine and feces. About 30% of a dose is excreted in urine and about 20% of a dose in feces via biliary elimination,96 and only 1% of a dose is excreted as unchanged drug in the urine.97 Haloperidol is a minor substrate of

CYP1A2 and a major substrate of CYP2D6 and CYP3A4. CYP2D6 inhibitors may increase the levels/effects of haloperidol.91 Haloperidol may increase the levels/effects of CYP2D6 substrates98 and it may decrease the bioactivation of CYP2D6 prodrugs substrates. Haloperidol also is a moderate inhibitor of CYP2D6 and CYP3A4. CYP3A4 inducers may decrease the levels/effects of haloperidol, whereas CYP3A4 inhibitors may increase the levels/effects of haloperidol. Centrally acting acetylcholinesterase inhibitors may increase the risk of antipsychotic-related EPS. The precise mechanism of antipsychotic action is unclear but is considered to be associated with the potent DA D2 receptor-blocking activity in the mesolimbic system and the resulting adaptive changes in the brain. Haloperidol is used primarily for the long-term treatment of psychosis and is especially useful in patients who are noncompliant with their drug treatment.

Haloperidol Decanoate. Haloperidol decanoate, 4-[4-(4-chlorophenyl)-4-hydroxypiperidino]-4-fluorobutyrophe-none decanoate (Haldol Decanoate), is the decanoate ester (prodrug) of haloperidol. Peak plasma concentrations occur within 3 to 9 days and then decrease slowly. Haloperidol decanoate has no intrinsic activity. Haloperidol decanoate

Metabolites Haloperidol

Figure 13.7 • Metabolic pathway for haloperidol.


Figure 13.7 • Metabolic pathway for haloperidol.

undergoes hydrolysis by plasma and/or tissue esterases to form haloperidol and decanoic acid, subsequently; haloperi-dol is metabolized in the liver. The pharmacological effects are those of haloperidol, which is released by bioconversion. Haloperidol decanoate is indicated for the treatment of long-term maintenance in schizophrenia, psychoses especially paranoid, and other mental and behavioral problems.

Droperidol, USP. Droperidol, 1-1-[3-(p-fluoroben-zoyl)propyl]-1,2,[3,6-tetrahydro-4-pyridyl]-2-benzimida-zolinone (inapsine). Centrally acting acetylcholinesterase inhibitors may increase the risk of antipsychotic-related EPS. CNS depressants may produce additive sedative effects (benzodiazepines, barbiturates, antipsychotics, ethanol, opiates, and other sedative medications). Droperidol in combination with certain forms of inhalation anesthetics may produce peripheral vasodilatation and hypotension. Metoclopramide may increase the risk of EPS produced by droperidol.

Pimozide, USP. Pimozide, 1-[1-[4,4-to(p-fluo-rophenyl)butyl]-4-piperidyl]-2-benzimidazolinone (Orap), is a white to creamy white solid (pK = 9.42). Pimozide is 50% absorbed after oral administration. it is metabolized by CYP450 enzymes, in particular the CYP3A4 and CYP1A2 isozymes, to inactive metabolites. Pimozide is excreted in the urine and to a lesser extent in the feces. Toxic effects may be produced with pimozide in the presence of inducers or inhibitors of CYP3A4 and CYP1A2. Pimozide is also a strong inhibitor of CYP2D6 without appearing to be an important substrate of this isoform.99 The use of pimozide in the United States is small, but it is a critical drug for many patients with Gilles de la Tourette disorder who cannot tolerate haloperidol.

Atypical Antipsychotic Agents

Atypical antipsychotics (also known as second-generations) include drugs such as clozapine, olanzapine, quetiapine, risperidone, aripiprazole, and ziprasidone. With the development of the first atypical antipsychotic, clozapine, a clear division in treatment outcomes was observed. Atypical antipsychotics have generally shown to provide a greater reduction in both the positive and negative symptoms of schizophrenia, as well as an improvement in cognitive function. Thus, atypical antipsychotics are currently considered to be the first line of treatment for individuals with schizo phrenia. Affinity for 5-HT2A receptors is a feature of several of the recently developed atypical antipsychotics. Many researchers believe that D2 receptor antagonism, coupled with 5-HT2A receptor antagonism, is responsible for the differentiation of effects observed with atypical antipsychotics. inhibitory 5-HT neurons terminate on presynaptic DA neurons in the striatum. Thus, antagonism of presynaptic 5-HT2A receptors leads to an increase in DA release. This increase in DA release is thought to attenuate D2 blockade caused by antipsychotics. The decreased EPS associated with some of the atypical antipsychotics has also been suggested to be caused by 5-HT2A receptor blockade.100 Nevertheless, high 5-HT2A receptor occupancy does not ensure that an antipsychotic will exhibit an atypical profile. Even at 80% to 90% 5-HT2A receptor occupancy, no an-tipsychotic effect is observed unless D2 receptor occupancy exceeds the 65% threshold.101,102

Other theories regarding the mechanisms of action of atypical antipsychotics have also been suggested. Kapur and Seeman101 proposed that a low occupancy of D2 receptors is sufficient to account for an atypical action. These investigators have suggested that a fast dissociation rate from D2 receptors allows for DA neurotransmission that is more physiological. Yet, this theory has been questioned because several typical antipsychotics dissociate at similar rates as atypical agents.103 The atypical profile of clozapine was initially suggested to be related to its high affinity for D4 receptors; however, classical antipsychotics such as chlorpromazine and haloperidol also bind with high affinity at the D4 receptor (Table 13.2). Additionally, the atypical antipsychotic, queti-apine, has no appreciable affinity for the D4 receptor. Thus, it seems that antagonism at the D4 receptor cannot explain the unique profile of atypical antipsychotics.104,105 In the end, no single theory to date has been able to globally define and/or differentiate the actions of antipsychotics. This is as much caused by the complexity of the disease and interpretation of respective drug-mediated behavioral effects, as it is to determining the actual mechanism of action of any individual drug.

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