A/-oxide metabolite because of their low concentrations in plasma are not thought to contribute to the overall effects of quetiapine.107,117
In human liver microsomes, four primary metabolites of quetiapine are formed. These include quetiapine sulfoxide, 7-hydroxyquetiapine, and the N- and O-desalkylated metabolites (Fig. 13.10). This study showed that CYP3A4 is the major isoform of P450 responsible for quetiapine metabolism. CYP3A4 inducers (carbamazepine) or CYP3A4 inhibitors (ketoconazole) can either decrease or increase plasma levels of quetiapine.118
Common side effects associated with quetiapine therapy are orthostatic hypotension and somnolence. These effects are presumably caused by ^-adrenergic and histamine H1 receptor blockade, respectively. As with other atypical antipsychotics, patients treated with quetiapine should be monitored for hyperglycemic symptoms. Also, children and adolescents with major depressive disorder may experience an increase in their depression or suicidal tendencies.23,107 Quetiapine binds with high affinity at a1, a2, H1, and 5-HT2A receptors but has much lower affinity for D2 and 5-HT1A receptors. The action of quetiapine at D2 and 5-HT2A receptors is that of an antagonist, whereas it shows agonist effects at 5-HT1A receptors.119,120 Quetiapine dissociates rapidly from D2 receptors, and this leads to lower D2 receptor occupancy compared with
typical antipsychotics such as chlorpromazine.121 This finding may explain the lack of EPS associated with quetiapine.107
Risperidone. Risperidone, 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2]pyrimidin-4-one (Risperdal), is a white to slightly beige powder that is essentially insoluble in water. Risperidone is also available as a 1-mg/mL oral solution and as orally disintegrating tablets (Risperdal M-Tab). Risperidone is well absorbed, and peak levels occur about 1 hour after administration. The absorption of risperidone is not affected by food. Risperidone is about 90% bound to albumin and a1-acid glycoprotein, whereas its metabolite 9-hydroxy-risperidone is bound about 77%.23 Risperidone is primarily metabolized in humans to the active metabolite 9-hydroxy-risperidone (Fig. 13.11). Although CYP2D6 was thought to be the major P450 isoform in the formation of the 9-hydroxy metabolite, a recent report suggests that CYP3A4 is in-volved.121 The potent CYP3A4 inducer, rifampin, was shown to significantly reduce plasma concentrations of risperidone,122 whereas ketoconazole, a CYP3A4 inhibitor, decreased the formation of the 9-hydroxy metabolite.123 The metabolism of risperidone appears to be stereoselective. In human microsomes, the CYP2D6 inhibitor, quinidine, strongly inhibited the formation of (+)-9-hydroxyrisperi-done, whereas the CYP3A4 inhibitor, ketoconazole, inhibited the formation of (—)-9-hydroxyrisperidone.124 Individuals concurrently on risperidone and other medications should be carefully monitored because impaired CYP2D6 activity could increase the risk for drug interactions.125,126 Renal excretion is the main route of elimination for risperidone and its metabolites. The mean half-life of risperidone is 3 hours in extensive metabolizers and 21 hours in poor metabolizers, respectively. The elimination half-life for the 9-hydroxy metabolite is similar to risperidone in extensive and poor metabolizers, with an overall elimination half-life of about 20 hours.23 The major side effects associated with risperidone therapy are orthostatic hypotension, dose-related hyperpro-lactinemia, mild weight gain, EPS, and insomnia.127 At higher doses (6 mg/day), risperidone is the atypical antipsychotic that most closely resembles conventional agents. A PET study in a group of individuals with schizophrenia showed that D2 receptor occupancy was dose dependent. If the dose was increased such that D2 receptor occupancy was 79% to 85%, the majority of patients developed EPS.126 Risperidone is associated with increased mortality in elderly patients with dementia-related psychosis and is not recommended for these individuals.23 Risperidone binds with high affinity at 5-HT2A, 5-HT7, D2, a1, a2, and H1 receptors. The antipsychotic action of risperidone has been proposed to be the result of D2 and 5-HT2A antagonism.23,107 Risperidone is effective in treating the positive and negative symptoms of schizophrenia and as adjunct therapy in bipolar mania.127 The U.S. Food and Drug Administration (FDA) granted ap proval of risperidone orally disintegrating tablets in October 2006 for the treatment of irritability in autistic children and adolescents.23
Paliperidone. Paliperidone, (± )-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H -pyrido[1,2-a ]pyrimidin-4-one (Invega), is essentially insoluble in water and is available as extended-release tablets. Paliperidone is delivered at a constant rate using an osmotic drug release device (Osmotic Release Oral Systems [OROS]). The absolute bioavailability of paliperidone is 28%, and studies in healthy subjects on a high-fat, high-calorie meal showed an increase in AUC. Paliperidone is 74% bound to plasma proteins. After a single, 1-mg dose of 14C-paliperidone, 59% of the dose was excreted in the urine as unchanged drug, and 32% of the dose was recovered as metabolites. Most of the drug (80%) is excreted by the kidneys. Paliperidone is metabolized by dealkylation, hy-droxylation, dehydrogenation, and scission of the benzoxa-zole ring. None of these metabolic pathways account for more than 10% of the dose. The terminal elimination half-life of paliperidone is 23 hours.23
Aripiprazole. Aripiprazole, (7-[4-[4-(2,3-dichloro-phenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1#)-quinolone, is an atypical antipsychotic that is available in tablets (Abilify), orally disintegrating tablets (Abilify Discmelt), and a 1-mg/mL oral solution. Unlike the other atypical antipsychotics, aripiprazole exhibits partial agonist activity at D2, D3, D4, and 5-HT1A receptors, and antagonist action at 5-HT2A receptors. Although aripiprazole exhibits a low incidence of EPS, the compound occupies about 95% of striatal D2 receptors at therapeutic doses. Additionally, aripiprazole does not have a fast rate of dissociation from D2 receptors. Although the mechanism of action of this compound remains to be elucidated, the atypical profile for aripiprazole may be related to its action at other monoamine receptors.105,128 The compound is well absorbed with peak plasma levels occurring 3 to 5 hours after oral administration. Food does not affect absorption of aripiprazole. Aripiprazole is extensively metabolized in the liver by the action of CYP2D6 and CYP3A4. The primary metabolite in humans is dehydroaripiprazole (Fig. 13.12). This metabolite represents about 40% of aripiprazole at steady state.23 In the presence of CYP3A4 and CYP2D6 inhibitors or inducers, dosage adjustments of aripiprazole may be required. The mean elimination half-lives in extensive and poor metabolizers are 75 hours and 146 hours, respectively.23 The major adverse effects of aripiprazole are headache, anxiety, and insomnia.129 Similar to other atypical antipsychotics, aripiprazole shows an increased risk in mortality in elderly patients with dementia-related psychosis.23 Aripiprazole demonstrates a different pharmacological profile from all other atypical antipsychotics. The compound exhibits partial agonist activity at 5-HT1A receptors and antagonist action at 5-HT2A receptors. The partial agonism at 5-HT1A may
contribute to the effects of aripiprazole against the negative symptoms of schizophrenia.130 Unlike other antipsychotics, aripiprazole acts as a partial agonist at D2 receptors. Additionally, the major metabolite, dehydroaripiprazole, shows similar pharmacological properties as aripiprazole, and it also acts as a partial agonist at D2 receptors.131 It has been suggested that a partial D2 agonist will exhibit functional agonist activity in areas of the brain (mesocortical pathway) that have low DA levels, whereas a D2 partial agonist can function as an antagonist in areas of the brain (mesolimbic pathway) where DA levels are high. Thus, positive symptoms of schizophrenia are reduced without significant EPS.132 Aripiprazole is indicated for schizophrenia and for acute mania that is associated with bipolar I disorder.23
Ziprasidone. Ziprasidone, 5- [2- [4-( 1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2-one, is available as the hydrochloride monohydrate for oral administration (Geodon) and as the mesylate trihydrate salt for intramuscular (IM) injection. The compound is well absorbed with peak plasma levels occurring at 6 to 8 hours after oral administration. The oral absorption is enhanced approximately twofold in the presence of food. Ziprasidone is bound about 99% to plasma proteins, primarily to albumin and a1-acid glycoprotein. Ziprasidone is not displaced in the presence of two highly protein bound drugs, warfarin and propranolol. Ziprasidone is extensively metabolized with only about 5 % of the drug excreted unchanged.23 In humans, two major pathways are responsible for the metabolism of ziprasidone: (a) oxidation by CYP3A4 (one third) and (b) reduction by aldehyde oxidase (two thirds).133,134 The combined action of these metabolic pathways leads to four major circulating metabolites: benzisothiazole piperazine sulfoxide (BITP-sulfoxide), benzisothiazole piperazine sulfone (BITP-sulfone), ziprasidone sulfoxide, and S-methyldihydroziprasi-done (Fig. 13.13).
Ziprasidone sulfone S-Methyldihydroziprasidone
Figure 13.13 • Metabolic pathway of ziprasidone.133,134
Ziprasidone sulfone S-Methyldihydroziprasidone
Figure 13.13 • Metabolic pathway of ziprasidone.133,134
Multidrug therapy involving ziprasidone does not appear to be a serious concern, because the reductive activity of aldehyde oxidase is not affected by other drugs.134 The elimination half-life of ziprasidone is 4 hours with about 20% of the drug excreted in urine and 66% eliminated in the feces.23,107 Ziprasidone has a low incidence of sedation, EPS, and postural hypotension. Unlike other atypical antipsychotics, ziprasidone does not cause weight gain or elevated glucose levels. Ziprasidone has been shown to cause a mild-to-moderate increase in the QTc interval.134 Prolongation of the QTc interval in some other drugs is associated with potentially life-threatening ventricular arrhythmias and sudden death. As with other atypical antipsychotic agents, ziprasidone can increase the risk of mortality in elderly patients with dementia-related psychosis and is not indicated in these individuals.23 Ziprasidone binds with high affinity at D2, D3, 5-HT1A, 5-HT1D, 5-HT2A, 5-HT2C, and ^-receptors. The compound acts as an agonist at 5-HT1A receptors and as an antagonist at D2 and 5-HT2A receptors. Ziprasidone also inhibits synaptic uptake of serotonin and norepinephrine. Thus, it has been postulated that ziprasidone has potential use as an anxiolytic and an antidepressant.107,135 Ziprasidone is indicated for schizophrenia and acute mania that is associated with bipolar disorder, whereas the injectable form of ziprasidone is indicated for the treatment of acute agitation in schizophrenic patients.23
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