Haliperidol

Während die vegetativen Nebenwirkungen eher in den Hintergrund treten, liegen die Hauptnebenwirkungen von Haloperidol in einer Beeinflussung der extrapyramidalen Motorik . Diese Symptomatik, die an Morbus Parkinson erinnert, wird Parkinsonoid genannt und ist nach derzeitigem Beobachtungsstand nach Beendigung der Substanzgabe größtenteils reversibel und zudem dosisabhängig. Sichtbare Symptome sind abnorme Bewegungen im Kopf- und Halsbereich sowie Schwierigkeiten beim Sprechen und Schlucken. Während der Verabreichung werden derartige Nebenwirkungen häufig durch Komedikation mit dem Antiparkinsonmittel Biperiden behandelt. Eine vollständige Rückbildung der Nebenwirkungen ist nicht in jedem Fall zu erwarten.

Haloperidol (HP) has been reported to undergo cytochrome P450 (P450)-mediated metabolism to potentially neurotoxic pyridinium metabolites; however, the chemical pathways and specific enzymes involved in these reactions remain to be identified. The aims of the current study were to (i) fully identify the cytochrome P450 enzymes capable of metabolizing HP to the pyridinium metabolite, 4-(4-chlorophenyl)-1-(4-fluorophenyl)-4-oxobutylpyridinium (HPP(+)), and reduced HP (RHP) to 4-(4-chlorophenyl)-1-(4-fluorophenyl)-4-hydroxybutylpyridinium (RHPP(+)); and (ii) determine whether 4-(4-chlorophenyl)-1-(4-fluorophenyl)-4-oxobutyl-1,2,3,6-tetrahydropyridine (HPTP) and 4-(4-chlorophenyl)-1-(4-fluorophenyl)-4-hydroxybutyl-1,2,3,6-tetrahydropyridine (RHPTP) were metabolic intermediates in these pathways. In vitro studies were conducted using human liver microsomal preparations and recombinant human cytochrome P450 enzymes (P450s 1A1, 1A2, 1B1, 2A6, 2B6, 2C9, 2C19 2D6, 2E1, 3A4, 3A5, and 3A7) expressed in bicistronic format with human NADPH cytochrome P450 reductase in Escherichia coli membranes. Pyridinium formation from HP and RHP was highly correlated across liver preparations, suggesting the same enzyme or enzymes were responsible for both reactions. Cytochrome P450s 3A4, 3A5, and 3A7 were the only recombinant enzymes which demonstrated significant catalytic activity under optimized conditions, although trace levels of activity could be catalyzed by NADPH-P450 reductase alone. NADPH-P450 reductase-mediated activity was inhibited by reduced glutathione but not catalase or superoxide dismutase, suggesting O(2)-dependent oxidation. No evidence was obtained to support the contention that HPTP and RHPTP are intermediates in these pathways. K(m) values for HPP(+) (34 +/- 5 microM) and RHPP(+) (64 +/- 4 microM) formation by recombinant P450 3A4 agreed well with those obtained with human liver microsomes, consistent with P450 3A4 being the major catalyst of pyridinium metabolite formation in human liver.

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Haloperidol is a typical butyrophenone type antipsychotic that exhibits high affinity dopamine D 2 receptor antagonism and slow receptor dissociation kinetics. [42] It has effects similar to the phenothiazines . [17] The drug binds preferentially to D 2 and α 1 receptors at low dose (ED 50 = and  mg/kg, respectively), and 5-HT 2 receptors at a higher dose (ED 50 =  mg/kg). Given that antagonism of D 2 receptors is more beneficial on the positive symptoms of schizophrenia and antagonism of 5-HT 2 receptors on the negative symptoms, this characteristic underlies haloperidol's greater effect on delusions, hallucinations and other manifestations of psychosis. [43] Haloperidol's negligible affinity for histamine H 1 receptors and muscarinic M 1 acetylcholine receptors yields an antipsychotic with a lower incidence of sedation, weight gain, and orthostatic hypotension though having higher rates of treatment emergent extrapyramidal symptoms .

Haliperidol

haliperidol

Haloperidol is a typical butyrophenone type antipsychotic that exhibits high affinity dopamine D 2 receptor antagonism and slow receptor dissociation kinetics. [42] It has effects similar to the phenothiazines . [17] The drug binds preferentially to D 2 and α 1 receptors at low dose (ED 50 = and  mg/kg, respectively), and 5-HT 2 receptors at a higher dose (ED 50 =  mg/kg). Given that antagonism of D 2 receptors is more beneficial on the positive symptoms of schizophrenia and antagonism of 5-HT 2 receptors on the negative symptoms, this characteristic underlies haloperidol's greater effect on delusions, hallucinations and other manifestations of psychosis. [43] Haloperidol's negligible affinity for histamine H 1 receptors and muscarinic M 1 acetylcholine receptors yields an antipsychotic with a lower incidence of sedation, weight gain, and orthostatic hypotension though having higher rates of treatment emergent extrapyramidal symptoms .

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