CNS depression potentiated with alcohol, other CNS depressants. Possible neurotoxicity with lithium: monitor, discontinue if occurs. Caution with drugs that prolong the QT interval (eg, ketoconazole, paroxetine). May be potentiated by CYP3A4 or CYP2D6 inhibitors/substrates (eg, itraconazole, nefazodone, buspirone, venlafaxine, alprazolam, fluvoxamine, quinidine, fluoxetine, sertraline, chlorpromazine, promethazine. May be antagonized by CYP3A4 inducers (eg, rifampin, carbamazepine); monitor and adjust doses. May increase intraocular pressure with anticholinergics, antiparkinson agents. Monitor anticoagulants.
In pharmacokinetic studies, mild to moderately increased haloperidol concentrations have been reported when haloperidol was given concomitantly with drugs characterized as substrates or inhibitors of CYP3A4 or CYP2D6 isoenzymes, such as itraconazole, nefazodone, buspirone, venlafaxine, alprazolam, fluvoxamine, quinidine, fluoxetine, sertraline, chlorpromazine, and promethazine.
When prolonged treatment (1 to 2 weeks) with enzyme-inducing drugs such as rifampin or carbamazepine is added to haloperidol therapy, this results in a significant reduction of haloperidol plasma levels.
In a study of 12 schizophrenic patients coadministered oral haloperidol and rifampin, plasma haloperidol levels were decreased by a mean of 70% and mean scores on the Brief Psychiatric Rating Scale were increased from baseline. In 5 other schizophrenic patients treated with oral haloperidol and rifampin, discontinuation of rifampin produced a mean -fold increase in haloperidol concentrations.
In a study in 11 schizophrenic patients co-administered haloperidol and increasing doses of carbamazepine, haloperidol plasma concentrations decreased linearly with increasing carbamazepine concentrations.
Thus, careful monitoring of clinical status is warranted when enzyme inducing drugs such as rifampin or carbamazepine are administered or discontinued in haloperidol-treated patients. During combination treatment, the haloperidol dose should be adjusted, when necessary. After discontinuation of such drugs, it may be necessary to reduce the dosage of haloperidol.
Sodium valproate, a drug known to inhibit glucuronidation, does not affect haloperidol plasma concentrations.
Haloperidol is a typical butyrophenone type antipsychotic that exhibits high affinity dopamine D 2 receptor antagonism and slow receptor dissociation kinetics.  It has effects similar to the phenothiazines .  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.  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 .