Neuroleptics drug interactions

Peroutka, S.J., U Prichard, D.C., Greenberg, D.A. and Snyder, S.H. (1977) Neuroleptic drug interactions with norepinephrine alpha receptor binding sites in rat brain. Neuropharmacology, 16, 549-556. 

Neuroleptic and antidepressant drugs interact with a number of different receptors in the brain, which may partly explain their PK-PD relationships. Figure 9 shows the bell shaped concentration-response relationship for the antidepressant drug nortriptyline. 

As it inhibits microsomal cytochrome P450 cimetidine has a high potential for drug interactions not shared by the other H2 receptor antagonists. The oxidative metabolism of agents such as anticoagulants, most antiepileptics, some beta-blockers, warfarin, theophylline and many hypnotics, neuroleptics and antidepressants may be reduced, leading to increased effects. 

Understanding of potential interference with cognitive and motor performance, potential for drug interactions, and risk factors for neuroleptic malignant syndrome (overheating, dehydration)... 

Bamrah IS, Kumar V, Krska 1, et al Interactions between procyclidine and neuroleptic drugs some pharmacological and clinical aspects. Br 1 Psychiatry 1986 149 726-733. 

Extrapyramidal side effects (EPS) associated with SSRI medications used as single agents were reported as early as 1979 (Meltzer et ah, 1979). Since then, several case reports have been published on use of fluoxetine (Elamilton and Opler, 1992), paroxetine (Nicholson, 1992), and sertraline (Opler 1994). The SSRI medications in combination with neuroleptics can cause severe EPS (Tate, 1989 Ketai, 1993) above and beyond what may be associated with increased levels of antipsychotic medications (Goff et ah, 1991), and are perhaps related to pharmacokinetic drug interactions. 

Detailed interaction studies have been performed with the neuroleptic drugs cis-and trans-flupentixol. These stereoisomers, like trifluoperazine, act as modifiers of multidrug resistance in tumor cell lines, in which it has been observed that the trans isomer is about three times as potent as the cis form. Surprisingly, it was found that, in the case of these two stereoisomers, the slope of the curve 1/T2 vs. lecithin concentration is different. The steeper slope for tram-flu perilixol suggests that it interacts about twice as strongly with lecithin as does cis-flupentixol (Figure 3.38) [133],... 

Interactions of SSRIs with neuroleptic drugs have been reported (110-112). 

Several cases of neurotoxicity in patients taking lithium and thioridazine have been reported. The cause of this interaction has not been resolved, but lithium seems compatible with all neuroleptic drugs, although patients should be carefully monitored (726-728). 

Drugs with a CNS depressant effect (antihistamines, hypnotics, sedatives, narcotic analgesics, alcohol, etc.) will have an increase in effect caused by interaction with neuroleptic drugs. 

Benzatropine and ethylbenzatropine are particularly likely to interact additively with other drugs with both anticholinergic and antihistaminic activity, such as neuroleptic drugs complications such as hyperpyrexia, coma, and toxic psychosis have been reported several times when such combinations were used (626-628). 

In a brief review, emphasis has been placed on pharmacokinetic interactions between neuroleptic drugs and benzodiazepines, as much information on their metabolic pathways is emerging (629). Thus, CYP3A4, which plays a dominant role in the metabolism of benzodiazepines, also contributes to the metabolism of clozapine, haloper-idol, and quetiapine, and plasma neuroleptic drug concentrations can rise. 

Neuroleptic drugs can precipitate from solution when mixed with coffee or tea (634), but the clinical significance of this physicochemical interaction is unknown (635). 

Neuroleptic drugs are often used in mood stabilizer combinations. However, there have been few controlled studies of the use of such combinations, and interactions are potentially dangerous. The advantages and disadvantages of all currently used mood stabilizer combinations have been extensively reviewed (641). Some effects are well known neurotoxicity, hypotension, somnambulistic-like events, and cardiac and respiratory arrest associated with the combination of lithium and traditional neuroleptic drugs considered as a first-line treatment for classic euphoric mania with psychotic features. 

Paroxetine and fluoxetine are potent inhibitors of CYP2D6, and can therefore interact with neuroleptic drugs that are metabolized by this enzyme. 

Gram LF, Christiansen J, Overo KF. Interaction between neuroleptics and tricyclic antidepressants. In Morselli PL, Garranttini S, Cohen SN, editors. Drug Interactions. New York Raven Press, 1974 271. 

The addition of low-dose fluvoxamine (50-100 mg/day) to neuroleptic drug treatment may improve the negative symptoms in patients with schizophrenia, but involves a risk of a drug interaction. In 12 in-patients with schizophrenia receiving 6 mg/day of haloperidol, incremental doses of fluvoxamine (25, 75, and 150 mg/day for 2 weeks each) respectively increased haloperidol plasma concentrations by 120%, 139%, and 160% of those before fluvoxamine co-administration in spite of the increase, there were no particular adverse effects (50). 

The pharmacology, efficacy, and safety of quetiapine, an atypical neuroleptic drug, have been extensively reviewed (1). Quetiapine interacts with a broad range of neurotransmitter receptors and has a higher affinity for serotonin... 

The potentiation of sedative effects from benzodiazepines when combined with centrally acting drugs with antihistamine properties (for example first-generation antihistamines, tricyclic antidepressants, and neuroleptic drugs) can pose problems (143). Antihistamines that do not have central actions do not interact with benzodiazepines as in the case of mizolastine and lorazepam (144), ebastine and diazepam (145), and terfenadine and diazepam (143). 

Because of the frequency of co-administration of benzodiazepines with neuroleptic drugs, it is important to consider possible adverse effects that can result from such combinations. In a brief review, emphasis has been placed on pharmacokinetic interactions between neuroleptic drugs and benzodiazepines, as much information on their metabolic pathways is emerging (166). Thus, the enzyme CYP3A4, which plays a dominant role in the metabolism of benzodiazepines, also contributes to the metabolism of clozapine, haloperidol, and quetiapine, and neuroleptic drug plasma concentrations can rise. Intramuscular levomepromazine in combination with an intravenous benzodiazepine has been said to increase the risk of airways obstruction, on the basis of five cases of respiratory impairment the doses of levomepromazine were higher in the five cases that had accompanying airways obstruction than in another 95 patients who did not (167). 

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