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CYP450 interactions: interactions of low-potency neuroleptics

In many areas there is no alternative for this group of drugs. However, they must be used responsibly.

Conventional antipsychotics are divided into low-potency, medium-potency and high-potency neuroleptics based on their neuroleptic potency. With increasing neuroleptic potency, the antipsychotic effect increases and the sedative effect decreases.

Low-potency neuroleptics have a weak antipsychotic effect, but are all the more sedating and psychomotor-depressing. They are rarely used in the antipsychotic indication, but are suitable for sedating psychomotor agitated patients. They are also used for insomnia and anxiety. The low-potency neuroleptics include:

  • Chlorprothixes
  • Levomepromazine
  • Melperon
  • Pipamperon
  • Promethazine
  • Prothipendyl

The low-potency neuroleptics can be chemically divided into butyrophenones and active ingredients with a tricyclic structure (phenothiazines and phenothiazine analogues) (1). The different side effect profiles of the active ingredients are derived from this.

The two butyrophenones melperon and pipamperon lack an anticholinergic effect. Alpha-1 adrenergic receptors are also only blocked to a small extent. Melperon and Pipamperon are therefore suitable for sedation in psychomotor states of excitement and for sleep induction even in old age (2). The PRISCUS list recommends both substances as possible therapy alternatives for potentially inadequate drugs in the elderly (3). Another advantage is that Melperon has no and Pipamperon only minor proconvulsive effects (4).

Phenothiazines and phenothiazine analogs, on the other hand, antagonize various postsynaptic receptors. Like thioridazine, which is no longer recommended because of its cardiotoxic risk, they have a pronounced anticholinergic and adrenolytic component. Thus, the tolerance is limited due to vegetative (especially cardiovascular) side effects. Chlorprothixen, levomepromazine, promethazine and prothipendyl should therefore only be used as a reserve if suitable alternatives fail (2).

For the assessment of the pharmacokinetic interaction potential of the low-potency neuroleptics at the level of the cytochrome P450 enzymes (CYP), the behavior of the individual substances towards the isoenzyme CYP2D6 is of decisive importance (table) (5).

Substrate of CYP2D6

The breakdown of chlorprothixene and promethazine depends on the functionality of the polymorphically expressed enzyme CYP2D6 (2, 6). As in patients with genetically determined inactive CYP2D6 (poor metabolizer, PM), concomitant medication with clinically relevant CYP2D6 inhibitors (graphic) can lead to an increase in plasma concentration. The risk of undesirable CNS effects and QTc prolongation including dangerous arrhythmias (torsade de pointes (TdP) tachycardia) is increased without dose adjustment (2, 6).

Inhibition of CYP2D6

Levomepromazine, melperone and promethazine are CYP2D6 inhibitors (table). Many drugs are broken down primarily via CYP2D6. For example, the beta blocker metoprolol is metabolized almost exclusively via this CYP isoenzyme. Co-medication with CYP2D6 inhibitors can lead to an increase in the plasma level of the beta blocker. Typical adverse drug reactions such as hypotension and bradycardia can be more pronounced (7).

"Silent interactions" can occur when a prodrug such as codeine is combined with CYP2D6 inhibitors. The low-potency opioid is pharmacologically inactive. The analgesic metabolite morphine is only formed from codeine through bioactivation via CYP2D6. If this step is prevented, there is a risk of subtherapeutic morphine plasma levels and thus treatment failure.

Similar considerations also apply to tramadol, whose metabolite O-desmethyltramadol, formed via CYP2D6, mainly contributes to its analgesic efficacy (8).

Other drugs whose metabolism is dependent on CYP2D6 are (2): Amitriptyline, aripiprazole, atomoxetine, carvedilol, clomipramine, darifenacin, dextromethorphan, diphenhydramine, donepezil, doxepin, duloxetine, flecainide, fluoxetine, flupoperenthidazine, fluoxetine, flupoperenthixol, , Imipramine, metoclopramide, nebivolol, nortriptyline, opipramol, paroxetine, perphenazine, promethazine, propafenone, propranolol, risperidone, sertindole, tamoxifen, tolterodine, trimipramine, venlafaxine, vortioxetine, zuclopenthixol.

Conclusion

From the group of low-potency neuroleptics, the two active ingredients melperon and pipamperon have the best risk-benefit ratio. When prescribing Melperon, its potential for pharmacokinetic interactions should be considered. ▄

DOI: 10.3238 / PersNeuro. 2015.12.04.07

Holger Petri

Central pharmacy of the Wicker clinics, Bad Wildungen

Conflict of interest: The author declares that there is no conflict of interest.

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www.aerzteblatt.de/lit4915

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