CHLORPROMAZINE

• Action to be taken: Caution with close monitoring for side effects
• Rationale: Administration of chlorpromazine with CYP1A2 inhibitors, in particular strong or moderate
  inhibitors leads to an increase in chlorpromazine plasma concentrations. Therefore, patients may experience any chlorpromazine dose-dependent adverse drug reaction. Chlorpromazine is a potent inhibitor of CYP2D6. Co-administration of chlorpromazine with  a CYP2D6 substrate, may lead to an increase in the plasma levels. In vitro studies have shown that cannabis undergoes minor metabolism by CYP2D6. Furthermore study with synthetic cannabis showed that it had inhibitory action on CYP1A2.  Based on available data patient should be monitored for adverse reactions associated with cannabis and chlorpromazine.

HALOPERIDOL

• Cytochrome P450 enzyme substrate: CYP2D6 and CYP3A4
• Action to be taken: Caution with close monitoring.
• Rationale: Haloperidol is metabolized by several routes, including glucuronidation and the cytochrome P450 enzyme
  system (particularly CYP 3A4 or CYP 2D6). Inhibition of these routes of metabolism by another drug or a decrease in CYP2D6 enzyme activity may result in increased haloperidol concentrations and an increased risk of adverse events, including QT-prolongation. Haloperidol is an inhibitor of CYP 2D6.In vitro studies have found that cannabis is a weak inhibitor of CYP450 enzymes, thus it may impact metabolism of Haloperidol. Furthermore, concurrent use of other CNS depressants concomitantly with Haloperidol tablets may result in additive CNS depression, respiratory depression, hypotension, profound sedation, or coma.

LOXAPINE

• Cytochrome P450 enzyme substrate: CYP2D6 and CYP3A4, CYP1A2
• Action to be taken: Caution with close monitoring
• Rationale: Loxapine is metabolized extensively in the liver following oral administration, with multiple metabolites formed. The main metabolic pathways include hydroxylation to form 8-OH-loxapine by CYP1A2 and 7-OH-loxapine by CYP3A4 and CYP2D6. In vitro studies have shown that cannabis undergoes major metabolism by CYP3A4 and CYP2C19 and minor metabolism by CYP2D6. Additionally studies have found that CBD is a potent inhibitor of CYP3A4.  Furthermore study with synthetic cannabis showed that it had inhibitory action on CYP1A2 ADASUVE is a central nervous system (CNS)depressant. The concurrent use of ADASUVE with other CNS depressants  can increase the risk of respiratory depression, hypotension, profound sedation, and syncope. Therefore, consider reducing the dose of CNS depressants if used concomitantly with ADASUVE
  

PERPHENAZINE

• Cytochrome P450 enzyme substrate: CYP2D6
• Action to be taken: Caution with close monitoring.
• Rationale: The concomitant administration of other drugs that inhibit the activity of P450 2D6 may acutely increase plasma concentrations of antipsychotics. In vitro studies have shown that cannabis undergoes major metabolism by CYP3A4 and CYP2C19 and minor metabolism by CYP2D6. Additionally studies have found that CBD is a potent inhibitor of CYP3A4.  Furthermore study with synthetic cannabis showed that it had inhibitory action on CYP1A2 .Medications that act on the central nervous system (CNS), may possibly increase the risk and severity of CNS-related side effects of antipsychotics, including somnolence, drowsiness, dizziness, and fatigue.

THIORIDAZINE

• Cytochrome P450 enzyme substrate: CYP2D6
• Action to be taken: Caution with close monitoring . Avoid combination
• Rationale:  Reduced cytochrome P450 2D6 isozyme activity drugs that inhibit this isozyme and certain other drugs appear to appreciably inhibit the metabolism of thioridazine. The resulting elevated levels of thioridazine would be expected to augment the prolongation of the QTc interval associated with Mellaril and may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes-type arrhythmias. Such an increased risk may result also from the additive effect of co-administering Mellaril with other agents that prolong the QTc interval. Therefore, Mellaril is contraindicated with these drugs. 

References

1. Watanabe K, Yamaori S, Funahashi T, et al. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sci. 2007;80:1415-1419.
   
2. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46:86-95.​​
3. Yamaori S, Ebisawa J, Okushima Y, Yamamoto I, Watanabe K. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: Role of phenolic hydroxyl groups in the resorcinol moiety. Life Sciences. 2011;88:730-736.
4. Thorazine (chlopromazine) package insert. Mylan Institutional Inc. Rockford Il, 2015
5. Haldol (haloperidol) package insert. Sandoz Inc., Princeton, NJ 2006
6. Adasuve (loxapine) package insert. Alexza Pharmaceuticals, Inc., Mountain View, CA 2012
7. Trilafon (perphenazine) package insert. Schering Corporation, Kenilworth, NJ 2002
8. Mellaril (thioridazine) package insert. Novartis Pharmaceuticals Corporation East Hanover, New Jersey 2000