Cardiovascular diseases (CVD) and psychiatric disorders and diseases are, according to reports from the World Health Organization (WHO), one of the main causes of disability in the world.
The authors of this article reviewed different meta-analyses that demonstrated that patients with mental illness, such as bipolar disorder (BD) or schizophrenia (ZZ), had an increased risk of suffering from CVD and a higher risk of death from it than general population, even taking into consideration factors such as age, obesity and smoking.
The use of polypharmacotherapy - defined as the use of several drugs at the same time - increases the risk of possible adverse drug interactions of a pharmacokinetic or pharmacodynamic nature.
The objective of this study was to evaluate the occurrence of adverse drug interactions between antipsychotics (used in the treatment of EZ and TB) and medications used in the treatment of cardiovascular diseases. The authors mention that in all the patients analyzed there were side effects, which were attributed to the combination of said drugs.
| Methods |
Data on drug-related complications come from the material of the University Center for Monitoring and Study of Clinical Adverse Effects of Drugs, at the Pharmacology Clinic of the Faculty of Medicine of the Jagiellonian University, in Krakow.
Data from the period from January 1, 2017 to March 30, 2018 were analyzed. To determine the correlation between the pharmacological treatment used and the adverse effects observed, a pharmaco-epidemiological analysis was carried out and the cause-effect relationship between the treatment and clinical picture of complications.
52 cases of adverse reactions were analyzed. The average number of drugs used in the patient was 6 (min.: 4, max.: 9). In all cases there was a probable (n = 41) or certain (n = 11) cause-effect relationship between the incorporation of cardiac drugs to antipsychotic pharmacological treatment and the appearance of complications. The mean age in the entire patient group was 63.13 (SD = 7.07).
| Results and discussion |
The highest number of interactions between cardiac drugs and antipsychotics in the group analyzed was observed between beta-blockers: atenolol, nebivolol, metoprolol and sotalol (n = 13, 25% of cases). The most common adverse reaction in this subgroup was cardiac arrhythmias (n = 6, approximately 11.5% of cases): atrial fibrillation (n = 1, risperidone with atenolol), bradycardia (n = 1, perphenazine with metoprolol) or ventricular arrhythmias (n=1, sertindole with metoprolol and (n=3), ziprasidone with sotalol.
In this last combination, in one case, death occurred. The second adverse reaction observed between antipsychotics and beta-blockers was hypotension (n=2, chlorprothixene with nebivolol or metoprolol). One patient using aripiprazole and metoprolol experienced a seizure. The mean age in the subgroup of patients who used beta-blockers was 63.62 years (SD = 5.87).
Adverse effects were due to pharmacokinetic, pharmacodynamic side effects, or additive effects. Metoprolol when used in combination with aripiprazole, clozapine, perphenazine, or sertindole significantly inhibited the metabolism of antipsychotics at the cytochrome P450 isoenzyme CYP2D6. The effect was an increase in the concentration of the antipsychotic in the blood followed by an increase in the risk of side effects and toxicity.
In this way, it produced bradycardia when used together with perphenazine, ventricular arrhythmias when combined with sertindole, generated an increase in salivation and a decrease in the seizure threshold with aripiprazole, and myoclonus and urine retention with clozapine.
Patients who used chlorprothixene concomitantly with metoprolol or nebivolol showed hypotonia/hypotension. The mechanism of these interactions probably consisted of the intensification of the hypotensive effect of beta-blockers by chlorprothixene, an antipsychotic that has an α-blocking effect.
The combination of another beta blocker, atenolol, and risperidone caused one patient to develop atrial fibrillation. As a possible mechanism, the worsening of the side effects of both drugs was identified, as was the ventricular arrhythmias observed in three patients who used ziprasidone and sotalol.
Another large group of interactions was between antipsychotics and statins (n = 12, approximately 23% of cases). In 11 cases, the interaction effects were muscle disorders, i.e. myalgia, myopathy or elevated creatine kinase. The interaction of atorvastatin with haloperidol (n = 1), quetiapine (n = 3) and risperidone (n = 1) and simvastatin with quetiapine (n = 5) and risperidone (n = 2) was observed. The mean age in this group was 58.92 years (SD = 8.41).
The potential mechanism of interaction could be the competition of both drugs for the active site of the CYP3A4 isoenzyme and consequently the increase in the level of serum statins and undesirable effects on the part of the muscular system.
The authors highlight that a case of interaction between atorvastatin and quetiapine caused lower limb edema. Another case, in which simvastatin was added to risperidone therapy induced an elevated serum statin level followed by rhabdomyolysis and a compartment syndrome in the lower limb.
A total of 11 interactions (n = 11, approximately 21%) were observed in patients using antipsychotics and antiarrhythmic drugs such as amiodarone (Williams class III antiarrhythmic drug), flecainide, or propafenone (class Ic). There were six cases of interactions involving amiodarone.
In the case of drug interaction with aripiprazole or clozapine, amiodarone inhibited CYP 2D6 activity and consequently antipsychotic metabolism was inhibited, resulting in extrapyramidal symptoms, akathisia and tremor (for aripiprazole) and sialorrhea, akathisia, tremor, hyperthermia (for clozapine).
Two other interactions of amiodarone, with ziprasidone or asenapine, the mechanism of which was probably the sum of the side effects of the drugs, caused the appearance of ventricular arrhythmias.
The observed propafenone interactions probably resulted from inhibition of cytochrome P450 isoenzymes by this antiarrhythmic drug. The combination with clozapine resulted in the inhibition of the metabolism of this drug at the level of CYP1A2 and the appearance of intense salivation in one patient. While three interactions of propafenone with olanzapine have been described, which appears to be supported by propafenone’s inhibition of CYP1A2 and CYP2D6 isoenzymes, resulting in gynecomastia, galactorrhea, akathisia and priapism.
Another antiarrhythmic drug, flecainide in combination with olanzapine, caused pancreatitis in one patient. Inhibition of the CYP2D6 isoenzyme by flecainide is also a likely mechanism here.
Six cases have been related to combinations of drugs from the group of calcium channel blockers (CBB) with antipsychotics (n = 6, approximately 11.5% of cases): two interactions with verapamil, two with diltiazem and one with amlodipine and lercanidipine.
There were two cases of haloperidol interactions in people using amlodipine or lercanidipine . The source of these interactions was probably the inhibition of BCC metabolism by haloperidol, which inhibits the activity of the CYP3A4 isoenzyme. Therefore, the interaction effect was the severity of BCC activity and the occurrence of hypotension.
There were two cases of interactions involving diltiazem . When this medication was combined with quetiapine, the patient developed blurred vision, and collapse with subsequent fracture of the femoral neck. In another patient, the interaction between diltiazem and sertindole was probably responsible for the development of ventricular arrhythmias.
For both interactions, the proposed mechanism is the inhibitory effect of diltiazem on CYP3A4 and, consequently, the decrease in the metabolism of quetiapine and sertindole. The analogous mechanism probably underlies other interactions described: verapamil with quetiapine.
With high probability, the inhibition of quetiapine metabolism by verapamil led to the patient’s restless legs syndrome. On the other hand, the interaction of verapamil with risperidone could be due to the combination of both drugs and the aggregation of side effects, resulting in bradycardia.
The remaining ten cases of interactions are related to cardiac medications other than beta-blockers, statins, antiarrhythmics, and calcium channel blockers.
In five patients, there was an interaction between doxazosin and antipsychotics; The addition of the alpha-blocking effect of doxazosin with pernazine, promazine or risperidone was associated with the appearance of hypotension, sometimes additionally with dizziness and falls.
A case of interaction between haloperidol and the oral anticoagulant dabigatran was reported, which resulted in a decrease in the effectiveness of dabigatran and the occurrence of peripheral thrombosis.
Two interactions were related to the use of ivabradine - a multifunctional drug with selective blockade of the sinus-vestibular channel, used to treat ischemic heart disease - where, most likely due to competition for the same isoenzyme (CYP3A4), the metabolism of the antipsychotics. This was associated with the development of fever in a patient who used clozapine and blurred vision, collapse, and subsequent fracture of the femoral neck in a person who took quetiapine.
In the case of the combination of risperidone with clozapine, aggravation of side effects in one patient triggered hypotension. An analogous mechanism was probably responsible for the development of atrial fibrillation in a patient treated with risperidone and losartan.
The authors mention that so far, none of the above-mentioned interactions between cardiac drugs and antipsychotics have been described in the literature.
| Conclusion |
- Due to the coexistence of mental illnesses such as bipolar disorder and schizophrenia with cardiovascular disease, the use of antipsychotics with cardiac drugs is a common phenomenon.
- Clinical decisions should be preceded by a detailed analysis of the risk-benefit ratio to seek drug combinations that are as safe as possible.
