Vasoconstrictors are included in local anesthetics to increase the duration of anesthesia, to prevent local anesthesia systemic toxicity, and to promote hemostasis in the local operative field.¹ Adrenaline (epinephrine) is the most common vasoconstrictor that is added to local anesthetics, and lidocaine and articaine with adrenaline are the most widely used local anesthetics for dental treatment. However, adrenaline has drug interactions with some medicines. It is widely believed that the combination of adrenaline with an antipsychotic can cause hypotension because antipsychotics have α-adrenergic blocker effects that can result in decreased peripheral resistance, and adrenaline has been shown to have significant β2-adrenergic mediated vasodilatory effects that also can cause hypotension. Therefore, the combination of adrenaline and an antipsychotic is contraindicated in Japan for fear of causing significant hypotension. However, there is insufficient evidence supporting this claim, and, in clinical settings, there are many situations in which the use of local anesthetics with adrenaline is appropriate for dental treatment of patients receiving antipsychotic therapy. Thus, the purpose of the present study was to clarify the changes in hemodynamics caused by a drug interaction between adrenaline and an antipsychotic and to evaluate the safety of the combined use of adrenaline with an antipsychotic in an animal study.

MATERIALS AND METHODS

RESULTS

Figure 1 shows the hemodynamic changes caused by the drug interaction between adrenaline and chlorpromazine. Intraperitoneal injection of 100 μg/kg adrenaline induced significant hypotension immediately in only chlorpromazine-pretreated rats (P = .008, 2-way ANOVA with post hoc Bonferroni's test; the interaction of main factor and time was significant), and induced significant tachycardia in chlorpromazine-pretreated rats and saline-pretreated rats (P = .015, 2-way ANOVA with post hoc Bonferroni's test; the interaction of main factor and time was significant). In contrast, in chlorpromazine and propranolol–pretreated rats, modest hypertension was induced by 100 μg/kg adrenaline injection (P = .021, 2-way ANOVA with post hoc Bonferroni's test; the interaction of main factor and time was not significant), and neither hypotension nor tachycardia was shown (Figure 2).

Figure 3 shows the dose-dependent effect of adrenaline on the drug interaction between adrenaline and chlorpromazine. Thus, adrenaline injection caused hypotension (saline: 101.3 ± 7.9%; 1 μg/kg: 99.0 ± 18.6%; 10 μg/kg: 84.7 ± 6.2%; 100 μg/kg: 71.5 ± 9.0%) and tachycardia (saline: 97.2 ± 5.8%; 1 μg/kg: 99.6 ± 6.4%; 10 μg/kg: 106.8 ± 9.4%; 100 μg/kg: 123.2 ±10.0%). The injection of 100 μg/kg adrenaline caused significant hypotension (P = .0036, 1-way ANOVA with Dunnett's post hoc test) and tachycardia (P = .0005, 1-way ANOVA with Dunnett's post hoc test).

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DISCUSSION

Our results show that the drug interaction between adrenaline and chlorpromazine induced hypotension in rats. In the presence of a nonselective β-blocker (propranolol), modest hypertension by α receptor action of adrenaline was shown and hypotension by the drug interaction between adrenaline and chlorpromazine was not induced. This suggested that the hypotension caused by the drug interaction between adrenaline and chlorpromazine occurred through the β-adrenergic receptor activity. Moreover, this reaction was dose dependent, with the 100 μg/kg adrenaline dose inducing significant hemodynamic changes.

Adrenaline has many drug-drug interactions. Tricyclic antidepressants, monoamine oxidase inhibitors, nonselective β-adrenoceptor antagonists, general anesthetics, cocaine, and antipsychotics such as chlorpromazine are listed as drugs that interact with adrenaline.^1,2 Of these drugs, some antipsychotics are listed as contraindicated in the adrenaline drug information insert, and it is prohibited in Japan to use adrenaline in patients taking phenothiazine (eg, chlorpromazine) or butyrophenone antipsychotics because they can induce severe hypotension.

Schizophrenia is a severe form of mental illness. The lifetime prevalence and incidence of schizophrenia are 0.33–0.66% and 10.2–22.0 per 100,000 person-years,³ respectively, and schizophrenia affects about 24 million people worldwide.⁴ Antipsychotics block D₂-dopamine receptors and reduce dopamine neurotransmission, and some also interact with D₁- and D₄- dopaminergic, 5-HT_2A and 5-HT_2C–serotonergic, and α-adrenergic receptors. Among antipsychotic drugs, chlorpromazine produces the most significant α receptor blockade.⁵

Antipsychotics are classed into 2 generations. Typical first-generation drugs include haloperidol, chlorpromazine, pimozide, and perphenazine, and second-generation drugs include clozapine, quetiapine, and risperidone. Second-generation antipsychotics have fewer side effects than first-generation; therefore, second-generation antipsychotics are regarded as a first-line therapy. However, first-generation drugs still remain as important and effective medicines for antipsychotic therapy,^6,7 and many patients are still taking first-generation antipsychotics.

Adrenaline is a potent stimulant of both α- and β-adrenergic receptors. α-1 adrenergic receptors are located in vascular and genitourinary smooth muscle and cause smooth muscle constriction. Located in pancreatic islets (β cell), platelets, nerve terminals, and vascular smooth muscle, α2 receptors decrease insulin secretion, increase aggregation, release norepinephrine, and cause vasoconstriction, respectively. On the other hand, β1 and β2 receptors are located in the heart and smooth muscle (vascular, bronchial, gastrointestinal, and genitourinary), respectively. Activation of β receptors increases the force and rate of the heart and the relaxation of smooth muscle. The effect of intravenous infusion of adrenaline in humans⁵ is increased systolic pressure and heart rate. Diastolic pressure usually falls and the mean blood pressure is not greatly elevated because of β2-mediated vasodilator action that is partially counterbalanced by vasoconstriction by α receptor activity. If an α receptor antagonist is given in the presence of adrenaline, the vasodilatation is more pronounced, total peripheral resistance is decreased, and mean blood pressure falls; this is known as adrenaline (epinephrine) reversal.⁵

Some previous reports have shown a drug interaction between adrenaline and chlorpromazine. Foster et al.⁸ and Ginsburg and Duff⁹ studied the drug interaction between adrenaline and chlorpromazine by measuring blood flow in humans. Foster et al.⁸ demonstrated the reversal of adrenaline vasoconstriction by chlorpromazine; however, Ginsburg and Duff⁹ showed no reversal action. Yagiela et al.¹⁰ also reported hemodynamic changes caused by drug interaction between adrenaline and chlorpromazine in dogs. They found that low-dose adrenaline (0.33 μg/kg) did not influence blood pressure or heart rate; however, high-dose adrenaline (2.5 μg/kg) induced hypotension and tachycardia.

Adrenaline prolongs the duration of the local anesthetic effect, and commercially prepared local anesthetics with adrenaline are available in dental local anesthetic cartridges. These products are very efficient, effective, and convenient. In the dental field, there are generally 4 different concentrations of adrenaline available in local anesthetics: 1 : 50,000 (20 μg/mL), 1 : 80,000 (12.5 μg/mL), 1 : 100,000 (10 μg/mL), and 1 : 200,000 (5 μg/mL). In the present study, only 100 μg/kg of adrenaline induced significant hemodynamic changes, and this adrenaline dose is equivalent to 300 mL local anesthetic with 1 : 50,000 adrenaline (assumed 60-kg patient). However, this huge dose would be inconceivable in human dental treatment. These findings suggest that a clinical amount of local anesthetic used with adrenaline in dental treatment should not induce severe hypotension in patients taking an antipsychotic. However, it is unclear whether we can equate the dose in rats with that in humans, and therefore this is a limitation of the present study.

In conclusion, we showed that hypotension and tachycardia were caused by a drug interaction between adrenaline and chlorpromazine, and this change was dose dependent. Our animal study therefore provides additional evidence that low-dose adrenaline added to local anesthetics may not induce severe hemodynamic changes, and that the use of local anesthetics with adrenaline may be safe for patients undergoing dental treatment who are taking antipsychotics such as chlorpromazine.