Amiodarone, lamotrigine and phenytoin, common anti-arrhythmic and anti-epileptic drugs, inhibit a persistent sodium current in neurons (INaP). Previous results from our laboratory suggested that INaP is critical for functionality of peripheral chemoreceptors. In this study, we determined the effects of therapeutic levels of amiodarone, lamotrigine and phenytoin on peripheral chemoreceptor response to hypoxia. Action potentials (APs) of single chemoreceptor afferents were recorded using suction electrodes advanced into the petrosal ganglion of an in vitro rat peripheral chemoreceptor complex. AP frequency (at PO₂150 mmHg and PO₂90 mmHg), conduction time, duration and amplitude were measured before and during perfusion with therapeutic dosages of the drug or vehicle. Hypoxia-induced catecholamine secretion within the carotid body was measured using amperometry. Using whole-body plethysmography, respiration was measured in unanesthesized rats while breathing room air, 12% O₂ and 5% CO₂, before and after IP administration of amiodarone, lamotrigine, phenytoin or vehicle. Lamotrigine (10 µM) and phenytoin (5 µM), but not amiodarone (5 µM), decreased chemoreceptor AP frequency without affecting other AP parameters or magnitude of catecholamine secretion. Likewise, lamotrigine (5 mg/kg) and phenytoin (10 mg/kg) blunted the hypoxic but not the hypercapnic ventilatory response. In contrast, amiodarone (2.5 mg/kg) did not alter the ventilatory response to hypoxia or hypercapnia. We conclude that lamotrigine and phenytoin at therapeutic levels impair peripheral chemoreceptor function and ventilatory response to acute hypoxia. These are consistent with INaP serving an important function in AP generation and may be clinically important in the care of patients using these drugs.