Ethanol-induced Depression of Hypoxic Drive and Reversal by Naloxone-A Sex Difference

Abstract

The effects of ethanol ingestion and subsequent intravenously administered naloxone on the ventilatory response to hypercapnic hypoxia in 8 normal males and 8 normal females were examined. The responses of controls were lower in the females (-0.63 +/- 0.07 L/min/% SaO2) than the males (-1.11 +/- 0.18 L/min/% SaO2). Alcohol depressed the male response to a mean of -0.50 +/- 0.08 L/min/%SaO2 (p less than 0.01) but increased the mean female response to -0.87 +/- 0.11 L/min/%SaO2 (p less than 0.01). Naloxone reversed the ethanol-induced depression of the hypercapnic hypoxic response in males, but had no effect on the female response. In males there was a direct correlation between the magnitude of the initial hypoxic response and the extent of depression by ethanol; the higher the response the greater the depression. Females showed a significant direct correlation between the blood alcohol and the increase in hypercapnic hypoxic slope, whereas males showed a weaker inverse correlation to blood alcohol level. These results demonstrate that ethanol depresses male but not female hypoxic ventilatory responsiveness and suggest that this is mediated by opioid-like mechanisms. Because the alcohol-induced depression was seen in subjects with a high control hypoxic response, the male-female difference might simply reflect initially lower control responses in females. This suggests a qualitative difference in hypoxic ventilatory control mechanisms between sexes.

Ventilatory control in patients with sleep apnoea and left ventricular dysfunction: comparison of obstructive and central sleep apnoea

“…Similar findings have been reported by other investigators [1-3, 8, 30]. This apparent gender difference may be at least partly explained by the influence of ventilatory responses, since both eucapnic hypoxic and hyperoxic hypercapnic ventilatory responses are significantly lower in females compared to males [21,33].…”

“…There were no differences in the ventilatory responses to hypoxia when tested at the patients' eucapnic level. The mean levels of these responses were similar (0.6 L·min -1 /% fall in Sa,O 2 in CSA and 0.5 L·min -1 /% fall in Sa,O 2 in OSA), values in the middle of a spectrum which, for normal males, is quite wide [20,21]. However, there was a difference of 0.8 kPa in the PET,CO 2 at which the patients were tested.…”

Comparison of effects of sustained isocapnic hypoxia on ventilation in men and women

“…In the awake state, women compared with men have been reported to have lower (32), higher (1), and equal (19,27) hypoxic ventilatory response. However, the ventilatory response to progressive short-term hypoxia has been found to be more depressed in men than in women after alcohol consumption (23) and during non-rapideye-movement sleep (31). We hypothesized that men might also be more susceptible to the ventilatory depressant effects of sustained isocapnic hypoxia.…”

Teaching From Catastrophe: Using Therapeutic Misadventures From Hydromorphone to Teach Key Principles in Clinical Pharmacology

“…29 Unfortunately, the drug reached its peak effect in the CNS only after the patient was discharged, resulting in his death at home. Furthermore, patient 4 also demonstrates the synergistic effect of alcohol (decreasing hypoxic drive) 37,38 while the concomitant administration of the opioid produced a rightward shift in the end-expiratory CO 2 concentration. 36 Therefore, only the conscious drive remained, resulting in apnea at the onset of sleep.…”

“…36 Sedative hypnotic drugs act synergistically with opioids by acting on receptors and channels distinct from mu opioid receptors. [37][38][39] Patients with underlying medical conditions, including obstructive sleep apnea and chronic obstructive pulmonary disease, also predispose to carbon dioxide retention, thereby placing these patients in an unfortunate positive feedback loop when opioids are administered to them at inappropriate doses or intervals. 20,40,41 Patients 2, 4, and 5 emphasize these principles.…”