The Effect of Long-Term Alcohol Use on Propofol

July 1, 2024

Cross-tolerance is a biological phenomenon where repeated exposure to one drug may reduce sensitivity to another.1 The most examined example of this event is the relationship between concomitant intake of nicotine and alcohol. For example, it has been shown that micro-infusions of nicotine in the mouse cerebellum attenuates ethanol-induced ataxia via the activation of nicotine acetylcholine receptors (nAChRs).2 These findings corroborate anecdotal and observational data from human studies, where co-consumption of both drugs is known to evoke higher cravings to both nicotine and alcohol, because exposure to one drug diminishes the aversive effects of the other. Of interest is what impacts substance use may have on medications. In particular, this article will discuss research on how alcohol use impacts propofol administration and other anesthetics.

Cross-tolerance between ethanol and cyclopropane, formerly used as an inhalational anesthetic, has been reported in rats, as well as between ethanol and isoflurane, a modern inhalational anesthetic, in mice.2,3 In the latter study, mice exposed to alcohol demonstrated a lack of muscular response to over-pressurization and required higher doses of isoflurane to experience anesthetic effects.3

Propofol is one of the most commonly administered intravenous anesthetic agents. Its rapid and smooth induction, lack of excitation phenomena, rapid terminal half-life, and low incidence of postoperative complications contribute to the drug’s favorable pharmacological profile.4 The relationship between propofol and alcohol use was examined in a prospective, non-randomized, open study conducted in patients undergoing elective ENT surgery. On average, patients in the alcoholic group (n=26) were older and lighter than the control patients (n=20); otherwise, no significant demographic differences were reported. Both groups had similar levels of propofol in their blood immediately following intravenous administration. However, patients in the alcoholic group required significantly larger doses of propofol for loss of verbal contact and loss of muscular control.5 The authors of the paper suggest this cross-tolerance may have a hepatic source; alcohol consumption has been found to change lipid metabolism and increase infiltration of the liver. A fourfold increase in liver solubility of volatile anesthetics was reported in an alcoholic rat model. Compared to other common intravenous anesthetics, propofol is highly lipid soluble. As such, propofol uptake by the liver during anesthesia administration may reduce the concentration of the drug available for the brain, decreasing its overall efficacy.5

In 1984, a study with nine control patients and 10 patients with chronic alcoholism (without signs of cirrhosis or hepatitis) examined the pharmacokinetics of thiopental anesthesia. After analyzing blood samples taken from all patients, it was observed the plasma clearance of thiopental increased significantly from 3.7 ml/min/kg in the controls to 5.4 ml/min/kg in the alcoholic group. The researchers conclude cross-tolerance between thiopental and alcohol is a likely explanation behind the increased clearance.6 More recently, a Parisian study assessed the pharmacokinetics of propofol in human patients with high levels of alcohol use.7 The intercompartmental clearance of propofol in the alcohol use group was found to be minimally higher than the clearance rate in the control group. The researchers concluded the amount of propofol necessary to maintain anesthesia in both alcoholic and nonalcoholic patients was not significantly different.7

Much of the extant literature on the possible cross-tolerance for propofol or other anesthetics with alcohol is conflicting, not recent, and based on small sample sizes. Further clinical research on this matter may enhance our understanding of the subject and improve our healthcare regimens. 

References 

  1. Abreu-Villaça, Yael, et al. “Tobacco and Alcohol Use during Adolescence: Interactive Mechanisms in Animal Models.” Biochemical Pharmacology, vol. 144, Nov. 2017, pp. 1–17. https://doi.org/10.1016/j.bcp.2017.06.113 
  2. Taslim, N., et al. “Attenuation of Ethanol-Induced Ataxia by Α4β2 Nicotinic Acetylcholine Receptor Subtype in Mouse Cerebellum: A Functional Interaction.” Neuroscience, vol. 157, no. 1, Nov. 2008, pp. 204–213. https://doi.org/10.1016/j.neuroscience.2008.08.046 
  3. Johnstone, Robert E., et al. “Effects of Acute and Chronic Ethanol Administration on Isoflurane Requirement in Mice:” Anesthesia & Analgesia, vol. 54, no. 3, May 1975, p. 277-281. https://doi.org/10.1213/00000539-197505000-00001 
  4. Sahinovic, Marko M., et al. “Clinical Pharmacokinetics and Pharmacodynamics of Propofol.” Clinical Pharmacokinetics, vol. 57, no. 12, Dec. 2018, pp. 1539–1558. https://doi.org/10.1007/s40262-018-0672-3 
  5. Fassoulaki, Argyro, et al. “Chronic Alcoholism Increases the Induction Dose of Propofol in Humans.” Anesthesia & Analgesia, vol. 77, no. 3, Sept. 1993, p. 553-556. https://doi.org/10.1213/0 0000539-199309000-00021 
  6. Couderc, E., et al. “Thiopentone Pharmacokinetics in Patients with Chronic Alcoholism.” British Journal of Anaesthesia, vol. 56, no. 12, Dec. 1984, pp. 1393–1397. https://doi.org/10.1093/bja/56.12.1393 
  7. Servin, Frédérique S., et al. “Pharmacokinetics of Propofol Administered by Target-Controlled Infusion to Alcoholic Patients.” Anesthesiology, vol. 99, no. 3, Sept. 2003, pp. 576–585. https://doi.org/10.1097/00000542-200309000-00012

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