Ethanol

Mechanism of Action

Antidote

• Methanol poisoning: Methanol is less toxic than its metabolized counterpart, formic acid. Alcohol dehydrogenase (ADH) converts methanol into formaldehyde. Aldehyde dehydrogenase (ADLH) converts formaldehyde into formic acid, a chemical responsible for the harmful effects associated with methanol poisoning, such as vision loss and Parkinsonian movements. This process is the same for ethanol. However, ethanol has a greater affinity for ADH and ADLH than methanol; ethanol administration competitively inhibits methanol metabolism, reducing the formation of formic acid.
• Ethylene glycol poisoning: Similar to methanol, ethylene glycol is metabolized by ADH in the liver to form glycolaldehyde, which ALDH converts to glycolic acid. Glycolic acid may be further metabolized into oxalic acid. Glycolic acid is more toxic than ethylene glycol, and oxalic acid can form calcium oxalate crystals in the kidney. Ethanol also has a greater affinity for ADH and ADLH than ethylene glycol and competitively inhibits ethylene glycol metabolism.

Hand Sanitizer and Sepsis Prevention

Many surveys have reported the global burden of healthcare-associated infections (HCAIs). Alcohols exhibit antimicrobial activity by denaturing and coagulating proteins within the microbial cell wall. Ethanol is also effective against viruses and can be combined with other alcohols to achieve a powerful synergistic effect against various microorganisms. 

• Ethanol lock therapy (ELT): This therapy primarily benefits patients receiving total parenteral nutrition. An ethanol lock created in the lumen of the IV catheter kills and prevents the growth of bacteria, significantly reducing catheter-related bloodstream infections (CRBSIs). No reports of bacteria exhibiting resistance to ethanol have been documented.

Ablative/Sclerosing/Embolic Agent

Ethanol may be used to treat various neoplasms, cysts, and vascular malformations or induce neurolysis. Ethanol is directly toxic and dehydrating to cells that form the endothelial lining, causing fibrotic changes. This fibrosis leads to ischemia and size reduction of tumors and other hyperplastic growths.[19]

Administration

Available Dosage Forms and Strengths

Ethanol solution is clinically available as a 95% solution in 1.0 mL and 5.0 mL vials for injection and as a 70% solution for use during ethanol lock therapy. Ethanol is also commercially available as a 10% solution. Intravenous infusion is the preferred method for patients with methanol or ethylene glycol poisoning. However, ethanol may also be administered orally or through a nasogastric tube.

Adult Dosing

Hand sanitizer:

Alcohol-based hand sanitizer (ABHS) is known to prevent nosocomial infections. However, the efficacy of these compounds against neutralizing microorganisms is dependent mainly on the effectiveness of their use. Several studies recommend applying 2.4 to 3 mL for a minimum of 30 seconds to ensure maximum possible disinfection.[1]

Methanol toxicity:

The loading and maintenance doses should be carefully monitored in an intensive care setting to prevent any toxic effect of ethanol itself.

Ethanol solution (95%):

• Loading dose (oral or NG tube): 600-700 mg/kg, diluted to ≤20% with water or juice

Ethanol solution (10%):

• Loading dose (IV):
  • 7.6 mL/kg (600 mg/kg) for a patient with a negative blood ethanol level
    • The dose is reduced for patients with a positive blood ethanol level
• Maintenance:
  • Intravenous:
    • 0.83 mL/kg/hr (65-155 mg/kg/hr) for healthy patients.
    • Patients with chronic alcohol use disorder or who are on hemodialysis require higher doses.
  • Oral:
    • 1.5 mL/kg/hr until a plasma ethanol level of 100 mg/dL is achieved.
    • Patient ethanol levels are obtained hourly until this threshold. Afterward, ethanol levels may be obtained every 2-4 hours.

Ethanol lock therapy:

Ethanol lock therapy (ELT) and regular antibiotic therapy may be co-administered over 4-6 hours. This regimen significantly reduces the incidence of catheter-related bloodstream infections (CRBSI).

Ablation or sclerosis:

Ethanol is injected directly into the lesion or parenchyma of the specific organ or tissue. Clinicians may be guided by endoscopic ultrasound or CT. 

Pediatric Dosing

Methanol toxicity:

Ethanol solution (95%):

• Loading dose (oral): 0.8-1.0 mL/kg
• Maintenance (oral): 0.1 mL/kg/h

Ethanol solution (10% = 7.9 g/dL):

• Loading dose (IV): 8-10 mL/kg, not to exceed 200 mL total
• Maintenance (IV): 0.83 mL/kg/h

Adverse Effects

During the liver's conversion of ethanol to acetaldehyde, the electron carrier NAD⁺ donates 2 electrons to this reaction. In the process, NAD⁺ is reduced to NADH, increasing the NADH/NAD⁺ ratio in the hepatocytes.

An elevated NADH/NAD⁺ ratio causes:

• Ketoacidosis: The citric acid (TCA) cycle inhibition increases acetyl-CoA levels. This excess acetyl-CoA is shunted into the ketogenesis pathway, resulting in increased production of ketoacids (eg, acetoacetic acid). 
• Fasting hypoglycemia: The increased NADH/NAD⁺ ratio inhibits the conversion of malate to oxaloacetate (OAA). The resulting reaction equilibrium forces OAA to be converted back into malate. Oxaloacetate may also be converted into phosphoenolpyruvate (PEP). By inhibiting the formation of OAA, an elevated NADH/NAD⁺ ratio impairs gluconeogenesis.
• Hepatic steatosis: An increased NADH/NAD⁺ ratio stimulates fatty acid and glycerol-3-phosphate synthesis. These combine to increase TAG levels, resulting in fatty liver.

Ingested ethanol is primarily metabolized in the liver; hepatic damage often accompanies chronic alcohol consumption. This damage can lead to steatosis, cirrhosis, and hepatic carcinoma. Other affected organs/organ systems include:

• Gastrointestinal: Gastritis, malabsorption, carcinoma 
• Cardiovascular: Hypertension, cardiomyopathy, arrhythmia
• Renal: Glomerulonephritis, AKI
• Reproductive: Infertility, premature birth, low birth weight, fetal alcohol syndrome
• Pancreas: Pancreatitis
• Breast: Carcinoma 
• Neurological/psychiatric: Stroke, depression, meningitis, cerebellar degeneration [20]

Contraindications

Ethanol must not be administered concurrently with fomepizole, which inhibits ethanol metabolism and prolongs its half-life. This inhibition can result in significantly elevated ethanol levels and possible manifestations of ethanol intoxication. Contraindications to ethanol administration also include pregnancy and breastfeeding.

Hand Sanitizer

Although there is no objective contraindication for alcohol-based hand sanitizer (ABHS) in any particular medical setting, it is common knowledge that ABHS doesn't kill all harmful microorganisms, including the spores of Clostridium difficile. ABHS is also ineffective against some protozoan oocysts (eg, Cryptosporidium) and non-enveloped viruses (eg, norovirus). Handwashing using soap and water is more effective against these organisms than ABHS.[1]

Ablation

Percutaneous ethanol injection as part of ablation therapy is contraindicated when:

• Prothrombin time (PT) is less than 40% of normal
• Platelet count <40,000/mm³ [21]

Monitoring

Ethanol demonstrates zero-order kinetics. Alcohol is primarily absorbed in the proximal small intestine, but a small fraction is also absorbed by the mucosal layer of the mouth, esophagus, and stomach. Alcohol is primarily metabolized in the liver; the rate of oxidation per unit time yields a linear curve. Insulin release stimulates ethanol metabolism, while conditions like starvation impair this process. Alcohol metabolism occurs via an oxidative and non-oxidative pathway. Various enzymes play a role in the oxidative pathway, including alcohol dehydrogenase (ADH) in the cytosol, aldehyde dehydrogenase (ALDH) in mitochondria, cytochrome P450 (CYP2E1) in microsomes, and catalase in peroxisomes. The non-oxidative pathway includes the enzymes fatty acid ethyl ester synthase (FAEES) and phospholipase D (PLD). The administration of medications that inhibit the oxidative pathway enzymes drive non-oxidative metabolism.[22]

In the oxidative pathway, ethanol is first converted to acetaldehyde by alcohol dehydrogenase (ADH) in the cytosol of hepatocytes. NAD⁺ serves as an electron carrier for this reaction and is reduced to NADH. This process significantly reduces the cytosol, predisposing to damage by reactive oxygen species (ROS) and other byproducts of alcohol metabolism. The drug fomepizole competitively inhibits ADH, preventing the formation of toxic metabolites. 

Acetaldehyde is further oxidized in the liver by acetaldehyde dehydrogenase (ALDH) to acetic acid, which is converted to acetyl-CoA by acetyl-CoA synthetase. Acetyl-CoA is eventually transformed into acetone through ketoacid intermediates. Acetone is oxidized to CO₂ in the cardiac and skeletal muscles and the brain. Administration of disulfiram (an acetaldehyde dehydrogenase inhibitor) delays acetaldehyde clearance, causing symptoms such as nausea, vomiting, chest and abdominal pain, dizziness, and worsening hangover. This medication may be used to help treat alcohol use disorders. Drugs that exhibit properties similar to disulfiram include metronidazole, sulfamethoxazole and trimethoprim, chloramphenicol, quinacrine, first-generation sulfonylureas, griseofulvin, and some cephalosporins such as cefotetan and cefoperazone.

The non-oxidative pathway produces fatty acid ethyl esters (FAEEs), which cause tissue damage and form phosphatidyl ethanol from phospholipase D. Given phospholipase D's role in cell signaling, excessive non-oxidative pathway activation can impair this communication.[22] Transient heart block can occur after alcohol septal ablation procedures, necessitating the insertion of a temporary pacemaker.[23] About 10% of these heart blocks persist and require a permanent pacemaker.

Toxicity

Alcohol intoxication causes CNS depression by enhancing the inhibitory effect of GABA on its receptors. Alcohol also inhibits the effects of glutamate on NMDA receptors, resulting in disinhibition and a blunted mental state. Ethanol intoxication manifests as slurred speech, stupor, and gait abnormalities. Severe intoxication may even result in a coma. 

Clinicians should first correct thiamine (vitamin B1) deficiency, which often accompanies chronic alcohol use disorder. Electrolyte derangements should be corrected through appropriate infusion. Extensive counseling is frequently required for patients with alcohol use disorder. Some medications that promote alcohol cessation include naltrexone (μ-opioid receptor antagonist), disulfiram (negative conditioning), topiramate, and gabapentin.

Alcohol withdrawal is another common morbidity that arises as a complication of alcohol use disorder (AUD). Alcohol withdrawal syndrome (AWS) occurs due to abrupt cessation of alcohol consumption after binge drinking or long-term dependence. The signs and symptoms range from mild (eg, anxiety, headache, palpitations) to severe (eg, seizures, delirium tremens). The features of AWS typically arise within 24 hours of discontinuing alcohol consumption. Treatment involves supportive therapy for complaints. Any associated comorbidities should be treated with a 'banana bag' of essential vitamins. Severe AWS is an indication for benzodiazepine administration.[24]

Enhancing Healthcare Team Outcomes

Ethanol has existed as a recreational beverage since the beginning of civilization. Over the past century, extensive research has demonstrated ethanol's uses for treating disease. Ethanol has become indispensable in preventing hospital-acquired infections as a component of hand sanitizer formulas. Healthcare providers (including clinicians, mid-level providers, nurses, and pharmacists) must sanitize their hands and wear gloves before touching the patient or handling equipment (eg, catheter tubes, cannulas). This principle is also the basis of ethanol lock therapy in an ICU setting to prevent sepsis associated with infected catheters.

Ethanol is currently being studied as an ablative agent for treating different neoplastic conditions that cannot be treated with surgery. The surgeon must evaluate appropriate candidates based on age, financial status, and comorbid conditions to appropriately recommend ethanol ablation over classic surgery for the purpose of preventing mortality.

Ethanol has been used for decades as a treatment for methanol or ethylene glycol poisoning. Even though fomepizole has emerged as a better antidote due to its superior neutralization of the offending agent, more predictable pharmacokinetics, and lower associated mortality, many still prefer ethanol due to its low cost and greater physician familiarity.  

Alcohol use disorder remains a global challenge, considering the mortality that correlates with misuse. More than 135 million Americans aged 12 and older actively use alcohol.[25] The clinician must identify and counsel these patients. If necessary, they should be hospitalized and receive appropriate treatment. The optimal therapeutic use of ethanol may be achieved through an interprofessional healthcare team, including clinicians (MDs, DOs, NPs, PAs), nursing staff, and pharmacists, who work collaboratively to achieve optimal patient outcomes with minimal adverse events.