A31: Antidotes in Depth

Ethanol is used therapeutically as a competitive substrate for xenobiotics metabolized by alcohol dehydrogenase, thus limiting the bioactivation of those xenobiotics to toxic metabolites. Methanol and ethylene glycol are potentially lethal xenobiotics metabolized by this pathway.^11,12 Ethanol may also inhibit the metabolism of short chain polyethylene glycols, such as di- and triethylene glycol,⁵³ and possibly compete with monofluoroacetate and fluoroacetamide for binding to the tricarboxylic acid cycle. Ethanol also affects the cytochrome P450 CYP enzyme system, especially CYP2E1, for which it has biphasic properties as an inducer and an inhibitor similar to fomepizole and isoniazid. The competitive relationship of ethanol with potentially toxic xenobiotics can be used to therapeutic advantage, but the effect of ethanol on the CYP system often leads to unwanted drug interactions and pharmacokinetic tolerance after several days of administration.

Ethanol has been used as an antidote for methanol poisoning since the 1940s and for ethylene glycol since the 1960s.²

Mechanism of Action

Ethanol works as a competitive substrate for alcohol dehydrogenase, inhibiting the metabolism of xenobiotics like methanol and ethylene glycol that use this enzyme.

Affinity for Alcohol Dehydrogenase

The dose of ethanol necessary to achieve competitive inhibition depends on the relative concentrations of the toxic alcohols and their affinity for the enzyme. An affinity constant, K_m, is used to express the degree of affinity: the lower the K_m value, the stronger the affinity. The following equates mmol or mg for alcohols: 1 mmol ethanol equals 46 mg, 1 mmol methanol equals 32 mg, and 1 mmol ethylene glycol equals 64 mg. A millimolar concentration means mmoles/L. A summary of in vitro experiments using human liver cells demonstrated a K_m of 30 mM for ethylene glycol, 7 mM for methanol, and 0.45 mM for ethanol.^29,42,43 This means that the molar affinity of ethanol for alcohol dehydrogenase is 67 times that of ethylene glycol and 15.5 times that of methanol. Studies in methanol-poisoned monkeys revealed that when ethanol was administered at a molar ethanol-to-methanol ratio (E:M) of 1:4, the metabolism of methanol was reduced by 70%; at a 1:1 E:M ratio, metabolism was reduced by greater than 90%.³² In these experiments, the dose of methanol was kept constant at about 1 g/kg (31 mmol/kg), whereas the dose of ethanol was varied. Although the serum methanol concentration was not measured, a calculation using this dose and a volume of distribution (Vd) of 0.6 L/kg would predict a serum concentration of about 166 mg/dL. Even in molar ratios as high as 1:8, methanol did not inhibit ethanol metabolism. When ethylene glycol and methanol are administered together in a 0.5:1 molar ratio, ethylene glycol did not inhibit methanol metabolism.³² When compared with methanol smaller amounts of ethanol are required to block the metabolism of ethylene glycol, as the affinity of ethylene glycol for alcohol dehydrogenase is less than that of methanol.^{22,29,42,43,45,51} Most authors^1,22,51 recommend either a serum ethanol concentration of 100 mg/dL, or at least a 1:4 molar ratio of ethanol to methanol or ethylene glycol, whichever is greater. Using this ratio, 100 mg/dL (∼ 22 mmol/L) of ethanol protects against 88 mmol/L (286 mg/dL) of methanol or 88 mmol/L (546 mg/dL) of ethylene glycol. Inhibiting the metabolism of methanol and ethylene glycol impedes the formation of toxic metabolites and prevents the development of metabolic acidosis.^13,16,21,51 After this toxic metabolic pathway is blocked with ethanol, renal, pulmonary, and extracorporeal routes of toxic alcohol removal become the sole mechanisms for elimination.

Ethanol administered orally is rapidly absorbed and achieves peak concentrations in about 1 to 1.5 hours.^8,15,30,52 The amount of ethanol absorbed after oral administration is highly variable and dependent on a number of factors, such as ethanol dose, fasting, nutritional status, accelerated gastric emptying, gender, genetics, chronic alcohol use, lean body mass, and increasing age, as well as the presence of certain H₂-receptor antagonists.^{6,9,15,25,27,37,54,57} Sufficient concentrations are generally achieved when 0.8 g/kg of ethanol is given orally over 20 minutes.^{6,8,9,15,27,52}

Given that the Vd for ethanol is approximately 0.6 L/kg,^10,58 the loading dose of ethanol is obtained by the following formula:

For a 70 kg person, the loading dose would be 42 g (70 kg × 0.6 g/kg) of ethanol, or 420 mL of 10% V/V (volume-to-volume) ethanol. This calculation assumes that the specific gravity of ethanol is 1 g/mL. However, a 0.8 g/kg or 8 mL/kg loading dose of a 10% ethanol solution is recommended in order to provide a margin of safety because of the variabilities in Vd and the ongoing metabolism that occurs during administration.^26,44 The intravenous (IV) loading dose should be administered over 20 to 60 minutes, as tolerated by the patient. The 10% ethanol concentration is preferable to the 5% concentration to limit the volume of fluid administered. It is also preferred over the more concentrated solutions to limit local venous irritation and avoid postinfusion phlebitis. Because of the free water content and significant hypertonicity of the 10% solution, the patient should be closely observed for the development of hyponatremia.

To maintain an ethanol concentration of 100 mg/dL, ethanol replacement must equal ongoing elimination (66–130 mg/kg/h). The average hourly dose for a 70 kg person is 4.6 g, but higher doses are required in ­ethanol tolerant patients (100–154 mg/kg/h) or others who may have induced enzymes, and in those undergoing hemodialysis (250–350 mg/kg/h; Chap. 10).^{12,22,33,40,41}

When administered in a timely fashion after the toxic alcohol ingestion and before the accumulation of the toxic metabolites, case reports confirm the efficacy of ethanol in preventing the sequelae of methanol and ethylene glycol poisoning.^7,9,24,50,55 In the presence of sufficient inhibitory concentrations of ethanol, the half-life of ethylene glycol in two patients with normal kidney function was 17.5 hours, which was comparable with 17 hours in a case series of patients receiving fomepizole alone with normal kidney function.^7,49 A half-life of 46.5 hours for methanol was reported in a patient who had received a sufficient blocking quantity of ethanol⁴⁰ which is quite similar to the 54 hours reported in a case series of methanol-poisoned patients treated only with fomepizole.^5,24

Problems encountered with the administration of ethanol include further risk of central nervous system (CNS) depression, behavioral disturbances, or ethanol related toxicity, such as hepatitis and pancreatitis, hypoglycemia, dehydration, fluctuating serum concentrations, and potential drug interactions resulting in disulfiramlike reactions.^{3,14,18,28,34,38,39,56,59}

Ethanol (injection) is US Food and Drug Administration pregnancy ­category C. Ethanol crosses the placenta and reaches the fetus. Ethanol is teratogenic, and the American Academy of Pediatrics (AAP) recommends that pregnant women abstain from all alcohol consumption. It is likely that the short duration of ethanol therapy, when used to compete with alcohol dehydrogenase, during the second or third trimester, has a minimal risk of inducing fetal alcohol syndrome. Ethanol should only be used following a risk benefit analysis, particularly in the first trimester. Ethanol crosses into breast milk and may cause CNS depression and ethanol toxicity in the breast-fed infant.

Ethanol can be given either orally or IV (Tables A31–1 and A31–2). ­Concentrations of 20% to 30% orally and 5% to 10% IV are well tolerated. Intravenous administration has the advantages of complete absorption²⁶ and avoidance of most gastrointestinal symptoms, and can be used in an unconscious or uncooperative patient. The disadvantages of IV ethanol include difficulty in obtaining and preparing an IV ethanol solution, the hyperosmolarity of a 10% ethanol solution (∼ 1900 mOsm/L), and the possibilities of osmotic dehydration, hyponatremia, and venous irritation.

Regardless of route, the objective is to rapidly achieve and maintain a serum ethanol concentration of at least 100 mg/dL, which is adequate for enzyme inhibition in most cases. Inhibition is best achieved by administering a loading dose of ethanol, followed by a maintenance dose.

Because ethanol elimination varies in each individual, frequent serum ethanol determinations should be obtained to ensure adequate dosing while also monitoring blood glucose and fluid and electrolyte status. In addition, any increase in the anion gap or decrease in bicarbonate concentration implies that the ethanol dose is inadequate to achieve blockade of alcohol dehydrogenase and the ethanol dosing should be increased.

A practical problem often involves preparing the ethanol to be given since commercial preparations of 5% ethanol in 5% dextrose are no longer available for IV administration.⁴ Not having a commercially available preparation increases the delay to administration of IV ethanol and the potential for a medication error in preparation. Sterile ethanol USP (absolute ethanol) can be added to 5% dextrose to make a solution of approximately 10% ethanol concentration; 55 mL of absolute ethanol is added to 500 mL of 5% dextrose to produce a total volume of 555 mL (10% = 10 mL in 100 mL; in this case, 55 mL in 555 mL or 55/555). If oral administration is chosen, then it is important to remember that in the United States the “proof” number on the label is double the concentration; that is, “100-proof” ethanol is 50% ethanol by volume (50 mL/100 mL). If there will be any delay in preparing ethanol for IV use and fomepizole is not available or used, then oral therapy with ethanol should be initiated immediately.

Although ethanol has been used as an antidote for toxic alcohols for many years in both adults and children,⁴⁶ and has the advantages of easy accessibilities to oral ethanol and low acquisition cost, fomepizole is a very potent inhibitor of alcohol dehydrogenase with many important advantages.^{17,19,23,31,35,36} Fomepizole does not produce CNS depression, is easier to dose, and does not require serum concentration monitoring. Although fomepizole is more costly than ethanol, its many advantages over ethanol make fomepizole the preferable antidote (Antidotes in Depth: A30 and Chap. 109).^28,48,56

• When administered appropriately, ethanol is an excellent first step in preventing further metabolism of methanol and ethylene glycol to their respective toxic metabolites.

• The disadvantages of ethanol compared with fomepizole (when available) make ethanol an outmoded antidote under most circumstances.

• Neither fomepizole nor ethanol affects the toxic metabolites already present in the body.

• Once alcohol dehydrogenase is blocked, the decision whether to use hemodialysis depends on the degree of end-organ damage that has occurred, how well the body can eliminate the parent compound ­without the benefit of hemodialysis, and the extent to which toxic metabolites are already present.

• With the use of either ethanol or fomepizole without subsequent hemodialysis, the increase in hospital length of stay in an intensive care unit or on a medical floor may be substantial for methanol poisoned patients.^20,47

References