the toxic alcohols

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Ethylene Glycol. Sweet, odorless, often brightly colored liquidCommon uses include:Automotive antifreeze and coolantHydraulic brake fluidGlass cleanerLethal dose 1.4-1.6 ml/kg. Ethylene Glycol Poisoning: Incidence. In the United States, 1999:6,077 exposures254 near-fatalities40 fatalitiesWatson WA, et al., 2002: Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. American Journal of Emergency Medicine 2003; 21(5):353-421. .

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1. The Toxic Alcohols Historical Treatment and Use of Antizol® for Methanol and Ethylene Glycol Poisoning This presentation will review the incidence, pathophysiology, clinical effects and treatment of methanol and ethylene glycol poisoning. In addition to historical therapy, it will describe Antizol®, the antidote for the treatment of these toxic alcohols. We will begin with a review of ethylene glycol poisoning.This presentation will review the incidence, pathophysiology, clinical effects and treatment of methanol and ethylene glycol poisoning. In addition to historical therapy, it will describe Antizol®, the antidote for the treatment of these toxic alcohols. We will begin with a review of ethylene glycol poisoning.

2. Ethylene glycol is a odorless, sweet-tasting solvent. It is most commonly available as radiator antifreeze and coolant for automobiles which is often brightly colored to distinguish it from other liquids. It is also widely used in industry. Related compounds are used as hydraulic brake fluid and glass cleaners. The lethal dose of ethylene glycol is estimated to be approximately 1.4-1.6 mL/kg, or about 100 mL (Barceloux, 1999) in an adult; although as little as 30 mL has been fatal. Despite the fact that it is widely recognized as a highly toxic substance, it is commonly found in and around the home where poisonings continue to occur.Ethylene glycol is a odorless, sweet-tasting solvent. It is most commonly available as radiator antifreeze and coolant for automobiles which is often brightly colored to distinguish it from other liquids. It is also widely used in industry. Related compounds are used as hydraulic brake fluid and glass cleaners. The lethal dose of ethylene glycol is estimated to be approximately 1.4-1.6 mL/kg, or about 100 mL (Barceloux, 1999) in an adult; although as little as 30 mL has been fatal. Despite the fact that it is widely recognized as a highly toxic substance, it is commonly found in and around the home where poisonings continue to occur.

3. Ethylene Glycol Poisoning: Incidence In the United States, 1999: 6,077 exposures 254 near-fatalities 40 fatalities Watson WA, et al., 2002: Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. American Journal of Emergency Medicine 2003; 21(5):353-421. The best source of information on the incidence of poisonings in the United States comes from an annual report produced by the American Association of Poison Control Centers. In the most recent report, consisting of data from 2002, there were a total of 6,077 exposures to ethylene glycol or products containing ethylene glycol. Of these, 254 cases were considered serious enough to have caused death had they not been treated; 40 cases resulted in death despite treatment. The number of ethylene-glycol poisoned patients who were found dead and were therefore not brought to the attention of a poison control center is unknown. The best source of information on the incidence of poisonings in the United States comes from an annual report produced by the American Association of Poison Control Centers. In the most recent report, consisting of data from 2002, there were a total of 6,077 exposures to ethylene glycol or products containing ethylene glycol. Of these, 254 cases were considered serious enough to have caused death had they not been treated; 40 cases resulted in death despite treatment. The number of ethylene-glycol poisoned patients who were found dead and were therefore not brought to the attention of a poison control center is unknown.

4. Ethylene Glycol Poisoning: Incidence Ingestions are nearly always a medical emergency Intentional as an alcohol substitute or suicide attempt (adults) Unintentional due to accidental ingestion (children) Although ethylene glycol poisonings occur relatively infrequently, they almost always represent a medical emergency. Most serious and fatal poisonings occur in adults and result from the intentional ingestion of large amounts of ethylene glycol. Intentional ingestions are usually an attempt at suicide or an effort to abuse it as an alcohol substitute (Watson, 2002). Fortunately, the more common accidental ingestions, seen with inquisitive children, are much less severe although they must be evaluated as potentially dangerous poisonings. Although ethylene glycol poisonings occur relatively infrequently, they almost always represent a medical emergency. Most serious and fatal poisonings occur in adults and result from the intentional ingestion of large amounts of ethylene glycol. Intentional ingestions are usually an attempt at suicide or an effort to abuse it as an alcohol substitute (Watson, 2002). Fortunately, the more common accidental ingestions, seen with inquisitive children, are much less severe although they must be evaluated as potentially dangerous poisonings.

5. Ethylene Glycol Poisoning Ethylene glycol itself is not very toxic Symptoms of serious poisoning are due to the accumulation of toxic quantities of metabolites (glycolic and oxalic acids) While ethylene glycol itself has a relatively low degree of toxicity, ethylene glycol metabolites, primarily glycolic and oxalic acid, are responsible for the systemic effects and tissue damage characteristic of ethylene glycol poisoning. Thus, a knowledge of the metabolism of ethylene glycol is crucial for understanding the pathophysiology of ethylene glycol poisoning and the rationale for antidotal therapy.While ethylene glycol itself has a relatively low degree of toxicity, ethylene glycol metabolites, primarily glycolic and oxalic acid, are responsible for the systemic effects and tissue damage characteristic of ethylene glycol poisoning. Thus, a knowledge of the metabolism of ethylene glycol is crucial for understanding the pathophysiology of ethylene glycol poisoning and the rationale for antidotal therapy.

6. Ethylene Glycol: Metabolism Ethylene glycol is metabolized primarily in the liver and occurs in several steps. Initially, it is metabolized via alcohol dehydrogenase to glycoaldehyde. Glycoaldehyde is rapidly converted to glycolic acid via aldehyde dehydrogenase. The next step, conversion of glycolic acid to glyoxylic acid occurs relatively slowly, allowing glycolic acid to accumulate (Barceloux, 1999). The accumulation of toxic concentrations of glycolic acid is the cause of the characteristic metabolic acidosis associated with ethylene glycol poisoning. In addition, glycolic acid may have direct cytotoxic effects (Barceloux, 1999). Because glyoxylic acid is formed only in micromolar concentrations, it does not contribute appreciably to toxicity. Glyoxylic acid is metabolized to oxalic acid which contributes to toxicity in two ways: it is a potent chelator of serum calcium, resulting in hypocalcemia. The resulting calcium oxalate is very insoluble and is therefore deposited in various tissues, especially the kidneys (Barceloux, 1999). Ethylene glycol is metabolized primarily in the liver and occurs in several steps. Initially, it is metabolized via alcohol dehydrogenase to glycoaldehyde. Glycoaldehyde is rapidly converted to glycolic acid via aldehyde dehydrogenase. The next step, conversion of glycolic acid to glyoxylic acid occurs relatively slowly, allowing glycolic acid to accumulate (Barceloux, 1999). The accumulation of toxic concentrations of glycolic acid is the cause of the characteristic metabolic acidosis associated with ethylene glycol poisoning. In addition, glycolic acid may have direct cytotoxic effects (Barceloux, 1999). Because glyoxylic acid is formed only in micromolar concentrations, it does not contribute appreciably to toxicity. Glyoxylic acid is metabolized to oxalic acid which contributes to toxicity in two ways: it is a potent chelator of serum calcium, resulting in hypocalcemia. The resulting calcium oxalate is very insoluble and is therefore deposited in various tissues, especially the kidneys (Barceloux, 1999).

7. Ethylene Glycol Poisoning: Clinical Course Stage 1 (30 minutes-12 hours) Central Nervous System Stage 2 (12 hours- 24 hours) Cardiopulmonary Stage 3 (24 hours- 3 days) Renal The clinical effects of ethylene glycol poisoning develop slowly as metabolism of the parent compound occurs and toxic concentrations of metabolites develop. These effects have been described as three classical stages (Barceloux, 1999): Stage 1: Central Nervous System, 30 min – 12 hours. In this stage, symptoms resembling ethanol intoxication may be observed, consisting of slurred speech, ataxia and somnolence are seen. Gastric irritation may cause nausea and vomiting. As the metabolism of ethylene glycol proceeds and acidosis begins to develop, CNS depression deepens. This stage may also include nystagmus, myclonic movements, cerebral edema and seizures. Stage 2: Cardiopulmonary, 12 hrs – 24 hrs. This stage is characterized by the accumulation of organic acids, resulting in tachycardia, hypertension and metabolic acidosis with compensatory tachypnea, Kussmaul's respiration and congestive heart failure. If the hypocalcemia is signficant, related effects including hyperreflexia, muscle spasms and ECG changes may be noted. Death occurs most commonly in this stage. Stage 3: The final phase of ethylene glycol poisoning is due to acute renal injury and is characterized by renal tubular necrosis, hematuria, proteinuria, flank pain, oliguria, anuria and renal failure. Renal failure may be reversible; however, the patient must sometimes be maintained on hemodialysis for weeks to months. Please note that these are only general guidelines: not all of these symptoms will occur in all patients or in the timeframes described.The clinical effects of ethylene glycol poisoning develop slowly as metabolism of the parent compound occurs and toxic concentrations of metabolites develop. These effects have been described as three classical stages (Barceloux, 1999): Stage 1: Central Nervous System, 30 min – 12 hours. In this stage, symptoms resembling ethanol intoxication may be observed, consisting of slurred speech, ataxia and somnolence are seen. Gastric irritation may cause nausea and vomiting. As the metabolism of ethylene glycol proceeds and acidosis begins to develop, CNS depression deepens. This stage may also include nystagmus, myclonic movements, cerebral edema and seizures. Stage 2: Cardiopulmonary, 12 hrs – 24 hrs. This stage is characterized by the accumulation of organic acids, resulting in tachycardia, hypertension and metabolic acidosis with compensatory tachypnea, Kussmaul's respiration and congestive heart failure. If the hypocalcemia is signficant, related effects including hyperreflexia, muscle spasms and ECG changes may be noted. Death occurs most commonly in this stage. Stage 3: The final phase of ethylene glycol poisoning is due to acute renal injury and is characterized by renal tubular necrosis, hematuria, proteinuria, flank pain, oliguria, anuria and renal failure. Renal failure may be reversible; however, the patient must sometimes be maintained on hemodialysis for weeks to months. Please note that these are only general guidelines: not all of these symptoms will occur in all patients or in the timeframes described.

8. Ethylene Glycol Poisoning: Diagnosis Often Difficult Clinical signs and symptoms are nonspecific and may resemble other poisonings or illnesses Patients are frequently unwilling or unable to provide information regarding ingestion Little correlation between blood concentrations of ethylene glycol and severity of poisoning Some patients present asymptomatic Timely ethylene glycol laboratory results are often unavailable Unfortunately, many of the signs and symptoms of ethylene glycol poisoning are relatively nonspecific and could be associated with a variety of other poisonings or illnesses. Examples include nausea, vomiting and CNS depression. A powerful aid to diagnosis of ethylene glycol poisoning is a good history from the patient, a friend or a family member. This can be become difficult when the patient is uncommunicative, confused or unconscious. Also, a patient may be asymptomatic on presentation and slowly become ill, leading to a confusing clinical picture if an ethylene glycol ingestion is not suspected. The most conclusive means of diagnosis is direct measurement of ethylene glycol in the patient’s serum. Unfortunately, this test is not commonly available, even in large hospitals. When serum ethylene glycol levels can be measured, they must be interpreted cautiously: depending on when the sample is obtained, the serum concentration may be low although metabolite concentrations are high and the patient is actually quite ill. Unfortunately, many of the signs and symptoms of ethylene glycol poisoning are relatively nonspecific and could be associated with a variety of other poisonings or illnesses. Examples include nausea, vomiting and CNS depression. A powerful aid to diagnosis of ethylene glycol poisoning is a good history from the patient, a friend or a family member. This can be become difficult when the patient is uncommunicative, confused or unconscious. Also, a patient may be asymptomatic on presentation and slowly become ill, leading to a confusing clinical picture if an ethylene glycol ingestion is not suspected. The most conclusive means of diagnosis is direct measurement of ethylene glycol in the patient’s serum. Unfortunately, this test is not commonly available, even in large hospitals. When serum ethylene glycol levels can be measured, they must be interpreted cautiously: depending on when the sample is obtained, the serum concentration may be low although metabolite concentrations are high and the patient is actually quite ill.

9. Ethylene Glycol Poisoning: Treatment Objectives Stabilize the Patient Correct Metabolic Acidosis Prevent further metabolism of ethylene glycol Hemodialysis to enhance elimination of unmetabolized toxin (and metabolites) If ethylene glycol poisoning is known or suspected, steps should immediately be taken to (Barceloux, 1999): -stabilize the patient. Depending on the patients’ condition, this may include intubation and ventilation, or performing other life-saving measures. -correct metabolic acidosis when severe. Mild acidosis should respond to antidotal therapy. -initiate antidotal therapy to block further ethylene glycol metabolism. -consider hemodialysis to remove unmetabolized ethylene glycol and well as toxic metabolites. The other toxic alcohol we will discuss is methanol…If ethylene glycol poisoning is known or suspected, steps should immediately be taken to (Barceloux, 1999): -stabilize the patient. Depending on the patients’ condition, this may include intubation and ventilation, or performing other life-saving measures. -correct metabolic acidosis when severe. Mild acidosis should respond to antidotal therapy. -initiate antidotal therapy to block further ethylene glycol metabolism. -consider hemodialysis to remove unmetabolized ethylene glycol and well as toxic metabolites. The other toxic alcohol we will discuss is methanol…

10. Methanol Clear, flammable liquid Common uses include: Windshield wiper fluid Gas line antifreeze Fuel for small stoves Adulterant in “bootleg” whiskey Lethal dose 1ml/kg Methanol, sometimes called methyl alcohol or wood alcohol, is a clear, flammable liquid. It is commonly available as automotive windshield wiper solvent and gas line antifreeze. It is also used as a fuel for small stoves and fondue pots. In recent years, it has been responsible for several mass poisonings when it was used to increase the potency of homemade liquor. Methanol is highly toxic with an estimated lethal dose of 1 ml/kg, although serious poisoning has occurred with much smaller amounts (Jacobsen, 1986). As with ethylene glycol, methanol poisonings often occur because it is readily available around the home.Methanol, sometimes called methyl alcohol or wood alcohol, is a clear, flammable liquid. It is commonly available as automotive windshield wiper solvent and gas line antifreeze. It is also used as a fuel for small stoves and fondue pots. In recent years, it has been responsible for several mass poisonings when it was used to increase the potency of homemade liquor. Methanol is highly toxic with an estimated lethal dose of 1 ml/kg, although serious poisoning has occurred with much smaller amounts (Jacobsen, 1986). As with ethylene glycol, methanol poisonings often occur because it is readily available around the home.

11. Methanol Poisoning Exposures In the United States, 2002: 2,610 exposures 55 near-fatalities 18 fatalities Watson WA, et al., 2002: Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. American Journal of Emergency Medicine 2003; 21(5):353-421. Looking again at the most recent report of the American Association of Poison Control Centers, there were 2,610 exposures to methanol or methanol-containing products. Fifty-five of these were serious enough to be considered life-threatening and 18 resulted in death. As with ethylene glycol, the number of deaths does not take into account patients who may have been found dead and were never reported to a poison control center.Looking again at the most recent report of the American Association of Poison Control Centers, there were 2,610 exposures to methanol or methanol-containing products. Fifty-five of these were serious enough to be considered life-threatening and 18 resulted in death. As with ethylene glycol, the number of deaths does not take into account patients who may have been found dead and were never reported to a poison control center.

12. Methanol Poisoning: Incidence Ingestions are always a medical emergency Intentional as an alcohol substitute or suicide attempt (adults) Unintentional due to accidental ingestion (children) A real or suspected methanol poisoning always represents a medical emergency. Because the toxic effects of methanol may include death or permanent disability, patient evaluation and possible treatment must be initiated as quickly as possible. The pattern of methanol poisonings is similar to ethylene glycol: Most serious and fatal poisonings occur in adults and are the result of intentional ingestions of large amounts of methanol either as a suicide attempt or from use as an alcohol substitute (Watson, 2003). The majority of methanol exposures are relatively minor ingestions occurring in children; however, these cases must also be aggressively evaluated.A real or suspected methanol poisoning always represents a medical emergency. Because the toxic effects of methanol may include death or permanent disability, patient evaluation and possible treatment must be initiated as quickly as possible. The pattern of methanol poisonings is similar to ethylene glycol: Most serious and fatal poisonings occur in adults and are the result of intentional ingestions of large amounts of methanol either as a suicide attempt or from use as an alcohol substitute (Watson, 2003). The majority of methanol exposures are relatively minor ingestions occurring in children; however, these cases must also be aggressively evaluated.

13. Methanol Poisoning Methanol itself is not very toxic Symptoms of serious poisoning are due to the accumulation of toxic quantities of metabolite (formic acid) Similar to ethylene glycol, the parent compound has a relatively low degree of toxicity; however, the accumulation of toxic metabolites, primarily formic acid, is responsible for the systemic effects and tissue damage commonly associated with this poison. Because the metabolism of methanol is similar to ethylene glycol, an understanding of this process is equally important for understanding the rationale for the antidotal therapy needed to treat this poison. Similar to ethylene glycol, the parent compound has a relatively low degree of toxicity; however, the accumulation of toxic metabolites, primarily formic acid, is responsible for the systemic effects and tissue damage commonly associated with this poison. Because the metabolism of methanol is similar to ethylene glycol, an understanding of this process is equally important for understanding the rationale for the antidotal therapy needed to treat this poison.

14. Methanol Metabolism Methanol is metabolized primarily in the liver. It is first converted to formaldehyde via alcohol dehydrogenase. Formaldehyde is then quickly metabolized to formic acid via aldehyde dehydrogenase. Formic acid undergoes further metabolism slowly and can therefore accumulate, eventually reaching toxic concentrations (Jacobsen, 1997). The accumulation of toxic concentrations of formic acid is the reason why metabolic acidosis is always seen in significant methanol poisonings. Although the exact mechanism remains unclear, the conversion of methanol to formic acid ultimately leads to blindness, and potentially death, in untreated cases (Jacobsen, 1997). Methanol is metabolized primarily in the liver. It is first converted to formaldehyde via alcohol dehydrogenase. Formaldehyde is then quickly metabolized to formic acid via aldehyde dehydrogenase. Formic acid undergoes further metabolism slowly and can therefore accumulate, eventually reaching toxic concentrations (Jacobsen, 1997). The accumulation of toxic concentrations of formic acid is the reason why metabolic acidosis is always seen in significant methanol poisonings. Although the exact mechanism remains unclear, the conversion of methanol to formic acid ultimately leads to blindness, and potentially death, in untreated cases (Jacobsen, 1997).

15. Methanol Poisoning: Clinical Course Drowsiness, confusion, ataxia Severe anion gap metabolic acidosis Ocular injury, blindness Coma, seizures, hypotension, death Methanol is a mild intoxicant similar to ethanol. Thus, early signs of toxicity include somnolence, nausea and headache. As metabolism proceeds and acidosis develops, visual complaints may develop and include blurred or misty vision, changes in color perception, constricted visual fields and sometimes complete loss of vision. As the metabolic acidosis becomes more profound, central nervous system depression deepens, eventually leading to coma. Left untreated, seizures, hypotension and death may ensue (Jacobsen, 1986). Methanol is a mild intoxicant similar to ethanol. Thus, early signs of toxicity include somnolence, nausea and headache. As metabolism proceeds and acidosis develops, visual complaints may develop and include blurred or misty vision, changes in color perception, constricted visual fields and sometimes complete loss of vision. As the metabolic acidosis becomes more profound, central nervous system depression deepens, eventually leading to coma. Left untreated, seizures, hypotension and death may ensue (Jacobsen, 1986).

16. Methanol Poisoning: Diagnosis Often Difficult Clinical signs and symptoms are specific for other poisonings and illnesses Patients are frequently unwilling or unable to provide information regarding ingestion Some patients present asymptomatic Timely methanol laboratory results may be unavailable Another similarity between methanol and ethylene glycol is the difficulty in confirming a diagnosis: early symptoms are nonspecific, often resembling other poisonings or illness. Patients are often uncommunicative and they may be relatively asymptomatic on presentation. Once again, useful laboratory analyses may be unavailable (Kearney, 1997). When serum measurement of methanol is available, the serum concentration must be interpreted with caution and the patient’s clinical condition, as well as the amount of time that has elapsed since ingestion, must be taken into account.Another similarity between methanol and ethylene glycol is the difficulty in confirming a diagnosis: early symptoms are nonspecific, often resembling other poisonings or illness. Patients are often uncommunicative and they may be relatively asymptomatic on presentation. Once again, useful laboratory analyses may be unavailable (Kearney, 1997). When serum measurement of methanol is available, the serum concentration must be interpreted with caution and the patient’s clinical condition, as well as the amount of time that has elapsed since ingestion, must be taken into account.

17. Methanol Poisoning: Treatment Objectives Stabilize the patient Correct metabolic acidosis Prevent further metabolism of methanol Enhance elimination of unmetabolized toxin (and metabolites) If methanol poisoning is known or suspected, steps should be taken to (Jacobsen, 1997): -stabilize the patient and perform whatever life-saving measures may be immediately needed. -correct severe metabolic acidosis. Mild acidosis should respond to antidotal therapy. -initiate antidotal therapy to block additional metabolism of methanol. -employ hemodialysis to remove unmetabolized methanol as well as toxic metabolites. If methanol poisoning is known or suspected, steps should be taken to (Jacobsen, 1997): -stabilize the patient and perform whatever life-saving measures may be immediately needed. -correct severe metabolic acidosis. Mild acidosis should respond to antidotal therapy. -initiate antidotal therapy to block additional metabolism of methanol. -employ hemodialysis to remove unmetabolized methanol as well as toxic metabolites.

18. Summary: Methanol and Ethylene Glycol Poisoning Metabolism of these compounds via alcohol dehydrogenase is responsible for the clinical effects characteristic of poisoning with these compounds Inhibition of alcohol dehydrogenase will prevent the formation of toxic metabolites In summary, the metabolism of methanol and ethylene glycol by alcohol dehydrogenase is responsible for the generation of toxic metabolites which are responsible for the morbidity and mortality associated with these compounds.In summary, the metabolism of methanol and ethylene glycol by alcohol dehydrogenase is responsible for the generation of toxic metabolites which are responsible for the morbidity and mortality associated with these compounds.

19. Historical Treatment of Ethylene Glycol and Methanol Poisoning Ethanol therapy has been the historical treatment Ethanol inhibits the production of the toxic metabolites of ethylene glycol and methanol Effective ethanol therapy is often difficult to accomplish and highly labor-intensive Historically, if serum methanol or ethylene glycol concentrations were sufficiently high, ethanol therapy was initiated. The rationale for this is that alcohol dehydrogenase has a higher affinity for ethanol compared to methanol or ethylene glycol. Thus, if the ethanol concentration is kept sufficiently high, the metabolism of methanol and ethylene glycol will not occur. Unfortunately, effective ethanol therapy is sometimes difficult to accomplish (Jacobsen, 1996). The awake patient may be administered an alcohol-containing beverage, such as liquor; however, the unconscious patient must receive ethanol intravenously, but IV forms of ethanol are not always available.Historically, if serum methanol or ethylene glycol concentrations were sufficiently high, ethanol therapy was initiated. The rationale for this is that alcohol dehydrogenase has a higher affinity for ethanol compared to methanol or ethylene glycol. Thus, if the ethanol concentration is kept sufficiently high, the metabolism of methanol and ethylene glycol will not occur. Unfortunately, effective ethanol therapy is sometimes difficult to accomplish (Jacobsen, 1996). The awake patient may be administered an alcohol-containing beverage, such as liquor; however, the unconscious patient must receive ethanol intravenously, but IV forms of ethanol are not always available.

20. Challenges of Ethanol Therapy Is very labor-intensive Requires toxic concentrations of ethanol Appropriate level of ethanol may be difficult to achieve Not FDA-Approved After ethanol therapy has been initiated, serum ethanol concentrations must be frequently monitored. They must be kept high enough to effectively inhibit alcohol dehydrogenase but not so high that the toxic effects of ethanol become additive with the toxic effects of methanol or ethylene glycol. This balance may be difficult to achieve, since the level can vary dramatically based on the patient’s history with alcohol consumption. This may require checking serum ethanol concentrations as often as every 1-2 hours during the first 8-12 hours of therapy. Therapeutic ethanol concentrations range from 100-150 mg/dL which may cause other types of adverse effects including CNS depression, hypoglycemia and liver injury. These adverse effects may be especially significant in children (Barceloux, 1999). It should also be mentioned that, despite its long history of use, ethanol therapy for either methanol or ethylene glycol has not been approved by the Food and Drug Administration (Barceloux, 1999).After ethanol therapy has been initiated, serum ethanol concentrations must be frequently monitored. They must be kept high enough to effectively inhibit alcohol dehydrogenase but not so high that the toxic effects of ethanol become additive with the toxic effects of methanol or ethylene glycol. This balance may be difficult to achieve, since the level can vary dramatically based on the patient’s history with alcohol consumption. This may require checking serum ethanol concentrations as often as every 1-2 hours during the first 8-12 hours of therapy. Therapeutic ethanol concentrations range from 100-150 mg/dL which may cause other types of adverse effects including CNS depression, hypoglycemia and liver injury. These adverse effects may be especially significant in children (Barceloux, 1999). It should also be mentioned that, despite its long history of use, ethanol therapy for either methanol or ethylene glycol has not been approved by the Food and Drug Administration (Barceloux, 1999).

21. Antizol® (fomepizole) Injection Antizol®,commonly referred to as fomepizole, 4-methylpyrazole, 4-MP Studied as an antidote since late 1960s Indicated as an antidote for confirmed or suspected ethylene glycol or methanol poisoning Antizol® (fomepizole) Injection, commonly referred to by its official generic name fomepizole or its chemical name 4-methylpyrazole or simply 4-MP, has been studied as an antidote for over 30 years and has been used in Europe since 1982. It was approved in the U.S. in 1997 and has been widely adopted as the treatment of choice. Antizol is indicated as an antidote for ethylene glycol (such as antifreeze) or methanol poisoning, or for use in suspected ethylene glycol or methanol ingestion, either alone or in combination with hemodialysis (Package Insert).Antizol® (fomepizole) Injection, commonly referred to by its official generic name fomepizole or its chemical name 4-methylpyrazole or simply 4-MP, has been studied as an antidote for over 30 years and has been used in Europe since 1982. It was approved in the U.S. in 1997 and has been widely adopted as the treatment of choice. Antizol is indicated as an antidote for ethylene glycol (such as antifreeze) or methanol poisoning, or for use in suspected ethylene glycol or methanol ingestion, either alone or in combination with hemodialysis (Package Insert).

22. Antizol® Treatment Rationale Antizol is a competitive inhibitor of alcohol dehydrogenase Antizol blocks the metabolism of ethylene glycol and methanol to their toxic metabolites Antizol is safe and easy to administer Antizol competitively inhibits alcohol dehydrogenase, the enzyme responsible for the initial step in the metabolism of methanol and ethylene glycol to their toxic metabolites (Brent, 1999; Brent, 2001). Antizol is easy to administer and no serious adverse events were reported in volunteers receiving 6-10 times the recommended dose (Jacobsen 1988).Antizol competitively inhibits alcohol dehydrogenase, the enzyme responsible for the initial step in the metabolism of methanol and ethylene glycol to their toxic metabolites (Brent, 1999; Brent, 2001). Antizol is easy to administer and no serious adverse events were reported in volunteers receiving 6-10 times the recommended dose (Jacobsen 1988).

23. Few side effects have been directly attributed to Antizol. These patients are very ill and present with many varied morbidities relating to their degree of poisoning but all symptoms were reported during the clinical trials making causality assignment very difficult. During clinical trials, Antizol was administered to ethylene glycol and methanol poisoned patients. Some were critically ill while others presented a variety of symptoms, making interpretation of potential adverse events difficult. In human volunteers the most frequent adverse reactions were: Headache (14%), nausea (11%), dizziness, increased drowsiness, and bad taste/metallic taste (6% each). The administration of Antizol in undiluted form or by bolus injection may cause venous irritation or phlebosclerosis.Few side effects have been directly attributed to Antizol. These patients are very ill and present with many varied morbidities relating to their degree of poisoning but all symptoms were reported during the clinical trials making causality assignment very difficult. During clinical trials, Antizol was administered to ethylene glycol and methanol poisoned patients. Some were critically ill while others presented a variety of symptoms, making interpretation of potential adverse events difficult. In human volunteers the most frequent adverse reactions were: Headache (14%), nausea (11%), dizziness, increased drowsiness, and bad taste/metallic taste (6% each). The administration of Antizol in undiluted form or by bolus injection may cause venous irritation or phlebosclerosis.

24. Serum methanol and ethylene glycol concentrations should be monitored during Antizol therapy to assure elimination of these toxins and determine the endpoint of treatment. The use of hemodialysis to remove unmetabolized toxin, as well as toxic metabolites, should always be considered.Serum methanol and ethylene glycol concentrations should be monitored during Antizol therapy to assure elimination of these toxins and determine the endpoint of treatment. The use of hemodialysis to remove unmetabolized toxin, as well as toxic metabolites, should always be considered.

25. Advantages of Antizol® Monitoring of serum Antizol not required Does not cause sedation or hypoglycemia Hemodialysis may be unnecessary in some cases Is FDA-approved The Antizol treatment regimen is designed to maintain efficacious drug concentrations during therapy without serum during monitoring. This makes therapy much simpler for medical staff (Package Insert, Antizol). Antizol administration does not cause any adverse effects which may worsen the symptoms of poisoning, such as sedation or hypoglycemia. In select cases of ethylene glycol poisoning, the use of Antizol may make hemodialysis unnecessary (Brent, 1999; Sivilotti, 2000). For example, Antizol-treated patients who are not acidotic, or who present before the development of acidosis, and have normal renal function, may not necessarily require hemodialysis (Brent, 1999). Antizol has been approved by the Food and Drug Administration for the treatment of both methanol and ethylene glycol poisoning. The Antizol treatment regimen is designed to maintain efficacious drug concentrations during therapy without serum during monitoring. This makes therapy much simpler for medical staff (Package Insert, Antizol). Antizol administration does not cause any adverse effects which may worsen the symptoms of poisoning, such as sedation or hypoglycemia. In select cases of ethylene glycol poisoning, the use of Antizol may make hemodialysis unnecessary (Brent, 1999; Sivilotti, 2000). For example, Antizol-treated patients who are not acidotic, or who present before the development of acidosis, and have normal renal function, may not necessarily require hemodialysis (Brent, 1999). Antizol has been approved by the Food and Drug Administration for the treatment of both methanol and ethylene glycol poisoning.

26. Antizol® Treatment Guidelines Begin Antizol treatment on suspicion of ethylene glycol or methanol poisoning or in presence of serum concentration >20 mg/dL Discontinue therapy when serum concentration is zero or when < 20 mg/dL and the patient is asymptomatic with normal pH Consider hemodialysis when serum concentration >50 mg/dL Antizol therapy should be started immediately upon suspicion of methanol or ethylene glycol poisoning based on (Package Insert): -patient history; to determine volume and type of agent ingested -measured serum methanol or ethylene glycol concentrations greater than 20 mg/dL or -other laboratory measures that support the diagnosis (osmolar gap, etc). In cases of ethylene glycol poisoning, hemodialysis should be considered in symptomatic patients and those with diminished renal function. In methanol poisoning, hemodialysis should be considered in symptomatic patients and patients with serum methanol concentrations greater than 50 mg/dL. Antizol treatment should continue until serum methanol and ethylene glycol concentrations are less than 20 mg/dL AND the patient is asymptomatic with normal pH.Antizol therapy should be started immediately upon suspicion of methanol or ethylene glycol poisoning based on (Package Insert): -patient history; to determine volume and type of agent ingested -measured serum methanol or ethylene glycol concentrations greater than 20 mg/dL or -other laboratory measures that support the diagnosis (osmolar gap, etc). In cases of ethylene glycol poisoning, hemodialysis should be considered in symptomatic patients and those with diminished renal function. In methanol poisoning, hemodialysis should be considered in symptomatic patients and patients with serum methanol concentrations greater than 50 mg/dL. Antizol treatment should continue until serum methanol and ethylene glycol concentrations are less than 20 mg/dL AND the patient is asymptomatic with normal pH.

27. Antizol® Administration Dilute dose in 100 ml normal saline or D5W, infuse over 30 minutes Dosed on a mg/kg basis Doses Q12H until ethylene glycol or methanol concentration sub toxic During hemodialysis, dose Q4H Antizol must be diluted in 100 mL of normal saline or 5% dextrose in water and infused over 30 minutes. A loading dose of 15 mg/kg should be administered upon presentation followed by doses of 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours until the concentration of methanol or ethylene glycol is less than 20 mg/dL AND the patient is asymptomatic with normal pH (Package Insert). Because Antizol is removed by hemodialysis, the frequency of Antizol administration must be increased to every 4 hours while the patient is undergoing hemodialysis (Package Insert). Antizol must be diluted in 100 mL of normal saline or 5% dextrose in water and infused over 30 minutes. A loading dose of 15 mg/kg should be administered upon presentation followed by doses of 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours until the concentration of methanol or ethylene glycol is less than 20 mg/dL AND the patient is asymptomatic with normal pH (Package Insert). Because Antizol is removed by hemodialysis, the frequency of Antizol administration must be increased to every 4 hours while the patient is undergoing hemodialysis (Package Insert).

28. Antizol® Formulation Provided as a sterile, preservative-free solution for intravenous use Supplied in packages of four 1.5 ml vials, with 1 gm/ml 3 year shelf life, return goods policy for unopened tray packs Sterile for at least 24 hours, discard diluted solution after that time Antizol is provided as a sterile, preservative-free solution for intravenous use, supplied in packages of four vials, each containing 1.5 gm of fomepizole (1.5 ml @ 1 gm/ml). Antizol has a 3-year shelf life when stored at controlled room temperature. The return goods policy allows unopened vials to be credited toward purchase of new tray pack after expiration. When diluted for use in normal saline or 5% dextrose in water, Antizol is sterile for 24 hours (Package Insert).Antizol is provided as a sterile, preservative-free solution for intravenous use, supplied in packages of four vials, each containing 1.5 gm of fomepizole (1.5 ml @ 1 gm/ml). Antizol has a 3-year shelf life when stored at controlled room temperature. The return goods policy allows unopened vials to be credited toward purchase of new tray pack after expiration. When diluted for use in normal saline or 5% dextrose in water, Antizol is sterile for 24 hours (Package Insert).

29. Antizol® Injection Additional Information To order Antizol, call 1-800-359-4304 For questions of a medical nature, call 1-888-8ORPHAN (1-888-867-7426) For more information about obtaining Antizol, call 1-800-359-4304. For questions of a medical nature, emergency medial assistance, to report adverse effects or to obtain a copy of the Material Safety Data Sheet (MSDS), call Orphan Medical, Inc at: 1-888-8ORPHAN (1-888-867-7426).For more information about obtaining Antizol, call 1-800-359-4304. For questions of a medical nature, emergency medial assistance, to report adverse effects or to obtain a copy of the Material Safety Data Sheet (MSDS), call Orphan Medical, Inc at: 1-888-8ORPHAN (1-888-867-7426).

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