Methanol poisoning دکتر امیر محمد کاظمی فر متخصص پزشکی قانونی و مسمومیت عضو هیئت علمی دانشگاه

METHANOL Alcohols are hydrocarbons that contain a hydroxyl group A compound with two hydroxyl groups is called a diol or a glycol Toxic alcohols commonly refer to methanol, ethylene glycol and isopropyl alcohol

Methanol Antifreeze (window washer fluid) Anti icing agent Octane booster Extraction agent Solvent Fuel source Varnish and paint removers Industrial solvent Manufacture of acetic acid, formaldehyde and inorganic acids

As methanol is cheaper than ethanol, it is sometimes used to fortify illicit spirits in developing countries. Methyl alcohol is a cheap and potent adulterant used in manufacture of illicit liquors. low methanol concentrations are found in a variety of alcoholic beverages as a result of the conversion of pectin to methanol during alcoholic fermentation.

فارماكوكينتيك: متانول به راحتي از دستگاه گوارش جذب شده و در عرض 90-30 دقيقه به ماكزيمم مقدار خود در خون مي رسد. جذب از راه پوست و ريه نيز مي تواند به اندازه اي باشد كه سبب بروز مسموميت شود. حجم توزيعي آن مشابه با اتانول ميباشد. 0.6 – 0.7 L/kg متانول در كليه ها ، كبد ، و دستگاه گوارش بيشترين غلظت را دارا ست ، وبا مقادير كمتر در مغز،عضلات و بافت چربي يافت مي شود0 همچنين با مقادير زياد در مايع زجاجيه و عصب اپتيك يا فت مي شود.

فارماكوكينتيك: 95%-90% آن در كبد متابوليزه مي شود.تنها 5%-2% بدون تغيير از كليه ها دفع مي شود. مقادير كمي بدنبال مصرف خوراكي از ريه ها دفع مي شود. سرعت اكسيداسيون متانول 10 برابر آهسته تر از اتانول بوده و در نتيجه نيمه عمر طولاني تري دارد. نيمه عمر متانول درمسموميتهاي خفيف 20-14 ساعت و در موارد شديد 30-24 ساعت و در صورت تجويز اتانول 35-30 ساعت و با همودياليز به 5/2 ساعت ميرسد.

Methanol and metabolism

Formic acid is considered to be the key toxicant; and in animal species with a poor ability to metabolize this product (primates and humans) fatal toxicity may occur from metabolic acidosis and neuronal toxicity . Un-dissociated formic acid readily crosses the blood brain barrier leading to CNS toxicity, aggressive alkaline therapy is required to maintain formic acid in the dissociated form

پاتو فيزيو لوژي مسموميت با متانول در نتيجه توليد دو متابوليت آن يعني فرمالدئيد و اسيد فرميك مي باشد.فرمالدئيد به سرعت متابوليزه شده وبه اسيد فرميك تبديل شده كه اين امر منجر به اسيدوز مي شود. متانول همانند اتانول باعث دپرسيون C.N.S ميشود. متانول اثر سكر آوري دارد.

As a moderate inhibitor of cytochrome c oxidase, formate may cause tissue oxygen utilization to be impaired leading to anaerobic respiration with subsequent increased lactate production, which may further contribute to the acidosis. Elimination of methanol as formic acid occurs primarily via urinary excretion. At high concentrations, methanol elimination is saturated and is zero order with a rate of approximately 85 mg L-1, about half the elimination rate of ethanol. Maximum excretion of formic acid may be as late as the second or third day following ingestion.

علائم كلينيكي: شروع علائم ميتواند بين 40 دقيقه تا 72 ساعت متغير باشد. نداشتن علائم شديد در زمان مراجعه نميتواند مطرح كننده عدم مسموميت ويا مسموميت خفيف باشد. علائم بيشتر درS C.N. ، چشمها و دستگاه گوارش ظاهر مي شود. اسيدوز شديد مي تواند منجر به ديس پنه و شوك شود. وجود تشنج، كوما و اسيدوز شديد متابوليك از علائم جدي و خطرناك محسوب مي شود.

علائم كلينيكي اثرات نورولوژيك: در موارد مسموميت خفيف تا متوسط:سردرد ، سر گيجه ، لتارژي در موارد شديد: تشنج و كوما( ادم مغزي) اثرات چشمي: تاري ديد –كاهش ميدان بينايي، فتو فوبي، مردمك هاي ثابت و ديلاته ، ادم رتين، پرخوني ديسك اپتيك در 25% موارد شديد مسموميت علائم چشمي ممكن است حتي با درمان بصورت پايدار باقي بماند. اثرات GI : تهوع ، استفراغ، دل درد، پانكراتيت، اسهال

Phases of clinical manifestation Central Nervous System depression Onset of 30 min - 2 h; intoxication may be of shorter duration and less pronounced than that arising from ethanol ingestion Asymptomatic latent period following central depression This period of varying duration: may last 8-24 h following ingestion, but occasionally up to 48 h. Patients describe no overt symptoms or signs during this period Severe metabolic acidosis occurs after latent phase Nausea, vomiting and headache may also occur and may be superimposed on the visual toxicity described below Ocular toxicity followed by blindness, coma and in extreme cases death. Visual disturbances range from mild photophobia and misty or blurred vision to markedly reduced visual acuity and complete blindness. Visual impairment usually takes the form of central scotoma or complete blindness secondary to optic atrophy.

Folate CH3OH Methanol ADH Formaldehyde CH2O ADH CHOOH Formic Acid CO2 + H2O

مقادير توكسيك دوز توكسيك: 0.1 ml / kg 6-10cc دوز كشنده: 1 ml / kg

Diagnosis The diagnosis of methanol poisoning is made by a combination of a history of suspected toxic alcohol intake, clinical features, and laboratory tests.

Diagnosis A documented plasma methanol level greater than 6.25 mmol/L (20 mg/dL) is diagnostic of methanol poisoning. However plasma methanol level may not be readily available. One should not wait for a methanol level before initiating treatment in cases of clinically suspected methanol poisoning . In emergency situation, the osmol gap and arterial blood gases are more useful in making the diagnosis and assessing the severity of methanol poisoning.

Osmol gap (OG) = Measured osmolality (OM) − Calculated osmolarity (OC) Calculated osmolarity (OC) = 2 (sodium) + glucose/18 + urea/2.8 + ethanol When the osmol gap is greater than 50 mOsm/L, it should be considered nearly diagnostic of toxic alcohol ingestion.5 However, a normal or negative osmol gap does not rule out toxic alcohol poisoning.

↑ AG CO₂ HCO₃¯ Hypervent H₂O BUFFERS (Hb, proteins) ACIDOSIS Formate¯ Cl¯ HCO ₃¯ Prot¯ CO₂ HCO₃¯ Hypervent H₂O BUFFERS (Hb, proteins) ACIDOSIS Formate¯ H + Formic acid Methanol ↑ OG Antidote …whereas formate would contribute to the anion gap….

Three stages of methanol poisoning ..and looking a bit closer on the different stages of the methanol poisoning; you will see why UNDERSTANDING of the relation between the toxicants and the gaps are important…

Clinical symptoms and mortality in methanol poisoning correlate closely with the degree of metabolic acidosis

The methanol challenge High morbidity and mortality, even with small doses (minimum lethal dose estimated 1 g/kg1) Specific and efficient treatment exists, but suffers from often late diagnosis and initiation of treatment Probably the most frequently reported toxicant in outbreaks

Obstacles Symptoms mimicking other diagnoses: Typical symptoms: Dyspnoea (15-41%) GI symptoms (18-67%) Visual disturbances (33-55%) Hyperventilation! Diffuse symptoms Often lacking Septic? Other MA?

TREATMENT CORRECTION OF METABOLIC ACIDOSIS BICARBONATE (AGGRESSIVE TREATMENT) CAN REVERSE VISUAL IMPAIRMENT REDUCES MOVEMENT OF FORMATE TO THE CNS MAY REQUIRE 400 TO 600 MMOL DURING FIRST FEW HOURS REHYDRATION

Management The management of a patient with methanol poisoning includes inhibition of the metabolism of methanol into formic acid with either fomepizole or ethanol, correction of metabolic acidosis with sodium bicarbonate, increasing the metabolism of formic acid to carbon dioxide by the administration of folinic acid or folic acid, and arrangement of hemodialysis if necessary. Both fomepizole and ethanol are potent inhibitors of ADH, and are considered as effective antidotes in methanol poisoning

Ethanol Ethanol is a competitive antagonist of ADH. Its affinity for ADH is estimated to be 10 times greater than that of methanol. If administered soon after methanol ingestion, ethanol prevents the formation of formic acid. This inhibition of hepatic methanol metabolism results in a significant increase in the elimination half-life of methanol. It was reported that the median elimination half-life of methanol during ethanol therapy was 43.1 hours (ranged 30.3-52 hours). The recommended blood ethanol concentration during ethanol therapy is 21.7 mmol/L (100 mg/dL).

Ethanol In order to attain this blood level rapidly, a loading dose of ethanol of 0.8 g/kg (0.8 ml/kg 100% ethanol) is recommended. Preferably the loading dose is to be given intravenously although oral loading is also acceptable with adjustment of the dosage to account for the oral bioavailability of ethanol. It should be diluted by intravenous fluid (e.g. 5% dextrose) to a 10% ethanol solution, and given intravenously over 20-60 minutes as tolerated by the patient.

Ethanol To maintain an ethanol concentration of 21.7 mmol/L (100 mg/dL), ethanol has to be administered at rate of 66-130 mg/kg/hr. A higher dose is required in chronic alcoholics (100-154 mg/kg/hr), and in those undergoing hemodialysis (250-350 mg/kg/hr). The patient should be monitored in an intensive care unit to observe for signs of central nervous system and respiratory sysyem.

Ethanol Ethanol therapy should be continued until the serum methanol concentration is <6.25 mmol/L (20 mg/dL) and the patient is asymptomatic with a normal arterial pH.

TREATMENT HAEMODIALYSIS METHANOL LOW MOLECULAR WEIGHT NOT PROTEIN BOUND LOW VOLUME OF DISTRIBUTION THEREFORE IDEAL FOR HAEMODIALYSIS

Hemodialysis Indications for hemodialysis in methanol poisoning include: significant metabolic acidosis (pH <7.25-7.30), renal impairment, clinically significant poisoning with visual impairment or deteriorating vital signs, or a high methanol concentration >15.6 mmol/L (50 mg/dL)

folic acid In animal models and in vitro human cell experiments, folinic acid and folic acid enhance the metabolism of formic acid, forming carbon dioxide and water. Since the toxic effects associated with methanol poisoning are attributed largely to formic acid accumulation, it is thereby postulated that the administration of folinic acid or folic acid can reduce methanol toxicity. Folinic acid is the metabolically reduced form of folic acid and is the primary bioactive form in enhancing formic acid metabolism. It is therefore the drug of choice in methanol poisoning.

TREATMENT FOLINIC ACID/FOLIC ACID 50 mg IV EVERY FOUR HOURS FOR 24 HOURS, OR WHILE FORMIC ACID MAY STILL BE ACCUMULATING MAGNESIUM MgSO4 TITRATED AGAINST BLOOD MAGNESIUM LEVELS

Fomepizole 15 mg/kg intravenous loading dose of fomepizole followed by further intravenous bolus doses of 10 mg/kg every 12 hours for four doses and then 15 mg/kg 12-hourly produced serum fomepizole concentrations in excess of 0.8 mg/L.

Ethanol vs Fompepizole - Oral or IV - CNS depression - Difficult titration - Frequent levels - Hypoglycemia Fomepizole: - IV - No CNS depression - Easy dosing - No levels to monitor - More predictable pharmacokinetcs - No Hypoglycemia - Cost