Toxicity of solvents

2. Toxicity of solvents suicide attempt directly toxicity

3. Toxicokinetic Absorption: concentration, time, dose, lipophilicity, blood flow Distribution: the more lipophilic solvents the more toxicity Metabolism: Metabolic inactivation (detoxification) Ex. toluene Metabolic activation (bioactivation) Ex. benzene Elimination: liver, renal, respiratory

4. ????????????????? Solvents ethanol methanol isopropranol (isopropyl alcohol) formaldehyde acetadehyde Gases carbonmonoxide (CO) cyanide

5. Commercial beer wine liquors colognes perfumes after-shaves mouthwashes pharmaceutical preparations Ex elixir

6. Mechanism of toxicity Central nervous system depression principal effect of acute ethanol intoxication Hypoglycemia impaired gluconeogenesis particularly in children and poorly nourished person trauma exposure induced hypothermia

7. pure ethanol 0.7 g/kg = 100 mg/dl (Blood alcohol concentration) level of 100 mg/dl is enough to inhibit gluconeogenesis and hypoglycemia >300 mg/dl coma 500-600 mg/dl coma (chronic alcoholism)

9. Toxicokinetic Absorption rapidly absorption especially in duodenum saturated lipid inhibit ethanol absorption 5% by inhalation and skin

10. Distribution: Vd =0.7 L/kg rapidly distribution ratio of distribution of alveolar and blood: 1:2100 Toxicokinetic

11. ethanol

12. Blood concentration < Km first order kinetic Blood concentration > Km zero order kinetic Km =8-14 mg/dl

13. Clinical presentation Acute intoxication mild to moderate intoxication euphoria, mild incoordination, ataxia, nystagmus, impaired judgement and reflex deep intoxication coma, respiratory depression, pulmonary aspiration, decrease blood pressure and pulse rate hypoglycemia/ hypoinsulinemia

14. Chronic intoxication Gastrointestinal bleeding (GASTRITIS) Pancreatitis hepatitis cirrhosis hepatic encephalopathy hypokalemia/hypophosphatemia/hypomanesemia thiamine deficiency alcoholic ketoacidosis Decreased resistance to infection

15. Alcoholic ketoacidosis (AKA) Chronic alcohol intake, Alcoholism Nausea, vomiting, hematemesis, abdominal pain Complex interaction of EtOH metabolism, decreased caloric intake, volume depletion Lack or oral intake & Volume depletion Decreased glucose � decreased insulin Increased NADH/ NAD inh. Gluconeogenesis � decrease glucose Decreased insulin � Increased lipolysis Increased NADH/ NAD ratio� favor production of Beta-hydroxybutyrate (ketone) Ketone clearance is impaired by volume depletion Tx� IV glucose, hydration

16. Other toxicity Alcohol withdrawal tremulousness, anxiety, overactivity of sympathetic nervous system

17. Enhancing toxicity Disulfiram CNS depressant drugs

18. Diagnosis History of ingestion the characteristic of smell of fresh alcohol, aldehyde others toxic symptoms nystagmus, ataxia, alter mental status Blood ethanol concentration Calculating the osmolar gap

19. Osmolar gap Osmolar gap = Measured osmolality � Calculated osmolality Calculated osmolality = 2[Na+] + [glucose]/ 18 + [BUN]/ 2.8 Normal calculated osmolality = 290 mOsm/ L Increased osmolar gap may occur from low molecular wt. substance� ethanol, other alcohol � increased measured osmolality

20. TREATMENT Supportive measure��.assist ventilation, prevent seizure glucose to relief ketosis benzodiazepine (diazepam 2-10 mg IV) to relief alcohol withdrawal emesis/gastric lavage is not indicated unless ingestion has occurred within a few minute of presentation.

21. wood alcohol, Columbian spirit, colonial spirit ingredient in many solvents windshield-washing solution duplication fluids paints removers an ethanol substitute by alcoholic methanol ??????????? wood alcohol, Columbian spirit, colonial spirit ????????????????????????????????????????????????????????????????? ?????????????????? methanol ????????????????????? methanol ???????????????????????? methanol ????????????? ???????????????????????????????????????????????????????????????? methanol ???????????????????? methanol ??????????????????????????????????????????? ??? methanol ???????????? ethanol ??????????? metabolites ????????? methanol ??? formic acid ?????????????????? metabolic acidosis, ????????????????? ???????????????????????? 6-30 ??????? methanol ??????????? wood alcohol, Columbian spirit, colonial spirit ????????????????????????????????????????????????????????????????? ?????????????????? methanol ????????????????????? methanol ???????????????????????? methanol ????????????? ???????????????????????????????????????????????????????????????? methanol ???????????????????? methanol ??????????????????????????????????????????? ??? methanol ???????????? ethanol ??????????? metabolites ????????? methanol ??? formic acid ?????????????????? metabolic acidosis, ????????????????? ???????????????????????? 6-30 ???????

22. Toxicokinetic Readily absorbed Quickly distributed to the water (Vd =0.6 L/kg) Not bound to plasma protein metabolized slowly by alcohol dehydrogenase Via Zero-order kinetic but slowly than ethanol Excreted unchanged by kidney and <10% by breath

23. The accumulation of formic acid is responsible for the presence of metabolic acidosis. Formic acid also inhibits cellular respiration leading to lactic acidosis. The ocular injury caused by methanol may be due to retinal injury, which results from intra-retinal metabolism of methanol and the accumulation of formic acid. Alternatively, it may be caused be the inhibition of normal metabolism in optic nerve calls (Jacobsen 1997).The accumulation of formic acid is responsible for the presence of metabolic acidosis. Formic acid also inhibits cellular respiration leading to lactic acidosis. The ocular injury caused by methanol may be due to retinal injury, which results from intra-retinal metabolism of methanol and the accumulation of formic acid. Alternatively, it may be caused be the inhibition of normal metabolism in optic nerve calls (Jacobsen 1997).

25. Mechanism of toxicity Toxicity is form metabolic products, formaldehyde and formic acid. Lactic acid and formic acid cause systemic acidosis. Formate cause blindness. Increase anion gap. Like ethylene glycol, methanol is relatively non-toxic; however, it is metabolized to highly toxic compounds that are responsible for the acidosis and blindness characteristic of methanol poisoning. As in ethylene glycol poisonings, the initial step in the metabolism of methanol involves the enzyme alcohol dehydrogenase (ADH) (see Figure 2). First, methanol is slowly oxidized by ADH to yield formaldehyde. Next,formaldehyde is oxidized by formaldehyde dehydrogenase to yield formic acid (or formate, depending on the pH). This oxidation occurs rapidly so that little formaldehyde accumulates in the serum. FInally, formic acid is metabolized to carbon dioxide and water, which are excreted by the kidneys and lungs.Like ethylene glycol, methanol is relatively non-toxic; however, it is metabolized to highly toxic compounds that are responsible for the acidosis and blindness characteristic of methanol poisoning. As in ethylene glycol poisonings, the initial step in the metabolism of methanol involves the enzyme alcohol dehydrogenase (ADH) (see Figure 2). First, methanol is slowly oxidized by ADH to yield formaldehyde. Next,formaldehyde is oxidized by formaldehyde dehydrogenase to yield formic acid (or formate, depending on the pH). This oxidation occurs rapidly so that little formaldehyde accumulates in the serum. FInally, formic acid is metabolized to carbon dioxide and water, which are excreted by the kidneys and lungs.

26. Anion gap = [Na+] � [Cl-] � [HCO3-] Normal = 8 � 12 meq/ L Anion gap acidosis usually occur from accumulation of lactic acid or other unmeasured acid anion, such as formic acid

27. 20-150 g minimun toxic dose = 100 mg/kg ACGIH recommended workplace exposure limit TLV-TWA) concentrated inhalation is 200 ppm as 8 h. time-weighted average Exposure to 6,000 ppm is considered to dangerous to life.

28. Clinical presentation In the first few hour inebriation and gastritis increase osmolar gap After latent periods up to 30 h metabolic acidosis visual disturbance �Like standing in the snow field� blindness seizure coma and death Initial symptoms of methanol poisoning may appear as soon as 12 hours post-ingestion, but usually develop 24 hours after ingestion. These may resemble ethanol intoxication and consist of drowsiness, confusion, and ataxia, as well as weakness, headache, nausea, vomiting, and abdominal pain. Collectively, these symptoms may mimic an alcohol hangover and are due to mild intoxication, caused by methanol itself. As methanol metabolism proceeds, a severe anion gap metabolic acidosis will develop. Severe metabolic acidosis in conjunction with visual effects are the hallmark of methanol poisoning. Patients usually describe blurred or misty vision, double vision, or changes in color perception. There my be constricted visual field and, occasionally, total loss of vision. Characteristic visual dysfunctions include pupillary dilation and loss of pupillary reflex (Burkhart 1990; Suit 1990). Further signs and symptoms may be shallow respiration, cyanosis, tachypnea, coma, seizures, electrolyte disturbances, and various hemodynamic changes including profound hypotension and cardiac arrest. There may be mild to profound loss of memory, confusion, and agitation, which may progress to stupor and coma as the severity of the acidosis increases (Suit 1990). In severe cases, death is possible. Surviving patients can be left with permanent blindness or with other neurological deficits (Jacobsen 1997).Initial symptoms of methanol poisoning may appear as soon as 12 hours post-ingestion, but usually develop 24 hours after ingestion. These may resemble ethanol intoxication and consist of drowsiness, confusion, and ataxia, as well as weakness, headache, nausea, vomiting, and abdominal pain. Collectively, these symptoms may mimic an alcohol hangover and are due to mild intoxication, caused by methanol itself. As methanol metabolism proceeds, a severe anion gap metabolic acidosis will develop. Severe metabolic acidosis in conjunction with visual effects are the hallmark of methanol poisoning. Patients usually describe blurred or misty vision, double vision, or changes in color perception. There my be constricted visual field and, occasionally, total loss of vision. Characteristic visual dysfunctions include pupillary dilation and loss of pupillary reflex (Burkhart 1990; Suit 1990). Further signs and symptoms may be shallow respiration, cyanosis, tachypnea, coma, seizures, electrolyte disturbances, and various hemodynamic changes including profound hypotension and cardiac arrest. There may be mild to profound loss of memory, confusion, and agitation, which may progress to stupor and coma as the severity of the acidosis increases (Suit 1990). In severe cases, death is possible. Surviving patients can be left with permanent blindness or with other neurological deficits (Jacobsen 1997).

29. Diagnostic Calculation of osmolar and anion gap can be used to estimate the methanol level and predict the severity of ingestion specific level >20 mg/dl Toxic >40 mg/dl Severe toxic After latent period dose not detect methanol because has been metabolized to formate. Anion gap = [Na+] � [Cl-] � [HCO3-] ??????? = 8- 12 meq/L ????????? anion gap acidosis ???????????????????? lactic acid ?????????????? acid anion ??????????????????????? ???? formic acid ??????????????? methanol poisoningAnion gap = [Na+] � [Cl-] � [HCO3-] ??????? = 8- 12 meq/L ????????? anion gap acidosis ???????????????????? lactic acid ?????????????? acid anion ??????????????????????? ???? formic acid ??????????????? methanol poisoning

30. Emergency and supportive measurement open airway treatment coma and seizure treat metabolic acidosis by NaHCO3 IV Specific antidote fomepizole or ethanol saturated alcohol dehydrogenase enzyme Not available measurement methanol serum level ethanol is less expensive. Folic acid 50 mg IV q 4 h increase conversion of formate to CO2+H2O ???????? 1. Emergency and supportive measure -?????????????? methanol ????????????????? ?????????????????? methanol ????????????????????????????????????????????????????????? ??????????????????????????????????????? ???????????????????????? acidosis ????????????????? methanol ??? metabolites ??????????????? -???????????????????????????????? -????????? metabolic acidosis ?????? sodium bicarbonate ???????????????????????? Specific drugs and antidotes -ethanol: ?????????????????????????????????????????????????????????????? alcohol dehydrogenase ?????????????????????? methanol toxic metabolites ??? methanol ???????? loading dose ???? 0.6-0.8 g/kg ?????? maintenance dose ???? 125-130 mg/kg/h ?????????????????? ethanol ??????????? 100 mg/dl ?????????????? methanol ??? metabolized ????? ?????????????????? ethanol ???????????????? osmolar gap ??????? 5 mOsm/L ??????????? methanol ?????????????? 20 mg/dl -folic acid, leucovorin calcium (folate analogue) ?????????????????????????????????? formate ???? CO2 ??? H2O ????????????? 50 mg ??? 4 ??????? -?? fomepizole ??????????????????????????? alcohol dehydrogenase enzyme ??????? methanol metaboiltes ?????????????????????????? methanol *?????????????? fomepizole ????????????????????????????????????????? ethanol ?????????????????* IntroductionFomepizole, commonly referred to a 4-methylpyrazole or 4-MP, is a relatively recent addition to the therapeutic regimens for ethylene glycol and methanol poisonings. Fomepizole, as either the sulfate or hydrochloride salt, has been available in France since 1981 through a centralized compounding pharmacy servicing French hospitals. Until about 1990, fomepizole was used there investigationally to treat ethylene glycol poisonings. Since 1990, fomepizole has been accepted as the standard of care in France for the treatment of ethylene glycol poisonings. In 1997, Antizol (fomepizole) Injection was approved by the FDA as an antidote for ethylene glycol (antifreeze) poisoning, or for use in suspected ethylene glycol ingestion. In 2000, Antizol was approved by the FDA for an additional indication as an antidote for methanol poisoning, or for use in suspected methanol ingestion. In 2000, Antizol was approved by Health Canada as an antidote for ethylene glycol poisoning, followed by approval in 2001 as an antidote for methanol poisoning. ChemistryAntizol is the free base form of fomepizole, which has a molecular formula of C4H6N2 and a molecular weight of 82.1 grams/mole. Antizol is a clear, colorless to yellow liquid at room temperature, but may solidify below 25� C (77� F). Solidification does not affect the efficacy, safety, or stability of Antizol [Antizol (fomepizole) Injection package insert]. Its chemical structure is shown in Figure 3. Figure 3. Chemical Structure of Antizol Mechanism of ActionAntizol is a competitive inhibitor of alcohol dehydrogenase, the enzyme that catalyzes the oxidation of ethanol to acetaldehyde. Alcohol dehydrogenase also catalyzes the initial steps in the metabolism of ethylene glycol and methanol to their toxic metabolites. Absorption, Bioavailability and DistributionIntended for administration by the intravenous route, Antizol is immediately and completely bioavailable. Antizol rapidly distributes to total body water. The volume of distribution is between 0.6 L/kg and 1.02 L/kg [Antizol (fomepizole) Injection package insert]. Metabolism and ExcretionIn healthy volunteers, only 1-3.5% of an administered dose of Antizol (7-20 mg/kg oral and IV) was excreted unchanged in the urine, indicating that metabolism is the major route of elimination (Jacobsen 1990). In humans, the primary metabolite of Antizol is 4-carboxypyrazole (4-CP), which is excreted in the urine. Other minor metabolites of fomepizole observed in the urine are 4-hydroxymethylpyrazole and the N-glucuronide conjugates of 4-carboxypyrazole and 4-hydroxymethylpyrazole. These metabolites are either inactive or are so weakly active (4-hydroxymethylpyrazole) that they do not contribute significantly to the inhibition of alcohol dehydrogenase (Weintraub 1988). The elimination of Antizol is enhanced after several doses have been administered at 12-hour intervals, suggesting that it induces its own metabolism. Following auto-induction, a first order kinetic model more closely describes the elimination of Antizol. The metabolism of Antizol to 4-CP occurs after an initial cytochrome P-450-mediated hydroxylation followed by further oxidation. As antizol is a potent inducer of cytochrome P-450-mediated drug elimination in animal studies, the auto-induction of Antizol elimination in humans over 36-48 hours may also involve the induction of cytochrome P-450 (Jacobsen 1990). The elimination of Antizol follows zero order, saturable Michaelis-Menten kinetics after acute doses and a first order kinetic model after induction of metabolism following chronic doses. Values for plasma half-life vary with dose and were therefore not calculated in early study reports.???????? 1. Emergency and supportive measure -?????????????? methanol ????????????????? ?????????????????? methanol ????????????????????????????????????????????????????????? ??????????????????????????????????????? ???????????????????????? acidosis ????????????????? methanol ??? metabolites ??????????????? -???????????????????????????????? -????????? metabolic acidosis ?????? sodium bicarbonate ???????????????????????? Specific drugs and antidotes -ethanol: ?????????????????????????????????????????????????????????????? alcohol dehydrogenase ?????????????????????? methanol toxic metabolites ??? methanol ???????? loading dose ???? 0.6-0.8 g/kg ?????? maintenance dose ???? 125-130 mg/kg/h ?????????????????? ethanol ??????????? 100 mg/dl ?????????????? methanol ??? metabolized ????? ?????????????????? ethanol ???????????????? osmolar gap ??????? 5 mOsm/L ??????????? methanol ?????????????? 20 mg/dl -folic acid, leucovorin calcium (folate analogue) ?????????????????????????????????? formate ???? CO2 ??? H2O ????????????? 50 mg ??? 4 ??????? -?? fomepizole ??????????????????????????? alcohol dehydrogenase enzyme ??????? methanol metaboiltes ?????????????????????????? methanol *?????????????? fomepizole ????????????????????????????????????????? ethanol ?????????????????* IntroductionFomepizole, commonly referred to a 4-methylpyrazole or 4-MP, is a relatively recent addition to the therapeutic regimens for ethylene glycol and methanol poisonings. Fomepizole, as either the sulfate or hydrochloride salt, has been available in France since 1981 through a centralized compounding pharmacy servicing French hospitals. Until about 1990, fomepizole was used there investigationally to treat ethylene glycol poisonings. Since 1990, fomepizole has been accepted as the standard of care in France for the treatment of ethylene glycol poisonings. In 1997, Antizol (fomepizole) Injection was approved by the FDA as an antidote for ethylene glycol (antifreeze) poisoning, or for use in suspected ethylene glycol ingestion. In 2000, Antizol was approved by the FDA for an additional indication as an antidote for methanol poisoning, or for use in suspected methanol ingestion. In 2000, Antizol was approved by Health Canada as an antidote for ethylene glycol poisoning, followed by approval in 2001 as an antidote for methanol poisoning. ChemistryAntizol is the free base form of fomepizole, which has a molecular formula of C4H6N2 and a molecular weight of 82.1 grams/mole. Antizol is a clear, colorless to yellow liquid at room temperature, but may solidify below 25� C (77� F). Solidification does not affect the efficacy, safety, or stability of Antizol [Antizol (fomepizole) Injection package insert]. Its chemical structure is shown in Figure 3. Figure 3. Chemical Structure of Antizol Mechanism of ActionAntizol is a competitive inhibitor of alcohol dehydrogenase, the enzyme that catalyzes the oxidation of ethanol to acetaldehyde. Alcohol dehydrogenase also catalyzes the initial steps in the metabolism of ethylene glycol and methanol to their toxic metabolites. Absorption, Bioavailability and DistributionIntended for administration by the intravenous route, Antizol is immediately and completely bioavailable. Antizol rapidly distributes to total body water. The volume of distribution is between 0.6 L/kg and 1.02 L/kg [Antizol (fomepizole) Injection package insert]. Metabolism and ExcretionIn healthy volunteers, only 1-3.5% of an administered dose of Antizol (7-20 mg/kg oral and IV) was excreted unchanged in the urine, indicating that metabolism is the major route of elimination (Jacobsen 1990). In humans, the primary metabolite of Antizol is 4-carboxypyrazole (4-CP), which is excreted in the urine. Other minor metabolites of fomepizole observed in the urine are 4-hydroxymethylpyrazole and the N-glucuronide conjugates of 4-carboxypyrazole and 4-hydroxymethylpyrazole. These metabolites are either inactive or are so weakly active (4-hydroxymethylpyrazole) that they do not contribute significantly to the inhibition of alcohol dehydrogenase (Weintraub 1988). The elimination of Antizol is enhanced after several doses have been administered at 12-hour intervals, suggesting that it induces its own metabolism. Following auto-induction, a first order kinetic model more closely describes the elimination of Antizol. The metabolism of Antizol to 4-CP occurs after an initial cytochrome P-450-mediated hydroxylation followed by further oxidation. As antizol is a potent inducer of cytochrome P-450-mediated drug elimination in animal studies, the auto-induction of Antizol elimination in humans over 36-48 hours may also involve the induction of cytochrome P-450 (Jacobsen 1990). The elimination of Antizol follows zero order, saturable Michaelis-Menten kinetics after acute doses and a first order kinetic model after induction of metabolism following chronic doses. Values for plasma half-life vary with dose and were therefore not calculated in early study reports.

31. Treatment (cont.) Do not induce vomiting Hemodialysis rapidly remove both methanol and formate Osmolar gap>10 mOsm/L and serum methanol concentration>40 mg/dl should elimination by dialysis and continued until methanol concentration is less than 20 mg/dl.

32. 3. Isopropanol ???? isopropyl alcohol Used as solvents antiseptic disinfectant often ingested by alcoholic a the cheap substitute for liquor Blue dye � Blue heaven� Isopropyl alcohol ???????????????????????? ????????????????????????? ??????????????????????????????? 70% (Antiseptic and disinfectant) ??????????????????????????????????? ethanol ?????????????? isopropyl alcohol ??? methanol ??? isopropyl alcohol ???????????????? toxic organic acid metabolite ????????? ??????????????????????????????????????????????????????????????????? (Vd=0.6 L/kg) ??? metabolized ???????????? alcohol dehydrogenase enzyme ??????? acetoneIsopropyl alcohol ???????????????????????? ????????????????????????? ??????????????????????????????? 70% (Antiseptic and disinfectant) ??????????????????????????????????? ethanol ?????????????? isopropyl alcohol ??? methanol ??? isopropyl alcohol ???????????????? toxic organic acid metabolite ????????? ??????????????????????????????????????????????????????????????????? (Vd=0.6 L/kg) ??? metabolized ???????????? alcohol dehydrogenase enzyme ??????? acetone

33. Isopropyl alcohol is not metabolized to highly toxic organic acid and not produce anion gap acidosis.

34. Mechanism of toxicity Potent CNS depressant of CNS ��especially with acetone Coma and respiratory depression Very large dose cause hypotension and myocardial depression Irritate gastrointestinal tract and cause gastritis -???????????????????? ??????????????????????????????????????????????????????????? ???????????????????? coma ??? ?????????? ?????????????????????????? isopropanol ????????????? acetone ??????????????????????????????????????????????????? ????????????????????????????????? isopropanol ??????? ethanol ?????? 2-3 ???? -????????????????????????????? hypotension ????????????????? isopropyl alcohol ????????? vasodilation ??? myocardial depression -??????????????????????????????????????????????????????????????-???????????????????? ??????????????????????????????????????????????????????????? ???????????????????? coma ??? ?????????? ?????????????????????????? isopropanol ????????????? acetone ??????????????????????????????????????????????????? ????????????????????????????????? isopropanol ??????? ethanol ?????? 2-3 ???? -????????????????????????????? hypotension ????????????????? isopropyl alcohol ????????? vasodilation ??? myocardial depression -??????????????????????????????????????????????????????????????

35. Toxic dose Ingestion >0.5-1 mg/kg > 240 ml fetal dose Inhalation 40-200 ppm ACGIH TLV-TWA 400 ppm 2,000 ppm immediately dangerous

36. Clinical presentation Similar to clinical presentation of ethanol toxicity slurred speech, ataxia, stupor, coma, hypotenion, respiratory depression GI: abdominal pain and gastritis CNS: CNS depressant from acetone (metabolite)

37. Diagnostic Smell of isopropanol or acetone after 1-3 h of ingestion present ketonuria and ketonemia serum isopropanol level > 150 mg/dl �..coma ???????????? isopropanol ??????????????????????????????????????????? 15-30 ???? ???????????????????????????????? 30-60 ????????????????????????????? ????????????????????????????????????????????? ethanol ???? slurred speech, ataxia, stupor ????????????????????????????????? ??????????????? ?????????? ????????? metabolic acidosis ????????????????? ethanol ???????? osmolar gap ???????????????? ?????????????????????????????????????????????????? acetone (????????????????????????????????????????????? methanol ??? ethylene glycol ???????????????????????????? isopropanol ??????????????????????????????????????????? 15-30 ???? ???????????????????????????????? 30-60 ????????????????????????????? ????????????????????????????????????????????? ethanol ???? slurred speech, ataxia, stupor ????????????????????????????????? ??????????????? ?????????? ????????? metabolic acidosis ????????????????? ethanol ???????? osmolar gap ???????????????? ?????????????????????????????????????????????????? acetone (????????????????????????????????????????????? methanol ??? ethylene glycol ????????????????

38. Treatment Emergency and supportive measurement No specific antidote activated charcoal is not effective because isoprapanol is rapidly absorbed. Dialysis is indicated when level are extremely high (>500 mg/dl) ????? * ????????????????? ???????????? ???????????? * ????? specific antidote * ????????? isoproppanol ?????????????????????????? activated charcoal ????????????? isopropanol ????????? 30 ?????????????????????????????????? * Decontamination ????????? isopropanol ????????????????????? ???????????????????????????????????????????????????? ?????? ????????????????????? ????????????????????????????? ???????????????????????????????????????????????? coma ??????????????????? ?????? hemodialysis ?????????????????????????????????????????????????????????? supportive care ???????????????????? isopropanol ?????? (>500-600 mg/ dl) ???????? hypotension ????????????? fluid ??? vasopressor????? * ????????????????? ???????????? ???????????? * ????? specific antidote * ????????? isoproppanol ?????????????????????????? activated charcoal ????????????? isopropanol ????????? 30 ?????????????????????????????????? * Decontamination ????????? isopropanol ????????????????????? ???????????????????????????????????????????????????? ?????? ????????????????????? ????????????????????????????? ???????????????????????????????????????????????? coma ??????????????????? ?????? hemodialysis ?????????????????????????????????????????????????????????? supportive care ???????????????????? isopropanol ?????? (>500-600 mg/ dl) ???????? hypotension ????????????? fluid ??? vasopressor

39. Ingredients of antifreeze intentionally consumed as alcohol substitute by alcoholic sweet taste ��..be careful in children ?????????????????????????????????????????????????????????????? ???? antifreeze ????????????????????????????????????????????????? ethylene glycol ??????????????????????????????????? ???????? ???????? Glycol ?????????????????????????? ethylene glycol ???? diethylene glycol ??????????????????????????????? sulfanilamide elixir ??????????????????????? ??????? ?????????????????? ??????????? ???? liver necrosis, renal tubular degeneration ??????????? ?????????????????????????????????????????????????????????????????????????????????????? ????????????????????? ??????????????????? (Vd =0.8 L/kg) ????????? plasma protein ?????????????????? 17 ??????? ??? metabolized ??? alcohol dehydrogenase enzyme ??????? glycoaldehyde ??????? metabolized ?????????? glycolic, glyoxylic ??? oxalic acid?????????????????????????????????????????????????????????????? ???? antifreeze ????????????????????????????????????????????????? ethylene glycol ??????????????????????????????????? ???????? ???????? Glycol ?????????????????????????? ethylene glycol ???? diethylene glycol ??????????????????????????????? sulfanilamide elixir ??????????????????????? ??????? ?????????????????? ??????????? ???? liver necrosis, renal tubular degeneration ??????????? ?????????????????????????????????????????????????????????????????????????????????????? ????????????????????? ??????????????????? (Vd =0.8 L/kg) ????????? plasma protein ?????????????????? 17 ??????? ??? metabolized ??? alcohol dehydrogenase enzyme ??????? glycoaldehyde ??????? metabolized ?????????? glycolic, glyoxylic ??? oxalic acid

40. And where does this noxious liquid end up after all the cars and trucks seize their last journal bearings?� Into the eco-system!� It drips out of the radiators upon the fertile junkyard soil, slowly seeping into the streams and aquifers, leading to the rivers and oceans, killing off the plankton that feed the fishies, until finally, the entire food chain is destroyed!And where does this noxious liquid end up after all the cars and trucks seize their last journal bearings?� Into the eco-system!� It drips out of the radiators upon the fertile junkyard soil, slowly seeping into the streams and aquifers, leading to the rivers and oceans, killing off the plankton that feed the fishies, until finally, the entire food chain is destroyed!

42. Mechanism of toxicity Metabolic acidosis oxalate precipitate with calcium to form insoluble calcium oxalate crystal Tissue injury from deposition of oxalate crystal and toxic effects of glycolic and glyoxylic acids

43. Toxic Metabolize Glycolic acid �severe high anion gap acidosis that develops Oxalic acid � Precipitation of calcium oxalate crystals in the kidney causes renal failure

45. Toxic dose Lethal dose of 95% ethylene glycol is 1.5 ml/kg.

46. Clinical presentation Stage 1: Intoxication Up to 12 hours post-ingestion An ethanol-like intoxicated state (without an appropriate odour on the breath) progressing to CNS depression A high anion gap metabolic acidosis develops Nausea, vomiting, arrhythmias and tetany (due to hypocalcaemia) may occur ???????????????????????????? ethylene glycol ????????????? ethanol ??????????????????????????????????????? ??? ?????? ???????? ??????? ????????????????????????????????? ????????????????????????????????????????? ?????????????? calcium oxalate ???????????????????????????? ???????? anion gap ?????????????????? metabolic acidosis ???????????????????????????? ethylene glycol ????????????? ethanol ??????????????????????????????????????? ??? ?????? ???????? ??????? ????????????????????????????????? ????????????????????????????????????????? ?????????????? calcium oxalate ???????????????????????????? ???????? anion gap ?????????????????? metabolic acidosis

47. Stage 2: Cardiorespiratory Changes From 12 to 24 hours post-ingestion. Tachycardia, tachypnoea. Shock may occur in major ingestions

48. Stage 3: Renal Toxicity At 24-72 hrs post-ingestion Acute anuric renal failure may occur due to precipitation of calcium oxalate crystals in the renal tubules.

49. Diagnosis History of ingestion oxalate crystal in urine metabolic acidosis serum level >50 mg/dl ��serious toxicity

50. Treatment Emergency and supportive measurement maintain airway, treat hypocalcemia with IV Ca gluconate specific antidote fomepizole and ethanol to saturate the ADH enzyme pridoxine, folate, thiamine Hemodialysis when osmolar gap> 10 mOsm/L, with renal failure, serum level> 20-50 mg/dl. -????????????????? ???????????? -????? fomepizole ???? ethanol ??????????????????????? alcohol dehydrogenase enzyme ????????????????? metabolism ??? ethylene glycol ?????????????????????????????????????? ethylene glycol ??????? 20 mg/dl -????? pyridoxine, folate, thiamine ???????????????????????????? glyoxylic acid ???????????????????? -???????????? hemodialysis ?????????? ethylene glycol ???????????? metabolic acidosis Ethanol: "Ethanol blocking" treatment is the traditional treatment but has the disadvantage of causing intoxication (CNS depression). It is also irritant and should be given via a central line. Fomepizole: This is currently approved for this use in some countries (eg USA and Canada as 'Antizol'). Its advantages are effectiveness, ease of administration and absence of intoxication. Its use may obviate the need for haemodialysis in patients without visual impairment or severe acidosis. -????????????????? ???????????? -????? fomepizole ???? ethanol ??????????????????????? alcohol dehydrogenase enzyme ????????????????? metabolism ??? ethylene glycol ?????????????????????????????????????? ethylene glycol ??????? 20 mg/dl -????? pyridoxine, folate, thiamine ???????????????????????????? glyoxylic acid ???????????????????? -???????????? hemodialysis ?????????? ethylene glycol ???????????? metabolic acidosis Ethanol: "Ethanol blocking" treatment is the traditional treatment but has the disadvantage of causing intoxication (CNS depression). It is also irritant and should be given via a central line. Fomepizole: This is currently approved for this use in some countries (eg USA and Canada as 'Antizol'). Its advantages are effectiveness, ease of administration and absence of intoxication. Its use may obviate the need for haemodialysis in patients without visual impairment or severe acidosis.

51. Pungent odor gas Commonly use for the production of urea foam insulation, cloth treated with formaldehyde-containing crease-resistant resin formalin (formadehyde aqueous solution, 37%) is used as disinfectant and tissue fixative. Formalin is usually stabilized with 6-15% methanol. ??????????? formaldehyde ?????????????????????? urea formaldehyde ???? insulator ??????????? formaldehyde ???????????? ???? formaldehyde ??????????????? ????????? ???????? ???????????????????????????????? formalin ??????????????? methanol 10-50% ??????????????????? polymerization ??????? formalin ??????????????????????????????????????????????????????????????? ???????????????????????? formaldehyde ?????????????????????? urea formaldehyde ???? insulator ??????????? formaldehyde ???????????? ???? formaldehyde ??????????????? ????????? ???????? ???????????????????????????????? formalin ??????????????? methanol 10-50% ??????????????????? polymerization ??????? formalin ??????????????????????????????????????????????????????????????? ?????????????

53. Mechanism of toxicity Precipitation of protein and cause coagulation necrosis of exposed tissue. Irritate respiratory tract and spasm of larynx metabolic acidosis from metabolites�..formic acid carcinogen ?????????????????????????????????????????????????? ???????? formaldehyde ??????????????????? ?????????????????????????????????????????????????????? ??????????????????????????????????????? ??????????????????? (carcinogen) ?????????? metabolite ??? formaldehyde ??? formic acid ???????????????????????????????? metabolic acidosis ???????????? ?????????????????????????????????????????????????? ???????? formaldehyde ??????????????????? ?????????????????????????????????????????????????????? ??????????????????????????????????????? ??????????????????? (carcinogen) ?????????? metabolite ??? formaldehyde ??? formic acid ???????????????????????????????? metabolic acidosis ????????????

54. Toxic dose Inhalation ACGIH TLV-C is 0.3 ppm (0.37 mg/m3) > 20 ppm immediately dangerous to life ingestion 30 ml of 37% formaldehyde solution is reported to death in adult. formaldehyde gas: ???????????????????????????, ??, ???????????????, ?????? ????????????: ????????????????????????????????????????????????formaldehyde gas: ???????????????????????????, ??, ???????????????, ?????? ????????????: ????????????????????????????????????????????????

55. Clinical presentation Formaldehyde gas irritate eyes, cough, wheezing, noncardiogenic pulmonary edema ingestion severe corrosive esophageal and gastritis injury lethargy and coma metabolic acidosis

56. Diagnosis Specific level formate level methanol and formate level for formalin solution contained methanol Other: Calculate osmolar gap ???????? * ????????????????????????? mucous membrane ?????????????????????????????????????? * ??????????? formate ??? methanol (????????????? formaldehyde) ???????????????????????????????????????????????? * ??? osmolar gap ??????????????????????????????? formic acid ??? methanol???????? * ????????????????????????? mucous membrane ?????????????????????????????????????? * ??????????? formate ??? methanol (????????????? formaldehyde) ???????????????????????????????????????????????? * ??? osmolar gap ??????????????????????????????? formic acid ??? methanol

57. Emergency and supportive measurement maintain air way to treat bronchospasm IV saline to replace fluid loss caused by gastroenteritis NaHCO3 to treat metabolic acidosis Antidotes ethanol and folic acid to treat toxicity from formalin solution folic acid to treat formate intoxication from formaldehyde ???????? *????????????????????????????? ???????????????? bronchospasm *???????????????????????????????? ?????????????? formaldehyde ????????????????????????? *?????? sodium bicarbonate ????????? metabolic acidosis *?????????????? alkalinization ????????????????????????? formate *?????????????? hemodialysis ??????????? formic acid ?????????????????????? metabolic acidosis ?????????????????? osmolar gap>10 mOsm/L???????? *????????????????????????????? ???????????????? bronchospasm *???????????????????????????????? ?????????????? formaldehyde ????????????????????????? *?????? sodium bicarbonate ????????? metabolic acidosis *?????????????? alkalinization ????????????????????????? formate *?????????????? hemodialysis ??????????? formic acid ?????????????????????? metabolic acidosis ?????????????????? osmolar gap>10 mOsm/L

58. Treatment (cont) Rescuers should wear self-contained breathing apparatus remove the victim from exposure and give O2 Do not induce vomiting because of the risk of corrosive injury hemodialysis when severe acidosis or osmolar gap > 10 mOsm/L Alkalinization of the urine help promote excretion of formate

59. 6. Acetadehyde (acetic aldehyde) Colorless liquid, fruity odor and irritation Corrosive severe burns to eyes and skin vapors strongly irritating to eyes and respiratory tract fetal development in animals carcinogen in test animals ACGIH TLV 25 ppm IDLH 2,000 ppm

60. Acetadehyde (cont.) Used with disulfiram cause �acetadehyde syndrome� Clinical presentation: flushing, throbbing headache, dypnea, anxiety, vertigo, vomiting, confusion, orthostatic hypotension reaction may occur up to several days after the last dose of disulfiram ????????????????????? ???????????? ??????????????????????????????????????? ???????????????????????????? ??????? ???????????????? ????????? ?????????????????????????????? formaldehyde ?????????????????????????????????????????????????? ????????????????????????????????????????????????? ????????? acetadehyde ?????????????????????????????? ?? disulfuram ????????????????????????? ethanol ?????? ??????? disulfiram ????????????????? alcohol dehydrogenase enzyme ????????????? acetadehyde ??????????????????????????????????????????????? �acetadehyde syndrome� ????????????????????? ????????????? ???????? ??????? ????? ????? ???????????????? ??????????????????????????????????????????????????????????????????? ????????????????????? ???????????? ??????????????????????????????????????? ???????????????????????????? ??????? ???????????????? ????????? ?????????????????????????????? formaldehyde ?????????????????????????????????????????????????? ????????????????????????????????????????????????? ????????? acetadehyde ?????????????????????????????? ?? disulfuram ????????????????????????? ethanol ?????? ??????? disulfiram ????????????????? alcohol dehydrogenase enzyme ????????????? acetadehyde ??????????????????????????????????????????????? �acetadehyde syndrome� ????????????????????? ????????????? ???????? ??????? ????? ????? ???????????????? ???????????????????????????????????????????????????????????????????

61. Carbon monoxide Cyanide

62. 1. Carbon monoxide (CO) Colorless, odorless, tasteless, nonirritating gas "silent killer" Produced by incomplete combustion of any carbon-containing material Common source Smoke inhalation in fire, automobile, exhaust fume, poorly ventilated charcoal, cigarette smoke methylene chloride Carbon monoxide can be a "silent killer" on many recreational powerboats. It is a colorless, odorless, tasteless deadly gas that is produced by gasoline engines and generators, cooking ranges, space heaters and water heaters. Cold or poorly tuned engines produce more carbon monoxide than warm, properly tuned engines. The gas enters your blood stream through the lungs and displaces the oxygen your body needs. Early symptoms of carbon monoxide poisoning include irritated eyes, headache, nausea, weakness and dizziness ???????????????????????????? ??????????????????????????? ???????????????????????????????????? ???????????? CO ?????????????????? ??????, ???????????, ??????????????????????????????????????????????, ?????????? ?????????????????? CO ??????? methylene chloride ????????????????????????? CO ???????? ?????????????????????????????????????, ??, ???????? ????????????????????????????? ???? methylene chloride ????????????????????????? CO ???????????????????????????????????????????????????????????????????????????????? ??????????????????????????? ?????????? ??????? ?????????????????????? ?????????????????????????????????? �??????????� ????????????????????????????????????????????????????????????? ???????????????????????????????????????????? Carbon monoxide can be a "silent killer" on many recreational powerboats. It is a colorless, odorless, tasteless deadly gas that is produced by gasoline engines and generators, cooking ranges, space heaters and water heaters. Cold or poorly tuned engines produce more carbon monoxide than warm, properly tuned engines. The gas enters your blood stream through the lungs and displaces the oxygen your body needs. Early symptoms of carbon monoxide poisoning include irritated eyes, headache, nausea, weakness and dizziness ???????????????????????????? ??????????????????????????? ???????????????????????????????????? ???????????? CO ?????????????????? ??????, ???????????, ??????????????????????????????????????????????, ?????????? ?????????????????? CO ??????? methylene chloride ????????????????????????? CO ???????? ?????????????????????????????????????, ??, ???????? ????????????????????????????? ???? methylene chloride ????????????????????????? CO ???????????????????????????????????????????????????????????????????????????????? ??????????????????????????? ?????????? ??????? ?????????????????????? ?????????????????????????????????? �??????????� ????????????????????????????????????????????????????????????? ????????????????????????????????????????????

64. Mechanism of toxicity Reversible bind to hemoglobin (COHb) with affinity 250 times of O2 Directly inhibit cytochrome oxidase ��.disrupt cell function bind to myoglobin contribute to impaired myocardial contractility Damage brain in animal model systemic hypotension ?????????? ????????????????? cellular hypoxia ??? ischemia ??? CO ????????????? cellular hypoxia ?????????????????? ?????? CO ?????? Hemoglobin (Hb) ????????????? Carboxyhemoglobin (COHb) ???? CO ?? affinity ??? Hb ??????? O2 ??? 250 ???? ??????????????????????? oxyhemoglobin ??? Hb ?????????????? O2 ?????????????????????????????? ??? CO ???????? oxyhemoglobin ????????????????? O2 ????????????????? CO ????????????????????????????? cytochrome oxidase ???????? cellular function ?????????????????? myoglobin ????????? impaired myocardial contractility ???? ????????????????????????????????????????????????? ???? ?????????????????????????????????????? CO ?????? ????????????????????????????????????????? ???????????????????? CO ??????????? ischemia ?????? ???????????? systemic hypotension?????????? ????????????????? cellular hypoxia ??? ischemia ??? CO ????????????? cellular hypoxia ?????????????????? ?????? CO ?????? Hemoglobin (Hb) ????????????? Carboxyhemoglobin (COHb) ???? CO ?? affinity ??? Hb ??????? O2 ??? 250 ???? ??????????????????????? oxyhemoglobin ??? Hb ?????????????? O2 ?????????????????????????????? ??? CO ???????? oxyhemoglobin ????????????????? O2 ????????????????? CO ????????????????????????????? cytochrome oxidase ???????? cellular function ?????????????????? myoglobin ????????? impaired myocardial contractility ???? ????????????????????????????????????????????????? ???? ?????????????????????????????????????? CO ?????? ????????????????????????????????????????? ???????????????????? CO ??????????? ischemia ?????? ???????????? systemic hypotension

65. Toxic dose ACGIH TLV-TWA 25 ppm as 8 h time weights average IDLH 1,200 ppm several minutes of exposure to 1,000 ppm result in 50% saturation of COHb >80% COHb cause rapidly death

66. Major toxicities are cellular hypoxia and ischemia

67. Toxicokinetic Elimination by breathing T1/2= 4-5 h %COHb = 6 L/min x %CO x min of exposure

68. Clinical presentation Predominately in organ with high O2 consumption�. brain and heart headache, dizziness, nausea, rash Pts with CHD may experience angina or MI Severe exposure cause impaired thinking, coma, convulsion, cardiac arrhythmia, hypotension, death Exposure during pregnancy may result in fetal. ??????????? CO ?????????? %COHb ???????????????????????????????????????????? O2 ??????????????????? ?????????????????? COHb ???????? 10% ????????????????? ?????????????????????? COHb ??????? 30-50% ??????????????????????????? ??????????????????????????????????????????????????? (???????? 4) ?????????????? CO ??????????????????????????????? CO ????????????????????? ????????????? ????????????????????????? ????????????????????????????? CO ?????????????????????????? anemia, COPD ???? cardiovascular heart disease ??????????????????? CO ??????? ????????????????????? ?? ???????????????????????????????????????????????????????? ????????????????????????????????????????????? ???????????????????????????????? ??????????????????????????????????????????????????????????????????????????? CO ?????????? %COHb ???????????????????????????????????????????? O2 ??????????????????? ?????????????????? COHb ???????? 10% ????????????????? ?????????????????????? COHb ??????? 30-50% ??????????????????????????? ??????????????????????????????????????????????????? (???????? 4) ?????????????? CO ??????????????????????????????? CO ????????????????????? ????????????? ????????????????????????? ????????????????????????????? CO ?????????????????????????? anemia, COPD ???? cardiovascular heart disease ??????????????????? CO ??????? ????????????????????? ?? ???????????????????????????????????????????????????????? ????????????????????????????????????????????? ???????????????????????????????? ????????????????????????????????????????????????????????????????

69. Diagnosis History of exposure No specific reliable clinical findings Cherry red skin coloration or bright venous blood is highly suggestive but not frequently noted. Specific carboxyhemoglobin concentration

70. Goal of Treatment CO toxicity Decrease cerebral and cardiac ischemia increase dissociation of COHb increase elimination rate of CO

71. Emergency and supportive treatment Maintain airway treat coma and seizure Antidote: O2 in highest concentration (100%) treat until the COHb level <5% Hyperbaric O2 (2-3 ATM of pressure, T1/2 =20-30 min) use for patient's who do not response to O2 at the ATM Be careful toxicity of large amount O2 ?????????????????????? ??????, ????????, ????????, ???????, ????????????????????????????????????????????????????, ??????, ????????????????, ???, ??????????????????,???????????????, ?????? ?????????????? ??????????? CO ????????????? ?????????????????????????????????(bright cherry red) ?????????????????????? COHb ??????? 25% ???????????????????? ??? ????? Decontamination ???????????????????????????????????????????????????????????????? ?????????????????????????????????????????????????????????????????? Emergency and supportive measure ??????????????????????????????? ?????????????????????????? ????????????? ECG ???????????????????????????????????????????? ?????????????????????????????? cyanide ???? irritated gas ????????? Specific drugs and antidote ????????????????????? O2 ???????????????????????????????????????? (100%) ?????????? 100% O2 ???????? half-life ??? COHb ??? 6 ????????????????? 1 ??????? ?????? O2 ?????? COHb ???????????????? 5% ?????? O2 ???????????????????????????? COHb ????????????????????? CO ??? ?????? Hyperbaric oxygen ????????? 100% O2 ????????????????? 2-3atm ??????????????????????? CO ??????????? ????????????????????????????????????????? ???? ????????????????? ******???????????????????????????????????????????????????????????????????????????????????????????????????????? tymphanic membrane rupture, damaged sinus******* ?????????????????????? ??????, ????????, ????????, ???????, ????????????????????????????????????????????????????, ??????, ????????????????, ???, ??????????????????,???????????????, ?????? ?????????????? ??????????? CO ????????????? ?????????????????????????????????(bright cherry red) ?????????????????????? COHb ??????? 25% ???????????????????? ??? ????? Decontamination ???????????????????????????????????????????????????????????????? ?????????????????????????????????????????????????????????????????? Emergency and supportive measure ??????????????????????????????? ?????????????????????????? ????????????? ECG ???????????????????????????????????????????? ?????????????????????????????? cyanide ???? irritated gas ????????? Specific drugs and antidote ????????????????????? O2 ???????????????????????????????????????? (100%) ?????????? 100% O2 ???????? half-life ??? COHb ??? 6 ????????????????? 1 ??????? ?????? O2 ?????? COHb ???????????????? 5% ?????? O2 ???????????????????????????? COHb ????????????????????? CO ??? ?????? Hyperbaric oxygen ????????? 100% O2 ????????????????? 2-3atm ??????????????????????? CO ??????????? ????????????????????????????????????????? ???? ????????????????? ******???????????????????????????????????????????????????????????????????????????????????????????????????????? tymphanic membrane rupture, damaged sinus*******

72. 2. Cyanide (hydrocyanic acid / prussic acid) Used as chemical synthesis, laboratory analysis, metal planting Hydrogen cyanide (HCN) Cyanide salt + acid Plastic burn Amagdalin (cyanogenic glycoside) � seeds of apple, peach, plum, cherry, almond Acrylnitrile, Propylnitrile Nitroprusside ????????????????????? ???????????? ????????????????????????????????????????????????????????????????????? ??????????? cyanide ?????? ??? aliphatic nitriles ?????????????????????????, ??????????????? (direct vasodilator) ???? nitroprusside ???????????????????? metabolized ??? cyanide ????????????????????????????????????? amygdalin ???????? cyanogenic glycoside ??????????????????? ???, ????, ??????, ????????, ???????? ???????????? metabolized ????????? hydrogen cyanide (HCN) ???????????????????? cyanide ???????????????????????????????????? ???????????????????????????????????? ???????????? ????????????????????????????????????????????????????????????????????? ??????????? cyanide ?????? ??? aliphatic nitriles ?????????????????????????, ??????????????? (direct vasodilator) ???? nitroprusside ???????????????????? metabolized ??? cyanide ????????????????????????????????????? amygdalin ???????? cyanogenic glycoside ??????????????????? ???, ????, ??????, ????????, ???????? ???????????? metabolized ????????? hydrogen cyanide (HCN) ???????????????????? cyanide ???????????????????????????????????? ???????????????

73. Mixing acid+cyanide= HCN gas combustion by product of burning plastic, wool Has bitter almond smell

74. Mechanism of toxicity Bind to Fe2+ Bind to cellular cytochrome oxidase CN- ???????? Fe2+ ????????? cellular hypoxia ????????? cytochrome oxidase ??????????????????????? electron ??? cytochrome ????? O2 ?? mitochrondia ???????????????????????? ATP ?????????????? O2 ???????????? ????????????????? metabolism ???? ????? pyruvate ????????????????? acetyl CoA ???????????? Kreb�s cycle ??????????????? lactate ????????? metabolic acidosis ?????????? cyanide ??????????????????????????????? O2 ???????????????????? O2 ?????? ??????????????????? CO ????????????????????? O2 ?????????? cyanide ?????????? hydrocyanic acid ??????????????????????????????????? bitter almonds ???????? cyanide ???? LD50 ???? 2 mg/kg ????????? cyanide ???????? 50-75 mg ??????????? (syncope) ?????????????????????? 2-3 ???? ???? halogenate cyanide ?????????????????????????????????????????????????????? ???? pulmonary edema ????????????????? ???????CN- ???????? Fe2+ ????????? cellular hypoxia ????????? cytochrome oxidase ??????????????????????? electron ??? cytochrome ????? O2 ?? mitochrondia ???????????????????????? ATP ?????????????? O2 ???????????? ????????????????? metabolism ???? ????? pyruvate ????????????????? acetyl CoA ???????????? Kreb�s cycle ??????????????? lactate ????????? metabolic acidosis ?????????? cyanide ??????????????????????????????? O2 ???????????????????? O2 ?????? ??????????????????? CO ????????????????????? O2 ?????????? cyanide ?????????? hydrocyanic acid ??????????????????????????????????? bitter almonds ???????? cyanide ???? LD50 ???? 2 mg/kg ????????? cyanide ???????? 50-75 mg ??????????? (syncope) ?????????????????????? 2-3 ???? ???? halogenate cyanide ?????????????????????????????????????????????????????? ???? pulmonary edema ????????????????? ???????

75. HCN: well absorbed across the skin 150-200 ppm can be fetal. IDLH: 50 ppm ACGIH TLV-C :4.7 ppm (5 mg/m3) Ingestion 200 mg of Na/K salt Rare toxicity in nitroprusside infusion or after ingestion amygdalin-containing seeds Cyanide ???????????????????????????????????????????????? ????? hydrogen cyanide ?????????????????????????? ???????????? cyanide ?????????????????????????????????????????????????????????????????????? ????????? hydrogen cyanide gas (HCN) ???? 150-200 ppm ?????????????????????????????????????????????????? ???????????????????????????? 200 mg ?????????????????????????????????????? Cyanide ???????????????????????????????????????????????? ????? hydrogen cyanide ?????????????????????????? ???????????? cyanide ?????????????????????????????????????????????????????????????????????? ????????? hydrogen cyanide gas (HCN) ???? 150-200 ppm ?????????????????????????????????????????????????? ???????????????????????????? 200 mg ??????????????????????????????????????

76. Clinical presentation Headache, nausea, dypnea, confusion heavy exposure exposure: syncope, seizure, coma, cardiovascular collapse

77. Diagnosis Lactic acidosis the elevated of venous O2 saturation bitter almond smell in some people (depend on genetic variable) Specific cyanide level >0.5-1mg/L consider to toxic Cigarette smokers may have level>0.1mg/L rapid nitroprusside infusion >1mg/L

78. Treatment Emergency and supportive measure Specific drugs and antidote 1.cyanide antidote package amyl and sodium nitrites produce cyanide-scavenging methemoglobinemia sodium thiosulfate conversion cyanide to thiosulfate ????????????????????????? cyanide ??????????????? CN- ?????????????? ?????????????????????? O2 ??? antidote ??? CN- ????????? sulfur transferase enzyme ???? thiosulfate ????????? CN- ???????????? Fe3+ ????????????????????? thiocyanate ???????????????????????????????????? ???????? Sulfur transferase Cyanide + thiosulfate thiocyanate + sulfate ???????????????? Cyanide antidote kit ???????? Specific antidote ?????????????????????? cyanide ?????? Amyl nitrite ?????? crushable ampule Sodium nitrite 3% ?????? injectable solution 300 mg IV Sodium thiosulfate (25%) 12.5 g IV????????????????????????? cyanide ??????????????? CN- ?????????????? ?????????????????????? O2 ??? antidote ??? CN- ????????? sulfur transferase enzyme ???? thiosulfate ????????? CN- ???????????? Fe3+ ????????????????????? thiocyanate ???????????????????????????????????? ???????? Sulfur transferase

79. Treatment (cont.) 2.Hydroxocobalamin investigate drug in USA Decontamination give O2 remove contaminate with water activated charcoal Hemodialysis /hemoperfusion are not indicated.

80. Thank you for your attention