Management of Specific Poisoning PDF

Principles of Toxicology 1140-115 Management of Specific Poisoning Dr. Bedoor Qabazard Objectives: Management of specific poisoning conditions: ✓ Ionizing radiation ✓ Benzene ✓ Carbon monoxide ✓ Cyanide ✓ Alcohols ✓ Acetaminophe...

Principles of Toxicology 1140-115 Management of Specific Poisoning Dr. Bedoor Qabazard Objectives: Management of specific poisoning conditions: ✓ Ionizing radiation ✓ Benzene ✓ Carbon monoxide ✓ Cyanide ✓ Alcohols ✓ Acetaminophen ✓ SalicylatesAsp  Poisons Physical agents Chemical agents Biological agents -Ionizing rad. Inorganic Organic Animals Plants/ microbes Nuclear radiation X-rays Oxygen Water Venoms Atropine Gamma rays CO Alcohols Snakes Ricin -Non-ionizing rad. Cyanide Benzene Frogs Taxol UV Lead Insecticides Scorpions Curarines Infra red Iron Herbicides Fish (TTX) Aflatoxin Microwaves Mercury Opiates Amanitin Radiowaves Arsenic Barbiturates Botolinium Electromagnetic Cocaine Tetanus fields Glycosides Analgesics nonionisation as xray changecancirreveameaa.gearenas Ionizing Radiation (IR) IR is an established cytotoxic and carcinogen Clinical effects: – Acute radiation syndrome: N/V, fall in blood count, fever, infection – Chronic radiation syndrome: radiation sickness, cancer Mechanism of toxicity: – production of free radicals (ROS) which are highly reactive with a single I unpaired electron. Scavenge electrons from biologically important molecules in the cell causing destruction. – e.g. ROS scavenge electrons from thymidine base causing DNA strand breaks and DNA damage (irreversible); X-ray contraindicated in pregnancy. I – Cellular damage due to radiation can induce mutation of the gene encoding IT o p53 (tumor suppressor) leading to p53 inactivation →increased cancer risk mmen (radiation-induced cancer). Treatment: mainly supportive, blood transfusions and antibiotics may be used in case of fever and infection due to neutropenia.  Aromatic Hydrocarbons- Benzene Benzene is a clear, liquid, petroleum-based chemical that has a sweet smell. Routes of Exposure: swallowing, inhalation, cigarette smoke. Clinical effects & Mechanism of toxicity - irritating to the skin, eyes, GI and respiratory tract. - Once absorbed, benzene causes CNS depression and may sensitize the myocardium to the arrhythmogenic effects of catecholamines. - Hematopoietic toxicity of chronic exposure to benzene, manifest initially BEGIN_ as anemia, leukopenia, thrombocytopenia, BM depression. 155 - Benzene metabolites bind covalently to GSH, proteins, DNA & RNA leading to mutations or apoptosis (benzene is a human carcinogen) - Oxidative stress contributes to benzene toxicity. Treatment Supportive care (caution: aspiration). No specific antidote T.it r 60 death Carbon Monoxide (CO) Colorless, tasteless, odorless, non-irritating gas (silent killer). Source: combustion of fuel, in-doors heating, smoke, automobile exhaust. Most common way of suicide in UK. Naturally produced in the body, endogenous gasotransmitter Hemoglobin (Hb) saturation with CO: 1-5% in non-smokers, usuallysymptoms.gg15i 5-10% in smokers (no symptoms). ace IiIiIiii Lab data: obtain COHb concentration (key for diagnosis), electrolytes, glucose, BUN, EE creatinine, troponin, ECG, lactate, ABGs, metabolic acidosis Mechanism of toxicity: ee n – CO Combines reversibly with O2-binding sites (iron sites) of Hb→ Carboxyhemoglobin I see (COHb) →cannot transport O2 to tissues→ Cellular hypoxia (reversible). – High affinity to Hb (220 times > O2). – CO also binds myoglobin and cytochromes, causes endothelial oxidative injury, impaired myocardial contractility, lipid peroxidation and triggers inflammatory cascades. – Target organ toxicity: heart and brain most affected. whishdoseof or 9ñEEts o  Carbon Monoxide (CO) Clinical Effects we cantolerate ions – Signs of acute CO intoxication are those of hypoxia: Headache, confusion, loss of visual acuity (at ≈20% COHb) Tachycardia, tachypnea, syncope, coma (at ≈40% COHb) Convulsion, shock, metabolic acidosis, respiratory failure, death ( ≥60%) so Treatment – Stop exposure, remove patient immediately (decontamination) – Maintenance of respiration, assist ventilation – Antidote: O2 (the CO antagonist) until COHb drops below 5% Iii Standard (Normobaric) O2 Therapy: 100% O2 by mask Hyperbaric O2 Therapy (HBOT): 100% O2 under pressure in hyperbaric chamber (controversial) Cyanide (CN) ask.int as Is HCN is a colorless gas with bitter-almond odor. O Sources: Fumigants, industrial chemicals, nail polish removers, burning plastics, fire. Metabolism of Sodium nitroprusside used to treat severe HTN produce five CN molecules, can be a source of toxicity. Be mpertension Mechanism of toxicity: Ji Acts as a cellular asphyxiant that inhibits cellular cytochrome oxidase, thus blocking itiiEiifE the aerobic utilization of O2. The body will shift to anaerobic metabolism leading to lactic acid accumulation & metabolic acidosis. man Toxicokinetics: Rapidly absorbed after oral or inhalation exposure (HCN gas more toxic than salt forms due to immediate absorption). Cyanide salts in solution are well absorbed e across the skin. Death may occur within minutes at blood concentrations exceeding 1-2 mg/mL. Laboratory data Cyanide levels (rarely available), ABGs, electrolytes, and ECG. Acutely elevated Lactate level (>8 mmol/L) is sensitive and specific for CN poisoning  Cyanide (CN) 110Th Clinical presentation headache, dyspnea, metabolic acidosis, nausea, vomiting, ataxia, coma, seizures, collapse and death. Treatment ✓ Supportive care, decontamination, 100% Oxygen (given immediately to all patients) an cobalamin Hydroxo vit.BR✓ Hydroxocobalamin adult dose is 5 g IV over 15 mins. Binds & detoxifies free cyanide and forms the nontoxic cyanocobalamin (vitamin B12), which is renally excreted. ✓ Cyanide antidote kit: an older treatment, based on 2 modalities: Sodium nitrite produces cyanide-scavenging methemoglobinemia while sodium thiosulfate serves as a sulfur donor for cyanide metabolism to thiocyanate. is i (1) Sodium nitrite 300 mg in 10-mL ampules, IV push. Nitrites convert hemoglobin to MetHb, which binds the free cyanide ion and becomes cyanomethemoglobin. Caution! Do not overtreat to avoid fatal methemoglobinemia (methylene blue is contraindicated) (2) Sodium thiosulfate 12.5 g in 50-mL ampules, IV push. Acts as a sulfur donor to detoxify cyanide to the less toxic & readily excreted thiocyanate by the enzyme rhodanese so Nitrite should not be given if mild symptoms or if uncertain diagnosis, especially if concomitant CO poisoning is suspected. Hydroxocobalamin is best for mixed poisoning o  Drug-Induced Methemoglobinemia Hemoglobin becomes methemoglobin (MetHb) when iron oxidized from ferrous (Fe2+) to ferric (Fe3+). chociatebrownblood MetHb is dark brown (like chocolate), can no longer carry oxygen→ tissue hypoxia. I sets MetHb is produced endogenously in small quantities; normally, less than 1–2% Causes: nitrites, some well water high in nitrates, nitrous oxide, chloroquine and primaquine, fFT sulfonamides, sulfones, dapsone, local anesthetics (lidocaine, benzocaine). e samisen Symptoms: correlate with the degree of methemoglobinemia→ asymptomatic cyanosis, dyspnea, and severe CNS depression. Treatment A. General Management supportive care and gastrointestinal decontamination B. Oxygen pregnant Only improve tissue oxygenation for mñY C. Methylene Blue Specific antidote for methemoglobinemia (if MetHb >20%). Alternatives: vitamin C 0 Significantly reduce MetHb concentrations in less than 1 hour. 1 Contraindicated in G6PD Patients (hemolysis!) and Pregnancy. Exchange transfusions may be required, or Vitamin C (ascorbic acid). Pregt31 eeE.ciiatranstuio ethanol was toxic Alcohol Poisoning Methanol and ethylene glycol are toxic alcohols that may be ingested iF accidentally or consumed as ethanol substitutes. Ethylene glycol (EG) commonly used as radiator antifreeze, and in coolants, polishes and cleansers. believed to cause over 100 deaths annually in the US. colorless and has a sweet taste. Toxicokinetics of EG: Hepatically metabolized by ADH to glycoaldehyde, which is metabolized by ALDH to glycolic acid. Glycolate is oxidized to glyoxylic acid, whose most toxic metabolite is oxalic acid. Pyridoxine promotes the metabolism of glyoxylate to glycine (less toxic). Thiamine promotes metabolism of glycolic acid to α-hydroxy-β-ketoadipate.  Ts.use vtoxi.is folate thiamine if f pyridoxine B iiiii T.IE Q Metabolic pathways for ethanol, methanol, and ethylene glycol. ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; FMD, formaldehyde dehydrogenase. (Adapted from CJASN). Clinical presentation of EG intoxication: ❑ Phase 1 (30 minutes to 12 hours after ingestion): - CNS depression E iEiti n - nausea & vomiting, ataxia, nystagmus, hallucinations, coma and seizures. ❑ Phase 2 (12 to 24 hours after ingestion) 12h 24h - Cardiorespiratory toxicity - hypotension, tachypnea, congestive heart failure, myositis, pulmonary edema. ❑ Phase 3 (24 to 72 hours after ingestion)24h 724 - Renal toxicity mpocacemias mail.ca ystascicatinblood - flank pain and oxalate crystalluria, followed by the development of oliguric renal failure that may necessitate long-term dialysis. Lab Findings & Diagnosis: OT ✓ Severe metabolic acidosis (increased anion gap) ✓ Hypocalcemiawatontheblood ✓ Ca-oxalate crystals in the urine analysis (characteristic for EG poisoning)  Methanol (wood alcohol) Widely used in industry, a component of perfumes, and cleansers. Toxicokinetics of methanol: Latency between ingestion and toxicity occurs because of the time required to convert methanol to toxic metabolites. Formaldehyde is highly toxic but is rapidly degraded to formic acid, the most toxic metabolite responsible for the metabolic acidosis and widened anion gap. Further metabolism of formic acid to carbon dioxide is dependent on folate. Clinical Presentation of methanol intoxication: ▪ Acute intoxication→ nausea, vomiting and abdominal pain. ▪ After a latent period of 24 hours, weakness & respiratory difficulty. ▪ Visual disturbances (flashes of light, blurring or blindness) due to I Eo formic acid accumulation within the optic nerve & myelin destruction. ▪ Parkinsonian motor impairment due to damage to the putamen. ▪ Coma, seizures and death from cardiorespiratory arrest may occur. Laboratory Findings & Diagnosis: ✓ metabolic acidosis and severe anion gap ✓ visual toxicity (characteristic for methanol poisoning) notantaneglycol  Management of ethylene glycol & methanol intoxication Resuscitation, stabilization (ABCD) and decontamination. i.ws Gastric lavage may be of benefit within 1 to 2 hours of ingestion (caution: aspiration risk). helpful AC is not helpful unless a poly-drug ingestion is suspected. 4 major treatment goals: 1) Inhibition of ADH to prevent toxic metabolite formation. 2) Correction of the acidosis with bicarbonate. acid downfolic Tree 3) Use of specific enzymatic cofactors such as folate, thiamine and pyridoxine to modify deleterious metabolic pathways. 4) Removal of the toxin and metabolites by hemodialysis. Of a I e ADH blockade (via competitive inhibition) Ethanol: indicated for any symptomatic patient with suspicious ingestion or +ve history, AG acidosis, & when serum levels > 20 mg/dL. Ethanol (IV) to achieve concs 100 -150 mg/dL, will saturate ADH binding sites and prevent it from metabolizing EG or methanol. Fomepizole (4-Methylpyrazole, 4-MP): antidote that reversibly inhibits ADH. Hemodialysis Indications for hemodialysis in confirmed overdose include metabolic acidosis, renal compromise, visual symptoms (with methanol), or serum conc >50 mg/dL. Alkalinization (if serum pH falls below 7.2) Toxic metabolites may generate excess acid resulting in severe metabolic acidosis. Sodium bicarbonate is indicated. It may help remove glycolic/oxalic acid & formic acid from the CNS and increase renal excretion by ion trapping. Co-factors Ethylene glycol poisoning→ thiamine and pyridoxine (100 mg IV daily) may decrease oxalic acid formation and shift metabolism to less toxic metabolites. Methanol intoxication→ folate (50 mg IV q4h) may enhance the elimination of formic acid, decreasing toxicity.  Acetaminophen Poisoning A common cause of drug-induced hepatotoxicity in children and adults in accidental poisoning or suicide. The leading cause of acute hepatic failure and the second most common cause of liver failure requiring transplantation in the US. High risk groups: - malnourished/anorexic patients & prolonged fasting I ii - liver disease patients if - HIV patients - chronic alcoholics - patients taking CYP450 enzyme inducers such as rifampicin, TB isoniazid, phenytoin, barbiturate, carbamazepine. s.ije E Children may be less susceptible to acetaminophen hepatotoxicity due to a developmentally associated increase in sulfation ability. 3 OEE.EE Toxicokinetics: o It is well absorbed from the GIT & has a t½ below 2-3 h. o Vd = 0.9 L/Kg o Less than 5% is excreted unchanged in the urine; the remainder is metabolized in the liver. Neet Maximum daily therapeutic dose: = 4 g (adults) 8 so toxicdose8,10 = 75 mg/kg/day, not to exceed 3750 mg/day (children) Minimum toxic doses: = 7.5 - 10 g (adults) = 150 - 200 mg/kg (children) N-acetylcysteine (NAC) is the antidote of choice in treating acetaminophen-induced hepatotoxicity. Approved for both oral and IV use.  Mechanism of acetaminophen toxicity Following ingestion a majority (>90%) of acetaminophen undergoes phase II metabolism (via glucuronidation and sulfation) to produce non-toxic metabolites. A small fraction (150 μg/mL reflects "possible" toxicity and Face requires NAC treatment. i About 60% of patients with values above the "probable" line (>200 μg/mL) develop hepatotoxicity. Key lab tests: Liver function test (ALT, AST, bilirubin) Renal function test (Scr, BUN) Coagulation studies (PT/INR, PTT)  D 100 needtreatment 80 90 needtreatment cased but bothways should betreated Nomogram for prediction of acetaminophen toxicity following acute overdose  Treatment Guideline of Acute Acetaminophen Overdose Adapted from: Guidelines for the Management of Acetaminophen Overdose, 2005 Management of Acetaminophen toxicity witL Gastrointestinal decontamination: AC within 1-4 h post ingestion. Patients with APAP levels below the “possible" line for hepatotoxicity on the Rumack-Matthew nomogram may be discharged home after they are medically cleared (no need for NAC). Patients with APAP plasma levels above the “possible" line on the Rumack- Matthew nomogram must receive treatment with NAC. 8hr NAC is nearly 100% hepatoprotective when it is started within 8 hours after lidar an acute APAP ingestion. Late initiation of NAC therapy 24-36 hours after 24 36ns maggie ingestion may be beneficial in some patients. Liver transplantation may be indicated as a lifesaving measure for patients who have severe hepatotoxicity and potential to progress to hepatic failure. Management of Acetaminophen toxicity Mechanism of action of N-Acetylcysteine as an antidote: (1) enhancing the synthesis of glutathione, which is required to detoxify the toxic APAP metabolite NAPQI. a (2) directly binding to NAPQI in the place of glutathione. (3) facilitating Lothway sulfation of APAP (4) facilitating NAPQI reduction. (5) may also act in multiple ways to protect the liver from inflammatory processes that result from NAPQI binding to hepatocytes. The optimal time for administration of N-acetylcysteine is within 8 hours from the time the ingestion began. IV and Oral Regimens for Acetylcysteine in the Treatment of Acute Acetaminophen Poisoning Characteristic IV (Acetadote®) Oral is dose i a 4 - 238 150 mg/kg in 200 mL D W 5 - 140 mg/kg, followed 4 hours later by Regimen infused over 1 hour, then - 50 mg/kg in 500 mL D5W over 4 - 70 mg/kg every 4 hours for a 1652 17 doses diluted to 5% with hours, followed by juice or soft drinks - 100 mg/kg in 1L D5W over 16 h so 100 - Acute flushing and erythema in Adverse effects first hour of the infusion that typically resolves spontaneously - Nausea, vomiting 88 - Anaphylactoid reactions (rash, hypotension, wheezing, dyspnea). Antihistamines and epinephrine for Antiemetics Supportive therapy, severe anaphylactoid reactions (e.g. metoclopramide) if needed  Salicylates hiddeninmanyprep Available dosage forms include several OTC products: oral, rectal, and topical. Aspirin (acetylsalicylic acid) overdose was one of the leading causes of accidental death in children Toxicokinetics: Salicylates (weak acids) are well absorbed after oral administration. The half-life is 6 to 12 hrs at lower doses. In overdose situations, the half-life may be prolonged to more than 20 hrs. timo.im *Minimum acute toxic dose is 150 mg/kg Mechanism of toxicity A. Stimulation of the respiratory center in the brain results in hyperventilation, leading to initial respiratory alkalosis, followed by dehydration and compensatory metabolic acidosis. B. Uncoupling of oxidative phosphorylation and interruption of glucose and fatty acid metabolism, which contribute to metabolic acidosis, hypoglycemia, hypokalemia. C. Cerebral and pulmonary edema –mechanism unknown but may be related to an alteration in capillary integrity. D. Alter platelet function and may also prolong the prothrombin time (bleeding risk). Clinical presentation Nausea, vomiting, dizziness, tinnitus (mild toxicity). Hyperventilation/tachypnea, ataxia and malaise (moderate toxicity) Lethargy, convulsions, coma, metabolic acidosis, GI bleeding, increased PT, hepatic toxicity, lung Teate injury, renal failure, and proteinuria (severe toxicity). Salicylates Laboratory data for the following 6-hr post-ingestion levels are: a. 400 to 600 mg/L: tinnitus (mild toxicity) i i b. 600 to 950 mg/L: moderate toxicity c. More than 950 mg/L: severe toxicity dialyses With the presence of acidemia and aciduria, evaluate ABGs, urine pH laboratory evaluation may show leukocytosis, thrombocytopenia, decreased serum glucose, hypokalemia, and increased serum BUN, creatinine, and ketones. Treatment a. Supportive care. Decontamination, AC, WBI for large ingestions and SR products, MDAC. mild b. Alkalinization of urine and plasma (sodium bicarbonate IV) to enhance salicylate excretion & prevent diffusion across BBB. This is indicated for levels 400 mg/L. c. Hemodialysis for severe salicylism when serum levels are 1000 mg/L. off d. Fluid and electrolyte replacement to correct dehydration; potassium to correct hypokalemia. Sodium bicarbonate to correct acidosis; glucose to correct hypoglycemia to_e e e. Vitamin K and fresh frozen plasma are used to correct any coagulopathy  References: ❖ Harrison's Principles of Internal Medicine. Chapter 50. Poisoning and Drug Overdosage. ❖ Dipiro et al., Pharmacotherapy: A Pathophysiologic Approach, 9e. Chapter 10. Clinical Toxicology. ❖ Casarett and Doull's Toxicology: The Basic Science of Poisons. Chapter 2. Principles of Toxicology. ❖ Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e. Chapter 4. Drug Toxicity and Poisoning. ❖ Goldfrank's Toxicologic Emergencies, 10e. Chapter10. ❖ Temple & Baggish. Guidelines for the Management of Acetaminophen Overdose, 2005. ❖ Rumack & Mathew. Acetaminophen poisoning and toxicity. Pediatrics. Vol. 55 No. 6. June 1, 1975. pp. 871 -876. Q1: What is the antidote for carbon monoxide toxicity? Q2: In case of fire, what diagnostic test can differentiate between carbon monoxide and cyanide toxicity? Q3: What is the best antidote to treat mixed carbon monoxide and cyanide poisoning? Q4: What are the major treatment goals in the management of alcohol intoxication? Q5: Explain the Mechanism of action of N-Acetylcysteine as an antidote Q7: Discuss the management of salicylate toxicity