Poison Management and Drug Abuse Methemoglobinemia Cyanide Poisoning Brian Faley, PharmD, BCPS Ernest Mario School of Pharmacy Rutgers, The State University of New Jersey Hackensack University Medical Center HYPERLINK "mailto:firstname.lastname@example.org" Bfaley@rci.rutgers.edu Goals and objectives Methemoglobinemia Describe how methemoglobin is produces and eliminated List drugs that cause methemoglobinemia Recognize the signs and symptoms of methemoglobinemia Recommend treatment and monitoring of methemoglobinemia Cyanide Poisoning Recognize the signs and symptoms of cyanide poisoning Describe the pathophysiology of cyanide Recommend appropriate treatment of cyanide toxicity Monitor for efficacy and safety of your therapeutic plan Both most commonly caused by drugs but are very rare. Reducing agent donates an electron. Oxidizing agent accepts an electron. Oxidation is loss of an electrno. Methemoglobinemia (MetHb) Introduction Methemoglobinemia occurs naturally in the human body (1%) Smokers often have a higher baseline MetHb(3-5 5) than non-smokers Etiology Drugs Table 1: Drug-induced methemoglobinemia Amyl nitrite Sodium nitrite Nitroglycerin Dapsone Lidocaine Prilocaine Nitroprusside Phenazopyridine Chloroquine Sulfonamides Water contaminated with nitrous waste from animals and fertilizers Foods containing high nitrite and nitrate concentrations Burn patients - most burn patients are treated with silver nitrate topical antibiotic. Skin is much thinner and adsorb more sliver Nitrate. Automobile exhaust (in addition to carbon monoxide poisoning) Chronic bactrim therapy can get methemoglobinemia. Amyl nitrate on street is known as rush (looks like smelling salts) is an antidote for cyanide. Patient on amyl nitrate came in bright blue. Amyl nitrate is a potent vasodilator - get hypotensive, dizzy, smooth muscle relaxer. Physiology of methemoglobinemia Production In normal hemoglobin, iron is in its ferrous state (Fe2+) Methemoglobin is hemoglobin in which the iron is oxidized (loses an electron) to it?s ferric state (Fe3+) (Iron in hemoglobin rusts) Iron become oxidized by abnormal unloading of O2 (physiologic) Drugs and other etiologies (list above) LEO the lion goes GER LEO=Loss of electrons is oxidation GER=Gain of electrons is reduction Physiologic effects MetHb is structurally different than hemoglobin and unable to carry oxygen In severe MetHb there is a decrease in oxygen delivery to the tissues, hypoxia Hypoxemia and production of lactate causing an anion gap metabolic acidosis Elimination of MetHb Erythrocytes have evolved to reduce MetHb to hemoglobin Nicotinamide Adenine Dinucleotide (NADH) Methemoglobin Reductase NADH is a reducing agent (loses an electron, and is therefore oxidized to NAD+) Donates an electron to iron in methemoglobin Figure 1: NADH MetHb Reductase NAD+ is then reduces by glyceraldehydes dehydrogenase to NADH. Glyceraldehyde dehydrogenase restores NADH. Infants are at high risk of getting MetHb. RF - bottled (have nitrogen) fed infants. Infants have thinner skin, can adsorb more nitrogen. Most infants <6 months, also small infants. Clinical manifestations of methemoglobinemia Related to a decrease in O2 delivery to the tissues (hypoxia) Table 2: Symptoms of methemoglobinemia Methemoglobin concentration (%) Signs and symptoms 1-3 (Normal) None 3-15 Slate-gray cutaneous coloration Low SaO2 15-20 Cyanosis Chocolate brown blood 20-50 Dyspnea Headache Fatigue 50-70 Tachypnea Metabolic acidosis CNS depression Seizures > 70 Coma Death Choclate brown blood coming out of Arteriol blood. As patient gets worse and worse symptoms get less descript. Most notable, patients develop cyanosis (turning blue) Diagnosis Cyanosis unresponsive to oxygen therapy, despite normal pO2 Arterial blood gas (ABG) Chocolate brown color O2 saturation (SaO2) is usually low High to normal pO2 Cooximeter - look at arteriol blood and measure wavelength, measure o2hb . Carboxyhb, Methb and % of each in there. Identifies the absorptive characteristics of hemoglobin at different wavelength Differentiate between oxyhemoglobin, deoxyhemoglobin, methemoglobin, and carboxyhemoglobin Identify oxidizing substance Treatment Mild methemoglobinemia usually requires no treatment Treat if patient presents with altered mental status, chest pain, respiratory distress Supportive and O2 therapy Methylene blue - antidote Utilizes the nicotinamide adenosine dinucleotide phosphate (NADPH) reductase pathway Methylene blue is reduced (accepts an electron) by NADPH to leukomethylene blue Leukomethylene blue will reduce MetHb to hemoglobin NADP+ will be reduced back to NADPH by glucose-6-phosphate dehydrogenase Figure 2: Methylene blue and MetHb --Dose is 1-2 mg/kg over 5 minutes (0.1-0.2 ml/kg of a 1% solution) Improvement should be noted within 1 hour: usually immediate improvement Can be repeated if Sx do not improve symptoms Adverse effects Burning at injection site Discolors the urine (blue or blue-green) Dysuria Hemolysis Case: After delivery 11 days later, cyanosis, tachycardic, SaO2 85 %, Tired, normal except cyanotic. ABG: Po2 190 (elavated means low o2 binding), -- Most suggestive of MetHb in this patient is the cyanosis unresponsive to therapy. Another risk factor is less than 6 months old, because that is when NADH system is fully developed. -- Cause of patient MetHb - possibly something happened in the circumcision, numb the area, numbing agent is lodcaine and prilocaine (emlo cream), notorious for causing MetHb To confirm the MetHb -- Co-Oximetry - measure wavelenght of light in blood % of MetHb, Carboxy hemoglobin, O2 hemoglobin. -- MetHb - 40 % - Methylene blue 1-2mg/kg over 5 minutes/. Cyanide Poisoning Introduction History Cyanide exposure is unavoidable - everyone is exposed Many organisms have evolved pathways to detoxify cyanide Current applications - and common exposure - Sx - bright red skin Laboratory reagent Photography - develop film with CN Metal refining - jewelry cleaning Poisoning agent - victims of smoke inhalation (burn rubber, plastics, release cyanide) Exposure Industrial exposure Laboratory workers Victims of smoke inhalation Ingestion or inhalation of acetonitrile (inhalation sx occur faster) Acetonitrile is in some nail polish removers, and solvent for manufacturing of pharmaceuticals, and flim. Symptoms delayed for 3-24 hours Acetonitrile is metabolized by the P450 system to formaldehyde and cyanide Figure 3: Biotransformation of acetonitrile Ingestion of amygdalin - has CN Found in pits of various fruits Apricots Bitter almonds Cherries Peaches (-glucosidase converts amygdalin to glucose, benzaldehyde and cyanide Figure 4: Biotransformation of amygdalin Nitroprusside - potent vasodilator used in OR to induce hypotension. Nitroprusside, each molecule of Nitroprusside releases 5 molecules of CN, this process is sped up in UV light. Must cover Nitroprusside with big black bag. Once reaction occurs solution changes color (blue, green, red - throw out, CN is in it). 3 things must occur to get CN piosioning for Na nitroprusisde, >3 day therapy >10mcg/min, and renal failure. Long duration, high dose, and renal failure increase risk of CN poisioning from Na Nitroprusside.* Toxicokinetics Absorption Readily absorbed via lungs and mucous membranes (skin, GI (slower)) Slower absorption from the GI tract Distribution Concentrates in red blood cells Metabolism Combines with sulfur to form thiocyanate - by 2 different enzymes Rhodanese or (-mercaptopyruvate-cyanide sulfur transferase (Both sulfur transferases to form thiocyanate , which is harmless) If sulfur stores get depleted then get CN toxic issues. Elimination Thiocyanate is excreted by the kidneys Half-life 2.5 days Pathophysiology Potent inhibitor of many enzymes: CN inhibits Cytochrome AA3 - happens at end of krebs cycle and develops lactic acidosis (AG lactic acidosis) Cytochrome oxidase Metalloenzyme containing iron Integral for oxidative phosphorylation Aerobic energy production Occurs in the mitochondria Converts final glucose products into high energy molecules Adenosine triphosphate Cyanide inhibits cytochrome a-a3 End of the electron transport chain Decreases utilization of oxygen Lactic acidosis Anaerobic metabolism Figure 5: Oxidative phosphorylation Detoxification Cyanide-cytochrome a3 is reversible Cyanide is metabolized by two enzymes Rhodanese (thiosulfate-cyanide sulfurtransferase) (-mercaptopyruvate-cyanide sulfur transferase Catalyzes the attachment of sulfur to cyanide producing thiocyanate Irreversible reaction Cyanide concentrates in the red blood cell Clinical Presentation Classic odor of bitter almonds May not be present 60% of population can not detect the odor 40 % can scent bitter almonds. not really diagnositic Oxygen sensitive organs effected due to hypoxia Table 3: Signs and symptoms of cyanide poisoning Central nervous system Headache Lethargy Convulsions Coma Cardiovascular Hypotension Respiratory Tachypnea Dyspnea Gastrointestinal Abdominal pain Emesis Skin Cherry red color Cyanosis Hallmark sign of CN - Cherry red color, at end it goes from Red to blue due to cardiovacsular collapse. Easily get brain damage from hypoxia. Terminal events Cardiovascular collapse Coma and anoxic brain damage Diagnosis High clinical suspicion Clinical findings History If patient is Found in laboratory If patient Ingestion of nail polish remover Patient had Smoke inhalation Laboratory studies Arterial blood gas (ABG) - results in minutes Elevate O2 saturation on venous blood gas (VBG) High SaO2 Lactate level (normal < 2mmol/L) - anaerobic metabolism Electrolytes Presence of an anion gap (AG) acidosis AG = Na+ - (Cl-+HCO3-) Cyanide levels - take 2-4 hours to get back. Not very helpful. Urinary thiocyanate - takes long time also to get results back Differential diagnosis Other substances causing anion gap metabolic acidosis MUDPILES Carbon monoxide poisoning - think fire Treatment - initiate therapy immediately Must be initiated prior to confirmatory laboratories Establish intravenous access immediately Administer 100% oxygen by face mask Gastric lavage (up to 30min - 1 hour after ingestion, only get what's in the stomach) in the case of cyanide or acetonitrile ingestion Charcoal binds to small amounts of cyanide - charcoal is useless not given Cyanide antidote kit Amyl nitrite (bullets) and sodium nitrite (injection) and Na thiosulfate injection. Nitrites are oxidizing agents - trying to induce MetHb Administration induces methemoglobinemia (the falling off of CN is slower than the Thiosulfate formation) Add Na thiosulfate and a nitrite Cyanide has a greater affinity for methemoglobin than for cytochrome a3 (inhibition is reversible, so add nitrogen) Cyanomethemoglobin Cyanomethemoglobin degrades back to cyanide and methemoglobinemia Rhodanese detoxifies cyanide at a rate greater than the degradation of cyanomethemoglobin Methemoglobin is reduced back to hemoglobin by methemoglobin reductase Goal of nitrite therapy Induce a methemoglobin level of 20-30% Amyl nitrite should be given only if IV access is delayed Sodium thiosulfate Serves as a sulfur donor for rhodanese Increases the biotransformation of cyanide to thiocyanate by 13 fold Figure 6: Sodium nitrite and thiosulfate Administration The two agents should be administered simultaneously - thiosulfate plus nitrite in IV push Table 4: Antidote dosing Antidote Dosing Monitoring Sodium Nitrite 3%* Adults Pediatrics 300 mg(10cc) over 2 minutes 10 mg/kg (0.33 ml/kg) MetHb 20-30% at 30 minutes ABG Blood pressure Resolution of symptoms Sodium Thiosulfate 25% Adults Pediatrics 12.5 grams (50cc) 1.65 ml/kg Resolution of symptoms * Dose reduction in anemic patients required ** target MetHb of 20-30 % Repeat antidote may be required if no symptom resolution Adverse effects Nitrites Hypotension Tachycardia Excess methemoglobinemia Thiocyanate Arthralgias Rash Vomiting Hydroxycobalamin (Cyanokit) - Good outcomes - The cobalt has high affinity to pull CN from cytochrome AA3 Vitamin B12 precursor Contains a metal complex containing cobalt Affinity for cyanide is great enough to pull cyanide from cytochrome A3 Form cyanocobalamin (Vitamin B12) - forms energy, B12 liquid is bright red. Will inhibit lab tests that try to find Red light. Ex. Pulse oximetry will be off with hydroxycobalamin. Dose is 5 grams of hydroxycobalamin by IV infusion - can be repeated Doses up to 10 grams can be used AE: Red urine, red skin discolorization, mild allergic reactions, transient elevations in blood pressure Case - Cherry red skin, AG - 42 (acidosis), Metabolic acidosis, lactic acidosis. cherry red skin, assume cyanide, which causes anaerobe metabolism. Suspect CN poisioning - History most important sign - Found in lab, Bright cherry red. Tx- Na nitrite with Na thiosulfate. -- Monitor - MetHb levels want 20-30 %. , look at BP and vitals for improvement. -- Characteristic of Methemoglobinemia - Chocolate colored blood -- Associated with CN poisoning -- Cherry Red Skin -- Administration of Hydroxycobalamin for CN poisoning results in production of -- Cyanocobalamin (B12) PAGE PAGE 15
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