Drugs causing methemoglobinemia

Pharmacologic and medical points about drugs which cause methemoglobinemia.

1. Methemoglobinaemia By M . H. Farjoo M.D. , Ph.D., Bioanimator Shahid Beheshti University of Medical Sciences

2. Methemoglobinaemia Introduction Pathophysiology Causes Symptoms Diagnosis Differential Diagnosis Treatment Cyanide Poisoning

3. Introduction Methemoglobin is an altered state of hemoglobin in which the ferrous (Fe++) irons of heme are oxidized to the ferric (Fe+++) state. A reducing substance is needed to convert the methemoglobin (ferric iron) back to oxyhemoglobin (ferrous iron). The auto-oxidation of hemoglobin to methemoglobin occurs spontaneously at a slow rate. In normal individuals, 0.5 to 3% of the available hemoglobin is converted to methemoglobin per day .

4. Pathophysiology There are two pathways for reduction of methemoglobin back to hemoglobin. The physiologically important pathway is the NADH-dependent reaction catalyzed by cytochrome b5 reductase ( b5R). the non active pathway utilizes NADPH generated by glucose-6-phosphate dehydrogenase (G6PD) in the hexose monophosphate shunt.

5. Pathophysiology There is no electron carrier in RBC to interact with NADPH methemoglobin reductase . Extrinsic electron acceptors, (methylene blue and riboflavin), are required for this pathway to be activated. This non-physiologic pathway becomes clinically important for the treatment of methemoglobinemia.

6. Causes of Methemoglobinaemia Methemoglobinemia may be congenital (rare) or acquired. In congenital form: The enzyme for reduction of methemoglobin is missing or there is a mutant globin that facilitates spontaneous oxidation of the ferrous iron to ferric . Affected patients have life-long cyanosis but are generally asymptomatic .

7. Causes of Methemoglobinaemia Acquired form may be induced by oxidizing agnet of drugs even in standard doses. Commonly implicated agents are topical anesthetics, and nitrates in infants and children.

8. Causes of Methemoglobinaemia; Medications Amino salicylic acid Benzocaine, lidocaine , prilocaine (even sprays and creams) Chloroquine Menadione (analog of vitamin K) Metoclopramide Methylene blue

9. Causes of Methemoglobinaemia; Medications Nitrates and nitrites (well water) Nitrofurantoin Phenazopyridine Primaquine Rasburicase (for hyperuricemia) Quinones Sulfonamides

10. Causes of Methemoglobinaemia ; Chemicals Acetanilide (used in varnishes, rubber, and dyes) Anilines and aniline dyes ( eg , diaper and laundry marking inks, leather dyes, red wax crayons) Antifreeze Benzene derivatives (used as solvents) Chlorates and chromates (used in chemical and industrial synthesis )

11. Causes of Methemoglobinaemia ; Chemicals Hydrogen peroxide (used as a disinfectant and cleaner) Naphthalene (used in mothballs) Naphthoquinone (used in chemical synthesis) Nitrobenzene (used as a solvent) Paraquat (used in herbicides) Resorcinol (used in resin melting and wood extraction)

12. Methemoglobin level Symptoms* 0 to 3 percent Normal range for adults (mean: 1 percent) 3 to 12 percent Minimal level associated with clinically detectable cyanosis or skin discoloration 3 to 20 percent Usually asymptomatic unless pre-existing condition present 20 to 50 percent Mild to moderate symptoms of hypoxemia ¶ 50 to 70 percent Severe, life-threatening symptoms of hypoxemia Δ >70 percent Usually fatal Symptoms of acquired methemoglobinemia

13. Symptoms of cquired methemoglobinemia The level is expressed as a percent of hemoglobin: 10% to 25%: Cyanosis 35% to 40%: Fatigue, dizziness, dyspnea, headache, tachycardia 60 %: Lethargy, stupor >70%: Death (adults)

14. Diagnosis of Methemoglobinaemia Sudden onset of cyanosis with symptoms of hypoxia after administration or ingestion of an oxidative agent. Hypoxia that does not improve with an increased oxygen . Abnormal coloration of the blood during phlebotomy (chocolate , or brownish to blue). Unlike deoxyhemoglobin , the color does not change when the blood is exposed to oxygen.

15. Diagnosis of Methemoglobinaemia Cyanosis during endoscopic procedures (bronchoscopy) may be due to airway obstruction. Another possibility is methemoglobinemia by topical anesthetic agent used prior to the procedure. Since such patients are often sedated, it is not possible for them to mention symptoms.

16. Diagnosis of Methemoglobinaemia Methemoglobinemia is strongly suggested when there is clinical cyanosis in the presence of a normal arterial pO 2 (PaO2). Thus , ABG may be deceptive because the PaO 2 is generally normal in methemoglobinemia. Pulse oximetry is also inaccurate in the presence of methemoglobinemia . High methemoglobin causes the oximeter to display 85% saturation, regardless of the true saturation.

17. Diagnosis of Methemoglobinaemia The patients with acute methemoglobinemia have a functional anemia. It means that the amount of functional hemoglobin is less than the measured level of total hemoglobin.

18. Diagnosis of Methemoglobinemia Note the chocolate brown color of methemoglobinemia. Tube 1 and tube 2 have a methemoglobin concentration of 70 percent; tube 3, a concentration of 20 percent; and tube 4, a normal concentration.

19. Diagnosis of Methemoglobinemia Samples of blood with varying methemoglobin levels displayed on white, absorbent material .

20. Differential Diagnosis of Methemoglobinaemia Rarely, cyanosis is present when levels of sulfhemoglobin exceed 0.5 g/ dL . The most common cause of cyanosis is decreased hemoglobin oxygen saturation. This is observed when the level of deoxyhemoglobin exceeds 4 to 5 g/ dL .

21. Treatment of Methemoglobinaemia In asymptomatic patient with a methemoglobin level <2%, just discontinue the offending agent(s). The treatment for methemoglobinemia is Ascorbic acid and/or methylene blue . Ascorbic acid is nontoxic (it acts by direct reduction) but is less effective than methylene blue. Ascorbic acid is inadequate for the treatment of acute methemoglobinemia requiring treatment. Both drugs can be given orally, IV or IM.

22. Methylene blue

23. Methylene blue 10 mg/1ml; 5 ml

24. Treatment of Methemoglobinaemia For urgent treatment, IV methylene blue 1–2 mg/kg over several minutes; it gives response within 30 min. The dose may be repeated in 1 hour if necessary. Excessive doses of methylene blue can cause methemoglobinemia (stimulates NADPH-dependent enzymes). Patients should be monitored for rebound methemoglobinemia .

25. Treatment of Methemoglobinaemia Methylene blue turns the urine blue and high concentrations can irritate the urinary tract. So fluid intake should be high when large doses are used. Blood transfusion, especially in anemic subjects, or exchange transfusion may be helpful in patients who are in shock .

26. Treatment of Methemoglobinaemia Methylene blue causes fatal serotonergic syndrome when used in combination with serotonergic drugs. Avoid concomitant use of methylene blue with SSRIs, SNRIs, and MAOIs. SSRIs = citalopram, escitalopram , fluoxetine, fluvoxamine, paroxetine, sertraline (Zoloft). SNRIs = atomoxetine, duloxetine, tramadol, venlafaxine MAOIs = selegiline, isocarboxazid , tranylcypromine, phenelzine Methylene blue is contraindicated in pregnancy.

27. Treatment of Methemoglobinaemia Methylene blue is contraindicated in G6PD deficiency since its action is dependent on NADPH produced by G6PD. In addition to being ineffective in G6PD deficiency, it induces hemolysis. Congenital methemogobinemia can be treated with oral methylene blue or ascorbic acid with partial effect.

28. Off-label Uses of Methylene blue Chromoendoscopy : Topical: 0.1 % to 1% solution sprayed via catheter or directly applied onto gastrointestinal mucosa during procedure. Ifosfamide -induced encephalopathy: Oral , IV; Note: Treatment may not be necessary; encephalopathy may improve spontaneously: Prevention : 50 mg every 6 to 8 hours. Treatment : 50 mg as a single dose or every 4 to 8 hours until symptoms resolve. Onychomycosis ( toenail): Topical: 2% solution applied to affected area(s) at 15 day intervals for 6 months; used in conjunction with photodynamic therapy.

29. Cyanide Poisoning Cyanide poisoning results in tissue anoxia by chelating the ferric part of cytochrome oxidase. It uncouples oxidative phosphorylation and inhibits cellular respiration. Poisoning may results from: Inhaling smoke from burning polyurethane foams in furniture Ingesting amygdalin (in the kernels of apricots , almonds and peaches) Excessive use of sodium nitroprusside for severe hypertension .

30. Sources of cyanide Industrial exposures Plastics production Photography Fumigation Pesticides/ Rodenticides Synthetic rubber production Fertilizer production Metal polish Hair removal from hides Electroplating Metallurgy

31. Sources of cyanide Plants and fruits Bamboo sprout Macadamia nuts Hydrangea plum , peach, pear, apple, bitter almond, cherry Miscellaneous Cigarette smoking Phencyclidine synthesis Artificial nail glue remover Product tampering Suicide/ Terrorist attack

32. Sources of cyanide Drugs Sodium Nitroprusside Laetrile (amygdalin) Combustion Wool Silk Polyurethanes Polyacrylonitriles Nylon Melamine resins Plastics

33. Cyanide Poisoning The symptoms are due to tissue anoxia (dizziness, palpitations, a feeling of chest constriction and anxiety). The breath smells of bitter almonds. In more severe cases there is acidosis and coma. Inhaled cyanide kills within minutes, but ingested salt require several hours. Inhalation of 2,000 parts per million hydrogen cyanide causes death within one minute, the LD50 for ingestion is 50-200 milligrams .

34. Cyanide Poisoning (General Treatment) Secure airway, breathing, and circulation. Intubation is usually required. Administer high-flow oxygen by nonrebreather face mask regardless of pulse oximetry reading. Do NOT perform mouth to mouth resuscitation in cases of suspected cyanide toxicity .. Give a single dose of activated charcoal if the airway is adequately protected (50 g in adults; 1 g/kg in children with maximum dose of 50 g) Treat hypotension with rapid IV boluses of isotonic fluid and vasopressors as needed. Treat seizures with a benzodiazepine ( eg , diazepam 5 mg IV).

35. Cyanide Poisoning (Treatment) hydroxocobalamin (5 g for an adult) which combines cyanide to form cyanocobalamin and is excreted by the kidney. Alternatively, IV sodium nitrite ( 10 mg/kg) produces methaemoglobin, and its ferric ion takes up cyanide as cyanmethaemoglobin . After sodium nitrite, IV sodium thiosulphate 25% (50 mL) , which forms thiocyanate .

36. Cyanide Poisoning (Treatment) It is reasonable to administer high-flow oxygen . When the diagnosis is uncertain, administration of thiosulphate plus oxygen is a safe course. Amyl nitrite or sodium nitrite is contraindicated in cases of potential carbon monoxide toxicity ( eg , from a fire ).

37. Cyanide poisoning

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