Pharmacologic and medical points about drugs which cause methemoglobinemia.

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

3. Methemoglobinaemia
 Introduction
 Pathophysiology
 Causes
 Symptoms
 Diagnosis
 Differential Diagnosis
 Treatment
 Cyanide Poisoning

4. 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.

5. 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.

7. 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.

8. 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.

9. 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.

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

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

12. 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)

13. 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)

14. 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

15. 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)

16. 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.

17. 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.

18. Diagnosis of Methemoglobinaemia
 Methemoglobinemia is strongly suggested when there
is clinical cyanosis in the presence of a normal
arterial pO2 (PaO2).
 Thus, ABG may be deceptive because the PaO2 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.

19. 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.

20. 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.

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

22. 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.

23. 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.

24. Methylene blue

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

26. 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.

27. 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.

28. 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.

29. 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.

30. 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.

31. 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.

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

33. 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

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

35. 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.

36. 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).

37. 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.

38. 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).

39. Cyanide poisoning

40. Thank you
Any question?