It Is the Specific Treatment for Symptomatic Drug Induced Methemaglobinemia

METHYLENE BLUE

Left: a beautiful volumetric flask of pure methylene blue, (Amanda Slater). Right: a medical ampoule of methylene blue.

Introduction

Methylene blue is tetramethylthionine.

It is the specific treatment for symptomatic drug induced methemaglobinemia.

It may also have a role in the treatment of refractory states of Distributive Shock, (though more work needs to be done in this area). 3

History

Methylene blue was once used as a treatment for malaria and for cyanide poisoning, until more effective treatments became available.

Chemistry

Methylene blue is a phenothiazine-related heterocyclic aromatic molecule.

It is a solid, odorless, dark green powder at room temperature that yields a striking blue solution when it is dissolved in water.

Preparation

Methylene blue trihydrate as:

Ampoules:

● 50 mg in 5 mls (i.e. a 1% solution)

Mechanism of action

In methemaglobin metabolism:

Methylene blue acts to greatly promote the minor metabolic pathway of met Hb metabolism.

Fe+++ Hb

NADPH dependent NADH dependent

Met Hb reductase Met Hb reductase

(5%) (95%)

Fe++ Hb

Methylene Blue (acts as a co-factor for the minor pathway and therefore greatly enhances the activity of this pathway)

For the role of methylene blue in the treatment of Distributive Shock - see Appendix 1 below.

Pharmacokinetics

Absorption:

● Methylene Blue is given intravenously.

Metabolism and excretion:

● Methylene blue is rapidly reduced to leucomethylene blue, which is then predominantly excreted in the urine as a salt complex.

Indications

For methemaglobinemia:

1. Consider in all cases above 20% met Hb 1

2. All symptomatic patients with elevated met Hb levels.

Symptoms usually will occur at around 15-30% met Hb.

For Distributive Shock:

Consider for cases of refractory distributive shock, in particular: 3

1. Septic shock.

2. Anaphylactic shock.

3. Some CVS drug overdoses, such as dihydropyridine calcium channel blockers.

Contraindications/ Precautions

1. G6PD deficiency:

● The lack of NADPH in this condition means that methylene blue will be ineffective as it cannot be reduced to leucomethylene blue. Hemolysis may also be induced.

2. Known hypersensitivity.

3. Renal impairment, (relative: requires dosage reduction).

Adverse reactions

1. Excessive doses (> 7 mg/Kg) have oxidizing properties of its own and can therefore paradoxically induce metHb in its own right!

Doses in this range may also induce an acute hemolytic anemia, and have detrimental effects on pulmonary function.

2. May induce mild hemolysis in normal individuals.

3. In those with G-6-P deficiency massive hemolysis can be induced. It is therefore contra-indicated in these patients.

4. Rarely patients may have a congenital deficiency of NADPH met Hb reductase.

5. May be irritating to the vein (follow doses with saline flushes)

6. Blue staining of mucous membranes (which may further mimic cyanosis) and urine.

Failure of Methylene Blue Treatment for Methemaglobinemia

The following will need to be considered.

1. Wrong diagnosis:

● e.g. In sulfhemoglobinemia or CO poisoning methylene blue is not effective.

2. The patient has NADPH met Hb reductase deficiency (very rare)

3. The dose of methylene blue given has been excessive.

4. The dose of methylene blue given has not been adequate.

5. There is ongoing formation of methemaglobinemia, such as continual GIT absorption of a toxic agent.

Dosing

For methemaglobinemia:

1 mg / Kg (= 0.1 ml / kg of the 1% solution) IV slowly over 5 minutes.

Up to 2 mg/kg (= 0.2 ml/ Kg of the 1% solution) IV slowly over 5 minutes may be given.1

Improvement is usually seen with a single dose, however the dose can be repeated in 30 minutes to one hour if necessary.

Follow each dose with a saline flush to reduce venous irritation.

Improvement should be seen within 30-60 minutes.

Therapeutic end points:

1. Resolution of symptoms

2. Falling methemoglobin levels.

● Levels should be measured hourly until a consistent fall is recorded.

If methylene blue fails to control methemaglobinemia consider exchange transfusion or hyperbaric oxygen therapy.

For Distributive shock:

The dosing regimen for methylene blue based on experimental and clinical data is not entirely clear but does seem to be similar to what is used for the treatment of methemoglobinemia, i.e. 1- 2 mg/kg. 3

The dosing used for refractory septic shock has included:

● A single bolus

● Repeated bolus based on response

● Low-dose infusions.

Appendix 1: Vasodilation as regulated by Nitric Oxide

Endothelial Nitric oxide synthase, (primarily within endothelial cells)

L- arginine Nitric Oxide (NO) + L-citrulline

Activates Inhibits

Guanylate cyclase METHYLENE BLUE

GTP (in vascular smooth muscle) cGMP

Activates

cGMP -dependant protein kinase

Decreased myosin sensitivity

And

Inhibition of stored calcium release from sarcoplasmic reticulum

And

Blockade of L -type Calcium channels (hence reducing available intracellular calcium)

VASODILATION

Excessive production of NO is implicated in the pathogeneses of vasodilation in cases of distributive shock. Methylene blue blocks guanylate cyclase, thus inhibiting this biochemical pathway.

References:

1. Methylene blue in L Murray et al. Toxicology Handbook 3rd ed 2015.

2. Zalstein S Methaemoglobinaemia case report in Emergency Medicine: 1993:5 p 71.

3. Jang D.H et al. Methylene Blue for Distributive Shock: A Potential New Use of an Old Antidote. J. Med. Toxicol. (2013) 9:242-249.