Methylthioninium Chloride

(BAN, rINN)
Methylthioninium Chloride Chemical formula
Synonyms: Azul de Metileno; Błękit metylenowy; Blu di Metilene; CI Basic Blue 9; Cloruro de metiltioninio; Colour Index No. 52015; Methylene Blue; Methylenii Caeruleum; Methylthioninii chloridum; Methylthioninii Chloridum Hydricum; Méthylthioninium, chlorure de; Methylthioninium-chlorid hydrát; Metilen Mavisi; Metiltioninio chloridas; Metiltionin-klorid; Metylotioniniowy chlorek; Metyltioniniumklorid; Metyylitioniniumkloridi; Schultz No. 1038; Tetramethylthionine Chloride Trihydrate. 3,7-Bis(dimethylamino)phenazathionium chloride trihydrate.
Cyrillic synonym: Метилтиониния Хлорид.

💊 Chemical information

Chemical formula: C16H18ClN3S,3H2O = 373.9.
CAS — 61-73-4 (anhydrous methylthioninium chloride); 7220-79-3 (methylthioninium chloride trihydrate).
ATC — V03AB17; V04CG05.
ATC Vet — QV03AB17; QV04CG05.

Pharmacopoeias.

In Chin. and US; in Eur. (as xH 2 O); in Int. (as anhydrous or 3H 2 O).

Ph. Eur. 6.2

(Methylthioninium Chloride). A dark blue, crystalline powder with a copper-coloured sheen, or green crystals with a bronze-coloured sheen. Soluble in water; slightly soluble in alcohol. Store in airtight containers. Protect from light.

USP 31

(Methylene Blue). Dark green crystals or crystalline powder with a bronze-like lustre. Is odourless or practically so. Solutions in water or alcohol are deep blue in colour. Soluble 1 in 25 of water and 1 in 65 of alcohol; soluble in chloroform. Store at a temperature of 25°, excursions permitted between 15° and 30°.

💊 Adverse Effects and Precautions

After high intravenous doses, methylthioninium chloride may cause nausea, vomiting, abdominal and chest pain, headache, dizziness, mental confusion, profuse sweating, dyspnoea, and hypertension; methaemoglobinaemia and haemolysis may occur. Haemolytic anaemia and hyperbilirubinaemia have been reported in neonates after intra-amniotic injection. Oral use may cause gastrointestinal disturbances and dysuria. Methylthioninium chloride should not be injected subcutaneously as it has been associated with isolated cases of necrotic abscesses. It should not be given by intrathecal injection as neural damage has occurred. Methylthioninium chloride should be used with caution in patients with severe renal impairment and is contra-indicated in patients with G6PD deficiency (see Uses, below). Methylthioninium chloride is used to treat methaemoglobinaemia but in large doses it can itself produce methaemoglobinaemia and methaemoglobin concentration should therefore be closely monitored during treatment. Methylthioninium chloride should not be used to treat methaemoglobinaemia induced by sodium nitrite during the treatment of cyanide poisoning, since cyanide binding will be reduced with resultant increased toxicity. It has also been contra-indicated in methaemoglobinaemia due to chlorate poisoning because of the risk that the more toxic hypochlorite may be formed, although several authorities consider its use to treat methaemoglobinaemia in severe chlorate poisoning appropriate. Methylthioninium chloride imparts a blue colour to saliva, urine, faeces, and skin, which may hinder a diagnosis of cyanosis.

Aniline poisoning.

It has been suggested1 that methylthioninium chloride should be used with caution in the treatment of aniline-induced methaemoglobinaemia since it may precipitate Heinz body formation and haemolytic anaemia. Methylthioninium chloride may reduce methaemoglobin concentrations, but repeated doses could aggravate haemolysis without further reducing methaemoglobinaemia.
1. Harvey JW, Keitt AS. Studies of the efficacy and potential hazards of methylene blue therapy in aniline-induced methaemoglobinaemia. Br J Haematol 1983; 54: 29–41.

Pregnancy.

Although intra-amniotic injection of methylthioninium chloride has been used to diagnose premature rupture of fetal membranes or to identify separate amniotic sacs in twin pregnancies, there have been several reports of haemolytic anaemia (Heinz-body anaemia) and hyperbilirubinaemia in neonates who had been exposed to methylthioninium chloride in the amniotic cavity.1-5 In most cases, exchange transfusions and/or phototherapy were required to control the jaundice; in 1 case phototherapy led to a phototoxic reaction.5 It has therefore been suggested3,6 that the use of methylthioninium chloride for detecting premature rupture of the membranes should be avoided. Multiple ileal occlusions have been reported in babies born to mothers who had twin pregnancies and who had received methylthioninium chloride by amniocentesis;4,7,8 in some cases it was possible to determine that methylthioninium chloride had been injected into the amniotic sac of the affected twin. Analysis of data from the EUROCAT registries9 for 1980 to 1988, which surveyed pregnancy outcomes in 11 countries, found a slightly higher risk of ileal and jejunal atresia or stenosis in twins regardless of whether they had received methylthioninium chloride, but the use of methylthioninium chloride was rare and no increased risk could be shown in babies exposed to it. A subsequent review6 from the Centers for Disease Control and Prevention concluded that the epidemiological evidence for the teratogenicity of methylthioninium chloride was quite strong and advised that it should not be used for midtrimester amniocentesis. A further difficulty in using methylthioninium chloride by amniocentesis for the diagnosis of premature rupture of the membranes is that the resultant staining of the skin and mucous membranes of the neonate hinders assessment of hypoxia, including the use of pulse oximetry.10
1. Cowett RM, et al. Untoward neonatal effect of intraamniotic administration of methylene blue. Obstet Gynecol 1976; 48 (suppl): 74s–75s
2. Serota FT, et al.
1. Preiser J-C, et al. Methylene blue administration in septic shock: a clinical trial. Crit Care Med 1995; 23: 259–64
2. Kirov MY, et al. Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study. Crit Care Med 2001; 29: 1860–7
3. Driscoll W, et al. Effect of methylene blue on refractory neonatal hypotension. J Pediatr 1996; 129: 904–8
4. Oliviera Neto AM, et al. Methylene blue: an effective treatment for contrast medium-induced anaphylaxis. Med Sci Monit 2003; 9: CS102–CS106
5. Peer G, et al. Methylene blue, a nitric oxide inhibitor, prevents haemodialysis hypotension. Nephrol Dial Transplant 2001; 16: 1436–41
6. Levin RL, et al. Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery. Ann Thorac Surg 2004; 77: 496–9
7. Schenk P, et al. Methylene blue improves the hepatopulmonary syndrome. Ann Intern Med 2000; 133: 701–6.

Ifosfamide encephalopathy.

See Glutaric Aciduria, above.

Methaemoglobinaemia.

Methaemoglobinaemia is a rare disorder of the blood in which there is an increase in the proportion of haemoglobin present in the oxidised form. Inherited methaemoglobinaemia may be due either to a deficiency of methaemoglobin reductase or to a structural abnormality of haemoglobin. Acquired methaemoglobinaemia may be caused by drugs1 or chemicals that oxidise haemoglobin, including nitrates and nitrites, sodium nitroprusside, dapsone, sulfonamides, phenacetin, and some local anaesthetics such as prilocaine; it may occur as a result of direct administration or occupational2 or environmental exposure. Exposure to low doses over long periods may lead to chronic methaemoglobinaemia whereas large doses may lead to an acute effect. Methaemoglobinaemia has a profound effect on oxygen transport by the blood; there is an increase in oxygen affinity leading to reduced tissue delivery and varying degrees of cyanosis. The presence of symptoms depends upon the degree and rapidity of methaemoglobin formation. Chronic mild methaemoglobinaemia is generally well tolerated although patients may appear cyanotic. Acute methaemoglobinaemia, particularly where methaemoglobin levels exceed 20%, is associated with dyspnoea, headache, malaise, giddiness, and altered mental state; methaemoglobin levels above 50% may lead to vascular collapse, coma, and death. Patients with inherited methaemoglobinaemia are usually asymptomatic but treatment may be given for cosmetic purposes to reduce the cyanotic skin colour. Patients with reductase deficiency generally respond to oral therapy with drugs that promote the reduction of methaemoglobin to haemoglobin, such as ascorbic acid, riboflavin, or methylthioninium chloride; methylthioninium chloride may also be given intravenously. Patients with structural abnormalities of haemoglobin do not respond. In acquired methaemoglobinaemia the causative agent should be identified and removed. Chronic or mild cases may not require treatment but acute symptomatic methaemoglobinaemia may be life-threatening and patients should be given intravenous methylthioninium chloride, along with oxygen and other supportive therapy as required. Toxicity is uncommon with methylthioninium chloride but it should not be used for methaemoglobinaemia due to the use of nitrites for cyanide poisoning since increased toxicity may result (for debate about its use after chlorate poisoning, see Adverse Effects and Precautions, above). Severe methaemoglobinaemia may require exchange transfusion; exchange transfusion with haemodialysis is the treatment of choice in patients with acute methaemoglobinaemia and haemolysis. Hyperbaric oxygen therapy has also been suggested in severe cases. Ascorbic acid is not useful in the acute situation since it acts too slowly but it may be of benefit where maintenance therapy is required.
1. Coleman MD, Coleman NA. Drug-induced methaemoglobinaemia: treatment issues. Drug Safety 1996; 14: 394–405
2. Bradberry SM. Occupational methaemoglobinaemia: mechanisms of production, features, diagnosis and management including the use of methylene blue. Toxicol Rev 2003; 22: 13–27.
ADMINISTRATION. In acute methaemoglobinaemia, methylthioninium chloride is usually given by intravenous bolus injection, but repeated doses may be needed and continuous intravenous infusion has also been used. Methylthioninium chloride was given at a dose of 7.5 to 10 mg/hour for 43 hours to control methaemoglobinaemia after dapsone poisoning.1The patient had responded to two bolus doses of 100 mg but methaemoglobinaemia had subsequently increased again owing to the long half-life of dapsone. Additional therapy included repeated doses of activated charcoal. A dosing schedule for methylthioninium chloride of 1 to 2 mg/kg as a bolus followed by a continuous infusion at an initial rate of 100 to 150 micrograms/kg per hour was suggested.
1. Dawson AH, Whyte IM. Management of dapsone poisoning complicated by methaemoglobinaemia. Med Toxicol Adverse Drug Exp 1989; 4: 387–92.

Priapism.

Priapism is usually treated with corporal aspiration or intracavernosal vasoconstrictors. There have been reports1-4 of the successful use of intracavernosal methylthioninium chloride, particularly in patients with drug-induced priapism; it is thought to act by blocking the vasodilator effects of nitric oxide. However, penile necrosis has occurred5 after the use of methylthioninium chloride and it should probably be avoided in patients with corporal fibrosis; aspiration of methylthioninium chloride about 5 minutes after injection has been suggested.2,3
1. Steers WD, Selby JB. Use of methylene blue and selective embolization of the pudendal artery for high flow priapism refractory to medical and surgical treatments. J Urol (Baltimore) 1991; 146: 1361–3
2. deHoll JD, et al. Alternative approaches to the management of priapism. Int J Impot Res 1998; 10: 11–14
3. Martínez Portillo FJ, et al. Methylene blue as a successful treatment alternative for pharmacologically induced priapism. Eur Urol 2001; 39: 20–3
4. Hübler J, et al. Methylene blue as a means of treatment for priapism caused by intracavernous injection to combat erectile dysfunction. Int Urol Nephrol 2003; 35: 519–21
5. Mejean A, et al. Re: Use of methylene blue and selective embolization of the pudendal artery for high flow priapism refractory to medical and surgical treatments. J Urol (Baltimore) 1993; 149: 1149.

💊 Preparations

BP 2008: Methylthioninium Injection; USP 31: Methylene Blue Injection.

Proprietary Preparations

Hung.: Metilenkek; USA: Urolene Blue. Multi-ingredient: Arg.: Lagrimas de Santa Lucia†; Mictasol Azul; Muelita; Visubril; Austria: Methyment; Braz.: Acridin; Cystex; Lisian†; Pilulas De Witt’s†; Sepurin; Vislin; Visodin; Visolux†; Canad.: Collyre Bleu†; Fr.: Collyre Bleu; Pastilles Monleon; Hong Kong: Clear Blue; Israel: Pronestin; Ital.: Mictasol Bleu†; Visustrin; NZ: De Witts Pills†; Pol.: Ginjal; Mibalin; Rus.: Neo-Anusol (Нео-анузол); Spain: Argentofenol†; Centilux; Tivitis; Switz.: Collyre Bleu Laiter; Turk.: Buco Bleu; Helmobleu; USA: Atrosept; Dolsed†; MHP-A; MSP-Blu; Prosed/DS; Trac Tabs 2X†; UAA; Urelle; Uretron; Uridon Modified†; Urimar-T; Urimax; Urised; Uriseptic; UriSym†; Uritact; Uro Blue; Urogesic Blue; Utira.
Published November 25, 2018.