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Dapsone in Dermatology: a Comprehensive Review 1 Dapsone in dermatology: a comprehensive review 1 Review Article Dapsone in dermatology: a comprehensive review J K K Seneviratne1 Sri Lanka Journal of Dermatology, 2019/2020, 21: 1-9 Introduction antiparasitic agent (pneumocystic jeroveci and malaria as well). Not many drugs have withstood the test of time. Some were found to be less efficacious, whereas others have Sulphapyridine, a sulphonamide, was success- fizzled out due to intolerable or serious side effects. fully used in 1947 to treat dermatitis herpeteformis However, certain drugs are still being used since (DH). Subsequently, dapsone became the drug of discovery. A few examples are metformin, and choice for the treatment of DH. relevant to dermatology, methotrixate and dapsone. The main groups of systemic drugs used in Since dapsone is widely used by dermatologists dermatology include antibacterials and a variety of in Sri Lanka, a better understanding of its pharma- anti-inflammatory agents and an impressive group cology, mechanism of action and mechanisms by of immunosuppressives. Since dapsone exhibits all which it causes damage to human tissue should result of the above properties, it is still being used widely in in its proper use and will allow us to maximize the dermatology worldwide. therapeutic benefits. It will also prevent/minimize the significant adverse effects and relieve the phobia Though dapsone was first synthesised in 1908, some have about this valuable drug. researchers only became interested in the drug after the discovery of the sulphonamide, prontosil, the first Pharmacology sulphonamide antibiotic to be discovered. The award of the Nobel Prize for Medicine for this discovery Dapsone is highly lipophilic and is therefore readily resulted in widespread interest in other related absorbed from the intestines and easily penetrates into human tissues. It penetrates well into all the cells compounds. 4-diaminodiphenylsulfone is the of the human body. Peak concentration is reached chemical name of dapsone. To date, it remains the within 2-8 hours. The elimination half-life is fairly prototypic drug of sulfones. long (1-1.5 days). This allows daily dosing. The metabolites of the drug remain in circulation as long Though structurally related, the two groups are as 30 days after the last dose. The latter is important metabolized differently by the human body, hence in managing dapsone hypersensitivity syndrome. their side effects differ. Other sulphur-containing compounds are sulphonylureas and thiazide diu- Dapsone’s incomparable effectiveness com- retics. Dapsone was first used to treat streptococcal pared to other members of the sulfones and sulpho- infections using a very high dose (1-2 g daily). The namides is due to its superior absorption and easy discovery of its antimycobacterial property in penetration into most cells, including activated animals led to its widespread use in treating leprosy, neutrophils and mononuclear cells. Hence its indis- a disease with a worldwide prevalence. In fact, putable efficacy in many granulomatous infectious dapsone was used for decades as monotherapy for disorders like leprosy. Dapsone is excreted in breast leprosy. Though bacteriostatic, dapsone remains a milk and crosses the blood-brain barrier. However, principal drug in multi-drug regimens for leprosy to its widespread use in leprosy in developing countries date. Since then, it has also been used as an has proven its safety in pregnancy and lactation. 1Consultant Dermatologist, Lady Ridgeway Hospital for Children, Colombo, Sri Lanka. Vol. 21, 2019 / 2020 2 J K K Seneviratne Metabolism Dapsone N-acetyl transferase N-hydroxylase Dapsone hydroxylamine (DDS – NOH) Monoacetyl dapsone Glucuronidation G6PD Strong oxidant damages RBC membrane Renal excretion Reduced metabolites Metabolism lation, hydroxylation also takes place, a part from the liver, in keratinocytes and also by polymorphonuclear In order to excrete a lipophilic drug like dapsone, leukocytes and mononuclear cells. DDS-NOH is the it needs to be converted to a hydrophilic compound. most effective metabolite of dapsone therapeutically This process (biotransformation) also results in it is a potent anti-inflammatory and antibacterial generation of reactive intermediate metabolites (bio- compound. Unfortunately, the same compound is activation). responsible for dapsone’s adverse effects. As shown above, dapsone is reversibly Dapsone undergoes significant enterohepatic acetylated in the liver by N-acetyl-transferase to circulation. Dapsone can be safely used in both liver N-acetyl-dapsone (MADDS) and deacytelated back and renal failure with minor dose adjustments. to diaminodiphenylsulfone (DDS). As a result, a Dapsone is well-absorbed in dermatitis herpetifomis state of equilibrium develops between these two (DH) despite the presence of gluten-sensitive compounds. enteropathy. The second metabolic pathway of dapsone is hydroxylation. This is a phase I drug metabolic Excretion pathway mediated by cytochrome P-450 enzymes Dapsone and its metabolites are conjugated in the (CYP-450). This process of hydroxylation generates liver and rapidly excreted as dapsone glucuronide dapsone hydroxylamine (DDS-NOH). Unlike acety- by the kidneys. Sri Lanka Journal of Dermatology Dapsone in dermatology: a comprehensive review 3 Mechanism of action Oxygen (Activated PMN) NADPH oxidase Superoxide radical Superoxide dismutase Hydrogen peroxide Chloride Myeloperoxidase Dapsone X Hypochlorite Other strong oxidants Mechanism of action disease, bullous SLE, DH and Sweet’s syn- drome. Dapsone’s therapeutic benefit in these Dapsone has both antimicrobial and inflam- conditions has been proven beyond a doubt matory properties, the latter by several mechanisms. worldwide. Similarly, corticosteroids too may have anti-neutrophilic effects and can be used As can be seen, myeloperoxidase plays an to contribute for a better therapeutic effect. Both important role in quenching the harmful effects of can be used concomittantly for an additive O -free radicals generated by neutrophils, eosinophils 2 effect. and monocytes. The latter cells play a key role in granulomatous dermatitis. 2. Neutrophil chemotaxis Dapsone binds to intergrins on the neutro- The main antibacterial effect of dapsone is by phils and inhibits adherence to endothelial inhibition of dihydropteroate synthetase, a key initial cells, thereby preventing chemotaxis. It is also enzyme in folic acid utilization. believed to inhibit LT4-mediated neutrophil chemotaxis. Since dapsone, therapeutic benefit is well-esta- 3. Neuroprotection blished in neutrophilic dermatoses. It is reasonable Recent research indicates that dapsone can to argue it affects a number of key inflammatory influence functions of the central nervous pathways of neutrophils. These include: system. Its neuroprotective function is well- 1. Myeloperoxidase – halide mediated cyto- seen in stroke patients, and is believed to be toxicity (part of neutrophil respiratory burst). mediated by its antioxidative and anti- As a major scavenger of reactive O2 species, convulsive properties. Of special interest is its dapsone reduces both H2O2 and free hydroxyl benefit in neuro-Sweet’s syndrome. Addi- radicals. It is well-known that neutrophil- tionally, it is also known to inhibit the growth mediated skin damage occurs in linear IgA of glioblastomas. Vol. 21, 2019 / 2020 4 J K K Seneviratne Over the years, dapsone has been established as a B) In combination with other antimicrobial/ very useful drug for dermatologists of the entire antiprotozoal agents world. Currently, no other drug used in dermatology 1. Leprosy exhibits such a wide array of benefits. Among these 2. Pneumocystis jeroveci infection in AIDS are: 3. Malaria 1. A combination of anti-inflammatory, anti- microbial and anti-protozoal effects. Dosage of dapsone in dermatology 2. Its proven safety in children, adults, the elderly Fixed dose regimens of WHO blister packs makes its and in pregnancy. use easier in leprosy. The newer uniform multi-drug therapy further simplifies its use. However, in other 3. Safety of long-term treatment (once used as inflammatory skin diseases, its dosage should be one life-long monotherapy of leprosy patients). of a minimum required to control the disease activity. 4. Unique, powerful disease-specific effects on Initial dosage in adults ranges from 50 to 100 mg dermatitis herpeteformis. daily. A higher dose upto 300 mg per day can be tried 5. Fast relief of loxoscelism associated with after 4 to 6 weeks of low dosage therapy. However, brown recluse spider bites. this will depend on the tolerability and monitoring laboratory results. Once control of the disease is 6. Its safety in combination with other drugs, e.g. achieved, the dose can be reduced to one of multi-drug therapy for leprosy, steroids. maintenance. 7. Its free availability and very low cost. For children, tablets can be crushed and dis- solved in a sweet syrup. The general recommended Clinical uses of dapsone dose is 2 mg/kg/day, doubled if necessary after four Indications weeks. Dapsone is currently used worldwide in the treatment Adverse effects of neutrophilic/eusinophilic/monocytic (granulo- matous) mediated skin diseases and in the treatment Adverse effects to dapsone are of two types – of leprosy, the latter as the World Health Organi- pharmacological and idiosyncratic. The first is dose- zation’s multi-drug therapy regimens (MDT). It can dependent, and the latter dose-independent, therefore be used as monotherapy or as part of combination the latter cannot
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