leprosy (Hansen’s disease) is a rare
entity in Western countries, it is a significant public health problem in Third
World nations such as India.
oil (with weak antileprotic property) had been used extensively in the olden
days before the advent of sulfones which constitute the sheet anchor of
antileprotic therapy today. Clofazimine is used in resistant cases, while drugs
such as rifampicin, ethionamide, thalidomide, thiac-etazone, and sulfadoxine
have also been used with varying degree of success. Newer drugs which appear
promising in the treatment of leprosy include minocycline, clarithromycin, pefloxacin,
The sulfones are chemically related
to sulfonamides and are derivatives of 4,4´-diaminodiphenylsulfone or dapsone,
which is in fact the most widely used antileprotic even today, more than 50
years after it was first introduced. Sulfoxone sodium (not yet available in
India) is used when dapsone produces severe gastric distress.
Dapsone is marketed in India by
Burroughs Wellcome as 25 mg, 50 mg, and 100 mg tablets for oral administration.
It is a bacteriostatic antileprotic and anti-inflammatory drug used in the
treatment of leprosy, dermatitis herpetiformis, vasculitis, pemphigus, and
generalised pustular psoriasis. It is also widely used in AIDS patients for the
treatment and prophylaxis of PCP (Pneumocystis
carinii pneumonia), and prophylaxis against toxoplasmosis.
Following absorption, dapsone is
widely distributed to tissues. The concentrations in most organs approximate
the plasma concentration. Dapsone readily penetrates into nerve tissue with a
nerve tissue concentration approximately the same as the plasma concentration.
Peak serum concentra-tions are found at 2 to 8 hours after oral dosing. The
mean elimination half-life of dapsone is about 30 hours, which may be prolonged
to 2 to 4 days after overdose. Dapsone is acetylated by N-acetyltransferase
found in the liver and jejunal mucosa primarily to monoacetyldapsone (MADDS).
It is also hydroxylated by the mixed function oxidase system in the pres-ence
of oxygen and NADPH. The hydroxylated metabolite, N-hydroxydapsone (NOH-dapsone),
may be responsible for the haematologic manifestations (methaemoglobinaemia and
haemolysis) seen in overdose. Dapsone and monoacetyldap-sone may be excreted in
the urine as glucuronide or sulfate conjugates.
Adverse effects of dapsone therapy include
haemolysis (with reticulocytosis and Heinz body formation),
methaemo-globinaemia, nausea, vomiting, headache, insomnia, blurred vision, and
peripheral neuropathy. Occasionally Sulfonesyndrome
may develop in some malnourished patients 5 to 6weeks after beginning the
therapy, which is characterised by fever, exfoliative dermatitis, hepatic
necrosis with jaundice, lymphadenopathy, methaemoglobinaemia, and anaemia.
Dapsone has been associated with clinical exacerbation of porphyria and is NOT
indicated in porphyric patients.
Cases of dapsone overdose have been
reported, usually due to calculation errors resulting in vomiting, abdominal
pain, haemolysis, methaemoglobinaemia, sulfhaemoglo-binaemia, deep cyanosis,
restlessness, blurred vision, and convulsions. Giddiness, hallucinations,
dizziness, agitation, and confusion have been reported following overdoses.
Methaemoglobinaemia, haemolysis, and CNS stimulation are the most common
manifestations. Death may occur. A glucose -6-phosphate dehydrogenase deficient
individual has about a 2-fold increase in sensitivity toward dapsone-induced
haemolytic anaemia. Animal studies have shown a decrease in methaemoglobin
formation when cimetidine was given concur-rently with a once a day dosing.
When tested in humans given 400 mg of cimetidine three times daily for 3 days
before and 4 days after dapsone, drug concentrations increased 30% (less
metabolism). This has not been tried in the overdose situation.
Dapsone is contraindicated in
pregnancy due to its ability to produce anaemia or methaemoglobinaemia.
Drug-induced psychosis has been
reported during both therapeutic use and following intentional ingestion (2.5
gm) resulting in extreme agitation and violence.
The usual fatal dose is 2 to 5 grams
for an adult. Plasma levels of over 10 mg/L are associated with serious
toxicity. Studies of haemolysis such as haptoglobin and free haemo-globin, and
reticulocyte counts may be useful to monitor haemolysis. Other tests that could
help aid the diagnosis of latent methaemoglobinaemia and haemolytic anaemia
include red cell fragility, Heinz bodies, and lactic acid dehydrogenase.
Monitor urine for haemoglobinuria. Dapsone and its metabolite monoacetyldapsone
(MADDS) levels can be measured in urine, and if available may be useful to follow
Treatment involves gastric
decontamination and adminis-tration of methylene blue (to correct
methaemoglobinaemia), at a dose of 1 to 2 mg/kg IV, given over 5 to 10 minutes.
This may have to be repeated several times over every 4 hours for a number of
days. Caution: Large doses of
methylene blue iself may cause methaemoglobinaemia or haemolysis. Infusion of
packed red blood cells may be required. If cyanosis fails to clear after
treatment of presumed methaemoglobinaemia with methylene blue, or recurs late
in the clinical course, sulfhae-moglobinaemia may be present. Convulsions can
be controlled by diazepam or phenytoin IV in the usual doses. Blurred vision
sometimes responds to prednisolone (75 mg/day for 1 week, and then tapered off).
However, corticosteroids are of no use in the management of haemolysis.
Ascorbic acid has been tried, but there is no clear-cut indication as to its
efficacy. Oxygen inhalation therapy is not beneficial.
Decontamination with activated
charcoal is useful in the early stages of dapsone overdose. Extracorporeal
methods of eliminating the drug from the blood stream can be tried, but they
have no proven value. However there are reports of beneficial effects with
charcoal haemoperfusion and haemodialysis.
It is a phenazine dye which is used
in dapsone-resistant leprosy and lepra reactions (erythema nodosum leprosum).
Adverse effects include a reddish or
brownish skin discol-ouration, diarrhoea, abdominal pain, loss of weight, and
bull’s eye retinopathy. There may be deposition of clofazimine crys-tals in gut
wall tissue, mesenteric lymph nodes, and cytoplasm of alveolar macrophages.
Clofazimine crosses the placenta and is present in breast milk. Infants may be
pigmented at birth, or subsequently from ingesting breast milk.
Diagnosis can be established by thin
layer chromatography, and X-ray abnormalities of small bowel (alternating
segments of constriction and dilation, cogency of mucosal folds, and
circumscribed “polypoid” areas).
Treatment is symptomatic and
supportive. Periodic fundos-copy (every 4 months) is advised in all patients