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Flashcards in 2 - Dapsone Deck (81):

Dapsone is a sulfone compound (cousin of sulfonamides)



Dapsone is the mainstay of leprosy (granulomatous condition) treatment due to its antimycobacterial activity

True (Mycobacterium Leprae)


70-80% of dapsone is absorbed from the gut



70-90% of dapsone is protein bound



Dapsone is excreted via the kidneys with significant enterohepatic recirculation (liver) resulting in an effective half life of approx 24-36 hours



Dapsone is lipid soluble



Dapsone has a long elimination half life of as long as 30 days after a single oral dose and may result in significant enterohepatic recirculation



The major metabolite of dapsone is mono-acetyldapsone (MADDS)



Dapsone is able to cross the placenta and is excreted into breast milk

True (haemolysis has been demonstrated to occur in nursing infants of mothers taking dapsone)


Dapsone is metabolised in 2 ways in the liver: N-acetylation and N-hydroxylation

True (the N-acetylation pathway yields water soluble inactive metabolites which is renally excreted, whereas the N-hydroxylation pathway yields hydroxylamine metabolite which serves as a strong oxidant that causes RBC damage and resultant haemolysis)


Slow acetylators of N-acetyl transferase (N-acetylation pathway of dapsone metabolism) do not have increased adverse effects with dapsone

True (dapsone efficacy and adverse effects are mediated by the N-hydroxylation pathway which produces the active/toxic hydroxylamine metabolite and strong oxidant)


N-hydroxylation of dapsone occurs in the liver via cytochrome P450 enzymes CYP3A4, CYP2E1 and CYP2C9



The hydroxylamine metabolite produced via the N-hydroxylation pathway of dapsone metabolism is thought to be responsible for the haematologic adverse effects associated with dapsone, including methemoglobinaemia and haemolytic anaemia

True (N-hydroxylation of dapsone can be inhibited by using cimetidine which has been demonstrated to reduce methaemoglobinaemia without reducing plasma levels of dapsone)


N-hydroxylation of dapsone can be inhibited by using cimetidine which has been demonstrated to reduce methaemoglobinaemia without reducing plasma levels of dapsone



Glucose-6-phosphate dehydrogenase (G6PD) is the antioxidant enzyme which reduces the dapsone hydroxylamine metabolite to inactive metabolites

True (therefore G6PD enzyme deficiency causes accumulation of hydroxylamine active metabolites which serve as a strong oxidant for RBC membrane damage and result in haemolysis)


Dapsone and its metabolites are conjugated (glucuronidation) in the liver, which are more water soluble and rapidly excreted via the kidneys

True (with the main parent drug and N-hydroxydapsone most often conjugated with glucuronide and then excreted via the kidneys)


The role of liver failure in the clinical use of dapsone has been evaluated in patients with cirrhosis, and although minor changes in the metabolism of dapsone have been documented, no dosage adjustment is needed



The N-hydroxylated forms of dapsone play a role in the haematologic adverse effects



Clinically it appears that dapsone is most useful in treating diseases with neutrophilic infiltrates in the skin

True (erythema elevatum diutinum, a variant of leukocytoclastic vasculitis; Sweets syndrome, pyoderma gangrenosum)


The lack of neutrophils in the skin of patients treated with dapsone suggests that dapsone may affect the chemotaxis of neutrophils



Besides neutrophils, Dapsone also inhibits the enzyme myeloperoxidase which is present in eosinophils and monocytes

True (reasoning why dapsone might also be effective in dermatoses in which these cell types have a central role in the pathogenesis I.e. Granuloma annulare (monocytes) and eosinophilic cellulitis (eosinophils)


The myeloperoxidase enzyme system is present in neutrophils, eosinophils and monocytes, and causes microbial destruction through its oxidative properties



Through inhibition of myeloperoxidase, dapsone reduces the oxidative damage to normal tissues in various neutrophilic dermatoses, as well as dermatoses in which eosinophils or monocytes play a pathogenic role



The inhibition of dihydropteroate synthetase (enzyme in reduction of folic acid) of the folate pathway is the probable mechanism of dapsone for clinical effect in leprosy patients

True (and not the myeloperoxidase enzyme system in inflammatory dermatoses)


Dapsone has been FDA approved for the treatment of dermatitis herpetiformis and leprosy

True (though dapsone has also shown consistent efficacy in linear IgA dermatoses, bullous eruption of SLE and erythema elevatum diutinum) - variable efficacy demonstrated for other autoimmune bullous dermatoses, vasculitis, neutrophilic dermatoses


Most often, if dapsone is going to be effective in the treatment of an inflammatory dermatosis, the patient will experience a relatively rapid response (within 24-48 hours) to dapsone therapy, with a similar relatively rapid recurrence of the disease after withdrawal of the medication



Dapsone is the drug of choice for the treatment of dermatitis herpetiformis

True (although patients may also be treated with a gluten-free diet with good results, the difficulty of consistently following that diet often makes treatment with dapsone the best option for many patients; in addition the clinical response to a gluten free diet in patients with DH may be delayed often for weeks or months)


Most DH patients will respond to dapsone within 24-36 hours of initiation with a marked decrease in both itching and new blister formation

True (similarly, withdrawal of dapsone results in a rapid within 24-48 hours recurrence of signs and symptoms of DH - this is a reproducible finding and should be the measure against which all therapy with dapsone is judged)


If no significant risk factors such as severe cardiac, pulmonary, or haematologic disease exist for the pharmacologic side effects of dapsone (haemolytic anaemia and methaemoglobinaemia), therapy can be started at 100mg daily



Toxicity of dapsone such as haemolysis is directly related to the dose of the drug

True (patients must be warned against self-medication and self-adjustment of the dosage in response to changes in disease activity)


Patients with linear IgA bullous disease (chronic bullous dermatosis in childhood) also respond to dapsone in a manner similar to that of patients with DH

True (Patients with linear IgA bullous disease generally present with clinical and histologic features very similar to those seen in patients with DH)


Patients with bullous eruption of SLE often have a dramatic response to dapsone therapy

True (these patients have a vesicular eruption with a histologic picture similar to that seen in patients with DH, and the presence of neutrophils in a vesicular eruption in a patient with SLE suggests that dapsone will be effective and therefore commonly reducing the need for systemic corticosteroids)


Patients with bullous eruption of SLE may have significant anaemia secondary to the inherent disease process that could increase the clinical severity of the pharmacologic effects of dapsone



Even though dapsone is the mainstay of leprosy treatment, monotherapy with dapsone is contraindicated because of greater likelihood of resistance



Erythema elevatum diutinum (distinct type of leukocytoclastic vasculitis) often respond dramatically to dapsone

True (neutrophilic infiltrate, and dosages used are similar to those for DH and other blistering diseases)


Diseases with the most consistent response are those with a predominant neutrophilic infiltrate

True (evaluating the nature of the histologic infiltrate and using dapsone when neutrophils are found to be the predominant inflammatory cell will increase the likelihood of a good therapeutic response to dapsone therapy)


Dapsone may be considered in some patients with severe brown recluse spider bites, although one of the manifestations of this condition is haemolytic anaemia, which is also an adverse event associated with dapsone

True (clear evidence supporting use of dapsone for this condition is not available)


Topical 5% dapsone gel is FDA approved for the treatment of acne vulgaris in patients 12 years and older

True (G6PD deficient patients can also use this)


Dapsone is associated with hypersensitivity reactions I.e. DRESS (idiosyncratic unpredictable reaction)

True (although the cross-sensitivity between dapsone, a sulfone and its cousin sulfonamide drugs such as sulfapyridine is rare) - Topical dapsone has not shown any cross-reactivity in sulfonamide-allergic patients


The development of haemolytic anaemia and methaemoglobinaemia have been established as pharmacologic dose-related adverse events associated with dapsone and occurs to some degree in all individuals who take dapsone

True (check FBC, also enquire about fatigue, headaches, dyspnoea)


Patients on dapsone may have an initial decrease in Hb, followed by partial correction owing to increased production of new RBC (reticulocytes) from the bone marrow

True (older RBC more susceptible to the oxidative stress and damage caused by the N-hydroxy metabolites of dapsone are removed from the circulation) - Also as the glycation of HBA1C increases with the age of the erythrocytes, the increased relative proportion of young erythrocytes in the circulation of the patient with chronic haemolysis may result in a misleadingly low HBA1C value and is not indicative of the overall glycemic control in the diabetic patient)


G6PD deficient individuals are more susceptible to oxidative stress, including those from dapsone metabolites, and the degree of haemolysis does not correlate with the acetylator phenotype of the individual (as the toxic metabolites are produced through the N-hydroxylation pathway)

True (G6PD is more likely deficient in individuals with African, Middle Eastern and Asian ancestry although significant variability in G6PD function exists in all races)


The clinical significance of methaemoglobin relates to its decreased oxygen-carrying capacity, and hence to the total haemoglobin and the clinical status of the patient's cardiopulmonary system

True (dapsone is therefore relatively contraindicated in patients with significant cardiopulmonary disease, significant liver or renal impairment due to effects on cardiopulmonary system)


Both haemolytic anaemia and methaemoglobinaemia are predictable events (pharmacological effects) in patients taking dapsone

True (safe use of dapsone relies on the clinician being aware of these adverse effects and accurately diagnosing any clinically significant effects on the patient and managing the dosage of dapsone)


Even though Vitamin E 800IU (antioxidant) daily has been demonstrated to provide a small amount of protection against the formation of methaemoglobin and haemolysis, the clinical benefit of this effect has not been documented



Cimetidine (H2 antihistamine) 400mg TDS has also been demonstrated to reduce methaemoglobin formation, which is thought to be mediated by inhibition of the formation of hydroxylamine metabolites of dapsone which causes haematologic toxicity



Oral methylene blue can be used acutely in an emergency to reduce methaemoglobin levels, although this drug is contraindicated and ineffective if the patient is G6PD deficient



Local amide anaesthetic (lidocaine, prilocaine) and general anaesthetic should be used with caution in patients on dapsone as these oxidants increase oxidative stress to RBC (just like dapsone) and potentiate haemolytic anaemia and methaemoglobinaemia

True (unmasking of previously quiescent dapsone-induced methaemoglobinaemia has been noted intraoperatively and postoperatively after these medications, and has been shown to respond to treatment with the antioxidant ascorbic acid)


Ascorbic acid (vitamin C) can be administered PO or IV for non-enzymatically reducing methaemoglobin

True (antioxidant effects)


Agranulocytosis is the most serious idiosyncratic reaction to dapsone

True (tends to develop within the first 3 months of therapy) - patients present with fever, pharyngitis and occasionally signs of sepsis and recover within 1-2 weeks after cessation of dapsone


G-CSF has been used successfully to speed granulocyte recovery in patients who develop agranulocytosis as an idiosyncratic reaction to dapsone



Patients on dapsone should be instructed to discontinue the medication if they develop persistent fevers or flu-like symptoms due to the possibility of these symptoms indicating agranulocytosis as an idiosyncratic reaction to dapsone



Peripheral neuropathy (primarily a distal motor neuropathy) is an idiosyncratic reaction from dapsone

True (patients present with distal motor weakness of the hands and/or legs and often demonstrating wasting of hand muscles) - sensory symptoms are uncommon, but when present are virtually always accompanied by motor signs and symptoms


Permanent retinal damage with optic atrophy is a neurological idiosyncratic reaction reported in patients with severe dapsone overdosage

True (it has been proposed that this damage was secondary to severe hypoxia from haemolytic anaemia or methaemoglobinaemia, and the associated RBC fragments found in patients with dapsone overdosage)


Acute psychosis is an idiosyncratic reaction to dapsone

True (aetiology Unknown)


Mild GI upset (gastric upset and anorexia) is a self-limited idiosyncratic reaction to dapsone therapy and can be controlled by taking dapsone with meals



Primary hepatocellular hepatitis (predominantly transaminase elevations) and cholestatic hepatitis are idiosyncratic reactions to dapsone, which resolve upon discontinuation of dapsone



Dapsone hypersensitivity syndrome or 'dapsone syndrome'/'sulfone syndrome' is a severe idiosyncratic reaction from dapsone (DRESS)

True (erythema multiforme and TEN has also been observed)


Previous allergic reactions to either penicillin or sulfonamide antibiotics (sulfamethoxazole) may slightly increase the subsequent risk of an allergic reaction to non-antibiotic sulfonamides/sulfones such as dapsone

True (this cross-reactivity is more serious if the previous allergic reaction to a sulfonamide antibiotic was more serious I.e. Urticarial with anaphylaxis or SJS, and dapsone therapy should be withheld)


Even though dapsone has been suggested as a weak carcinogen in animal studies, no human studies have confirmed that dapsone is a carcinogen in man



Dapsone can be safely used in pregnancy on a selective basis, based on case series of patients with linear IgA disease and leprosy

True (although still classified as pregnancy category C)


Dapsone can be secreted in breast milk and can rarely cause haemolytic anaemia in breastfeeding infants



Baseline FBC with differential, LFTs, U&Es and G6PD level, should be performed prior to dapsone therapy

True (consider iron studies, folate and vitamin B12 levels and treat these deficiencies before and during dapsone therapy to facilitate the increase in bone marrow activity after the institution of dapsone)


In evaluating the pre-treatment FBC, particular attention should be paid to the Hb level as patients with mild iron, folate and vitamin B12 deficiency will not be able to respond to the normal increase in bone marrow activity after the institution of dapsone, and thus may have a more significant drop in the Hb

True (if these deficiencies are recognised and treated before or during dapsone therapy, significant patient morbidity may be reduced)


Methaemoglobin levels need not be measured during dapsone therapy unless the patient is experiencing symptoms such as excessive fatigue, headaches, or increasing cardiac or pulmonary symptoms



All patients on dapsone will show some degree of increase in their reticulocyte count owing to expected low-grade haemolysis

True (when patients on dapsone fail to show some increase in reticulocyte count due to a persistent anaemia, there is a possibility of an iron, folate or Vitamin B12 deficiency)


At follow up visits, patients on dapsone should be evaluated for worsening pre-existing cardiopulmonary disease and development of signs of a peripheral motor neuropathy



Patients on dapsone should be reminded to stop the drug if prolonged febrile illnesses occur and report to the physician if prolonged 'viral symptoms' I.e. Nausea, vomiting, malaise, weakness develop

True (various dapsone idiosyncratic toxicities such as dapsone hypersensitivity syndrome, agranulocytosis, drug induced hepatitis and neuropathy can cause these symptoms)


The pharmacologic adverse effects of haemolytic anaemia and methaemoglobinaemia increase with increasing dose of dapsone



St. Johns Wort may reduce serum dapsone levels and loss of efficacy due to CYP3A4 enzyme induction



Antimycobacterial antibiotics (rifabutin and rifampin) may reduce serum dapsone levels and loss of efficacy due to CYP3A4 enzyme induction



Anticonvulsants (carbamazepine, phenytoin) may reduce serum dapsone levels and loss of efficacy due to CYP3A4 enzyme induction



Griseofulvin antifungal agent may reduce serum dapsone levels and loss of efficacy due to CYP3A4 enzyme induction



Antacids (aluminium, calcium, magnesium; PPI, H2 antihistamines) may reduce serum dapsone levels and loss of efficacy by decreasing GI absorption of dapsone



Probenecid may increase the serum levels of dapsone and its potential toxicity due to decreased excretion of dapsone metabolites



Sulfonamide antibacterial agents I.e. Sulfamethoxazole may increase the haematologic risk of dapsone as these inhibit the same dihydropteroate synthetase enzyme in the folate pathway as dapsone



MTX and trimethoprim may increase the haematologic risk of dapsone as these inhibit dihydrofolate reductase enzyme in the folate pathway which results in megaloblastic anaemia



Sulfonamide antibiotics are oxidants which increase oxidative stress to RBC (like dapsone) and cause oxidation-induced haemolysis of RBC resulting in haemolytic anaemia and methaemoglobinaemia



Antimalarial agents (chloroquine, hydroxychloroquine, primaquine) are oxidants which increase oxidative stress to RBC (like dapsone) and cause oxidation-induced haemolysis of RBC resulting in haemolytic anaemia and methaemoglobinaemia



The HIV drug zicalcitabine poses an additive risk for peripheral neuropathy when used concomitantly with dapsone

True (peripheral motor neuropathy is an idiosyncratic reaction to dapsone)


PABA may reduce the efficacy of dapsone possibly through the folate metabolic pathway