2 - Dapsone

Question 1

Dapsone is a sulfone compound (cousin of sulfonamides)

Answer 1

True

Question 2

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

Answer 2

True (Mycobacterium Leprae)

Question 3

70-80% of dapsone is absorbed from the gut

Answer 3

True

Question 4

70-90% of dapsone is protein bound

Answer 4

True

Question 5

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

Answer 5

True

Question 6

Dapsone is lipid soluble

Answer 6

True

Question 7

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

Answer 7

True

Question 8

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

Answer 8

True

Question 9

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

Answer 9

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

Question 10

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

Answer 10

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)

Question 11

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

Answer 11

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

Question 12

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

Answer 12

True

Question 13

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

Answer 13

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

Question 14

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

Answer 14

True

Question 15

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

Answer 15

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)

Question 16

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

Answer 16

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

Question 17

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

Answer 17

True

Question 18

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

Answer 18

True

Question 19

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

Answer 19

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

Question 20

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

Answer 20

True

Question 21

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

Answer 21

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)

Question 22

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

Answer 22

True

Question 23

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

Answer 23

True

Question 24

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

Answer 24

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

Question 25

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

Answer 25

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

Question 26

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

Answer 26

True

Question 27

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

Answer 27

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)

Question 28

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

Answer 28

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)

Question 29

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

Answer 29

True

Question 30

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

Answer 30

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

Question 31

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

Answer 31

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

Question 32

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

Answer 32

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)

Question 33

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

Answer 33

True

Question 34

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

Answer 34

True

Question 35

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

Answer 35

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

Question 36

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

Answer 36

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)

Question 37

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

Answer 37

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

Question 38

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

Answer 38

True (G6PD deficient patients can also use this)

Question 39

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

Answer 39

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

Question 40

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

Answer 40

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

Question 41

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

Answer 41

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)

Question 42

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)

Answer 42

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)

Question 43

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

Answer 43

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

Question 44

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

Answer 44

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)

Question 45

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

Answer 45

True

Question 46

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

Answer 46

True

Question 47

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

Answer 47

True

Question 48

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

Answer 48

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)

Question 49

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

Answer 49

True (antioxidant effects)

Question 50

Agranulocytosis is the most serious idiosyncratic reaction to dapsone

Answer 50

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

Question 51

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

Answer 51

True

Question 52

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

Answer 52

True

Question 53

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

Answer 53

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

Question 54

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

Answer 54

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)

Question 55

Acute psychosis is an idiosyncratic reaction to dapsone

Answer 55

True (aetiology Unknown)

Question 56

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

Answer 56

True

Question 57

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

Answer 57

True

Question 58

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

Answer 58

True (erythema multiforme and TEN has also been observed)

Question 59

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

Answer 59

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)

Question 60

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

Answer 60

True

Question 61

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

Answer 61

True (although still classified as pregnancy category C)

Question 62

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

Answer 62

True

Question 63

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

Answer 63

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)

Question 64

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

Answer 64

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

Question 65

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

Answer 65

True

Question 66

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

Answer 66

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)

Question 67

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

Answer 67

True

Question 68

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

Answer 68

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

Question 69

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

Answer 69

True

Question 70

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

Answer 70

True

Question 71

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

Answer 71

True

Question 72

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

Answer 72

True

Question 73

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

Answer 73

True

Question 74

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

Answer 74

True

Question 75

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

Answer 75

True

Question 76

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

Answer 76

True

Question 77

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

Answer 77

True

Question 78

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

Answer 78

True

Question 79

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

Answer 79

True

Question 80

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

Answer 80

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

Question 81

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

Answer 81

True