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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5648_Библиотеки_им_академика_М_И_Перельмана.pdf
162 Pharmaceutical Chemistry
Several small, irregular red lesions are seen,
Moderate sensory loss is seen,
It either goes back to the previous stage or progresses to the next.
Borderline
lepromatous
leprosy
Multibacillary
Hansen’s disease
(lepromatous
leprosy)
Several lesions such as plaques, macules, papules, and nodules are seen.
Lesions have a characteristic inverted saucer-like appearance.
Early symptoms:
Several lesions such as plaques, macules, papules, and nodules are seen,
Nasal congestion, discharge and bleeding is observed,
Inflammation of the leg and ankles.
Progressive symptoms:
Thickening of the dermis (skin) in the forehead and ear lobes,
Loss of eyebrows and eyelashes,
Eye defects such as glaucoma and blindness,
Nodules in the legs break and form ulcers,
Enlargement of the breast and sterility occurs in the males,
Internal infection results in the enlargement of the liver and lymph nodes,
Loss of sensation in the peripheral nerves. Deformation of the fingers and toes results due
to painless repeated trauma.
Classification
These drugs have been classified on the basis of structure as follows:
1. Sulfones: Dapsone, Solapsone (Sulphetrone), Acedapsone
2. Phenazines: Clofazimine (Lamprene)
3. Thiosemi carbazones: Amithiazone
4. Antitubercular drugs: Rifampicin, Ethionamide
5. Antibiotics: Ofloxacin, Clarithromycin, Minocycline
6. Natural oils: Chaulmoogra oil, Hydnocarpus oil
7.6 LEPROSY CO-EXISTING FACTORS
Poverty: Poverty could increase the risk of the disease as it results in poor sanitation, lack
of education and awareness among the people.
Genetic: There are evidences of genetic response against the leprae bacillus infection.
Human leukocyte antigen (HLA-DR2) is associated with the tuberculoid type of infection
while HLA-MTI and HLA-DQ1 with lepromatous disease.
Travelling to underdeveloped countries: It is confined mainly but not exclusively to the
underdeveloped areas of the tropics and the southern hemisphere. South, South East Asia
and Brazil are the most affected areas.
Close association with infected person: Leprosy, though is not a highly communicable
disease, can spread to people who are in close contact with the infected person.
7.7 DAPSONE
Dapsone has been in clinical use for more than 60 years. Dapsone, also known as
diaminodiphenyl sulfone, is an antibiotic commonly used in combination with rifampicin
Anti-Leprosy Drugs 163
and clofazimine for the treatment of leprosy. Dapsone is of prime importance in the
treatment of leprosy and a wide variety of infectious diseases, including malaria and other
parasites. It is both bacteriostatic and weakly bacteriocidal against M. leprae.
In addition, it has been effective in the treatment of a
diversity of cutaneous disorders, particularly those
O
O
S
characterized by a neutrophilic infiltrate but also cutaneous
manifestations of lupus erythematosus (LE), erythema
nodosum, cutaneous vasculitides, pyoderma gangrenosum,
bullous dermatoses, and dermatitis herpetiformis. Thus,
H2N NH
Dapson
2
dapsone has antileprotic, anti-infective and anti-fungal activity and the action is similar to
that of sulphonamides, which involves the inhibition of folic acid synthesis in susceptible
organisms. It has been suggested that dapsone may act as an immunomodular when used
to suppress dermatitis herpetiformis.
7.7.1 Specification
Name : 4,4’-diaminodiphenylsulphone; 4,4’-Sulfonylbisbenzenamine
Molecular formula : C
12H12N2O2
Molecular weight : 248.31 g/mol
Melting point : 175–180°C
Physical state : White crystalline powder
Solubility : Water insoluble and soluble in many polar organic solvents.
S
7.7.2 Synthesis of Dapsone
Nitrothiophenol derivative on oxidation gives nitrosulfone which on reduction leads to
dapsone. The synthesis was first reported by E. Fromm and J. Wittmann in 1908.
O
O
S
NO
2
O2N
Sn/HCl
[H]
Cl
Na2S
O2N
O
O
S
H2N
Dapson
NH
S
NO
2
2
Cr2O
[O]
2
7
O2N
7.7.3 Mode of Action
Dapsone acts in leprosy and other infectious diseases in the same way as sulfonamides,
inhibiting the synthesis of dihydrofolic acid through competition with p-aminobenzoate
for the active site of dihydropteroate synthetase.
164 Pharmaceutical Chemistry
The anti-inflammatory effect of dapsone is not related to its antibacterial effect.
Dermatoses that respond to dapsone are in general associated with the accumulation of
large numbers of polymorphonuclear leukocytes, mainly neutrophils. After stimulation,
neutrophils release the heme-containing enzyme myeloperoxidase, which converts
nicotinamide adenine dinucleotide phosphate-dependent oxygen to toxic oxygen
intermediates, such as hydrogen peroxide, superoxide anion, hydroxyl radical, hydroxyl
ion, and peroxide anion. These intermediates seem to allow microbial killing and to
contribute to the ongoing tissue injury during inflammation. Dapsone has been shown to
protect cells from neutrophil-mediated auto-oxidative tissue injury by converting
myeloperoxidase to an inactive compound, thus suppressing the formation of toxic oxygen
intermediates. Dapsone has also been shown to suppress neutrophil chemotactic migration
and to interfere with ǃ2-integrin-mediated adherence of neutrophils. Furthermore, it has
been suggested that dapsone inhibits the generation of 5-lipoxygenase products in
polymorphonuclear leukocytes, lysosomal enzyme activity, and the alternative pathway
of complement as well as leukotriene-B4 binding to neutrophils and the neutrophil
chemotactic response to leukotriene-B4, thus reducing the inflammatory effect. In addition,
it has been reported that dapsone may prevent the generation of prostaglandin-D2 in mast
cells.
7.7.4 Metabolism of Dapsone
After oral administration, dapsone is well absorbed from the gastrointestinal tract, with a
bioavailability of more than 86%. Peak serum levels are reached 2–6 hours after a single
dose is administered. After 8–10 days of therapy at a constant dosage level, the serum level
stabilizes and remains at that point unless the dosage is changed. The elimination half-life
ranges from 12–30 hours, which may be due to the enterohepatic circulation of the drug
and extensive protein binding. Dapsone is 70–90% bound to plasma protein, and its monoacetylated metabolite [MADDS] is almost entirely 99% protein bound (Fig. 7.1). Dapsone
seems to be distributed throughout the body, including the skin, liver, kidneys, and
erythrocytes. Dapsone crosses the blood-brain barrier and the placenta and is excreted in
breast milk.
H2N
O
O
S
NH
Dapsone
Fig. 7.1: Major metabolites of dapsone
H2N
2
O
O
S
MADDS
NHCOCH
3
Dapsone shows low oral clearance in man with a threefold inter-individual variation.
After absorption in the gastrointestinal tract, dapsone is transported to the liver, where it
undergoes different metabolic transformations. Data shows two major pathways of
metabolism in man: N-acetylation to the mono- and diacetyl-dapsone (DADDS); and
Anti-Leprosy Drugs 165
N-hydroxylation to N-hydroxy-dapsone (DDS-NOH) and N-hydroxymonoacetyl-dapsone
(MADDS-NOH). DDS-NOH is in part, conjugated and excreted as the N-glucuronide. The
partial clearance by N-hydroxylation has been reported as a mean of 23% of total clearance
with a range of 11-36%, making this pathway a significant but minor route of elimination.
Variation in the activity of this pathway was calculated to contribute 94% of the variability
in the oral clearance of dapsone. The acetylated derivative (MADDS, DADDS) are subject
to deacetylation such that body levels reflect the equilibrium between acetylation and
deacetylation rates, and litte MADDS appears in the urine. Thus, although acetylation
rates in man follows fast and slow acetylator phenotypes, the acetylation phenotype has
little effect on overall clearance, indicating that MADDS acts as a reservoir for dapsone.
Recent studies, however, have raised the possibility that high level of MADDS may tend
to suppress the N-hydroxylation of dapsone (Fig. 7.2). Collectively, urinary recovery of
dapsone and its known metabolites in man has been reported to be only 50% of the dose;
the remainder has been suggested to be an N-glucuronide but it is still possible that other
oxidative pathways may contribute to the overall elimination. The N-oxidation of dapsone
in man has been associated with P4503A4 activity. Human P4501A4, which is active
towards many arylamine pro-carcinogens, appears not to utilize dapsone as a substrate.
S
Dapsone
NH
NH
S
MADDS
NHCOCH
NH
2
3
O
O
2
O
O
2
NHCOCH
S
NHOH
MADDS-NOH
3
NHOH
O
S
O
NH
2
DDS-NOH
Fig. 7.2: Metabolites of dapsone (MADDS = mono-acetyldapsone, DDS-NOH = N-hydroxy-dapson,
O
O
MADDS-NOH = N-hydroxymonoacetyl-dapsone)
7.7.5 Monitoring and Prevention of Side Effects
Before the onset of dapsone therapy a complete blood cell count with differential white
count should be obtained. Also, the glucose-6-phosphate dehydrogenase and
methemoglobin levels should be tested, since haemolysis and methemoglobinemia are
well-known dapsone-dependent side effects. Once therapy has been initiated, the complete
blood cell count should be obtained weekly for the first month and then, if stable, every
two weeks for another two months. Thereafter, the complete blood cell count should be
done periodically. Serum creatinine and liver enzyme levels should also be measured
before therapy starts and should be frequently monitored thereafter. To minimize the risk
of side effects, the lowest effective dose of dapsone (generally 100 mg/day) should not be
exceeded. In addition, concomitant administration of drugs associated with haemolysis
166 Pharmaceutical Chemistry
and blood dyscrasias, such as sulfonamides, isoniazid, aspirin, ibuprofen, and primaquine,
should be avoided.
7.7.6 Side Effects
The common side effects are increase in reticulocyte, haemolysis, haemoglobin decrease,
methemoglobinemia, tachycardia, fever, headache, phototoxicity, abdominal pain, nausea,
pancreatitis, and vomiting. In general, side effects could be categorised into two kinds,
pharmacological and idiosyncratic. The former is related to the dosage of the drug, which
includes methemoglobinemia, haemolytic anaemia, etc. The latter is not related to the
dosage but to cell-mediated hypersensitivity (dapsone hypersensitivity syndrome, DHS),
ranging from mild cutaneous manifestations to severe life-threatening complications, such
as exfoliated dermatitis, liver function failure, agranulocytosis, toxic epidermal necrolysis,
nephritis and renal failure, Stevens-Johnson syndrome, etc.
7.8 CLOFAZIMINE (LAMPRENE)
It is a phenazine derivative which is a secondary drug class for the
treatment of leprosy and commonly used as a component of multidrug
Cl
therapy. It also acts as an antibiotic used for the treatment of
Mycobacterium avium complex (MAC) infection. It may also be used to
treat a number of other conditions. This drug shows activity because
it binds to mycobacterial DNA and inhibits bacterial growth.
N
N
N
NH
It acts as bacteriostatic and mildly bactericidal effect on M. leprae
(Hansen’s bacillus) present in man. Its mechanism of action is not
similar to dapsone and rifampicin thus, no cross-resistance occurs
with the latter drugs. It also possesses anti-inflammatory properties.
Clofazimine
Cl
Its use is best in multidrug therapy treatment in combination with
dapsone and rifampicin, which serves as treatment for multi-bacillary (MB) forms of
leprosy, such as lepromatous (LL), borderline lepromatous (BL), and mid-borderline (MB)
leprosy, as well as erythema nodosum leprosum (ENL). To prevent the development of
drug-resistance, it should be used only as a part of combination therapy for initial treatment
of lepromatous (multibacillary) leprosy.
7.8.1 Specification
Name : (4-Chloro-phenyl)-[5-(4-chloro-phenyl)-3-isopropylimino-3,5 dihydro-phenazin-2-yl]-amine
Molecular formula : C
Molecular weight : 473.40 g/mol
Melting point : 210-212°C
Physical state : Solid, reddish-brown powder
27H22Cl2N4
Anti-Leprosy Drugs 167
Solubility : Soluble in chloroform, readily soluble in benzene, and sparingly
soluble in polar solvents while poorly soluble in acetone and ethyl
acetate.
7.8.2 Synthesis of Clofazimine
7.8.3 SAR of the Clofazimine
Phenyl group, imino group and lower phenyl group are the key targets of substitution to
make more molecules more effective. SAR study is as follows (Fig. 7.3):
Cl
The chemical phenazine nucleus is
essential for antimycobacterial and
immuno suppressive properties.
Clofazimine was first used to treat
advanced leprosy unresponsive to
dapsone or STM in 1966.
Halogen substitution on para
position of the 2 phenyl at C-3
and N-10 enhance activity.
The following order of activity
has been reported as
Br > Me > EtO > H or F
9
10
8
7
6
Fig. 7.3: SAR study of clofazimine
1
N
N
5
N
2
NH
3
4
Cl
Substituents on the imino group
at position 2 is essential. Imino
group is substituted with alkyl
and cycloalkyl groups activity is
increase .d
168 Pharmaceutical Chemistry
7.8.4 Mode of Action
It exerts mildly bactericidal effect on Mycobacterium leprae (Hansen’s bacillus). It inhibits
mycobacterial growth and binds preferentially to mycobacterial DNA. It is also known for
its anti-inflammatory properties in treating erythema nodosum leprosum reactions. It also
exerts antimycobacterial activity, thus the mechanism of action may be postulated through
its membrane directed activity including the bacterial respiratory chain and ion transporters.
Intracellular redox cycling, involving oxidation of reduced clofazimine, leads to the
generation of antimicrobial reactive oxygen species (ROS), superoxidehydrogen peroxide
(H2O2). Secondly, lysophospholipids synthesized by the interaction of clofazimine with
membrane phospholipids, exerts antimicrobial effects, which promote membrane
dysfunction, resulting in interference with K+ uptake. Both mechanisms result in the
interference with cellular energy metabolism by disrupting ATP production. Antiinflammatory activity of clofazimine is primarily through the inhibition of T lymphocyte
activation and proliferation. It may indirectly interfere with the proliferation of T cells by
promoting the release of ROS and E-series prostaglandins (PGs), especially PGE2 from
neutrophils and monocytes.
7.8.5 Absorption, Metabolism and Excretion
The exact mechanism of clofazimine absorption from the gastrointestinal tract is not clear.
It is absorbed gradually (45–62%) via oral administration. Administering the drug with
food increases bioavailability in terms of AUC (area under the concentration-time curve)
and tends to accelerate the absorption rate. It is strongly lipophilic in nature so accumulates
in fatty tissue and in the macrophages of the reticulo-endothelial system. It is unable to
cross the intact blood-brain barrier, while crosses the placenta and passes into the breast
milk in sufficient quantities to colour the milk. After repeated oral doses of clofazimine
there are three metabolites found in the urine of leprosy patient, while information on the
metabolism of clofazimine is limited. Two conjugated metabolites are 3-(E-D-
glucopyranosiduronic acid)-10-(p-chlorophenyl)-2,10-dihydro-2-isopropyl iminophenazine
(III) and 3-(p-chloroanilino)-10-(p-chlorophenyl)-4,10-dihydro-4-(E-D glucopyranosiduronic
acid)-2-isopropyl iminophenazine (II), and the third metabolite is not conjugated
3-(p-hydroxy aniline)-10-(p-chlorophenyl)-2,10-dihydro-2-isopropyl iminophenazine (I)
(Fig. 7.4). It is retained in the human body for a long time and is eliminated slowly from
the plasma. The half-life of clofazimine following repeated oral doses is estimated to be at
least 70 days. These metabolites are excreted in very small amounts constituting only 0.6%
of the daily dose (assuming 70% drug absorption), while 1% is excreted unchanged. It is
excreted via the bile mainly in the faeces; the amount recovered representing biliary
excretion as well as unabsorbed drug.
Anti-Leprosy Drugs 169
Cl
N
N
I
Fig. 7.4: Metabolites of clofazimine [3-(Hydroxy)-10-(p-chlorophenyl)-2,10-dihydro-2-isopropyl iminophenazine
(I), 3-(p-chloroanilino)-10-(p-chlorophenyl)-4,10-dihydro-4-hydroxy-2-isopropyl iminophenazine (II) and
3-(p-chloroanilino)-10-(p-chlorophenyl)-2,10-dihydro-2-isopropyl iminophenazine (III)]. Metabolite I and II are
excreted in urine after conjugated to D-glucopyranosiduronic acid, while metabolite III is extracted in free form.
N
OH
Cl
N
N
II
NH
NH
OH
Cl
Cl
N
N
III
N
NH
OH
7.8.6 Side Effects
It may cause pink or red to brownish-black skin and eye discolouration. It may cause skin
and eye dryness, burning, irritation and itchiness which may be overcome by using a good
hydrating cream to avoid skin dryness. Discolouration (red-brownish black) of faeces,
lining of the eyelids, sputum, sweat, tears and urine commonly occurs. Many people have
risk of nausea, vomiting, stomach upset (due to abdominal and epigastric pain, diarrhoea,
nausea, vomiting, gastrointestinal intolerance). If these effects are bothersome, inform
your doctor or pharmacist. Autopsies have revealed crystalline deposits of clofazimine in
various tissues including the intestinal mucosa, liver, spleen, and mesenteric lymph nodes.
7.9 SOLAPSONE (SULPHETRONE)
It is a bacteriostatic sulphone
derivative which includes high
antibacterial activities to streptococci,
pneumococci, M. tuberculosis, and is
used in chemotherapeutic studies.
–
+
NaO3S
Ph
–
+
NaO3S
N
H
Solapsone
It was first prepared in 1936 by
Gray and Henry and attracted attention on re-examination in 1941 by the reason of its
freedom from toxicity and its potent antituberculotic activity. No acute toxic effects have
been observed in humans as compared to sulphanilamide dose.
O
O
–
N
H
+
SO3Na
SO
Ph
–
+
Na
3
S
7.9.1 Specification
Name : 1,1’[Sulphonyl bis (4,4’-phenyleneimino)]bis[3-phenyl-1,3-propane
disulphonic acid]tetra sodium
Molecular formula : C
Molecular weight : 892.5 g/mol
30H28N2Na4O14S5
170 Pharmaceutical Chemistry
Physical state : Solid white powder
Solubility : Water soluble and insoluble in all organic solvents
7.9.2 Synthesis of Solapsone
H2N
Dapsone
4NaHSO
O
O
S
NH
3
+
NaO
–
3
Ph
2 PhCH=CH-CHO
2
–
+
NaO
S
3
S
N
H
-2H2O
O
Solapsone
Ph
O
S
N
H
SO3Na
N
–
+
–
SO3Na
Ph
O
O
S
N
+
Ph
7.9.3 Metabolites of Solapsone
This drug was administered to two female tuberculous patients for a period of twelve
months with the intake of average 6.5 gm daily. The recovery of sulphetrone from urine
was good, 90-95%, but only 75–82% could be obtained from faeces. The concentration of
sulphetrone in urine is high, usually 10 to 20 times that in the blood and contains a dark
smoky-brown colour of urine. Sulphetrone in the faeces does not indicate only the amounts
which remain unabsorbed, since some secretion takes place into the bile and from the
ileum. It is impossible to relate the amount of sulphetrone in the urine to the amount
absorbed, for still other channels of excretion are open to it. After the initial period of
adjustment, as little as two-fifths, and later as much as three-fifths, pass through the
kidneys; as much as two-fifths and as little as one-fifth was recovered from the faeces.
7.9.4 Absorption, Distribution and Excretion
Sulphetrone is given orally to the patients. It is very soluble in water but still it is absorbed
slowly from the intestinal tract mostly from the small intestine, little from the large. It
rapidly penetrates all tissues except brain, but it appears in cerebrospinal fluid more slowly
than do sulphonamides. Sulphetrone is excreted by the kidney very fast, and fluid must be
limited to maintain blood-sulphetrone concentrations; there is also a substantial excretion
into the bile and to a lesser extent into the ileum. The drug is not conjugated; so there is no
danger of crystaluria. In rabbits the clearance was 58% of that of creatinine, or two or three
times as fast as that of sulphanilamide, while in the dogs the clearance was five times as
fast as that of sulphanilamide. It seems that, in man, tubular resorption of sulphetrone is
small, and that the rate of clearance is about four times as fast as with sulphanilamide.
Anti-Leprosy Drugs 171
7.10 ETHIONAMIDE (ETHIONAMIDUM)
N
It is a potent bactericidal antileprotic as well as an antibiotic agent. Presently,
it is used in the combination therapy for the treatment of leprosy. It was
discovered in 1956 and approved for medical use in 1965 in USA.
7.10.1 Specification
NH
S
Ethionamide
2
Name : 2-Ethylthioisonicotinamide; 2-ethyl-4-pyridinecarbothimide
Molecular formula : C
8H10N2S
Molecular weight : 166.2 g/mol
Melting point : 162°C
Physical state : Yellow crystalline powder
Solubility : Insoluble in water, soluble in methanol, sparingly soluble in ethanol,
slightly soluble in ether.
7.10.2 Synthesis of Ethionamide
NC
CO2Et
N
O
Et
H
EtO
O
OEt
O
O
NaOEt
OO
OEt
O
O
H2N
Pyridine
CN
NC
CO2Et
HCl
N
O
Et
H
COOH
N
O Et
H
i) POCl
ii) EtO
/PCl
3
5
Cl Et
COOH
N
H2/Pd
COOH
N
i) NH
ii) P2O
Et
CN
3
H2S
N Et
S
Ethionamide
2
N
Et
NH
7.10.3 Absorption, Distribution and Excretion
The oral absorption of this drug appears to be rapid. Peak plasma ethionamide concentration
is reported to be reached in about 90 minutes. Lack of evidence of significant faecal
elimination of the unmetabolised drug and the systemic availabilities calculated for
ethionamide suggests complete absorption from the gut and an absence of the first pass
metabolism. According to research studies, the half-life of this drug is 2 hours. Metabolite
of this drug is S-oxides which have inhibitory and bactericidal activity against M. leprae.
The excretion of this drug has been reported to be around 0.15% of the administered dose.
7.10.4 Side Effects
Common side effects include loss of appetite, abdominal pain, diarrhoea, nausea, liver
inflammation, and liver depression.