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DIMAS P. NUGRAHA
BAGIAN FARMAKOLOGI FK UR
Principles of Anti-Leprosy Therapy
Dapsone
Dapsone (DDS, diamino-diphenylsulfone) or 4'-
diaminodiphenylsulfone (Fromm and Wittman
in 1908)
Mechanism of Action
Dapsone is a structural analog of para-
aminobenzoic acid (PABA) and a competitive
inhibitor of dihydropteroate synthase
(folP1/P2) in the folate pathway
Effects of antimicrobials on folate metabolism and
deoxynucleotide synthesis
ABSORPTION, DISTRIBUTION, AND
EXCRETION
Absorbed rapidly and nearly completely from
the GI tract.
Peak concentrations of dapsone in plasma 2–8
hours after administration
t1/2 20–30 hours
distributed throughout total body water and are
present in all tissues
excreted in the urine as an acid-labile monoN-
glucuronide and mono-N-sulfamate.
Therapeutic Uses
Dapsone is combined with chlorproguanil for
the treatment of malaria.
Dapsone is also used for P. jiroveci infection
and prophylaxis, and for the prophylaxis for
T. Gondii.
The anti-inflammatory effects are the basis
for therapy for pemphigoid, dermatitis
herpetiformis, linear IgA bullous disease,
relapsing chondritis, and ulcers caused by
the brown recluse spider
Adverse Effect
Hemolysis
Methemoglobinemia
Induce an exacerbation of lepromatous leprosy →
“sulfone syndrome” (fever, malaise, exfoliative
dermatitis, jaundice with hepatic necrosis,
lymphadenopathy, methemoglobinemia, and
anemia) may develop 5–6 weeks after initiation of
treatment
RIFAMPICIIN
Rifampicin is rapidly bactericidal for M.
leprae with a minimal inhibitory
concentration of <1 mg/mL.
Infectivity of patients is reversed rapidly
by therapy that includes rifampin.
in a dosage of 600 mg daily is highly
effective in lepromatous leprosy
CLOFAZIMINE (LAMPRENE)
mechanism of action is unknown but may involve
DNA binding→ ↑ mycobacterial phospholipase A2
activity, and inhibits microbial K+ transport.
Exerts an anti-inflammatory effect and prevents
the development of erythema nodosum leprosum.
recommended as a component of multipledrug
therapy for leprosy.
It also is useful for treatment of chronic skin ulcers
produced by Mycobacterium ulcerans.
orallyabsorbed and accumulates in
tissues
The daily dose of clofazimine is usually
100 mg.
Patients treated with clofazimine may
develop red discoloration of the skin.
Alternative Regimen
Clofazimine 50 mg
Ofloxacin 400mg
Minocycline 100 mg
Reaksi Kusta
Reaksi Tipe 1
Tipe borderline, ↑imunitas seluler→PB
delayed hypersensitivity
Simptom :
- Lesi awal makin merah, ulcerasi
- gangguan konstitusi
- Neuritis saraf tepi
Reaksi Tipe 2
(Eritema Nodosum leprosum)
Penderita MB
Reaksi humoral→basil→Ag (Antibodi
&komplemen)→Ag+Ab+C
Arthus-type reaction
Simptom :
- Neuritis
- intracutan Nodul
- Gangguan konstitusi, demam
- Komplikasi organ lain : ginjal, mata, sendi
Penatalaksanaan Reaksi Kusta
Imobilisasi
Analgesik, sedatif
Early clofazimin (tipe 1) dan Prednison
30mg/hr
MDT diteruskan
Protozoal infections
Amebiasis
Protozoal infections
1. Difficult to be treated than bacterial infections.
2. Protozoal cells (Eukaryotes) have metabolic
processes closer to human host than
prokaryotic bacterial pathogens.
3. Many of antiprotozoal drugs cause toxic effects
on the host.
4. Cells with high metabolic processes in the host
are susceptible.
5. Examples: bone marrow stem, renal tubular
cells, intestinal & neuronal cells.
6. Antiprotozoal are not safe during pregnancy.
Amebiasis
Mixed amoebicide.
Drug of choice for intestinal &
extraintestinal amoebiasis.
Acts on trophozoites.
Has no effect on cysts.
Nitro group of metronidazole is reduced by
protozoan leading to cytotoxic reduced product
that binds to DNA and proteins resulting into
parasite death.
Pharmacokinetics
Given orally or IV.
Absorption is rapid and complete.
▪ Due to rapid absorption from GIT, not reliably
effective against luminal parasites.
Wide distribution to all tissues and body fluids
(CSF, saliva, milk).
Plasma protein binding is low ( < 20%).
Plasma half life is 8 h
Pharmacokinetics
Metabolized in liver by mixed function
oxidase followed by glucouroidation.
Excreted in urine as unchanged drug plus
metabolites.
Clearance is decreased in liver impairment.
1. GIT:
Nausea
Vomiting
Dry mouth
Metallic taste
Diarrhoea
Oral Thrush (Moniliasis, yeast infection).
Adverse effects
alcohol aldehyde
dehydrogenase dehydrogenase
Thiabendazole
Absorbed rapidly after oral ingestion. A
fatty meal enhances absorption
Reaches peak plasma concentrations
after 1 hour
Excreted in the urine within 24 hours as 5-
hydroxythiabendazole, conjugated either
as the glucuronide or the sulfate
Mebendazole
Tablet formulations of mebendazole are poorly
and erratically absorbed, and plasma
concentrations are low
The low systemic bioavailability (22%) of
mebendazole results from a combination of poor
absorption and rapid first-pass hepatic
metabolism
THERAPEUTIC USES
For control of
Albendazole
For treatment of
TOXICITY, SIDE EFFECTS
Thiabendazole is hepatotoxic and should be used
with caution in patients with hepatic disease
Mebendazole →Transient symptoms of abdominal
pain, distention, and diarrhea have occurred with
massive infestation and expulsion of GI worms.
Rare side effects in patients treated with high
doses of mebendazole include allergic reactions,
alopecia, reversible neutropenia, agranulocytosis,
and oligospermia
Albendazole →The most common side
effect is an increase in serum
aminotransferases, which return to
normal upon drug cessation; rarely
jaundice or cholestasis may occur
Liver function tests should be monitored
during protracted albendazole therapy,
and the drug is not recommended for
patients with cirrhosis
Use in Pregnancy
Both albendazole and mebendazole are
embryotoxic and teratogenic in rats
A review of the risk of congenital
abnormalities from BZAs concluded that
their use during pregnancy is not
associated with an increased risk of major
congenital defects, → recommended that
treatment should be avoided during the
first trimester of pregnancy
Use in Young Children
Praziquantel
a pyrazinoisoquinoline derivative
Mechanism of Action
low concentrations, it causes increased muscular
activity, followed by contraction and spastic
paralysis
At slightly higher concentrations, praziquantel
causes tegumental damage, which exposes a
number of tegumental antigens. The tegument of
schistosomes seems to be the primary site of
action; the drug causes an influx of Ca2+ across
the tegument via unknown mechanisms
Mechanism of Action Praziquantel
PK/PD
Readily absorbed after oral administration, and
maximal levels in human plasma occur in 1–2 hours
The drug is ~80% bound to plasma proteins
Its plasma t ½ is 1–3 hours but may be prolonged in
patients with severe liver disease, including those
with hepatosplenic schistosomiasis
About 70% of an oral dose of praziquantel is
recovered as metabolites in the urine within 24
hours; most of the remainder is metabolized in the
liver and eliminated in the bile
THERAPEUTIC USES
FDA approved for therapy of schistosomiasis
and liver fluke infections, but also is used to
treat infections with many other trematodes and
cestodes
Praziquantel is the drug of choice for
schistosomiasis caused by all Schistosoma
species.
Although dosage regimens vary, a single oral
dose of 40 mg/kg or three doses of 20 mg/kg
each, given 4–6 hours apart, generally produce
cure rates of 70–95% and consistent reductions
(>85%) in egg counts.
TOXICITY AND SIDE EFFECT
Abdominal discomfort, nausea, diarrhea, headache,
dizziness, and drowsiness may occur shortly after taking
praziquantel; these direct effects are transient and dose-
related
In neurocysticercosis, inflammatory reactions to
praziquantel may produce meningismus, seizures,
mental changes, and CSF pleocytosis. These effects
usually are delayed in onset, last 2–3 days, and respond
to symptomatic therapy such as analgesics and
anticonvulsants.
High doses of praziquantel increase abortion rates in rats
kontraindikasi
Praziquantel
Pyrantel Pamoate
a broad-spectrum anthelmintic directed
against pinworm, roundworm, and
hookworm infections.
Mechanism of Action :
depolarizing neuromuscular blocking agent
that opens nonselective cation channels
and induces marked, persistent activation
of nicotinic acetylcholine receptors, which
results in spastic paralysis of the worm
PK/PD
Side effect, Precaution
Transient and mild GI symptoms occasionally are observed, as are headache, dizzines
DIETHYLCARBAMAZINE
Diethylcarbamazine is a first-line agent for control and
treatment of lymphatic filariasis and for therapy of
tropical pulmonary eosinophilia caused by W. bancrofti
and Brugia malayi
Mechanism of action :
Diethylcarbamazine appears to exert a direct toxic
effect on W. bancrofti microfilariae; it also kills worms
of adult L. loa and probably adult W. bancrofti and B.
malayi. Diethylcarbamazine may impair intracellular
processing and transport of certain macromolecules to
the helminth plasma membrane.
PK/PD
At<8–10 mg/kg/daycarbamazine,
including anorexia, nausea, headache,
and vomiting, are rarely severe and
usually disappear within a few days
despite continued therapy
Ivermectin
Mechanism of action :
Avermectins affect a group of glutamate-
gated Cl channels found in nematode
nerve or muscle cells, causing
hyperpolarization and paralysis by
increasing Cl permeability of the cell
membrane
PK/PD
Onchocerciasis
Single oral doses of ivermectin (150 µg/kg) given every
6–12 months are considered effective, safe, and practical
for reducing the number of circulating microfilariae in
adults and children 5 years of age or older
Lymphatic Filariasis
• Single annual doses of ivermectin (400 µg/kg) are
effective and safe for mass therapy of infections with W.
bancrofti and B. malayi.
• Ivermectin is as effective as diethylcarbamazine for
controlling lymphatic filariasis and can be used in regions
where onchocerciasis, loiasis, or both are endemic.
cutaneous larva migrans
Taken as a single 200-µg/kg oral dose,
ivermectin is a first-line drug for treatment of
cutaneous larva migrans
Infections with Intestinal Nematodes
• The finding that a single dose of 150–200
ivermectin can cure strongyloidiasis is
encouraging, because this drug also is
efcoexisting ascariasis, trichuriasis, and
enterobiasis
Cutaneus Larva migrans (creeping eruption)
Toxicity, Side Effects, and
Precautions
After treatment of O. volvulus infections with
ivermectin, side effects usually are limited to
pruritus and swollen, tender lymph nodes
Rarely, more severe reactions include high fever,
tachycardia, hypotension, prostration, dizziness,
headache, myalgia, arthralgia, diarrhea, and
edema; these may respond to glucocorticoids
Because of its effects on GABA receptors in the
CNS, ivermectin is contraindicated in conditions
associated with an impaired blood–brain barrier
(e.g., African trypanosomiasis and meningitis)
Infecting Organism Drug of Choice Alternative Drugs
Roundworms
(nematodes)
Ascaris lumbricoides Albendazole or pyrantel Ivermectin, piperazine
(roundworm) pamoate or mebendazole
Trichuris trichiura Mebendazole or Ivermectin
(whipworm) albendazole
Necator americanus Albendazole or
(hookworm); Ancylostoma mebendazole or pyrantel
duodenale (hookworm) pamoate