OLEH :

DIMAS P. NUGRAHA
BAGIAN FARMAKOLOGI FK UR
 Principles of Anti-Leprosy Therapy

 Therapy for leprosy is based on multi-drug

regimens using rifampicin, clofazimine, and
dapsone
 The reasons for using combinations of
agents include :
 reduction in the development of resistance,
 the need for adequate therapy when primary
resistance already exists, and
 reduction in the duration of therapy
 Tujuan Terapi
1. Menyembuhkan dan mencegah kecacatan
Pauci-Bacillary Leprosy (I, TT, BT)
 The WHO regimen consists of a single dose
of oral rifampin, 600 mg, combined with
dapsone, 100 mg, administered under direct
supervision once every month for 6 months,
and dapsone, 100 mg a day (home), in
between for 6 months.
 In the U.S., the regimen consists of dapsone,
100 mg, and rifampin, 600 mg, daily for 6
months, followed by dapsone monotherapy
for 3-5 years.
Multibacillary Therapy (BB,BL, LL)
 The WHO recommends the same regimen as for
paucibacillary leprosy, with two major changes.
First, clofazimine (lamprene), 300 mg/month,
Lamprene : 50mg/day (home). Second, the
regimen lasts 1 year instead of 6 months.
 In the U.S., the regimen is also the same as for
paucibacillary, but dual therapy continues for 3
years, followed by dapsone monotherapy for 10
years. Clofazimine (an orphan drug) is added
when there is dapsone resistance or chronically
reactional patients.
 Drugs Used in Leprosy

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

Amebiasis is a protozoal infection of the

intestinal tract that occurs due to ingestion
of foods or water contaminated with
Entameba Histolytica cysts
LIFE CYCLE
 Clinical Presentations
Asymptomatic Intestinal infection
ANTIAMOEBIC DRUGS
 LUMEN AMOEBICIDES

 Acts on the parasites in the lumen of

the bowl.
 used for treatment of asymptomatic
amebiasis.
Include
 Diloxanide Furoate
 Iodoquinol
 Antibiotics
- Paromomycin
- Tetracyclines
- Erythromycin
 Tissue Amoebicides (systemic)

 acts on the intestinal wall and liver (or any other

extra-intestinal tissue).
 Used for treatment of systemic form of the disease
(intestinal wall infection or liver abscesses).
 Emetine
 Dehydroemetine
 Chloroquine (liver only)
Amoebiasis Cutis
 Mixed amoebicides

Effective against both luminal and systemic

forms of the disease. Although luminal
concentration is too low for single drug –
treatment.
 Metronidazol
 Tinidazole
 METRONIDAZOLE

 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.

Tinidazole has longer duration, simpler

dosing regimen, less toxicity, than
metronidazole, but is equally active.
 Clinical Uses

 Extraluminal amoebiasis (combined with

luminal amebicide).
 Giardiasis
 Trichomoniasis
 Broad spectrum of Anaerobic bacteria e.g.,
 Helicobacter pylori infection
 Pseudomembranous colitis (Clostridium
defficile).
 Adverse effects

1. GIT:
 Nausea
 Vomiting
 Dry mouth
 Metallic taste
 Diarrhoea
 Oral Thrush (Moniliasis, yeast infection).
 Adverse effects

2. CNS: Neurotoxicological effect

 Insomnia, dizziness
 peripheral neuropathy, paresthesia
 encphalopathy, convulsion ( IV infusion, rare).
3. Dysuria, dark urine.
4. Neutropenia
5. Disulfiram-like effect if taken with alcohol.
 disulfiram like -effect
 When metronidazole is given with alcohol
abdominal distress, nausea, vomiting, flushing, or
headache, tachycardia, hyperventilation

alcohol aldehyde
dehydrogenase dehydrogenase

Ethanol Acetaldehyde Acetate

Drug interactions:

 Enzyme inhibitors (cimetidine, ketoconazole)

increase duration of action of metronidazole
 Inducers (phenytoin and phenobarbitone).
 inhibits CYP family 2C9 & 3A4
 potentiate anticoagulant effect of warfarin.
 potentiates lithium toxicity.
CONTRAINDICATIONS / PRECAUTIONS:

▪ Pregnancy and nursing women

▪ Alcohol intake
▪ CNS diseases
▪ Severe hepatic disease
 Severe renal disease
Anthelmintic Drugs
The major
 Benzimidazoles (BZAs)

→thiabendazole, mebendazole, and albendazole

Mechanism of action
 inhibition of microtubule polymerization by
binding to -tubulin
 Drug resistance in nematodes may involve
expression of a mutated -tubulin
Mechanisme of action mebendazole and other
Benzimidazole
 PK/PD

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

 Absorbed rapidly from the GI tract.

 Peak plasma levels occur within 1–2
hours, and the plasma t1/2 varies from 2
to 10 hours, depending on urinary pH.
 Metabolism is rapid and extensive
 Dosage reduction may be required in
people with renal dysfunction or sustained
alkaline urine.
 THERAPEUTIC USES
W. Bancrofti, B. Malayi, and B. Timori
 The standard regimen for LF has been a 12-day, 72mg/kg
(6 mg/kg/day) course of diethylcarbamazine. A single dose
of 6 mg/kg had comparable macrofilaricidal and
microfilaricidal efficacy to previous regimens. Single-dose
therapy may be repeated every 6–12 months, as necessary.
 Diethylcarbamazine remains the best drug for therapy of
loiasis. Treatment is initiated with test doses of 50 mg (1
mg/kg in children) daily for 2–3 days, escalating as tolerated
to daily doses of 9 mg/kg in Three doses for a total of 2–3
weeks.
 TOXICITY AND SIDE EFFECTS

 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

 Peak plasma levels of ivermectin are

achieved 4-5 H
 Ivermectin is ~93% bound to plasma
proteins. The drug is extensively
converted by hepatic CYP3A4 to at least
10 metabolites, mostly hydroxylated and
demethylated derivatives.
 THERAPEUTIC USES

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

Strongyloides stercoralis Ivermectin Albendazole or

(threadworm) thiabendazole

Enterobius vermicularis Mebendazole or pyrantel Albendazole

(pinworm) pamoate
Trichinella spiralis Mebendazole or
(trichinosis) albendazole; add
corticosteroids for severe
infection
Infecting Organism Drug of Choice Alternative Drugs
Roundworms
Albendazole
(nematodes)
Trichostrongylus species Pyrantel pamoate or Albendazole
mebendazole
Cutaneous larva migrans Albendazole or ivermectin Thiabendazole (topical)
(creeping eruption)
Visceral larva migrans Albendazole Mebendazole
Angiostrongylus Albendazole or
cantonensis mebendazole
Wuchereria bancrofti Diethylcarbamazine Ivermectin
(filariasis); Brugia malayi
(filariasis); tropical
eosinophilia; Loa loa
(loiasis)
Onchocerca volvulus Ivermectin
(onchocerciasis)
Dracunculus medinensis Metronidazole Thiabendazole or
(guinea worm) mebendazole
Capillaria philippinensis Albendazole Mebendazole
(intestinal capillariasis)
Infecting Organism Drug of Choice Alternative Drugs
Flukes (trematodes)
Schistosoma haematobium Praziquantel Metrifonate
(bilharziasis)
Schistosoma mansoni Praziquantel Oxamniquine
Schistosoma japonicum Praziquantel

Clonorchis sinensis (liver Praziquantel Albendazole

fluke); Opisthorchis species
Paragonimus westermani Praziquantel Bithionol
(lung fluke)
Fasciola hepatica (sheep Bithionol or triclabendazole
liver fluke)

Fasciolopsis buski (large Praziquantel or niclosamide

intestinal fluke)

Heterophyes heterophyes; Praziquantel or niclosamide

Metagonimus yokogawai
(small intestinal flukes)
Infecting Organism Drug of Choice Alternative Drugs
Tapeworms (cestodes)

Taenia saginata (beef Praziquantel or niclosamide Mebendazole

tapeworm)

Diphyllobothrium latum (fish Praziquantel or niclosamide

tapeworm)

Taenia solium (pork Praziquantel or niclosamide

tapeworm)

Cysticercosis (pork Albendazole Praziquantel

tapeworm larval stage)

Hymenolepis nana (dwarf Praziquantel Niclosamide, nitazoxanide

tapeworm)

Echinococcus granulosus Albendazole

(hydatid disease);
Echinococcus multilocularis
Scabies

 Communicable skin desease

 Disebabkan mites sarcoptes scabiei var hom.
 Karakteristik ;
1. Rasa gatal yang hebat
2. Peradangan yang luas
3. Papul yang sering digaruk
Scabies
Predileksi Scabies
Farmakoterapi :
1. Permethrine
2. Lindane→CNS toxicity
3. Ivermectine
Pediculosis

 Disebabkan Pediculous capitis (head louse),

pediculus humanus (body louse), Pthirus
pubis (pubic louse)
 Farmakoterapi :
1. Topikal permethrine (head and body louse)
2. Topikal pyrethrine (pubic louse)
Endoparasites and ectoparasites: therapeutic agents
 SEKIAN
TERIMA KASIH !!

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