FARMAKOLOGI OBAT

KUSTA DAN ANTIPARASIT

OLEH :
DIMAS P. NUGRAHA
BAGIAN FARMAKOLOGI FK UR
 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
1. Menyembuhkan dan mencegah
kecacatan

2. Memutuskan rantai penularan

Definitive Therapy: Standard Therapy

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.
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
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.
 orally absorbed and accumulates in
tissues
 The daily dose of clofazimine is usually
100 mg.
 Patients treated with clofazimine may
develop red discoloration of the skin.
 Clofazimine 50 mg
 Ofloxacin 400mg
 Minocycline 100 mg
 Tipe borderline, ↑imunitas seluler→PB
 delayed hypersensitivity
 Simptom :
- Lesi awal makin merah, ulcerasi
- gangguan konstitusi
- Neuritis saraf tepi
 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
 Imobilisasi
 Analgesik, sedatif
 Early clofazimin (tipe 1) dan Prednison
30mg/hr
 MDT diteruskan
Amebiasis

Malaria

Giardiasis

Leshmaniasis

Toxoplasmosis

Trypanosomiasis
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
 Clinical Presentations

Asymptomatic Intestinal infection (Carriers, passing

cysts)

Mild to moderate intestinal disease (Nondysenteric

Colitis)

Severe Intestinal infection (Dysentery)

Hepatic abscess, ameboma (localized granulomatous

lesion of colon) and other extraintestinal disease
▪ Luminal Amebicides

▪ Tissue or systemic amebicides

▪ Mixed Amebicides
 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)
 Effective against both luminal and systemic
forms of the disease. Although luminal
concentration is too low for single drug –
treatment.
 Metronidazol
 Tinidazole
 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.
 Extraluminal amoebiasis (combined with
luminal amebicide).
 Giardiasis
 Trichomoniasis
 Broad spectrum of Anaerobic bacteria e.g.,
 Helicobacter pylori infection
 Pseudomembranous colitis (Clostridium
defficile).
1. GIT:
 Nausea
 Vomiting
 Dry mouth
 Metallic taste
 Diarrhoea
 Oral Thrush (Moniliasis, yeast infection).
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
Anthelmintics are drugs that act either
locally within the gut lumen to cause
expulsion of worms from the GI tract,
or systemically against helminths
residing outside the GI tract
The major soil-transmitted helminths
(STH) infections (ascariasis
[roundworm], trichuriasis [whipworm],
and hookworm infection) are among the
most prevalent infections in developing
countries

Because STH worm burdens are higher

in school-aged children than in any
other single group, the WHO advocate
school-based administration of broad-
spectrum anthelmintics on a periodic
and frequent basis
→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
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
Thiabendazole generally has been replaced by
newer agents

Mebendazole always is taken orally, and the same

dosage schedule applies to adults and children >2
years of age. For treatment of enterobiasis, a single
100-mg tablet is taken, repeated after 2 weeks
For control of ascariasis, trichuriasis, or hookworm
infections, the recommended regimen is 100 mg of
mebendazole taken in the morning and evening for 3
consecutive days (or a single 500-mg tablet administered
once)

If the patient is not cured 3 weeks after treatment, a

second course should be given. The 3-day mebendazole
regimen is more effective than single doses of either
mebendazole (500 mg) or albendazole (400 mg)
For treatment of enterobiasis, ascariasis, trichuriasis,
and hookworm, taken as a single oral 400-mg dose by
adults and children >2 years of age.

In children between the ages of 12 and 24 months, the

WHO recommends a reduced dose of 200 mg.

Cure rates for light-to-moderate Ascaris infections

typically are >97%, although heavy infections may
require therapy for 2–3 days

A 400-mg dose of albendazole appears to be superior to

a 500-mg dose of mebendazole for curing hookworm
infections.
 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
 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
The WHO concluded that the BZAs may be used
to treat children past the first year who are at risk
for adverse consequences caused by STHs; a
reduced dose of albendazole (200 mg) is used in
children between the ages of 12–24 months
 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
 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
 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.
 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
Praziquantel is contraindicated in ocular
cysticercosis because the host response
can irreversibly damage the eye
 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
Poorly absorbed from the GI tract, a
property that contributes to its selective
action on GI nematodes.

Less than 15% is excreted in the urine as

parent drug and metabolites. Most of an
administered dose is recovered in the feces
Transient and mild GI symptoms occasionally are
observed, as are headache, dizziness, rash, and fever.

Pyrantel pamoate use in pregnant patients and children

<2 years of age is not recommended.

Because pyrantel pamoate and piperazine are mutually

antagonistic in their neuromuscular effects on parasites,
they should not be used together.
 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.
 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.
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.
 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
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
 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.
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
 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
(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
 Communicable skin desease
 Disebabkan mites sarcoptes scabiei var hom.
 Karakteristik ;
1. Rasa gatal yang hebat
2. Peradangan yang luas
3. Papul yang sering digaruk
Farmakoterapi :
1. Permethrine
2. Lindane→CNS toxicity
3. Ivermectine
 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 !!

Let’s make the world around us

better….. 84