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Year Level 6 [Module 5: Basic Pathology 2 – Infectious Diseases]
ANTI-PARASITIC DRUGS: ANTIHELMINTHICS & ANTI-PROTOZOAL
Dr. Henrietta de la Cruz | Pharmacology
OUTLINE:
I. Introduction
II. Anti-Helminthic Drugs
A. Nematodes
B. Filariasis
C. Paragonimiasis and Fascioliasis
D. Schistosomiasis
III. Anti-Protozoal Drugs
A. Tissue Amebecides
B. Luminal Amebecides
C. Leishmaniasis
D. Trypanosomiasis
I.
INTRODUCTION

Parasitic diseases are preventable
o There are 14 diseases currently listed as
Neglected Tropical Diseases.
o Children are the most vulnerable.
o Most of the endemic countries with high
incidence of parasitic diseases are the highly
indebted ones with obviously very limited
purchasing power; 60-70% of the people live
below the poverty line.
o 8 out of 14 NTDs are parasitic:
o Buruli
ulcer,
Chagas
disease,
cholera/epidemic
diarrhoeal
diseases,
dengue/dengue
haemorrhagic
fever,
dracunculiasis (guinea-worm), endemic
treponematoses (yaws, pinta, endemic
syphilis), human African trypanosomiasis
(sleeping sickness), leishmaniasis, leprosy,
lymphatic
filariasis,
onchocerciais,
schistosomiasis,
soil-transmitted
helminthiasis, and trachoma.
⌘Developing countries are more prone to parasitic
infections, but drug availability is less.
____________________________________________________
II.
ANTI-HELMINTHIC DRUGS
A. Nematodes
o Ascaris
o Ancylostomiasis (Hookworm
o Strongyloides stercoralis (threadworm)
o Enterobius vermicularis (pinworm)
o Trichiuris (whipworm)
o Trichinella spiralis
o Guinea worm disease
o Onchocerciasis (river blindness)
o Lymphatic filariasis
o Loaisis

Anti-helminthics
o Ascaris (1:4 persons on earth) = 1.3 billion
persons infected with 1.3 billion persons
infected with Ascaris
September 10, 2009
o
o
300 million with schistosomiasis
Typically infections in tropical countries are
greatest, with infestations commonly with more
than 1 type of helminth
1. Benzimidazoles
a. Albendazole

Mechanism of action
o Binds to beta-tubulin
o Prevents microtubule assembly in intestinal
and tegmental cells of helminth and larva
o Beta-tubulin dependent glucose uptake

Other potential mechanisms
o Inhibits fumarate reductase (parasite
specific)
o Decreases levels of NADH
o Degradation of endoplasmic reticulum and
mitochondria
o Decreased production of ATP causing
energy depletion, immobilization, and
worm death.

Treatment for intestinal nematodes
o Better spectrum of activityBetter
pharmacokinetics
o Ascaris lumbricoides
o Trichurius trichuria
o Hookworms
o Pinworm
o Cutaneous larva migrans
o Drug of choice for Echinococcus /
Cystercercosis (hydatid disease)
o Certain filarial species

Adverse events
o Embryotoxic in animals
o Rare:
Leukopenia (reversible), Fever,
Increased ICP, Rash, Renal toxicity 10%
o Central nervous system: Headache (11% N; 1% - H)
o Hepatic: LFTs Increased (~15% - H; <1% - N)
1% to 10%
o Central nervous system: Dizziness, vertigo,
fever (1%); intracranial pressure increased
(1% - N), meningeal signs (1% - N)
o Dermatologic: Alopecia (2% - H; <1% - N)
o Gastrointestinal: Abdominal pain (6% - H;
0% - N); nausea/vomiting (3% to 6%)
Migration of worm, Reversible alopecia,
Increased LFTs
o Hematologic: Leukopenia (reversible) (<1%)
o Miscellaneous: Allergic reactions (<1%)
o <1%:
Acute
renal
failure,
agranulocytopenia,
allergic
reaction,
granulocytopenia, pancytopenia, rash,
thrombocytopenia, urticaria

Mechanism of Resistance
o Loss of affinity to tubulin seen

Dose
Team 8 |Agoncillo, Carandang, Chua, Dela Cruz, Joaquin, Rayel, Redota, Teo, Uy
Page 1 of 13
ANTI-PARASITIC DRUGS: ANTIHELMINTHICS & ANTI-PROTOZOAL
Year Level 6 [Module 5: Basic Pathology 2]|September 10, 2009
o
Cysticercus cellulosae (unlabeled use): 15
mg/kg/day (maximum: 800 mg/day) in 2
divided doses for 8-30 days; may be repeated
as necessary
o Echinococcus
granulosus
(tapeworm)
(unlabeled use): 15 mg/kg/day (maximum:
800 mg) divided twice daily for 1-6 months
o Neurocysticercosis:
<60 kg: 15 mg/kg/day in 2 divided
doses (maximum: 800 mg/day) for 830 days
60 kg:400 mg twice daily for 8-30 days
o Ancylostoma caninum, Ascaris lumbricoides
(roundworm), Ancylostoma duodenale, and
Necator americanus (hookworms) (unlabeled
use): 400 mg as a single dose
⌘ Don’t do deworming without indication of
infection.
b. Mebendazole

Treatment for
o Intestinal helminths (mixed)
o Trichinella spiralis

Mechanism of action
o Binds to beta-tubulin
o Prevents microtubule assembly
o Beta-tubulin dependent glucose uptake

Mechanism of resistance
o Not report in humans, but not well studied

Adverse effects
o Frequency not defined
o Cardiovascular: Angioedema
o Central nervous system: Fever, dizziness,
headache, seizure
o Dermatologic: Rash, itching, alopecia (with
high doses)
o Gastrointestinal: Abdominal pain, diarrhea,
nausea, vomiting
o Hematologic: Neutropenia (sore throat,
unusual fatigue)
o Neuromuscular & skeletal: unusual weakness

Dose
o Pinworms: 100 mg as a single dose; may
need to repeat after 2 weeks; treatment
should include family members in close
contact with patient
o Whipworms, roundworms, hookworms: One
tablet twice daily, morning and evening on 3
consecutive days; if patient is not cured
within 3-4 weeks, a second course of
treatment may be administered
o Capillariasis: 200 mg twice daily for 20 days
⌘ Available commercially; same reaction as
Albendazole.
2. Pyrantel Pamoate
 Combantrin, TapeCare Plus
 a veterinary drug
 Treatment for:
o Roundworms
Team 8
o Pinworms
o Hookworms
 Mechanism of action
o Depolarizing neuromuscular blocking agent
(cholinestrease inhibition), causing contraction,
followed by paralysis of migratory helminths;
ineffective against ova
 Pharmacokinetics
o Poorly absorbed=good for intestinal nematodes
o Alternative to mebendazole
o Treatment should be repeated after 2 weeks
 Adverse effects

Mild GI upset, dizziness, rashes, fever
3. Ivermectin

Initially for cattle, horses, & pigs

Derived from Streptomyces

Treatment for Helminths

Drug of choice for
o Strongyloides, Onchoceriasis
o Ectoparasites: scabies & lice

Mechanism of action
o Activates opening of gated chloride channels
o Paralysis of pharyngeal pumping mechanisms of
helminthes
⌘Causes paralysis by inhibiting acetylcholine.

Mechanism of resistance
o Not known

Pharmacokinetics
o Well absorbed in GI with entero-hepatic
recirculation
o t1/2: 12 hours
o Highly protein bound
o Collects in adipose

Dose: 100-150 mcg/kg dose

Adverse effects: low (14% inc)
o Common: itching, dizziness
o Occasional: Mazzoti reaction- fever pruritus,
tender lymph node, headache, joint pains,
seizures
o Rare: hypotension

Onchocerca volvulus, family filariidae, vector
simulium – larval transm, 99% yemen and latin
america, river blindness/ elephantiasis
4. Thiabendazole

Mechanism of action: same as benzimidazole

Use: Roundworm infections such as threadworm,
hookworm/creeping eruption (cutaneous larva
migrans), and visceral larva migrans (toxocariasis);
other types of roundworm infections such as
pinworm, whipworm, large roundworm (ascariasis),
and trichinosis when other therapies have failed or
are unavailable.

Usual Adult Dose for Angiostrongylosis
o 25 mg/kg (up to 1 g) orally 2 to 3 times a day for
3 days

Usual Adult Dose for Capillariasis
o 25 mg/kg (up to 3 g) orally once a day for 30
days
Page 2 of 13
ANTI-PARASITIC DRUGS: ANTIHELMINTHICS & ANTI-PROTOZOAL
Year Level 6 [Module 5: Basic Pathology 2]|September 10, 2009

Usual Adult Dose for Ascariasis
o Orally 2 times a day for 2 successive days.
Alternatively, a single dose of 20 mg/lbs (50
mg/kg) may be used
o Recommended maximum daily dose is 3000 mg.

Adverse effects
o Central nervous system: Seizures, hallucinations,
delirium, dizziness, drowsiness, headache, chills
o Dermatologic: Rash, Stevens-Johnson syndrome,
pruritus, angioedema
o Endocrine & metabolic: Hyperglycemia
o Gastrointestinal: Anorexia, diarrhea, nausea,
vomiting, drying of mucous membranes,
abdominal pain
o Genitourinary: Malodor of urine, hematuria,
crystalluria, enuresis
o Hematologic: Leukopenia
o Hepatic: Jaundice, cholestasis, hepatic failure,
hepatotoxicity
o Neuromuscular
&
skeletal:
Numbness,
incoordination
o Ocular: Abnormal sensation in eyes, blurred
vision, dry eyes, Sicca syndrome, vision
decreased, xanthopsia
o Otic: Tinnitus
o Renal: Nephrotoxicity
o Miscellaneous: Anaphylaxis, hypersensitivity
reactions, lymphadenopathy
⌘Not a good alternative due to adverse effects.
B. Filariasis
 Endemic in over 80 countries in Africa, Asia, South
and Central America and the Pacific Islands
 Wuchereria bancrofti, Brugia malayi, Brugia timori
 W. bancrofti are mainly transmitted by Culex
quinquefasciatus mosquitoes and some species of
Anopheles. Brugia parasites are mainly transmitted by
Mansonia mosquitoes.
 Infective larvae develop into adult worms
(macrofilariae) in the afferent lymphatic vessels,
causing severe distortion of the lymphatic system.
(Refer to Figure 2 on last page.)
 The treatment strategy is now based on annual,
single-dose,
2-drug
regimens
of
ivermectin+albendazole in countries that are coendemic for onchocerciasis, and of DEC+albendazole
in all other countries.
1. Ivermectin (already mentioned)
2. DEC (Diethylcarbamazine)
 Treatment for Filaria
 Mechanism of Action
o Effective in adult, not filarial
o Alteration of surface membranes
o Immobilization due to a hyperpolarizing effect
 Pharmacokinetics
High bioavailability with oral administration
Rapid absorption & peak drug levels
Metabolized: liver
Excreted >50% unchanged in urine
Team 8
 Dose: 2 to 3 mg per kg of body weight three times a
day for 2-4 wks
 Adverse effects:
o Major
Mazzoti reaction (Arthralgia, edema, fever,
lymphadenopathy, ocular damage, pruritus,
rash, synovitis)
Seizure
Encephalitis
Ocular lesions (due to worm death)
o Minor: Anorexia/Vomiting
3. Triclabendazole

Drug of choice against fascioliasis: Fasciola hepatica
(liver fluke)

Paragonimus sp. (fluke)

Mechanism of action
o Binds to beta tubulin
o Prevents microtubule assembly and beta tubulin
dependent glucose uptake
⌘Not a systemic drug; more active in the GIT.

Adverse effect
o Most common are abdominal
o Pain, epigastric pain and sweating. Less common
are nausea, vomiting, dizziness, cough, fever,
urticaria and pruritus. Skin rash is uncommon

Dose: 10 mg/kg x 2 d

Pharmacokinetics:
o 99% protein bound
o Metabolized – liver
o Excreted – renal
C. Paragonimus and Fasciola
1. Bithionol

Mechanism of Action
o Unknown, bithionol may work may uncoupling
oxidative phosphorylation, thus reducing the
production of ATP in the helminth

Use
o Drug of choice for fascioliasis; no longer
recommended due to its prolonged treatment
course with moderate to low cure rates and
frequent adverse reactions (WHO, 2007)
o A bacteriostatic agent. It is used as an algicide,
antihelmintic, agricultural fungicide
⌘Used as a last result; not available commercially.

Adverse effect
o Diarrhea, anorexia, nausea, vomiting, pruritus,
urticaria and abdominal pain
o Rare: hepatotoxicity

Dose: 30–50 mg/kg per day, divided into 3 oral doses
on alternate days for 20–30 day
___________________________________________________
D. Schistosomiasis

Endemic in 74 developing countries, > 80% of infected in
sub-Saharan Africa

Trematode flatworms (flukes) of the genus Schistosoma

Transmission occurs in freshwater when intermediate
snail hosts release infective forms of the parasite
Page 3 of 13
ANTI-PARASITIC DRUGS: ANTIHELMINTHICS & ANTI-PROTOZOAL
Year Level 6 [Module 5: Basic Pathology 2]|September 10, 2009

Larval forms of the parasites (known as cercariae),
released by the snails, penetrate the skin of people in
the water

Adult male and female schistosomes pair and live
together in human blood vessels. The females release
eggs, some of which are passed out in the urine (in S.
haematobium infection) or stools (S. mansoni, S.
japonicum), but some eggs are trapped in body tissues.
⌘Endemic in Samar, Leyte, Northern Mindanao.
⌘Reaction to egg causes the pathology. It takes years before
the reactions arise.
o
Rare: neuropsych, convulsions
1. Praziquantel

Treatment for:
Cestodes (tapeworms):Taenia, Diphyllobothrium
latum, Echinococcus
Trematodes:
Schistosomiasis,
Chlonorchis
sinensis, Paragonimus, Cysticercosis
 Mechanism of action:
o Tapeworms: release of Ca from endogenous
stores= paralysis and expulsion of worm
o Schistosomes: damage of tegumen resulting in
vacuolation & increased permeability to Ca
causing paralysis, Sequestered Ag exposed to
parasite surface allowing for immune recognition
 Pharmacokinetics:
o Well absorbed in GI (= 80%)
o
t1/2: 4-8
o Highly protein bound
o Collects in adipose
o CSF penetration 15-20 %
o Metabolism: liver
o Excreted: urine
 Dose: 10-25 mg/kg/dose, single dose
 Adverse events:
o Frequent: abdominal pain, diarrhea, malaise,
dizziness
o Occasional: sedation, fever, sweating, nausea,
eosinophilia
o Rare: pruritus, rash, edema, hiccups
2. Oxamniquine
 Indication: Only for S. mansoni, 2nd choice to
praziquantel
 Mechanism of action
o Activated to unstable phosphate ester that
alkylates essential macromolecules
o Anticholinergic property
o Causes worms to shift from the mesenteric veins
to the liver where the male worms are retained;
the female worms return to the mesentery, but
can no longer release eggs
 Pharmacokinetics
o Readily absorbed on oral ingestion
 Dose
o 15 milligrams (mg) per kilogram (kg) of body
weight two times a day for one, two, or three
days.
 Adverse effects:
o Mild: Dizziness, ha, drowsiness, nausea, diarrhea
Team 8
Page 4 of 13
ANTI-PARASITIC DRUGS: ANTIHELMINTHICS & ANTI-PROTOZOAL
Year Level 6 [Module 5: Basic Pathology 2]|September 10, 2009
II.
ANTI-PROTOZOAL DRUGS

One of 7 amoebae commonly found in humans

Only one that causes significant disease =intestinal
disease and extraintestinal disease (liver primarily)

Trophozoites attach to galactose receptors mucosal
lesions of colonsubmucosa� bloodstream
portal vein abscesses in liver

Dormant cysts survive for months in moist, warm
environments contaminate food and water
A. Tissue Amebicides
1. Metronidazole (Flagyl)

Indication: Amoeba, Giardia, Trichomonas, anaerobe

Mechanism of Action:
o Nitro group of metronidazole is chemically
reduced by ferredoxin (or a ferredoxin-linked
metabolic process) and the products are
responsible for disrupting the DNA, thus
inhibiting nucleic acid synthesis
o A prodrug: it is converted in by the redox
enzyme pyruvate-ferredoxin oxidoreductase
(Refer to Figure 3 on last page.)

Pharmacokinetics
o Good absorption
o Liver metabolism with two principal metabolites;
both with anti-trichomonal activity

Mechanism of resistance
o decreased PFOR activities
o Ferredoxin (Fd) Gene resistance

Adverse effects
o Minor side effects include nausea, headaches,
loss of appetite, a metallic taste, and rarely a
rash.
o Serious side effects of metronidazole are rare.
Serious side effects include seizures and damage
of nerves resulting in numbness and tingling of
extremities (peripheral neuropathy).
o Urine may be reddish brown due to pigments
from drug

Amebic dysentery: 750 mg orally 3 times daily for 510 days

Amebic liver abscess: 500-750 mg orally three times
daily for 5-10 days

Anaerobic infections: 7.5 mg/kg orally every 6 hours
not to exceed 4 grams daily

Bacterial Vaginosis: 750 mg (extended release tablets)
once daily for 7 days. One applicator-full of 0.75%
vaginal gel, once or twice daily for 5 days.

Giardia: 250 mg orally three times daily for 5 days

Clostridium difficile infection: 250-500 mg orally 4
times daily or 500-750 orally 3 times daily
⌘Used mostly for amoeba, but also for some bacteria at
times. Used for extraluminal amoebiasis; effectively
eliminates intestinal and extraintestinal infections.
2. Emetine

Mechanism of Action: binding to the 40S subunit of
the ribosome (Jimenez et al., Enzymatic and
nonenzymatic translocation of yeast polysomes.
decreases ribosomal/RNA interaction to decrease
Team 8




protozoal protein synthesis. It also blocks adrenergic
and cholinergic transmission in humans.
Use: used to induce vomiting, sweating at the onset
of influenza, and small amounts of the extract have
been incorporated into cough syrups as expectorants.
Adverse effects
o Cardiovascular: Cardiotoxicity
o Central nervous system: Lethargy
o Gastrointestinal: Protracted vomiting, diarrhea
o Neuromuscular & skeletal: Myopathy
Dose:
o The usual dose range for the syrup is 10 to 30
mL, yielding a dose of alkaloids 12 to 48 mg. For
children 6 to 12 months of age, ipecac 5 to 10 mL
with 120 to 240 mL of water usually is a
sufficient dose
Psychotria ipecacuanha or ipecac is a small perennial
tropical plant that grows to about 60 cm in height.
B. Luminal Amoebicide
1. Diloxanide furoate

Indications
o Luminal amoebicide
o Asymptomatic cyst passers
o Not effectivce for extraintestinal amebiasis

Mechanism of action: unclear

Dose
o Adults: 500 milligrams (mg) three times a day for
ten days.
o Children:20 mg per kilogram (kg) per day given in
three divided doses for ten days

Pharmacokinetics
o Well absorbed and well tolerated
⌘Easily absorbed in the GI.

Adverse effects
o More common: Full feeling or passing gas;
nausea.
o Less common: Diarrhea; loss of appetite;
stomach pain.
2. Iodoquinol




Mechanism of Action: unknown mechanism in
intestinal lumen
Use
o Amebiasis, extraintestinal
o Balantidiasis
Dose
o Oral: Children: 30-40 mg/kg/day (maximum: 650
mg/dose) in 3 divided doses for 20 days; not to
exceed 1.95 g/day
o Adults: 650 mg 3 times/day after meals for 20
days; not to exceed 1.95 g/day
Adverse effects
o Central nervous system: Fever, chills, agitation,
retrograde amnesia, headache
o Dermatologic: Rash, urticaria, pruritus
o Endocrine & metabolic: Thyroid gland
enlargement
Page 5 of 13
ANTI-PARASITIC DRUGS: ANTIHELMINTHICS & ANTI-PROTOZOAL
Year Level 6 [Module 5: Basic Pathology 2]|September 10, 2009
o
o
o
o
Gastrointestinal: Diarrhea, nausea, vomiting,
stomach pain, abdominal cramps
Neuromuscular
&
skeletal:
Peripheral
neuropathy, weakness
Ocular: Optic neuritis, optic atrophy, visual
impairment
Miscellaneous: Itching of rectal area
3. Paromomycin

Mechanism of Action: aminoglycoside (inh 30s
ribosomal subunit)

Use: intestinal amebiasis

Poorly absorbed after oral administration, with
almost 100% of the drug recoverable in the stool

Nausea, abdominal cramps, and diarrhea on doses
over 3 g daily.

Heartburn, emesis, and pruritus ani. Superinfections,
especially by monilia.

Usual dose — 25 to 35 mg/kg body weight daily,
administered in three doses with meals, for five to
ten days.
4. Nitazoxanide

Indications
o Intestinal protozoa
o Cryptosporidium

shortens duration of diarrhea
o Giardia

Mechanism of action
o Metabolized rapidly to active form- tizoxanide
o May be due to interference with the pyruvate
ferredoxin oxidoreductase enzyme-dependent
electron transfer reaction essential for anaerobic
metabolism

Pharmacokinetics
o » 70% > absorption with suspension vs. tablet
o » >99% protein bound
o » Metabolism: hepatic
o » Excretion: urine, bile and feces

Dose: variable by indication
o » 100 BID to 500 BID

Adverse Events:
o Common: HA, GI complaints (Abdominal pain,
diarrhea, nausea, vomiting)
o Body as a Whole: asthenia, fever, pain, allergic
reaction, pelvic pain, chills and fever, flu
syndrome.
Nervous System:
dizziness, somnolence,
insomnia,
tremor,
hypesthesia.
Urogenital System: discolored urine, dysuria,
amenorrhea,
kidney
pain,
Metabolic & Nutrition: increased SGPT.
Hemic & Lymphatic Systems: anemia,
leucocytosis
Skin:
rash,
pruritus
Special Senses: eye discoloration, ear ache.
Respiratory System: epistaxis, pharyngitis .
Cardiovascular System: tachycardia, syncope,
hypertension.
Team 8
Muscular System: myalgia leg cramps,
spontaneous bone fracture
⌘It is not used as a first line of defense as it has a lot
of side effects.
5. Furazolidone (Furoxone),

Indications
o Giardia, Trichomonas, other bacterial inf
(staphylococci, enterococci, Escherichia coli,
Salmonella spp., Shigella spp., and Vibrio cholera

Mode of action:
o Interference with several bacterial enzyme
systems, possibly including prevention of
acetylation of coenzyme A.

Pharmacokinetics:
o FZD is poorly absorbed and is inactivated in the
intestine. About 5% of an
o Oral dose of FZD is excreted in the urine as
unchanged drug and metabolites, which may tint
the urine brown.

Adverse effects
o Headache, stomach upset, nausea, vomiting,
dizziness or weakness may occur especially the
first several days; Allergies
o This medication may cause the urine to turn
brown in color.
C. Leishmaniasis

Parasitic protozoa of the genus Leishmania,
transmitted to humans by sandflies subfamily
phlebotominae, tiny sand-coloured blood-feeding
flies that breed in forest areas, caves, or the burrows
of small rodents

Endemic in 88 countries on 4 continents. More than
90% of cutaneous leishmaniasis cases occur in Iran,
Afghanistan, Syria, Saudi Arabia, Brazil and Peru.
More than 90% of visceral leishmaniasis cases occur
in Bangladesh, Brazil, India and Sudan

4 Main Forms:
1. Visceral leishmaniasis (VL) - the most serious form
is fatal if left untreated (e.g. Kala azar due to L.
donovani s.l.)
2. Cutaneous leishmaniasis (CL) - the most common
form, causes 1-200 simple skin lesions which selfheal within a few months but which leave unsightly
scars. (e.g. Baghdad ulcer, Delhi boil or Bouton
d’Orient, due to infection with L. major in Africa
and Asia)
3. Mucocutaneous leishmaniasis (MCL), due to L.
braziliensis infection, begins with skin ulcers which
spread, causing dreadful and massive tissue
destruction, especially of the nose and mouth
4. Diffuse cutaneous leishmaniasis (DCL) produces
disseminated and chronic skin lesions resembling
those of leprotamous leprosy. It is difficult to treat.
Page 6 of 13
ANTI-PARASITIC DRUGS: ANTIHELMINTHICS & ANTI-PROTOZOAL
Year Level 6 [Module 5: Basic Pathology 2]|September 10, 2009
1. Sodium stibogluco

Pentamidine

Mechanism of action
o Decreases DNA, RNA, protein, and phospholipid
synthesis. The exact mechanism is not known
but may inhibit synthesis of parasitic DNA by
blocking thymidine synthase

Use
o May be used to treat pneumocystis pneumonia
and sleeping sickness; Trypanosoma brucei,
Leishmania

Pharmacokinetics
o Poor oral bioavailability so used by aerosol or IV

Excretion: urine

Dose: variable by indication

Adverse Events
o Severe hypotension. It is also toxic to the beta
cells of the islets of Langerhans in the
pancreas. This may manifest as an initial
hypoglycæmia (caused by initial insulin release)
followed
by
hyperglycæmia
and
the
development of diabetes mellitus
o Blood dyscrasias and hepatotoxicity
o Major: Immediate with IV: hypotension,
tachycardia, nausea, vomiting, syncope, etc.,
Urticaria, Renal failure; Cardiac dysrythmia;
Leukopenia; Thrombocytopenia

Dose
o 4 mg/kg (as base) in each of 7-10 intramuscular
injections administered either daily or on
alternate days for four days.

Mechanism of Resistance
o Unclear, Failures reported in literature
⌘Cannot be given in mass deworming.
2. Miltefosine

Treatment for Leishmania sp.

Mechanism of action
o Alkyl phospholipid- oral antineoplastic
o Phosphocholine analogue- affects cell signaling
and membrane synthesis

Pharmacokinetics
o Well absorbed in mice
o No human data

Dose: variable dosing by age; 100 mg/day over 4
weeks

Adverse Events
o Pregnancy: ?
o Major: retinal degeneration, hepatitis, renal
failure
o Minor: itching, rash, N/V/D, leukocytosis
⌘Alternative to pentamidine.
D. Trypanosomiasis
 Transmitted by the insect Glossina called the tsetse
fly

Affects mostly poor populations living in remote
rural areas of Africa.

Following the bite of the infected fly the parasite
will multiply in the lymph and the blood causing
Team 8
headaches, fever, weakness, sweating, pain in the
joints, and stiffness; over time, it will cross the
blood-brain barrier migrating to the central
nervous system causing a panoply of neurological
disorders including psychiatric disorders, seizures,
coma and ultimately death
 T.b. rhodesiense infections, the disease is acute,
lasting from a few weeks to several months (Tx:
suramin)
 in T.b. gambiense infections the disease is chronic,
generally lasting several years without any major
signs or symptoms (Tx: Pentamidine)
1. Suramin sodium

Ind: first stage T. b. rhodesiense African
trypanosomiasis

MOA: inhibits trypanosomal enzymes

A complex derivative of urea with antiprotozoal
activity

Not absorbed from the gastrointestinal tract and
must be administered by intravenous injection. It
dissociates slowly from plasma proteins and is
detectable unchanged in the urine for up to 3 months
after the last dose.

Pharmacokinetics: extensive protein binding; enters
the extracellular space but does not cross the bloodbrain barrier

Not metabolized, 80% renal clearance

Adverse effects:
o Heavy proteinuria, stomal ulceration, exfoliative
dermatitis, severe diarrhoea, prolonged high
fever and prostration.
o Lesser symptoms, which are common, include
tiredness, anorexia, malaise, polyuria, increased
thirst and tenderness of the palms and soles.
 Storage: Powder for injection 1 g; should be kept in
well-closed containers protected from light.
⌘IV drug; gradual increase in dosing; hard to excrete this
drug.
2. Melarsoprol
 Injection 36 mg/ml solution in propylene glycol (1,2 –
propanediol)
 Treatment for:
o Confirmed
second
stage
cases
(meningoencephalitic involvement) of T. b.
gambiense or T. b. rhodesiense African
trypanosomiasis.

Used only in hospitals and specialized treatment
centres.

MOA
o Melarsoprol is an organic arsenical compound
o Unclear: inhibitor of a large number of enzymes

Relapse occurs in less than 5% of cases, however in
certain endemic areas rate of relapses have been
much higher (up to 20%).

Pharmacokinetics
o Unreliably absorbed from the gastrointestinal
tract; irritant for intramuscular administration.
o Good entry to the central nervous
Page 7 of 13
ANTI-PARASITIC DRUGS: ANTIHELMINTHICS & ANTI-PROTOZOAL
Year Level 6 [Module 5: Basic Pathology 2]|September 10, 2009
o


Excreted in the urine and faeces within a few
days.
Adverse Effects
o Reactive encephalopathy characterized by
headache, tremor, slurring of speech,
convulsions and ultimately coma, this is the most
serious complication.
o Frequent, less severe, adverse effects include
myocardial
damage,
albuminuria
and
hypertension.
o Agranulocytosis is a particularly dangerous but
rare reaction.
o Dose-related renal and hepatic dysfunction can
occur during the later phases of treatment.
Other adverse effects include hyperthermia,
urticarial rashes, headache, diarrhoea and
vomiting.
Dose: low doses initially, then gradually increased to
the maximum daily dose of 3.6 mg per kg of body
weight 3-4 d
Figure 1. Melarsoprol Dosing.
3. Eflornithine

Eflornithine is an ornithine derivative with activity
that is specific against T. b. gambiense.

Mechanism of Action:
inhibiting the enzyme
ornithine decarboxylase, which is involved in
polyamine synthesis in trypanosomes.

Kinetics: The plasma half-life is 3.0-3.5 hours.
Eflornithine readily crosses the blood-brain barrier to
enter the brain and is mainly excreted by the kidneys.

Use: for the treatment of T. b. gambiense African
trypanosomiasis in both the early and the late stages.
Eflornithine is not effective for the treatment of T.b.
rhodesiense infections.

Adverse effects: diarrhoea, anaemia, leukopenia,
thrombocytopenia and convulsions. Impaired hearing
has also been reported. Less commonly, vomiting,
anorexia, alopecia, abdominal pain, headache, facial
oedema, eosinophilia and dizziness have occurred.
These are reversible on withdrawal of the drug.
Team 8



Prep:
Injection
200
mg
of
eflornithine
hydrochloride/ml solution in 100-ml bottle
Dose: 100 milligrams (mg) per kilogram (kg) (45 mg
per pound) of body weight injected slowly into a vein
over a period of at least forty-five minutes. This dose
is given every six hours for fourteen days.
Chagas Disease:
o Northern South America, Central America and
Mexico, where the vector lives both inside and
outside dwellings
o The protozoan parasite (Trypanosoma cruzi),
which enters the human body though broken
skin
1) By bloodfeeding "Assassin bugs’ (sub-family
Triatominae), They emerge at night to bite and
suck blood. The faeces of the insects contain
parasites which can enter the wound left after
the bloodmeal, usually when it is scratched or
rubbed
2) Through transfusion with infected blood
3) Congenitally, from infected mother foetus

A small sore develops at the bite where the
parasite enters the body. If this is near the eye,
the eyelid becomes swollen (known as Romaña’s
sign). Within a few days, fever and swollen
lymph nodes may develop. This initial acute
phase may cause illness and death, especially in
young children. More commonly, patients enter
a symptomless phase lasting several months or
years, during which time parasites are invading
most organs of the body, often causing heart,
intestinal and oesophageal damage and
progressive weakness. In 32% of those infected,
fatal damage to the heart and digestive tract
occurs during this chronic phase.
4. Nifurtimox

Treatment for: Trypanosoma cruzi

Mechanism of action
o Synthetic nitrofuran
o May act by increasing oxidative stress through
production of free radicals

Pharmacokinetics
o GI absorption 80% in animal models (lower in
humans)
o Metabolism: liver (extensive P-450)
o Excretion: renal (1% as native drug)

Dose: variable dosing by age
o 8-10 mg/kg divided 3 times a day for 90 days

Adverse events
o Pregnancy: ?
o Major
o Usually hospitalize to monitor for side
effects
o Hemolytic anemia
o Multiple CNS effects
o Renal failure
o Minor
o Rash
o N/V/ Abdominal pain
Page 8 of 13
ANTI-PARASITIC DRUGS: ANTIHELMINTHICS & ANTI-PROTOZOAL
Year Level 6 [Module 5: Basic Pathology 2]|September 10, 2009
o
o
Team 8
Increased LFTs
Leukopenia
5. Benznidazole
 Treatment for:
o Trypanosoma cruzi
o Current treatment of choice for acute cases
 Mechanism of action:
o Same as Nitroimidazole
o DNA binder
 Pharmacokinetics
o 92% bioavailability after oral dose
o 44% protein bound
o Metabolism: ?
o Excretion: urine and bile
 Dose: variable dosing by age
o 5-6 mg/kg divided 2 times a day for 60 days
 Adverse events
o Major

Bone marrow depresison

Carcinogenesis
o Minor

Rash

Itching

Peripheral neuropathy
Page 9 of 13
Year Level 6 [Module 5: Basic Pathology 2 – Infectious Diseases]
ANTI-PARASITIC DRUGS: ANTIHELMINTHICS & ANTI-PROTOZOAL
Dr. Henrietta de la Cruz | Pharmacology
September 10, 2009
Figure 2. Filaria life cycle (filariasis).
Figure 3. Life cycle of Entameba histolytica showing the sites of action of amebecidic drugs.
Team 8 |Agoncillo, Carandang, Chua, Dela Cruz, Joaquin, Rayel, Redota, Teo, Uy
Page 10 of 13
Year Level 6 [Module 5: Basic Pathology 2 – Infectious Diseases]
ANTI-PARASITIC DRUGS: ANTIHELMINTHICS & ANTI-PROTOZOAL
Dr. Henrietta de la Cruz | Pharmacology
September 10, 2009
SUMMARY TABLE:
Name of Drug
ANTI-HELMINTHIC DRUGS
Albendazole
Indications for Use
Mechanism of Action
Adverse Effects
Ascaris, Trichuris, Hookworms, Pinworms,
Drug of choice for: Echinococcus
Binds to beta-tubulin  retards glucose
uptake  retards parasite
Prevents microtubule assembly in intestinal
and tegmental cells of helminth and larva
Same as Albendazole
Well tolerated but with hematologic side
effects
Benzimidazoles
Mebendazole
Ascaris, Trichuris, Hookworms, Pinworms,
Capillariasis, Trichinella spirallis
Roundworms, Pinworms, Hookworms
Pyrantel pamoate (Combantrin)
Ivermectin
Thiabendazole
Filariasis, Strongyloides, Onchoceriasis, Scabies
& Lice
Threadworm, cutenaous and visceral larva
migrans, pinworm, whipworm, large
roundworm (ascariasis), and trichinosis when
other therapies have failed or are
unavailable.
Filariasis
Mazzoti reaction- fever pruritus, tender lymph
node, headache, joint pains, seizures
More severe reactions  STEVEN JOHNSON
syndrome
Mazzoti reaction
Drug of choice for fascioliasis (liver flukes)
More active in GIT; same as benzimidazoles
Fascioliasis
Unknown MOA but presumed to be disruption
of oxidative phosphorylation; no longer
recommended by the WHO
Tapeworms: release of Ca from endogenous
stores= paralysis and expulsion of worm
Abdominal symptoms: epigastric pain with
sweating
Diarrhea, anorexia, nausea, vomiting, pruritus,
urticaria and abdominal pain
Bithionol
Cestodes
(tapeworms):Taenia,
Diphyllobothrium latum, Echinococcus
Praziquantel
Mild GI upset, dizziness, rashes, fever
Effective in adults not in filarial larval forms;
can be given orally
Alteration of surface membranes 
Immobilization due to a hyperpolarizing effect
DEC (Diethylcarbamazene)
Triclabendazole
Depolarizing neuromuscular blocking agent
(cholinestrease
inhibition),
causing
contraction, followed by paralysis of migratory
helminths; ineffective against ova
Activates opening of gated chloride channels
 paralysis of pharyngeal pumping
mechanisms of helminthes
Same as benzimidazoles
More serious hematologic side effects
Trematodes: Schistosomiasis, Chlonorchis
sinensis, Paragonimus, Cysticercosis
Team 8 |Agoncillo, Carandang, Chua, Dela Cruz, Joaquin, Rayel, Redota, Teo, Uy
Frequent: abdominal pain, diarrhea, malaise,
dizziness
Schistosomes: damage of tegumen resulting in
vacuolation & increased permeability to Ca
causing paralysis, Sequestered Ag exposed to
parasite surface allowing for immune
recognition
Page 11 of 13
ANTI-PARASITIC DRUGS: ANTIHELMINTHICS & ANTI-PROTOZOAL
Year Level 6 [Module 5: Basic Pathology 2]|September 10, 2009
ANTI-PROTOZOAL DRUGS
Amoeba,
bacteria
Giardia,
Trichomonas,
anaerobe
Metronidazole (Flagyl)
Emetine
Diloxanide Furoate
Iodoquinol
induce vomiting, sweating at the onset of
influenza, and small amounts of the extract
have been incorporated into cough syrups as
expectorants
Luminal amoebicide
Asymptomatic cyst passers
Not effectivce for extraintestinal amebiasis
Extraintestinal amebiasis, Balantidiasis
Intestinal amebiasis
Paromomycin
Intestinal protozoa, Cryptosporidium, Giardia
Nitazoxanide
Furazolidone
Sodium stibogluco
Miltefosine
Team 8
Giardia,
Trichomonas,
other
bacterial
infections
(Staphylococci,
Enterococci,
Escherichia coli, Salmonella spp., Shigella spp.,
and Vibrio cholera)
A PRODRUG: it is converted in by the redox
enzyme pyruvate-ferredoxin oxidoreductase.
Nitro group of metronidazole is chemically
reduced by ferredoxin (or a ferredoxin-linked
metabolic process) and the products are
responsible for disrupting the DNA, thus
inhibiting nucleic acid synthesis
binding to the 40S subunit of the ribosome 
enzymatic and nonenzymatic translocation of
yeast polysomes 
ribosomal/RNA
interaction to decrease protozoal protein
synthesis. It also blocks adrenergic and
cholinergic transmission in humans.
Unclear MOA with poor tissue penetration
nausea, headaches, loss of appetite, a metallic
taste, and rarely a rash
Unknown mechanism in intestinal lumen
Longer period and MORE SIDE EFFECTS  not
primary drug
Nausea, abdominal cramps, and diarrhea on
doses over 3 g daily. Heartburn, emesis, and
pruritus ani. Superinfections, especially by
monilia.
NEPHROTOXICITY and AUTOTOXICITY
asthenia, fever, pain, allergic reaction, pelvic
pain, chills and fever, flu syndrome. NOT USED
AS FIRST LINE OF DEFENSE BECAUSE OF MANY
SIDE EFFECTS
Aminoglycoside  inhibits 30S subunit to
inhibit protein synthesis
Poorly absorbed after oral administration,
with almost 100% of the drug recoverable in
the stool
Metabolized rapidly to active form tizoxanide
 interference with the pyruvate ferredoxin
oxidoreductase enzyme-dependent electron
transfer reaction essential for anaerobic
metabolism
Interference with several bacterial enzyme
systems, possibly including prevention of
acetylation of coenzyme A.
May be used to treat pneumocystis pneumonia
and sleeping sickness; Trypanosoma brucei,
Leishmania
Poorly excreted thus longer half-life;
Decreases DNA, RNA, protein, and
phospholipid synthesis. The exact mechanism
is not known but may inhibit synthesis of
parasitic DNA by blocking thymidine synthase
Leishmania sp.
Alkyl phospholipid- oral antineoplastic
Phosphocholine analogue- affects
signaling and membrane synthesis
Urine may be reddish brown due to pigments
from drug
Cardiovascular: Cardiotoxicity
Central nervous system: Lethargy
Gastrointestinal: Protracted vomiting, diarrhea
Neuromuscular & skeletal: Myopathy
Full feeling or passing gas; nausea
Headache, stomach upset, nausea, vomiting,
dizziness or weakness may occur especially the
first several days; Allergies.
May affect normal intestinal flora.
URINE MAY TURN BROWN IN COLOR.
Severe hypotension. It is also toxic to the beta
cells of the islets of Langerhans in the pancreas
 diabetes, tachycardia, nausea, vomiting,
syncope, etc., Urticaria, Renal failure; Cardiac
dysrythmia; leukopenia;
thrombocytopenia
retinal degeneration, hepatitis, renal failure
cell
Page 12 of 13
ANTI-PARASITIC DRUGS: ANTIHELMINTHICS & ANTI-PROTOZOAL
Year Level 6 [Module 5: Basic Pathology 2]|September 10, 2009
Suramin Sodium
Melarsoprol
Eflornithine
first stage T.
trypanosomiasis
b.
rhodesiense
African
Confirmed
second
stage
cases
(meningoencephalitic involvement) of T. b.
gambiense or T. b. rhodesiense African
trypanosomiasis
Specificity for T. b. gambiense early and late
stages; not effective for the treatment of T.b.
rhodesiense infections
Trypanosoma cruzi
Nifurtimox
Benznidazole
Team 8
Trypanosoma cruzi (current drug of choice)
inhibits trypanosomal enzymes
Organic arsenical compound, MOA unclear –
inhibits many enzymes
inhibiting
the
enzyme
ornithine
decarboxylase, which is involved in polyamine
synthesis in trypanosomes
A synthetic nitrofuran; may act by increasing
oxidative stress through production of free
radicals, good GI absorption
Same as nitroimidazole – acts as a DNA binder
Heavy proteinuria, stomal ulceration,
exfoliative dermatitis, severe diarrhoea,
prolonged high fever and prostration.
Reactive encephalopathy characterized by
headache, tremor, slurring of speech,
convulsions and ultimately coma
diarrhea, anaemia, leukopenia,
thrombocytopenia convulsions, impaired
hearing
Hemolytic anemia, Multiple CNS effects, Renal
Failure
Carcinogenesis, bone marrow depression
Page 13 of 13