Drugs used in treatment of worm
and protozoal infestations
James E Masanyiwa
(MSc. Clinical Pharmacology)
12/26/2023
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OBJECTIVES
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CLASSIFICATION OF ANTIPROTOZOAL DRUGS
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Treatment of
dysentery, amebiasis and
Schistosomiasis
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Treatment of dysentery and
amebiasis
Objectives
• To understand different causes of dysentery.
• To describe different classes of drugs used in treatment of
both bacillary dysentery and amebic dysentery.
• To be able to describe actions, side effects of drugs for
treating bacillary and amebic dysentery.
• To understand the pharmacokinetics, actions, clinical
applications and side effects of antiamebic drugs.
• To be able to differentiate between three types of
antiamebic drugs; luminal amebicides, tissue amebicide and
mixed amebicides.
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Dysentery
Dysentery: is an inflammatory disorder of the
intestine, that results in severe diarrhea
containing mucus and/or blood in the feces with
fever and abdominal pain.
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Causes of Dysentery
The two most common causes are:
– Amebic dysentery (protozoal infection mainly by
Entamoeba Histolytica).
– Bacillary dysentery (bacterial infection mainly
by shigella).
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Treatment of Dysentery
– Maintain fluid intake using oral rehydration
therapy or Intravenous fluid therapy.
– Antimicrobial agents should not be given until
stool analysis is done.
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Amebiasis
Amebiasis is a protozoal infection of the
intestinal tract that occurs due to ingestion of
foods or water contaminated with cysts of
Entamoeba Histolytica.
The patients show varying degree of illness
from no symptoms to mild diarrhea to severe
dysentery.
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Clinical Findings
Roughly 90% of those infected have asymptomatic infections,
but they may be carriers, whose feces contain cysts that can
be transmitted to others
Acute intestinal amebiasis presents as dysentery (i.e., bloody,
mucus-containing diarrhea) accompanied by lower abdominal
discomfort, flatulence, and tenesmus.
Amebic abscess of the liver is characterized by right upperquadrant pain, weight loss, fever, and a tender, enlarged liver.
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Life Cycle
1. Cysts ingestion in contaminated food or
water.
2. Liberation of trophozoites in the colon.
3. Invasion & penetration of intestinal wall.
4. Multiplication of trophozoites within colon
wall.
5. Systemic invasion to liver.
6. Cyst formation in rectum and excretion in
feces.
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LIFE CYCLE
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ANTIAMEBIC DRUGS
▪ Luminal Amebicides
▪ Tissue or systemic amebicides (not
commonly used)
▪ Mixed Amebicides
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Luminal amebicides
• Acts on the parasites in the lumen of the
bowel.
• Used for treatment of asymptomatic amebiasis
(carriers).
Include
• Diloxanide furoate
• Iodoquinol
• Antibiotics
- Paromomycin
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Tissue or systemic amebicides
• Acts on amoeba in 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).
Include
• Emetine
• Dehydroemetine
• Chloroquine (liver only)
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Mixed amoebicides
Effective against both luminal and systemic
forms of the disease. Although luminal
concentration is too low for single drugtreatment.
Include
• Metronidazole
• Tinidazole
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METRONIDAZOLE
• Mixed amoebicide.
• Drug of choice for treating
amebic infections (intestinal &
Extra-intestinal).
• Acts on trophozoites.
• Has no effect on cysts.
• Metronidazole inhibits DNA replication.
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Mechanism of action
• Metronidazole undergoes a reductive bioactivation
of its nitro group by ferredoxin (present in anaerobes
and parasites) to form reactive cytotoxic products.
• It disrupt DNA of microbial cells and hence inhibits
DNA synthesis
• The mechanism of Tinidazole is assumed to be
similar.
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Mechanism of action
5-nitroimidazole
Ferrodoxine oxidoreductase enzyme
Free radical
Electron transfer
Multiple DNA breaks
No replication
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No transcription
No repair
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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 half life is 8 h
• Metabolized in liver by mixed function oxidase
followed by glucuronidation (consider drug
interactions).
• Excreted in urine.
• Clearance is decreased in liver impairment
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Clinical Uses
• Extra-luminal amoebiasis: is the drug of
choice in all tissue amebiasis (should be
combined with luminal amebicide).
• Giardiasis (cause by G. lamblia & common
in children)
• Trichomoniasis
• Broad spectrum of anaerobic bacteria e.g.,
– Helicobacter pylori infection
– Pseudo-membranous colitis (Clostridium
difficile).
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Adverse effects
GIT:
• Dry mouth, metallic taste
• Nausea, vomiting
• Oral Thrush (Moniliasis, yeast infection).
CNS: Neurotoxicological effect
• Insomnia, dizziness
• peripheral neuropathy, paresthesia
• encephalopathy, convulsion (IV infusion, rare).
Dysuria, dark urine.
Neutropenia
Disulfiram-like effect if taken with alcohol.
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Disulfiram like -effect
When metronidazole is given with alcohol abdominal
distress, nausea, vomiting, flushing, or headache,
tachycardia, hyperventilation
alcohol
dehydrogenase
Ethanol
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Metronidazole inhibits these
enzymes
aldehyde
dehydrogenase
Acetaldehyde
Acetate
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Drug interactions:
• Enzyme inhibitors (cimetidine, ketoconazole)
increase duration of action of metronidazole
• Inducers (phenytoin and phenobarbitone).
decrease duration of action of metronidazole
• Metronidazole inhibits CYP family 2C9 &
3A4 so
– increases anticoagulant effect of warfarin.
– Increases lithium toxicity.
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CONTRAINDICATIONS / PRECAUTIONS:
▪ Pregnancy and nursing women.
▪ Alcohol intake
▪ CNS diseases
▪ Severe hepatic disease
• Severe renal disease
• Dose: 500mg PO q8hrs for 5-10days
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Tinidazole
Tinidazole has similar activity but better
potency than metronidazole, With longer
duration of action (12-14h), a simpler dosing
regimen and a better toxicity profile than
metronidazole.
- Well tolerated in Children.
- Dose:2g/day PO for 3-5days
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Tissue or systemic amebicides
Emetine and dehydroemetine

Emetine is an alkaloid derived from ipeca
while dehydroemetine is a synthetic analog,
 Both are effective against tissue trophozoites of
E. histolytica.
 Because of major toxicity concerns they have
been almost completely replaced by
metronidazole
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Mechanism of action
• Emetine and dehydroemetine inhibit protein
synthesis by blocking chain elongation.
• Causing irreversible block of protein
synthesis.
• Protein synthesis is inhibited in parasite and
mammalian cells, but not in bacteria
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Emetine and Dehydroemetine
• These drugs are used parenterally
(subcutaneously or intramuscularly) as backup
drugs for treatment of severe intestinal or
hepatic amebiasis together with a luminal agent
in hospitalized patients.
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• The drugs may cause severe toxicity, including
gastrointestinal distress, muscle weakness,
and cardiovascular dysfunction (arrhythmias
and congestive heart failure).
• The drugs are restricted to use in severe
amebiasis when metronidazole cannot be
used.
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Clinical Uses
• Amoebic liver abscess.
• Intestinal wall infections.
• Severe forms of amebiasis acute amoebic
dysentery
• Dehydroemetine is preferable due to less
toxicity (3-5 days).
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Chloroquine
• Anti-malarial drug
• Used in combination with metronidazole or
dehydroemetine and luminal amebicide for
amebic liver diseases.
Now not commonly used in amebiasis.
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Luminal amoebicides
Include
• Diloxanide furoate
• Iodoquinol
Antibiotics
- Paromomycin
-Tetracyclines
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Diloxanide furoate
• Given orally.
• It splits in the intestine, most of diloxanide is
absorbed, conjugated to form a glucoronide
which is excreted in urine (90%).
• The unabsorbed diloxanide is the amoebicidal
agent (10%).
• Direct amoebicidal action against luminal
forms
• Not active against trophozoites in intestinal wall
or extra-intestinal tissues.
• Mechanism of action is unknown
• Dose: 500mg q8hr for 10 days
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Diloxanide furoate
• Diloxanide is a luminal amebicide, however
the mechanism of action of diloxanide is
unknown.
• Diloxanide destroys the trophozoites of E.
histolytica that eventually form into cysts.
• The cysts are then excreted by persons
infected with asymptomatic amebiasis.
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Therapeutic Uses
• Drug of choice for asymptomatic intestinal
infection (drug of choice in cysts passers).
• For complete eradication of amebic infections
given along with tissue amebicides eg
metronidazole.
Adverse Effects
• Flatulence
• Nausea, vomiting, abdominal cramps.
• No serious adverse effects
Contraindications:
- Pregnancy
- Children (less than 2 years).
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Iodoquinol
•
•
•
•
A halogenated 8-hydroxyquinolone
Is given orally
Not absorbed (90%), excreted in feces.
10% enter circulation, excreted as glucuronide
in urine.
• Mechanism of action is unknown
• Effective against the luminal trophozoites.
Uses
• luminal amoebicide for
asymptomatic amebiasis.
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Mechanism of action of Iodoquinol
• The exact mechanism of action of Iodoquinol is
unknown
• Iodoquinol acts against the trophozoites of Entamoeba
histolytica
• Iodoquinol produces its amebicidal effect at the site of
infection, since it is poorly absorbed from the
gastrointestinal tract and can reach high concentrations
in the intestinal lumen.
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Adverse Effects
• GIT: Nausea, vomiting, diarrhea.
• Peripheral neuropathy including optic neuritis
• Enlargement of the thyroid gland.
• Iodine sensitivity
• Interference with thyroid function tests
(increase protein-bound serum iodine,
decrease in measured (131I uptake).
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• Iodoquinol should be used with caution in
patients with optic neuropathy, renal or
thyroid disease.
• Discontinued if it produces persistent
diarrhea or signs of iodine toxicity
(dermatitis, urticaria, pruritus, fever).
• DOSE: 650mg PO q8hr for 20 days not to
exceed 2g/day
• Long-term use of drug should be avoided
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Paromomycin Sulphate
•
•
•
•
Aminoglycoside antibiotic.
It is given orally and Not absorbed from GIT
Effective against luminal forms of ameba
Has direct amebicidal action (causes leakage by its
action on cell membrane of parasite).
• Paromomycin inhibits protein synthesis by binding to
16S ribosomal RNA
• Indirect killing of bacterial flora essential for
proliferation of pathogenic amoebae.
• Use in chronic amebiasis to eliminate cysts (in cysts
passers (Diloxanide and Iodoquinol are best for this
purpose)
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Paromomycin Sulphate
Adverse effects
• Gastrointestinal distress and diarrhea.
Precautions
• Severe renal disease
• Patients with GIT ulceration
• Safe in pregnancy
• Dose: 25-35mg/kg/day PO divided q6hr for 510 days
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Tetracyclines
• Very weak direct amoebicidal action.
• Acts mainly indirectly on bacterial flora.
• Used in severe cases of amoebic dysentery not
responding to metronidazole combined with
dehydroemetine.
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Bacillary dysentery
Treated by:
• Fluoroquinolones such as ciprofloxacin
• Cotrimoxazole (trimethoprim- sulfamethoxazole)
• Children or patient allergic to sulpha drugs
parenetral ceftriaxone or oral cefixime (3rd
gen cephalosporin) are safe and effective.
• Cotrimoxazole is commonly used in travelers
diarrhea.
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Ciprofloxacin
• Active against a variety of gram-positive and gramnegative bacteria.
• Block bacterial DNA synthesis.
• Used in treatment of
1. Bacterial diarrhoea (caused by shigella, salmonella,
and E coli).
2. Urinary tract infections
3. contraindicated in pregnancy and children under
age 18
TOXICITY: GIT, CNS and Tendon related (ciprofloxacin)
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SUMMARY
• Maintain fluid intake (oral rehydration therapy or
Intravenous fluid therapy).
• asymptomatic luminal amebiasis is treated by
luminal amebicides (diloxanide furoate, or
paromomycin ).
• Intestinal and extra-intestinal amebiasis is treated
by tissue amebicides (metronidazole is drug of
choice usually being given first, followed by luminal
amebicides to ensure complete eradication).
• Ciprofloxacin is the drug of choice in bacillary
dysentery. In children and pregnancy ceftriaxone
or cefixime is the choice.
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PREVENTION
Public education about personal hygiene, especially the sanitary disposal of
feces
Education of food handlers about proper food and equipment handling and
hygiene
Advice infected individuals to avoid food preparation
Educate about risk of sexual practices that permit fecal-oral contact.
Test private water supplies for the presence of parasitic contamination
Advice infected individuals against using public swimming pools.
Contaminated water can be a source of transmission of enteric pathogens.
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Tissue Amoebicides
• Metronidazole: 500 mg IV q8 hourly. For 7–10 days for
extraintestinal amoebiasis. 400 mg thrice daily orally for 7–10 days
(40–60 mg/kg body weight in children)
• Tinidazole: 2 g as single dose for 2–3 days. 300 mg twice daily
orally for 7 days (50–60 mg/kg body weight in children)
• Ornidazole: 1.5 g once daily for 3 days. 500 mg twice daily orally
for 7–10 days (40 mg/kg body weight in children)
• Secnidazole: 2 g as single dose
• Nitazoxanide: 500 mg twice daily for 3 days (age > 12 years), 200
mg twice daily for 3 days (4–11 years) or 100 mg. Twice daily (1–3
years)
• Chloroquine: 300 mg twice daily followed by 300 mg daily for 21
days
as an adjunct to metronidazole
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Luminal Amoebicides
-These are recommended to prevent relapses following the
course of tissue amoebicides:
• Diloxanide furoate: 500 mg thrice daily for 10 days (20 mg/kg
body weight in children)
• Quinodocholor: 500 mg twice daily for 10 days
• Iodochlorhydroxyquin: 500 mg twice daily for 10 days
• Paromomycin: 30 mg/kg body weight thrice daily for 7 days (25
mg/kg body weight in children).
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Anti-schistosomiasis drugs
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Anti-schistosomiasis drugs
•Schistosomiasis is caused by Schistosoma infection.
•There are five kinds of Schistosoma caused
Schistosomiasis of human: S. japonia, S. heamatobium,
S. mansoni, S. intercalatum and S. mekongi.
•In our country, the schistosomiasis is caused mainly by
S. haematobium.
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Anti-schistosomiasis drugs
praziquantel
Praziquantel
Anti-parasite effects:
It is a highly effective and broad spectrum
anti-parasite drug.
It can kill schistosoma directly; and it can
kill other trematode too, e.g. clonorchis
sinensis,lung fluke, fasciolopsis; certain
intestinal parasites(e.g. tapeworm.
Mechanism of anti-schistosoma effects:
It can increase the membrane permeability
to certain monovalent
and divalent cation,
2+
particularly Ca , to cause schistosoma muscular
contraction and spastic paralysis.
Praziquantel works by causing severe spasms and
paralysis of the worms' muscles. This paralysis is 2+
accompanied - and probably caused - by a rapid Ca influx
inside the schistosome.
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Anti-schistosomiasis drugs
praziquantel
Clinical uses:
①Schistosomiasis
It is effective to both acute & chronic schistosomiasis.
To acute schistosomiasis:
It is to bring down the fever, and alleviate the systematic
symptoms fast, the late results reach 90%;
To chronic schistosomiasis:
The curative effect is well too, only 1～2 days of course of
treatment, the late results reach 90% too.
To the later period patients with cardiac and hepatic complication:
can accept the course of treatment smoothly.
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Anti-schistosomiasis drugs
praziquantel
Adverse reaction
After oral administration, it can cause
abdominal pain, nausea, dizziness, and
headache in short-term.
DOSE: Schistosomiasis 20mg/kg and
Clonorchiasis 75mg/kg PO TID for 1 day
(at intervals 4-6 hr)
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GIARDIASIS
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General consideration
Giardia Lamblia is a flagellate protozoon which infects
children and adults by oral-faecal contamination and
mostly lives as a commensal in the intestine.
Clinical presentation:
It sometimes invades the mucosal and causes acute
watery short duration diarrhea with foul smelling
stools, gas and abdominal cramps.
If untreated, it may pass on to chronic diarrhea with
greasy or frothy stools but no blood or mucus.
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Treatment
 Quinacrine/ mepacrine is the drug of choice
It is used in the treatment of giardiasis (as an alternative to the
nitroimidazoles)
Its mechanism against protozoa is uncertain though thought to act against
protozoan’s cell membrane
Oral administration and rapidly absorbed from gastrointestinal tract
 Half life is 5-14 days
 It crosses the placenta
 Eliminated mainly via urine
But metronidazole and furazolidone (a nitrofuran antibacterial agent and
monoamine oxidase inhibitor) are suitable alternatives
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Furazolidone
• Is a nitrofuran antibacterial agent and monoamine
oxidase inhibitor
• Furazolidone is used to treat bacterial and protozoal
infections.
• It works by killing bacteria and protozoa, it is believed to
work by crosslinking of DNA thereby interfering with
DNA replication and protein production.
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Furazolidone
• Orally administered
• Side effects; gastrointestinal disturbance, tremors,
convulsion
• Drug interaction: SSRI antidepressants eg fluoxetine,
sedative drugs, antidepressant eg amitriptyline
• Eliminated mainly via urine
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TOXOPLASMOSIS
• Toxoplasma belong to the group of pathogenic Sporozoa.
• The cat is the definitive host of Toxoplasma gondii (only
host in which the sexual cycle can occur and expels the
infectious cysts in its faeces)
• Humans can become intermediate hosts for reserving the
serasexual form of the parasite.
• Ingested oocysts develop into sporozoites, then to
trophozoites and finally cyst goes in the tissues.
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Life cycle of Toxoplasma gondii
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 In most individuals it is asymptomatic or selflimiting, although intrauterine infections can
severely damage the developing fetus and it
may cause fatal generalized infection
• In immunosuppressed patients or those with
AIDS, toxoplasmic encephalitis may occur
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• In humans T. gondii infects numerous cell types and
has a highly virulent replicative stage.
• The treatment of choice is pyrimethamine–
sulfadiazine, trimethoprim-sulfamethoxazole (cotrimoxazole)
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MOA
+
Dihydropteridine
Dihydropteroic acid Synthetase
Static
PABA
Sulfonamides (PABA analogues)
Sulfomethoxazole (Bacterial)
Sulfadiazine (Bacterial)
Sulfodoxine (Malarial)
Dihydropteroic acid
Glutamate
+
Cotrimoxazole
Dihydrofolate Reductase
Folic
Acid
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Cidal
Dihydrofolic Acid
Dihydrofolate
Reductase
(Mammalian)
Cotrimazine
Trimethoprim (Bacterial) /
Pyrimethamine (Malarial)
Static
Tetrahydrofolic Acid
RNA
DNA
Proteins
Nucleic Bases
Amino Acids
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LEISHMANIASIS
Is the parasitic disease caused by leishmania
parasite.
These parasites live in infected sandflies
Transmission is from a bite from an infected sandfly
There are three forms of disease.
1. Cutaneous leishmaniasis affects the skin and is usually not
serious
2. Visceral leishmaniasis also known as kalazar (This type of
leishmaniasis affects the internal organs, usually the spleen, liver
and bone marrow)
3. Mucocutaneous leishmaniasis can lead to partial or complete
destruction of mucous membrane found in the nose, throat and
mouth.
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General Consideration
• Leishmaniasis is transmitted by the bite of the female
sandfly phlebotomus.
• In the fly the parasite exists in the flagellate
extracellular(promastigote) form, while in man it is
found only intracellurarly within macrophages in the
non flagellate (amastigote) form.
• Mucocutaneous and dermal leishmaniasis are caused
respectively by L. braziliensis and L. tropica (also
other species).
• Visceral leishmaniasis(VL) is fatal unless treated.
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Treatment
The currently used drugs for treatment of VL
are.
– Sodium stibogluconate (SSG)
– Amphotericin B (AMB)
– Miltefosine
– Paromomycin
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PK and PD
Stibogluconate Sodium (Pentostam)
Effective against all leishmania: therapy is 10 or 30 days course and my need
repeated
 The mechanism of action and the basis of selective toxicity to
the leishmania amastigote is unclear.
 However, it is thought to stem from the inhibition of
macromolecular synthesis via a reduction in available ATP
and GTP, likely secondary to inhibition of the citric acid cycle
and glycolysis
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PK and PD..
• Administered parentally, IM well absorbed
• Cleared unchanged by the kidney
• Half life of elimination is 6-12 hours
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Adverse effects
• Include GI (Anorexia, nausea, vomiting,
abdominal pain, diarrhoea), pain and stiffness
of injected muscle and electrocardiographic
disturbances
• Contraindicated in patients with
cardiovascular, liver or renal diseases
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Amphotericin B (AMB)
 This antifungal antibiotic is available in two types of
preparations
 The older and less expensive one is formulated with
deoxycholate ( AMB-DOC), while in the newer one it is
incorporated in liposomes(L-AMB) and is very expensive
 Like fungi, Leishmania has high percentage of ergosterol and
is susceptible to this antibiotic which has high affinity for
ergosterol and acts by binding to it
 AMB is the drug with highest cure rate in Kala-azar: up to
99% clinical and parasitological cure
 It is the drug of choice in pregnancy women and breast
feeding mothers
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• It is the drug of choice in pregnant women and breast
feeding mothers.
• It is the 2nd line treatment of VL under NVBDCP
(Directorate of National Vector Borne Disease Control
Programme (NVBDCP), though the WHO
recommendations accord it higher preference over
Miltefosine.
• It is also useful in mucocutaneous leishmaniasis
• Some activity against L. braziliensis and L. Mexicana.
• Also used when antimonials are ineffective or
contraindicated.
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Miltefosine
• It is derivative of alkyl phosphocholine with potent antileishmania activity was approved only in 2002 as the first
orally active drug for kala-azar
• The mechanism of anti-leishmania action of miltefosine
is not known.
• However studies suggest that, the mechanism of action
of miltefosine is likely to involve interaction with lipids
(phospholipids and sterols), including membrane lipidsinhibits lipids metabolism, inhibition of cytochrome c
oxidase (mitochondrial function), and apoptosis-like cell
death
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Cont…
• Leishmania can develop resistance to
miltefosine and this may be due to mutation
limitation limiting transport of the drug into
the parasite cell.
• To prevent development of resistance to this
useful drug, combination therapy with
paromomycin or AMB is being promoted.
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• Rapidly absorbed after oral medication and
widely distributed in the body.
• Side effects such as anorexia, vomiting and
diarrhoea are common.
• It is contraindicated to pregnant women, if
used ensure do not get pregnant during and
till 3 months after miltefosine course.
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Paromomycin
• The WHO recommends 21 day paromomycin
treatment as an alternative to miltefosine
• Though it produces ototoxicity in 2% recipients
reversible elevation of serum transaminase and
injection site pain, but renal toxicity is rare
• It has proven to be an effective, less expensive and
easier to use alternative to AMB in kala-azar.
• Topical paromomycin is effective in dermal
leishmaniasis.
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Combination therapy
Like in the case of TB, leprosy, HIV and malaria,
combination therapy with 2 effective drugs has several
advantages in the treatment of VL. These are:
• Limiting risk of development of drug resistance ,
thereby prolonging the effective life-time of available
medicines.
• Attaining higher efficacy and cure rate.
• Shortening of duration of therapeutic regimen;
better compliance and convenience.
• Reduction of overall dose; lower toxicity and cost.
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Cont..
• Each of these combinations yielded 98-99% cure
rate.
• As such, these combinations are recommended
with high preference by WHO.
• However, cost of L-AMB (even single dose) is high
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HIV and leishmania co-infection
• A. L-AMB (5mg/kg iv single dose) + Miltefosine
(oral) daily x 7 days
• B. L-AMB (5mg/kg iv single dose) +
Paromomycin (i.m) daily x 10 days
• C. Miltefosine (oral) daily x 10 days +
Paromomycin (i.m) daily x 10 days
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Drugs used locally for dermal
leishmaniasis (oriental sore)
Dermal leishmaniasis is not a life-threatening condition; many
cases are treated by local application of drugs.
1. Sodium stibogluconate: infiltrate 2ml of the solution (100mg
antimony/ml) round the sore.
2. Paromomycin (15%) ointment: applied topically on the sore,
twice daily for 20 days. Small and mild lesion may heal by
itself in a few months. Multiple sores and severe cases should
be treated by systemic drugs as for kala-azar. Antibiotics may
be needed for secondary infection of the sore.
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TRYPANOSOMIASIS
• Trypanosomes belong to the group of pathogenic
flagellate protozoa, the three main species that cause
disease in humans are
– Trypanosoma gambiense
– Trypanosoma rhodesiense
– Trypanosoma cruz cause chagas disease
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• The vector is the tsetse fly. In both types of disease, there
is an initial local lesion at the site of entry, which develop
into a painful chancre (ulcer or sore).
• This is followed by bouts of parasitaemia and fever as
the parasite enters the haemolymphatic system
• Second phase of the disease cause organ damage. This
manifests as ‘sleeping sickness’ when parasites reach the
CNS causing neurological breakdown
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Treatment
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Pentamidine (Pentam)
• Administered IM
• Adverse effects include pain and allergic
reaction at injection site; high incidence of
renal toxicity (24%), liver abnormalities,
hypotension, and hypoglycemia.
• Used for L. donovani when antimonials have
failed or are contraindicated
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MOA
• The mechanism seems to vary with different organisms and is not well
understood. However, pentamidine is suspected to work through various
methods of interference of critical functions in DNA, RNA, phospholipid and
protein synthesis.
• Pentamidine binds to adenine-thymine-rich regions of the Trypanosoma
parasite DNA, forming a cross-link between two adenines four to five base
pairs apart.
• The drug also inhibits topoisomerase enzymes in the mitochondria
of Pneumocystis jirovecii. Similarly, pentamidine inhibits type II
topoisomerase in the mitochondria of the Trypanosoma parasite, resulting in a
broken and unreadable mitochondrial genome
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Suramin
• Complex dye structure
• The main drugs used for African sleeping sickness are
suramin with pentamidine as an alternative, in the
haemolymphatic stage of the disease
• The mechanism of action for suramin is unclear, however, it
is thought that parasites are able to selectively uptake
suramin via receptor-mediated endocytosis of drug that is
bound to low-density lipoproteins and to a lesser extent,
other serum proteins.
– Once inside parasites, suramin combines with proteins,
especially trypanosomal glycolytic enzymes to inhibit energy
metabolism
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Suramin
• Administered by Iv infusion; persists in circulation for days.
• Does not penetrate CSF, therefore it is the treatment of
choice for sleeping sickness without central nervous
system involvement
• Not metabolized.
• Adverse effects can be severe and include nausea, vomiting
and shock, also may cause renal dysfunction.
• Useful for African trypanosomiasis i.e. Sleeping sickness (T.
gambiense, T. rhodesiense) in the hemolytic stage; not
effective against T. cruzi)
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Melarsoprol
• Melarsoprol is a medication used for the treatment of
sleeping sickness (African trypanosomiasis).
• It is specifically used for second-stage disease caused by
Trypanosoma brucei rhodesiense when the central nervous
system is involved.
• Melarsoprol is a prodrug, which is metabolized to melarsen
oxide (Mel Ox) as its active form.
• Mel Ox is an phenylarsonous acid derivative that irreversibly
binds to sulfhydryl groups on pyruvate kinase, which disrupts
energy production in the parasite
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Melarsoprol
• Administered by i.v infusion; penetrates CSF
• Side effects include hypertension abdominal pain,
and rashes. Potentially fatal side effect is reactive
encephalopathy (1-5%)
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Nifurtimox
• Nifurtimox is the drug of choice in American trypanosomiasis,
an alternative agent in African forms of the disease, and has
also been effective in mucocutaneous leishmaniasis.
• The drug causes significant toxicity, including allergies,
gastrointestinal irritation, and CNS effects.
• Contraindicated: severe liver or kidney disease or background
of neural disorder
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MOA
• Nifurtimox forms a nitro-anion radical metabolite that reacts
with nucleic acids of the parasite causing significant breakdown
of DNA.
• Its mechanism is similar to that proposed for the antibacterial
action of metronidazole.
• Nifurtimox undergoes reduction and creates oxygen radicals such
as superoxide.
• These radicals are toxic to T. cruzi. Mammalian cells are protected
by presence of catalase, glutathione, peroxidases,
and superoxide dismutase.
• Accumulation of hydrogen peroxide to cytotoxic levels results in
parasite death
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Benznidazole
•
•
•
•
•
It is the first-line treatment of chagas disease of T.cruz
Highly effective in early disease
It is taken orally with bioavailability of 92%
Elimination mainly through metabolism by liver.
The metabolites of benznidazole appear to be primarily
excreted in the urine
• Minimal side effect compared to Nifurtimox
• Adverse effect rash, fever, muscle pain, loss of appetite,
trouble sleeping
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MOA
• Benznidazole is thought to be reduced to various electrophilic
metabolites by nitroreductases present in Trypanosoma cruzi
• These metabolites likely bind to proteins, lipids, DNA, and
RNA resulting in damage to these macromolecules
• Benznidazole has been found to increase trypanosomal death
through interferon-γ which is likely present in increased
amounts due to inflammation caused by macromolecule
damage
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DRUGS FOR PNEUMOCYSTOSIS
Trimethoprim / Sulfamethoxazole
Clinical use
• TMP-SMZ is the first choice in prophylaxis and
treatment of pneumocystis pneumonia (PCP).
• Prophylaxis in AIDS patients is recommended
when the CD4 count drops below 200 cells/μL.
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• Oral treatment with the double-strength
formulation 3 times weekly is usually
effective.
• The same regimen of TMP-SMZ is prophylactic
against toxoplasmosis and infections caused
by Isospora belli.
• For treatment of active PCP, daily oral or
intravenous administration of TMP-SMZ is
required.
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Toxicity
• Adverse effects from TMP-SMZ occur in up to
50% of AIDS patients.
• Toxicity includes gastrointestinal distress, rash,
fever, neutropenia, and thrombocytopenia.
• These effects may be serious enough to
warrant discontinuance of TMP-SMZ and
substitution of alternative drugs.
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REFERENCES
 Rang and dale’s, pharmacology, 8th Edition
 Lippincotts illustrated reviews of pharmacology.
 Essentials of Medical Pharmacology, Eighth Edition
KD TRIPATHI MD Ex-Director-Professor and Head of
Pharmacology Maulana Azad Medical College and
associated LN and GB Pant HospitalsNew Delhi, India.
 Katzung Trevor 21st Ed
 WHO guideline-Antiprotozoa
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