ANTI-PROTOZOAL DRUGS
PHARMACOLOGY
DR CHANG’ P. – PHARMACOLOGY I
ANTIAMOEBIC DRUGS
PROTOZOAL INFECTIONS:
Amebiasis – Entamoeba hystolytica
Malaria – Plasmodium falciparum, P. vivax, P.
ovale, P. malariae
Giardiasis – Giardia lamblia
Leshmaniasis – Leishmania donovani
Toxoplasmosis – Toxoplasma gondii
Trypanosomiasis – Trypanasoma brucei, T. cruzi
GENERAL FEATURES ABOUT PROTOZOAL
INFECTIONS:
Protozoal cells (eukaryotes) have metabolic
processes closer to the human host than
prokaryotic bacterial pathogens.
They are more difficult to treat than bacterial
infections.
Many antiprotozoal drugs cause toxic effects on
the host.
Cells with high metabolic processes in the host
ANTIPROTOZOAL DRUGS:
Chemotherapy of amebiasis
Chemotherapy of malaria
Chemotherapy of giardiasis
Chemotherapy of leshmaniasis
Chemotherapy of toxoplasmosis
Chemotherapy of trypanosomiasis
AMEBIASIS
It occurs due to ingestion of food contaminated
with Entameba histolytica cysts.
Life cycle of E. histolytica:
It exists in two forms
1. Cysts (Infective)
They can survive outside the human body.
They are incapable of reproduction.
They can transform to trophozoites.
2. Trophozoites (non-infective, invasive)
They are capable of reproduction
They invade the wall of the large
intestine causing ulceration, and they
may migrate to other tissues –especially
the liver.
They transform to cysts which are
Life Cycle of E.histolytica
Ingestion of cysts
Formation of trophozoites
Penetration of intestinal wall
Multiplication of trophozoites within the intestinal
wall
Systemic invasion
Cyst formation in the rectum and excretion in feces
Clinical Presentation of Amebiasis:
Asymptomatic intestinal infection (carriers; passing
cysts)
Mild to moderate intestinal disease (non-dysenteric
colitis)
Severe intestinal infection (dysentery)
Hepatic abscess
Ameboma (localized granulomatous lesion of the colon)
Extraintestinal disease (other than hepatic abscess)
ANTIAMOEBIC DRUGS:
1. Luminal amebicides
2. Tissue or systemic amebicides
3. Mixed amebicides
Luminal Amebicides
Diloxanide Furoate
Halogenated Hydroxyquinolines: Iodoquinol and
Clioquinol
Antibiotics: Tetracyclines, Paromycin and
Erythromycin
They act on the parasites in the lumen of the
bowel.
They are used for the treatment of asymptomatic
amebiasis.
DILOXANIDE FUROATE:
Chemistry: It’s a dichloroacetamide.
Ester of diloxanide and furoic acid
Pharmacokinetics:
It’s given orally.
It’s split in the intestine, and most of diloxanide is
absorbed which then becomes conjugated to form
a glucouronide that is excreted in urine.
The unabsorbed moiety is the amebicidal agent
(10%).
Pharmacodynamics:
It has an unknown mechanism of action.
It has a direct amebicidal action against luminal forms.
It’s NOT active against tissue trophozoites.
Therapeutic Uses:
It’s the drug of choice for asymptomatic intestinal
infections.
It’s used for the eradication of infection given along with
tissue amebicide (metronidazole).
It’s given in a dose of 500 mg three times daily for 10
days.
Adverse Effects:
Flatulence
Nausea, vomiting, and abdominal cramps
No serious adverse effects
Contraindications:
Pregnancy and children less than 2 years
PAROMYCIN SULPHATE:
It’s an aminoglycoside.
It is not absorbed and is effective against luminal
forms
Mechanism of Action:
Direct amebicidal action (causes leakage by its action
on the cell membrane of the parasite)
Indirect killing of bacterial flora which is essential for
the proliferation of pathogenic ameba.
Pharmacokinetics:
It’s taken orally.
It’s not significantly absorbed from the GIT.
A small amount is absorbed and excreted unchanged
in urine (it may accumulate in cases of renal
insufficiency).
Adverse Effects: - Gastrointestinal distress and diarrhea
Precautions:
Severe kidney disease and in patients with GI
ulcerations
TETRACYCLINES:
They have very weak direct amebicidal actions.
They mainly act indirectly on bacterial flora.
They are used in severe cases of amebic dysentery
which don’t respond to metronidazole combined with
dehydroemetine.
Iodoquinol - Clioquinol
Pharmacokinetics:
Absorption is poor (90%); they are excreted in feces.
10% enters the circulation, and they are excreted as
glucouronides in urine.
They have a half-life of 11-14 hours.
Mechanism of Action:
Unknown
They are effective against organisms in the GIT only
not intestinal walls or liver.
Uses:
Luminal amebiasis
Eradication of infection given along with tissue
amebicide (metronidazole)
Adverse Effects:
Peripheral neuropathy including optic neuritis
Nausea, vomiting, diarrhea
Enlargement of the thyroid gland
Agranulocytosis
Iodine sensitivity
They interfere with thyroid function tests
Contraindications:
Optic neuropathy
Thyroid disease and sensitivity to iodine
Severe liver disease
Severe kidney disease
They should be discontinued if it produces
persistent diarrhea or signs of iodine toxicity
(dermatitis, urticaria, pruritus, fever)
Tissue or Systemic Amebicides(Emetine,
Dehydroemetine & Chloroquine (liver only)
Act principally in the intestinal wall, liver, or any
other extra-intestinal tissue.
Treatment of systemic forms of the disease, such
as liver abscesses or intestinal wall infections.
EMETINE & DEHYDROEMETINE:
Chemistry:
Emetine hydrochloride is an alkaloid plant
derived from ipecac.
Dehydroemetine is a synthetic analogue.
Pharmacokinetics:
Erratic oral absorption
They’re preferably given subcutaneously, but it
could be given intramuscularly.
THEY SHOULD NEVER EVER BE GIVEN
INTRAVENOUSLY.
They have a plasma half-life of 5 days.
Emetine is concentrated in the liver, lungs, spleen,
kidneys, cardiac muscles, and intestinal walls.
Emetine is metabolized and excreted slowly
via the kidneys; it has a cumulative effect.
Trace amounts could be detected in urine 1-2
months after the last dose.
Emetine should not be used for more than 10
days (usually 3-5 days).
Pharmacological Actions:
Emetine acts on trophozoites causing
irreversible block of protein synthesis.
It depresses cardiac conduction and contraction;
therefore, arrhythmias, heart failure, and death
can occur
Antiadrenergic action may lead to hypotension.
Nausea and vomiting of central origin.
Decrease in serum potassium.
Clinical Uses:
Amebic liver abscess
Intestinal wall infections
Severe forms of acute amebic dysentery
(dehydroemetine and tetracyclines for a short
period followed by metronidazole)
Adverse Effects:
Dehydroemetine is less toxic than emetine.
Pain at the site of injection, abscesses
Nausea, vomiting, and diarrhea
Neuromuscular weakness
Serious toxicities (Cardiotoxicity) manifesting as:
Arrhythmias; Hypotension
Congestive heart failure
Contraindications:
Heart disease; Renal disease; Pregnancy; Children
CHLOROQUINE:
It’s an antiamoebic drug.
It’s an antimalarial drug.
It’s used in combination with metronidazole and
diloxanide furoate for amebic liver diseases.
Mixed Amebicides (Metronidazole – Tinidazole)
They are effective against both luminal and
systemic forms of the disease although luminal
concentration is too low for single-drug treatment.
METRONIDAZOLE:
It’s a mixed amebicide.
It’s the drug of choice for intestinal and extra-
intestinal amebiasis.
It acts on trophozoites.
It has NO effect on cysts.
The nitro group of metronidazole is reduced by
protozoa leading to cytotoxic-reduced product
that binds to DNA and proteins resulting in the
death of parasites.
Pharmacokinetics:
It’s given orally or intravenously.
Its absorption is rapid and complete.
Due to its rapid absorption from the GIT, it’s
less effective against parasites in the lumen.
It has a wide distribution to all tissues and body
fluids (CSF, saliva, and milk).
Plasma protein binding is low (>20%).
It has a plasma half-life of 8 hours.
It’s metabolized by oxidation in the liver by mixed-
function oxidase followed by glucouronylation.
It’s excreted in urine as an unchanged drug plus
metabolites.
Its clearance is decreased in cases of liver
impairment.
Clinical Uses:
Amebiasis (with luminal amebicide)
Giardiasis (Giardia lamblia)
Trichomoniasis (Trichomonas vaginalis)
Anaerobic bacterial infections (boad-spectrum)
Helicobacter pylori infections (H. pylori)
Pseudomembraneous colitis (C. defficile)
Adverse Effects: Tinidazole has a toxicity profile
that is greater than metronidazole, but it’s
equally active.
Gastrointestinal Effects: Nausea; Vomiting; Dry
mouth; Metallic taste; Diarrhea; Oral thrush (yeast
infections)
CNS (Neurotoxicological Effects): Insomnia;
Dizziness; Peripheral neuropathy; Numbness or
paresthesia in the peripheral nervous system
Ataxia, encephalopathy, and convulsions (rare)
Dysuria and dark urine
Neutropenia
Disulfiram-like effect if taken with alcohol
When metronidazole is given with alcohol, abdominal
distress, nausea, vomiting, flushing, headache,
tachycardia, and hyperventilation can occur.
Drug Interactions:
Enzyme inhibitors (cimetidine, ketoconazole)
Enzyme inducers (phenytoin, phenobarbitone, rifampin)
It inhibits the CYP family 2C9 & 3A4.
It potentiates the anticoagulant effect of warfarin.
It potentiates lithium toxicity.
With disulfiram, it can cause a confusional and psychotic
state
Contraindications & Precautions:
Pregnant and nursing ladies
Alcohol intake
CNS disorders
Severe liver disease
Severe kidney disease
Clinical Syndrome Drug
Iodoquinol
Asymptomatic Cyst
Paromycin
Carrier
Diloxanide furoate
Metronidazole +
Diarrhea/Dysentery Iodoquinol
Extraintestinal Paromycin
Diloxanide furoate
