Anti protozoal agents

ANTI-PROTOZOAL
AGENTS
(NON-MALARIAL)
DR. J.N. CHATURVEDI
ASSOC. PROF. (DESIG.), PHARMACOLOGY
S.S. MEDICAL COLLEGE, REWA (M.P.)

INTRODUCTION- IMPORTANT PROTOZOAL
INFECTIONS
Protozoal Infection Causative organism
Amebiasis E. histolytica, E. dispar, and E. moshkovskii
Giardiasis Giardia intestinalis, a flagellated protozoan
Trichomoniasis Trichomonas vaginalis
Toxoplasmosis Toxoplasma gondii
Cryptosporidiosis Cryptosporidium parvum, Cryptosporidium hominis
Trypanosomiasis Trypanosoma brucei (African), Trypanosoma cruzi (American)
Leishmaniasis Leishmania spp.
Babesiosis Babesia microti or B. divergens
Balantidiasis Balantidium coli
Other coccidial infections Cyclospora cayetanensis, Cystoisospora belli, Microsporidia

DRUGS USED FOR IMPORTANT PROTOZOAL
INFECTIONS
Protozoal Infection Drug(s)
Amebiasis • Nitroimidazole group: Metronidazole, Tinidazole etc.
• Luminal amebicides: Paromomycin, iodoquinol, nitazoxanide
Giardiasis • Nitroimidazole group: Metronidazole, Tinidazole etc.
• Nitazoxanide
Trichomoniasis • Nitroimidazole group: Metronidazole, Tinidazole etc.
Toxoplasmosis • Pyrimethamine + sulfadiazine + folinic acid (leucovorin)
• Pyrimethamine-clindamycin
• Azithromycin/ Clarithromycin/ Atovaquone/ Dapsone +
trimethoprim-sulfamethoxazole/ pyrimethamine
• Spiramycin
Cryptosporidiosis • Nitazoxanide

DRUGS USED FOR IMPORTANT PROTOZOAL
INFECTIONS
Protozoal Infection Drug(s)
African trypanosomiasis, or
“sleeping sickness,”
Early-stage: pentamidine for T. brucei gambiense and suramin
for T. brucei rhodesiense.
Late-stage: NECT (nifurtimox-eflornithine combination) or
Melarsoprol for T. brucei gambiense and Melarsoprol for T. brucei
rhodesiense.
American
or Chagas disease
Nifurtimox and Benznidazole
Leishmaniasis • Pentavalent antimony compounds: Sodium stibogluconate
• Miltefosin
• Liposomal amphotericin B
Babesiosis Mild or moderate infections: Azithromycin + Atovaquone
Severe infection: Clindamycin + quinine
Balantidiasis • Tetracycline
Other coccidial infections trimethoprim-sulfamethoxazole

INDIVIDUAL AGENTS: AMPHOTERICIN B
• Antiprotozoal Effects:
• Leishmania spp.
• Mechanism of Action:
complexes with ergosterol precursors in the cell membrane,
forming pores that allow ions to enter the cell.
Cell Death

INDIVIDUAL AGENTS: AMPHOTERICIN B
• Therapeutic Uses & Dosage:
1. Visceral leishmaniasis
• 3 mg/kg intravenously on days 1–5, 14, and 21 for a total dose of
21 mg/kg
2. Cutaneous leishmaniasis
• 3 mg/kg/d intravenously for 7-10 days.

INDIVIDUAL AGENTS: EFLORNITHINE
• Trypanosoma spp.
Enters cell via an amino acid transporter
Irreversible catalytic (suicide) inhibitor of ornithine decarboxylase
Inhibition of the first and rate limiting step in the biosynthesis of polyamines
(putrescine, spermidine, and spermine) that are required for cell division and for
normal cell differentiation

• Pharmacokinetics:
Given i.v
D= well distributed and penetrates into the CSF.
M= Not significant
E= 80 % unchanged in urine
• Therapeutic Uses:
1. Late-stage West African trypanosomiasis along with Nifurtimox (NECT)
• 200 mg/kg IV every 12 h by 2-h infusion for 7 days plus nifurtimox (orally at 15 mg/kg/d in three
divided doses [every 8 h]) for 10 days.

• Toxicity and Side Effects:
1. Abdominal pain and headache (MC).
2. Reactions at the injection sites.
3. fever peaks,
4. seizures, and
5. Diarrhea
For NECT, severe adverse events were reduced compared to eflornithine alone.

INDIVIDUAL AGENTS: 8-HYDROXYQUINOLINES
• Halogenated 8-hydroxyquinolines: iodoquinol and clioquinol.
1. As luminal agents to eliminate intestinal colonization with E. histolytica and
combined with metronidazole to treat amebic colitis or amebic liver abscess.
• Adults: 650 mg orally three times daily for 20 days,
• Children: 30–40 mg/kg body weight orally, divided three times a day (not to exceed 1.95
g/d) for 20 days
• Adverse Reactions:
1. Neuropathy
• Subacute myelo-optic neuropathy
• Peripheral neuropathy.

INDIVIDUAL AGENTS: MELARSOPROL
MelarsoprolMelarsen oxide
React avidly and reversibly with vicinal sulfhydryl groups and thereby inactivate many
enzymes (melarsen oxide–trypanothione adduct that inhibits trypanothione reductase)
Free radical damage

1. Late meningoencephalitic stage of East African
(Rhodesian) trypanosomiasis.
2. Late stage West African (Gambianse) trypanosomiasis
not responding to NECT.
• 2.2 mg/kg/d IV for 10 days

• Treatment with melarsoprol is associated with significant
toxicity and morbidity.
1. Febrile reaction.
2. Reactive encephalopathy (Serious)
3. Peripheral neuropathy.
4. Hypertension and myocardial damage
5. Albuminuria
6. Vomiting and abdominal colic.

• Precautions and Contraindications:
1. Should be given only to patients under hospital supervision.
2. Administration of melarsoprol to leprous patients may
precipitate erythema nodosum.
3. Severe hemolytic reactions have been reported in patients
with deficiency of glucose-6- phosphate dehydrogenase.
4. Contraindicated during epidemics of influenza.

INDIVIDUAL AGENTS: NITROIMIDAZOLE
• Metronidazole and its analogs (tinidazole, secnidazole, and ornidazole).
• Antimicrobial spectrum:
1. Antibacterial:
• All anaerobic cocci;
• Anaerobic gram-negative bacilli, including Bacteroides spp.;
• Anaerobic spore-forming, gram-positive bacilli such as Clostridium; and
• Microaerophilic bacteria such as Helicobacter and Campylobacter spp.
2. Antiprotozoal:
• T. vaginalis,
• E. histolytica, and
• G. lamblia

• In anaerobic/ microaerophilic organisms:
Pyruvate Acetyl CoA
Ferridoxin (ox) Ferridoxin (red)
Nitroimidazole Nitro radical anion
Free radical damage to DNA
PFOR
e-
e-

• Available for oral, i.v and topical use.
A= Complete oral absorption
D= aVd ≈ TBW
M= Hepatic
E= Renal
T1/2= 8hrs

1. Trichomoniasis:
• 2 g metronidazole/ Tinidazole as a single oral dose for both males and females
may be repeated after 4-6 weeks
• In addition to oral therapy, the use of a 500- to 1000-mg vaginal suppository may
be beneficial in refractory cases.
2. Amebiasis (along with luminal amebicides): Metronidazole is the agent of
choice for the treatment of all symptomatic forms of amebiasis, including
amebic colitis and amebic liver abscess
• Adults: 500–750 mg metronidazole taken orally three times daily for 7–10 days.
• Children: 35–50 mg/kg/d given in three divided doses for 7–10 days

3. Giardiasis:
• Tinidazole is approved for the treatment of giardiasis as a single 2-g dose and is
appropriate first-line therapy.
• Toxicities and Contraindications:
• Headache, nausea, dry mouth, and a metallic taste are common.
• Vomiting, diarrhea, and abdominal distress are experienced occasionally.
• Dysuria, cystitis, and a sense of pelvic pressure have been reported.
• Dizziness, vertigo, and, very rarely, encephalopathy, convulsions, incoordination, and ataxia
are neurotoxic effects that warrant drug discontinuation.
• Hypersensitivity reactions.

• Drug Interactions:
1. Metronidazole has a disulfiram-like effect, and some patients experience abdominal
distress, vomiting, flushing, or headache if they drink alcoholic beverages during or
within 3 days of therapy
2. CNS signs of lithium toxicity in patients receiving high doses of lithium.
3. Prolong the prothrombin time of patients receiving therapy with warfarin
anticoagulants.

INDIVIDUAL AGENTS: MILTEFOSINE
• An alkylphosphocholine analogue developed originally as an
anticancer agent.
• Antiprotozoal Spectrum:
• Leishmania spp.
• Mechanism of action:
• Not fully understood
• Possibly alter ether-lipid metabolism, cell signaling, or
glycosylphosphatidylinositol anchor biosynthesis

• Detailed pharmacokinetic data are lacking,
• It is well absorbed orally and distributed throughout the body.
• Has a long t1/2 (1–4 weeks).
1. Visceral and cutaneous leishmaniasis:
• 100-150mg/kg/d in two divided doses for 28 days.

1. Vomiting and diarrhea are reported as frequent side effects,
in up to 60% of patients.
2. Elevations in hepatic transaminases and serum creatinine.
• Contraindication:
1. Pregnancy

INDIVIDUAL AGENTS: NIFURTIMOX &
BENZNIDAZOLE
• Trypanosome spp.
• Not fully understood
Nifurtimox / Beznidazole Nitro free radicals
Cellular damage that includes lipid peroxidation and
membrane injury, enzyme inactivation, and damage to
DNA.
NADH Dependent
mitochondrial nitroreductase

BENZNIDAZOLE
Nifurtimox Beznidazole
A= Well absorbed orally
D= Widely distributed incl. CNS
M= Hepatic
E= Biliary
T1/2 = 3h
D= Widely distributed incl. CNS
M= Hepatic
E= Biliary
T1/2 = 12h

BENZNIDAZOLE
Therapeutic Uses & Dosage:
1. American Trypanosomiasis (T.cruzi):
• Nifurtimox: 8–15 mg/kg/d (depending upon weight of pt.) in three to four divided
doses for 90 days
• Benznidazole: 5–7 mg/kg/d in two divided doses (Adult), 10–15 mg/kg/d in two
divided doses for 60 days
2. Nifurtimox is also used in African sleeping sickness along with eflornithine.
Toxicity and Side Effects:
1. Hypersensitivity reactions.
2. Nausea & vomiting resulting in weight loss on chronic therapy.
3. Peripheral neuropathy

INDIVIDUAL AGENTS: NITAZOXANIDE
• Cryptosporidium parvum.
• G. lamblia
• E. histolytica, and
• T. vaginalis

Interferes with the PFOR enzyme-dependent electron transfer reaction
Interference with anaerobic metabolism
M= Metabolized to active form tizoxanide
D= Tizoxanide >99.9% bound to plasma proteins
E= Urine, bile, and feces

• Therapeutic uses & Dosage:
1. Cryptosporidiosis
2. As luminal Amebicide.
3. Giardiasis.
• Children: Tab.100 mg PO q12h for 3 days (1-4 years); Tab. 200 mg PO q12h for 3 days (4-11
years).
• Adults: Tab. 500 mg PO q12h for 3 days.
• Toxicity and Side Effects: (Rare)
1. greenish tint to the urine

INDIVIDUAL AGENTS: PAROMOMYCIN
• Aminoglycoside of the neomycin/kanamycin family.
• E. Histolytica
• G. lamblia
• C. parvum
• T. vaginalis
• Leishmania spp.

• Same mechanism of action as neomycin and kanamycin
(binding to the 30S ribosomal subunit) and has the same
spectrum of antibacterial activity.
• Not absorbed from the GI tract; thus, the actions of an oral
dose are confined to the GI tract, with 100% of the oral
dose recovered in the feces

1. Amoebiasis (colitis/ hepatic) along with Nitroimidazole as luminal amebicide.
2. Giardiasis where Metronidazole is C/I (pregnancy)
• Dosing for adults and children is 25–35 mg/kg/d in three divided oral doses.
3. Cutaneous Leishmaniasis: 15% ointment twice daily for 20 days.
4. Visceral leishmaniasis: Paromomycin sulphate 15mg/kg (11 mg/kg base) i.m daily for 21 days ±
liposomal amphotericin B/Miltefosine.
5. Trichomoniasis : Metronidazole resistant trichomoniasis with 6.25% vaginal cream for 2 weeks as
add on therapy.
• Adverse Effects: (Rare)
• Abdominal pain and cramping, epigastric pain, nausea and vomiting, steatorrhea, and diarrhea.

INDIVIDUAL AGENTS: PENTAMIDINE
• Pentamidine is a positively charged aromatic diamine.
• Antimicrobial Spectrum:
• Antifungal:
• P. jiroveci
• Antiprotozoal:
• Leishmania spp.
• Mechanism of action: Not Known

Given parenteral (i.v/ i.m/ inhalation).
A= Poor oral absorption but well absorbed from i.m site
D= 70 % plasma protein bound, do not cross BBB.
M= Not metabolized
E= Unchanged in urine.
1. Early stage of African trypanosomiasis (T. brucei gambiense):
• i.m or i.v injection in doses of 4 mg/kg daily for 7 days.
2. Cutaneous leishmaniasis:
• 2–3 mg/kg IV or IM daily or every second day for 4–7 doses

• Toxicity and Side Effects: Common (Approximately 50% of individuals receiving the
drug at recommended doses show some adverse effect):
1. Hypotension, tachycardia, and headache on i.v. administration.
2. Hypoglycemia. Paradoxically, pancreatitis, hyperglycemia, and the development of
insulin-dependent diabetes have been seen in some patients.
3. Nephrotoxicity.
4. Rashes
5. Thrombophlebitis,
6. Anemia, neutropenia, and
7. Elevation of hepatic enzymes.
8. Sterile abscesses at the i.m injection site

INDIVIDUAL AGENTS: SODIUM STIBOGLUCONATE
• Pentavalent (Sb+5) antimony compound.
• Leishmania spp.

• Mechanism of action
Pentavalent antimonials Toxic Sb+3 form
interfere with the trypanothione redox system
loss of thiol reduction potential in the cells
Killing of amastigotes within the phagolysosomes

• Given i.v./ i.m
A= Rapidly absorbed from i.m. site
D= aVd- 0.22l/kg
E= Renal
T1/2= Biphasic (2 hrs & 33-76 hrs)

• Therapeutic Uses: Now obsolete in India
1. Visceral leishmaniasis:
• i.m/i.v. 20 mg/kg/d for 28 days
2. Cutaneous leishaniasis:
• i.m/i.v. 20 mg/kg/d for 20 days

1. Chemical pancreatitis
2. Elevation of serum hepatic transaminase levels;
3. Bone marrow suppression,
4. Muscle and joint pain
5. Weakness and malaise
6. Reversible polyneuropathy

INDIVIDUAL AGENTS: SURAMIN
• Mechanism of action : Unknown
• Given i.v
D= 99.7% plasma protein bound, do not cross BBB.
E= Renal
T1/2= 41-78 days.

1. Early-stage T. brucei rhodesiense infection: First line therapy
• After a test dose of 100 mg (adults) or 2mg/kg (pediatric) for detecting sensitivity
• Adult: 1g slow i.v infusion on days 1, 3, 5, 14, and 21.
• Pediatric: 20 mg/kg, given according to the same schedule as adults.

• Toxicity & side effects:
1. Malaise, nausea, and fatigue are common immediate reactions.
2. The most serious immediate reaction, consisting of nausea, vomiting, shock,
and loss of consciousness, is rare (~1 in 2000 patients)
3. The most common problem encountered after several doses is renal toxicity.
4. Delayed neurological complications, including headache, metallic taste,
paresthesias, and peripheral neuropathy.

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