ANTIPROTOZOAL

DRUGS

Dr Manik Ghadlinge
Protozoal Infections

Parasitic protozoa: live in or on humans

 Malaria
 Leishmaniasis- Na stilbogluconate, Ampotericin B
 Amebiasis
 Giardiasis
 Trichomoniasis
 Pneumocystosis
 Toxoplasmosis
 Protozoal Infections
Transmission
 Person to person

 Ingestion of contaminated water or food

 Direct contact with the parasite

 Insect bite (mosquito)

 Most of the protozoal infections are due to

unhygienic conditions.
 Amebiasis

Amebiasis is a protozoal infection of the

intestinal tract that occurs due to ingestion
of foods or water contaminated with
Entameba Histolytica cysts
LIFE CYCLE

Entamoeba histolytica exists in two forms:

1. Cysts (infective):
• can survive outside the human body.
• transform to trophozoites.

2. Trophozoites (non-infective; invasive):

• Can reproduce
• They may feed on intestinal bacteria or invade
and ulcerate wall of large intestine, and may
migrate to liver or other tissues.
• transform to cysts which are excreted in feces.
LIFE CYCLE
 Life Cycle

1. Cysts ingestion.
2. Formation of trophozoites
3. Penetration of intestinal wall
4. Multiplication of trophozoites within colon wall.
5. Systemic invasion.
6. Cyst formation in rectum and excretion in feces.
Clinical presentations

 Asymptomatic Intestinal infection

(Carriers, passing cysts)
 Mild to moderate intestinal disease
(Nondysenteric Colitis)
 Severe Intestinal infection (Dysentery)
 Hepatic abscess, ameboma (localized
granulomatous lesion of colon) and other
extraintestinal disease- only trophozoites
 The Complications
 Complications of Intestinal amoebiasis:
 Fulminant Amoebic Colitis with Perforation
 amoebomas
 amoebic Stricture
 Resulting from fibrosis of intestinal wall. Can involve rectum, anus or
sigmoid.
 Complications of Extra-Intestinal
Amoebiasis:
 Amoebic Liver Abcess- rt lobe
 Pleuropulmonary amoebiasis
 ANTIAMEBIC DRUGS
▪ Luminal Amebicides

▪ Tissue or systemic amebicides

▪ Mixed Amebicides
 Drugs
 Tissue amoebicide
 Intestinal & extra-Intestinal
 Nitroimidazole
 Metronidazole, tini, secni, orni, satranidazole
 Alkoid
 Emetine, dehydroemetine
 For Extra Intestinal
 Chloroquine
 Luminal amoebicide
 Diloxanide furoate, Nitazoxanide
 quinodochlor, iodoquinol,- Subacute myelooptic neuropathy' (SMON)
 Tetracyclines, paromomycin
 LUMEN AMOEBICIDES
 Acts on the parasites in the lumen of the bowl.
 used for treatment of asymptomatic amebiasis.
Include
 Diloxanide Furoate
 Iodoquinol
 Antibiotics

- Paromomycin
- Tetracyclines
 Tissue Amoebicides (systemic)
 acts on the intestinal wall and liver (or any other extra-
intestinal tissue).
 Used for treatment of systemic form of the disease (intestinal
wall infection or liver abscesses).
 Emetine

 Dehydroemetine

 Chloroquine (liver only)

Mixed amoebicides
Effective against both luminal and systemic forms of the disease.
Although luminal concentration is too low for single drug –
treatment.
Metronidazol
Tinidazole
Metronidazole is the drug of
choice for amebiasis
 Introduced for trichomoniasis
 Metronidazole (Flagyl) is the DOC for
invasive amoebiasis s
 should be combined with a lumenicidal drug
as it is not fully effective on luminal stages)
 Metronidazole is a prodrug which is activated
by an enzyme involved in the microaerobic
fermentation metabolism of E. histolytica
(PFOR)
 Mixed amoebicide.
 Drug of choice for intestinal & extraintestinal
amoebiasis.
 Acts on trophozoites.
 Has no effect on cysts.
Metronidazole is activated by PFOR
 Entamoeba uses a pyruvate
ATP ferredoxin oxidoreductase
ADP acetate (PFOR) to break down pyruvate
 This process depends on the
CO2 absence (or low level) of oxygen
 This enzyme system is limited
to anaerobic bacteria and some
protozoa and humans lack this
enzyme
 PFOR and ferredoxin can transfer
an electron to metronidazole
producing a highly toxic
nitroradical
 Reduced metro is cytotoxic to
anaerobes protozoa, & binds to
protozoal protein to disrupt
replication, transcription, & repair
process of DNA resulting in cell
death- interfere with DNA function
 Bactericidal activity
 Trichomonas
 Giardia
 Entamoeba
 Anaerobic organism- B. fragilis, Fusobacterium,
C. perfringes, H.pylori,peptococci, spirochetes,
anaerobic streptococci
 Guineaworm

 Aerobic bact.- no action

 Inhibit CMI
 Induce Mutagenesis
 Cause radiosensitization

 P/K
 Complete absorption
 Wide distribution
 Vaginal fluid, Semen, CSF, Saliva,
 Liver- glucuronide
 8hrs
s/e
 Nausea, metallic taste, cramp
 Headache, glossitis, rash,
 Peripheral neuropathy, seizures
 Thrombophlebitis

 C/I
 Neurological diseases,
 Blood dyscrasia
 Pregnancy
 alcohol
disulfiram like -effect
When metronidazole is given with alcohol
abdominal distress, nausea, vomiting, flushing,
or headache, tachycardia, hyperventilation

alcohol aldehyde
dehydrogenase dehydrogenase

Ethanol Acetaldehyde
Acetate
Uses
 Amoebiasis 400 mg TDS for 5-7 day
 Giardiasis
 Trichomonas- Partner
 Anaerobic infections- colorectal, pelvic
 Pseudomembranous colitis
 Ulcerative gingivitis
 H. pylori
 Tinidazole-12 hr, better tolerated
 Tinidazole has longer duration, simpler dosing regimen,
less toxicity, than metronidazole, but is equally active.
 Secnidazole- 18- 28 hr
 Ornidazole- 12-14 hr
EMETINE AND DEHYDROEMETINE
Chemistry:
 Emetine hydrochloride is a plant alkaloid
derived from ipeca.
 Dehydroemetine is a synthetic analogue

Pharmacokinetics:
 Erratic oral absorption.
 Given preferably subcutaneously but could be
given by IM, NEVER I.V.
 Plasma half life is 5 days.
EMETINE
 Concentrated in Liver, Lungs, Spleen, Kidney,
Cardiac muscle and Intestinal wall.
 Metabolized & Excreted slowly via kidney so it
has a cumulative effect.
 Trace amounts could be detected in urine 1-2
month after last dose.
 Should not be used for more than 10 days
(usually 3-5 days).
Mechanism
 Directly acting, kills trophozoites .
 No effect on cyst
 Act on tissue trophozoites causing irreversible
block of protein synthesis.
Adverse Effects
 High toxicity, cumulative
 Dehydroemetine is less toxic than emetine
 pain at site of injection, abcesses.
 GIT: nausea, vomiting, diarrhoea, abdominal
cramp
 Neuromuscular weakness
 Serious toxicities: cardiotoxicity
- cardiac arrhythmias, ECG changes, myocarditis
- Hypotension
- heart failure
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).
Chloroquine
 Kill trophozoite
 Conc. In liver
 Absorbed in upper GIT-invasive
 With Luminal amoebicide always
 600 mg 2 days then 300mg 2-3 weeks
 No resistance
 Diloxanide furoate
Chemistry
 Ester of diloxanide + furoic acid .

Pharmacokinetics
 Given orally.

 Split 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%).
Pharmacodynamics:
 Unkown mechanism of action

 Direct amoebicidal action against luminal forms.

 No systemic activity

 Less effective in invasive. Not active against

trophozoites in intestinal wall or extraintestinal
tissues.
Therapeutic Uses

 Drug of choice for asymptomatic intestinal

infection.
 For eradication of infection given along with
metro for all forms of amebiasis.
 Dose: 500 mg three times/day for 10 days.
Adverse Effects
 Flatulence
 Nausea, vomiting, abdominal cramps.
 No serious adverse effects

Contraindications:
- Pregnancy
- Children (less than 2 years).
 Paromomycin Sulphate
 Aminoglycoside, not absorbed.
 Effective against luminal forms of ameba

Mechanism of action
 Direct amebicidal action (causes leakage by its
action on cell membrane of parasite).
 Indirect killing of bacterial flora essential for
proliferation of pathogenic amoebae.
Kinetics
 Orally

 Not significantly absorbed from the GIT

 Small amount absorbed is excreted unchanged in

urine (may accumulate with renal insufficiency).
Adverse effects
 Gastrointestinal distress and diarrhea.

Precautions
 Severe renal disease

 patients with GIT ulceration

Tetracyclines
 Very weak direct amoebicidal action.

 Mainly act indirectly on bacterial flora.

 Used in severe cases of amoebic dysentery not

responding to metronidazole combined with
dehydroemetine.
 Iodoquinol
 SMON
 Tetracycline – higher conc
Invasive-
Chronic cyst passers
Amoebic liver abscess
Antiprotozoals
Mechanism of Action and Indications

Metronidazole (Flagyl)
 Disruption of DNA synthesis as well as nucleic acid synthesis

 Bactericidal, amebicidal, trichomonacidal

 Used for treatment of trichomoniasis, amebiasis, giardiasis,and

antibiotic-associated pseudomembranous colitis

 Also has anthelmintic activity

Adverse Effects: Metronidazole (Flagyl

 Metallic taste, nausea, vomiting, diarrhea,

abdominal cramps, many others

 Anti-helminthic drugs
Three major groups of helminths (worms) are
Nematodes
Trematodes
Cestodes
 Anti-helminthic drugs
Nematodes :
► Round worm --- Ascariasis
► Hook worm --- Ancylostoma duodenale ,
Nectar Americans
► Pin worm --- Enterobiasis
► Thread worm --- Strongyloides
► Whipworm --- Trichuris trichuria
 Anti-helminthic drugs
Nematodes :
► Trichinosis – trichinella spiralis
► Filariasis – Wucheria bancrofti
► Onchocerciasis ( River blindness )
-Onchocerca volvulus
 Anti-helminthic drugs
TREMATODES ( FLUKES ) :
► Chinese liver fluke – Clonorchis sinesis
► Lung fluke ---- Paragonimus westermani
► Schistosomiasis – Schistosoma sp
 Anti-helminthic drugs
Cestodes – Tape worm
► Beef tape worm – Taenia saginata
► Pork tape worm – Taenia solium
► Fish tape worm – Diphyllobothrium latum
► Dog tape worm – Echinococcus granulosis
 Anti-helminthic drugs
Drugs for helminths
► Nematodes : Mebendazole,
Diethylcarbamazine, Ivermectin, Pyrantal
pamoate, Thiabendazole
► Trematodes : Praziquantel
► Cestodes : Albendazole, Niclosamide
 Classification
► Drugs inhibiting polymerization of beta tubulin:
Albendazole, mebendazole, thiabendazole,
triclabendazole
► Drugs causing spastic paralysis (NN receptor
agonist): Pyrantel pamoate, levamisole
► Drugs causing flaccid paralysis (GABAA agonist):
Piperazine, ivermectin
► Drugs altering microfilarial membrane and
increasing phagocytosis: Diethylcarbamazine (DEC)
► Drugs causing uncoupling of oxidative
phosphorylation: Bithionol, niclosamide
► Drugs causing influx of calcium: Praziquantal
 Anti-helminthic drugs
Benzimidazole : Thiabendazole, Albendazole
and Mebendazole
► Effective against wide spectrum of
nematodes
► It acts by binding and interfering the
assembly of microtubules
► It also decreases the glucose uptake
 Anti-helminthic drugs
Benzimidazole :
► Albendazole and Mebendazole are poorly
absorbed from GIT whereas thiabendazole
is well absorbed.
► Albendazole and Mebendazole are well
tolerated , thiabendazole causes
hallucinations
► Contraindicated in pregnancy
 Anti-helminthic drugs
Benzimidazole :
► Mebendazole and Albendazole are used to
treat intestinal nematode infections
► Thiabendazole is preferred drug of choice in
cutaneous larva migrans.
 Anti-helminthic drugs
Ivermectin :
► Acts by acting on parasites GABA chloride
channel receptors – chloride influx in
enhanced – hyperpolarisation and paralysis
of the worm.
 Anti-helminthic drugs
Ivermectin :
► Well absorbed orally, metabolized in liver and
excreted in feces.
► Contraindicated in pregnancy
► Used for Onchocerca volvulus, strongyloides and
cutaneous larva migrans.
► Mazotti reaction (Fever and hypotension) - is due
to killing of the microfilaria
 Anti-helminthic drugs
Diethylcarbamazine :
► It acts by immobilizing the microfilaria and
render them susceptible to host defense
► Well absorbed orally
► Used mainly in the drug of choice for
Filariasis and Visceral larva migrans
 Anti-helminthic drugs
Pyrantal Pamoate :
► It acts as a depolarizing neuromuscular
agent – persistent activation of nicotinic
receptors – paralyzing the worm – expelled
from the intestinal tract.
► Used to treat round worm, hook worm and
pin worm
 Anti-helminthic drugs
TREMATODES ( FLUKES ) :
► Chinese liver fluke – Clonorchis sinesis
► Lung fluke ---- Paragonimus westermani
► Schistosomiasis – Schistosoma sp
 Anti-helminthic drugs
Praziquantel :
► It acts by increasing the permeability of
tegument to calcium – paralysis of the
parasite.
► Well absorbed orally
► Good tissue distribution – CNS.
► Metabolites are excreted in bile and urine
 Anti-helminthic drugs
Praziquantel :
Active against trematodes like
Chinese liver fluke – Clonorchis sinesis
Lung fluke ---- Paragonimus westermani
Schistosomiasis – Schistosoma sp
Also active against Cestodes
 Anti-helminthic drugs
Praziquantel :
► Not advised for ocular cysticercosis –
because of destruction of the organism in
the eye may damage eye.
 Anti-helminthic drugs
► Bithionol used for the treatment of fasciola
hepatica – sheep liver fluke.
 Anti-helminthic drugs
Cestodes – Tape worm
► Beef tape worm – Taenia saginata
► Pork tape worm – Taenia solium
► Fish tape worm – Diphyllobothrium latum
► Dog tape worm – Echinococcus granulosis
 Anti-helminthic drugs
Niclosamide
► Acts by inhibition of parasite mitochondrial
phosphorylation of ADP to ATP.
► The drug is lethal for Cestodes scolex and
segments but not for ova.
► Laxative is used to purge all the dead
segments of the intestine – ova liberation
and absorption can lead to cysticercosis.
► It is used for most Cestodes infections.
 Anti-helminthic drugs
Albendazole :
► It is used in the treatment of Cestodes
infections like cyticercosis - taenia solium
and hydatid disease – echinococcus
granulosis
► Hepatotoxicity and granulocytopenia when
used for long term in hydatid disease