Slides Anti-Infectives Antimicrobials

Pharmacology
Antiparasitic Agents
With Dr. Pravin J. Shukle
Anubhav Mishra, anmishra013@gmail.com

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Pharmacology Antiinfectives 7
Antiprotozoal agents Antihelminthic agents
Antimalarial agents Nematodes
Amebicides Trematodes
Cestodes

Antimalarial Agents Chloroquine
Mechanism of action blood schizonticide

• Chloroquine prevents the polymerization of heme.
• Intracellular heme is toxic to the parasite.
Mechanism of resistance
• Malaria organisms develop membrane transporters
to eject intracellular heme.
• P. falciparum can also develop a transporter

for chloroquine itself!
• Coded by the pfcrt gene
Ute Frevert and Margaret Shear, https://commons.wikimedia.org/wiki/File:Malaria.jpg, CC-BY 2,5

Antimalarial Agents Chloroquine
Side effects at low doses

• GI disturbances (nausea, cramping, diarrhea)
• Skin Rash
• Headaches
High doses
• Severe skin reactions
• Peripheral neuropathies, toxic psychosis,
retinal and auditory damage
• Myocardial depression
• May precipitate porphyria attacks
Antimalarial Agents Drugs Derived From Artemisinin
Artesunate, artemether, dihydroartemisinin

Blood schizonticides
Mechanism of action
• Accumulate in food vacuoles
• Form toxic free radicals
• Will work against multidrug resistant

strains; used in combination
• Rare adverse events of nausea, vomiting,
diarrhea
• No increase in congenital problems or
stillbirths in women taking these drugs

Antimalarial Agents Quinine
Blood schizonticide
• Combines with dsDNA, prevents strand
separation
• Blocks replication and transcription
• Used in chloroquine resistant P. falciparum
• Often combined with doxycycline or
clindamycin
• Used to shorten duration and limit
toxicity
Antimalarial Agents Quinine
Blood schizonticide
Toxicity
• Cinchonism (gastrointestinal distress,
headache, vertigo, blurred vision, tinnitus)
• Hemolysis in G6PD deficient patients
• Blackwater Fever: intravascular hemolysis

Antimalarial Agents Mefloquine
Blood schizonticide
• Chemically related to quinine
• First line agent; taken weekly (four
weeks before, one week after)
Mechanism of action
• Creates toxic heme particles in food
vacuoles

Antimalarial Agents Mefloquine
Blood schizonticide
Toxicity
• GI distress, skin rash, headache,
dizziness
• Nightmares
• May cause cardiac conduction
defects, seizures at high doses

Antimalarial Agents Primaquine
Tissue schizonticide and gametocide

• Eliminates liver stages of P. vivax and P. ovale
• Use in conjunction with a blood schizont
Mechanism of action
• Forms quinolinequinone metabolites that act as oxidants

Antimalarial Agents Primaquine
Toxicity
• Gastrointestinal distress, headaches

• Methemoglobinemia, toxicity in G6PD deficient patients (hemolysis)
• Contraindicated in pregnancy

Antimalarial Agents Antifolate Drugs
Blood schizonticides
Proguanil, pyrimethamine, sulfadoxine, dapsone
• May combine pyrimethamine and sulfadoxine
• Synergistic effects through sequential blockade
Mechanism of action
• Antimetabolites; block folic acid synthesis
Toxicity
• Skin rash, gastrointestinal distress
• Contraindicated in pregnancy

Antimalarial Agents Doxycycline
• Used for chemoprophylaxis for travellers

• Unknown mechanism

Antimalarial Agents Amodiaquine
Inexpensive; used extensively in 3rd world

• Used in fixed dosing with artesunate
Toxicity
• Hematological: agranulocytosis and aplastic anemia

Antimalarial Agents Atovaquone
Erythrocide
Malarone R is atovaquone plus proguanil
• Used as treatment and as once daily prophylaxis
• Is an alternative treatment for P. jiroveci infection
Mechanism of action
• Disrupts mitochondrial electron transport

Antimalarial Agents Atovaquone
Erythrocide
Toxicity
• Abdominal pains
• GI effects

Antimalarial Agents Halofantrine
Erythrocide
• Active against erythrocytic forms of all 4 malaria organisms
• Not used as a chemoprophylactic agent
• High potential for cardiotoxicity; prolonged QT interval
• Embryotoxic; contraindicated in pregnancy

Antimalarial Agents Prevention of Malaria
Consult local guidelines

• Will vary from country to country
• Will vary with seasons

Antimalarial Agents Prevention of Malaria
Principles of prevention
• Chloroquine remains first choice in
areas without resistant P. falciparum
• Mefloquine remains first choice in areas

with chloroquine-resistant P. falciparum
• In areas with multidrug-resistant malaria

• Doxycycline or MalaroneR
(atovaquone plus proguanil)
• Primaquine used in terminal prophylaxis

of P. vivax and P. ovale

Amebicides
Tissue amebicides act on organisms in the tissue and liver.

Chloroquine, emetines, metronidazole, tinidazole
Luminal amebicides act on organisms in the bowel wall and liver.

Diloxanide, iodoquinol, paromomycin

Amebicides Emetines
Emetine, dehydroemetine
Mechanism of action
• Blocks ribosomal movement along
mRNA
• Inhibits protein synthesis
Toxicity (severe toxicity common)

• GI distress
• Muscle weakness
• Arrhythmia, congestive heart failure
Image: Centres for disease control
Amebicides Metronidazole and Tinidazole
Mechanism of action
• Bio activation by anaerobes to form cytotoxic products
• Nitro group reduced by ferredoxin
• Drug of choice in severe intestinal wall disease and hepatic abscess

• Works very well in extra intestinal disease
• Metronidazole is drug of choice in trichomoniasis and several other
anaerobic infections
• Tinidazole is effective against metronidazole-resistant organisms

Amebicides Diloxanide (Diloxanide Furoate)
Mechanism of action
• Luminal amebicide
• Converted in the gut to diloxanide freebase
• The freebase form is an amebicide through an

unknown mechanism.
• Drug of choice in asymptomatic amebiasis
• Used in mild intestinal disease in combination

with other drugs
• Toxic effects are mild and rare

• Bloating or diarrhea
Amebicides Iodoquinol
Mechanism of action
• Luminal amebicide
• Used in mild to severe infections
• Toxic effects are mild and common

• Bloating or diarrhea
In overdose; systemic absorption can occur:

• Thyroid enlargement
• Skin reactions due to iodine toxicity
• Neurotoxicity: peripheral neuropathy, visual dysfunction

Amebicides Paromomycin
Mechanism of action
• Luminal amebicide and an aminoglycoside
antibiotic
• May be superior to diloxanide in

asymptomatic infection
• Used in combination with tetracyclines

(i.e. doxycycline) for mild disease
Toxicity
• Headaches, dizziness, rashes, arthralgia
• Toxicity risk proportional to renal function

Amebicides Nitazoxanide
Has activity against multiple protozoans:

• Entamoeba, Helminths
• Giardia lamblia, Cryptosporidium parvum
• Metronidazole resistant strains of protozoa

Amebicides Overview of Treatment
Disease form Drug(s) of choice Alternative drug(s)

Asymptomatic intestinal Diloxanide furoate Iodoquinol, paromomycin
infection
Mild to moderate intestinal Metronidazole plus Tinidazole or tetracycline or

infection luminal agent (see above) erythromycin plus luminal agent
Severe intestinal infection Metronidazole or Tetracycline or emetine or

tinidazole plus luminal dehydroemetine plus luminal agent
agent
Hepatic abscess and other Metronidazole or Emetine or dehydroemetine plus
extraintestinal disease tinidazole plus luminal chloroquine (for liver abscess) plus
agent luminal agent

Nematicidal Agents Albendazole
Mechanism of action
• Inhibits microtubule assembly
• Ovicidal in: ascariasis, ancylostomiasis,
trichuriasis
• Larvicidal in: ascariasis, cysticercosis
(pork tapeworm), hookworm, hydatid
disease

Nematicidal Agents Albendazole
• Used in ascariasis, hookworm,

pinworm, whipworm, hydatid disease,
pork tapeworm
Toxicity
• Short duration of therapy; toxicity is
rare
• Reversible leukopenia, elevated liver
enzymes with prolonged use

Nematicidal Agents Diethylcarbamazine
Mechanism of action
• Immobilizes microfilariae by
unknown mechanism
• Used in eye worm and others
Toxicity
• Reactions to proteins of dying
filariae include fever, rash, ocular
damage

Nematicidal Agents Ivermectin
Mechanism of action
• Single dose
• Intensifies γ-aminobutyric acid (GABA)
neurotransmission in nematodes
• Causes spasm and immobilization of
parasites
• Used in cutaneous larva migrans,
strongyloidiasis, filariasis
Cutaneous larva migrans

Nematicidal Agents Ivermectin
Toxicity
• Reactions to proteins of dying worms

include fever, rash, ocular damage

Nematicidal Agents Mebendazole
Mechanism of action
• Less than 10 % absorbed
systemically
• Inhibits microtubule synthesis and
glucose uptake in nematodes
• Primary drug for ascariasis,

pinworm, whipworm
• Backup drug for visceral larval
migrans
Ascariasis in bowel
Ascariasis in the bowel of a 4 year old boy. SuSanA Secretariat,

https://en.wikipedia.org/wiki/Ascariasis#/media/File:Piece_of_intestine,_blocked_by_worms_(16424898321).jpg, CC-BY 2.0
Nematicidal Agents Thiabendazole
Structural congener of mebendazole
Mechanism of action
• Absorbed systemically; much more systemic side effects
• Inhibits microtubule synthesis and glucose uptake in nematodes
• Alternative for systemic infections (i.e. Strongyloides, trichinosis (adult worms))
Toxicity
• GI irritation, intrahepatic cholestasis, liver failure, headache, dizziness, drowsiness
• Leukopenia, hematuria, allergic reactions
• Stevens-Johnsons syndrome (can be fatal)

Trematodicidal Agents Praziquantel
Mechanism of action
• Increases membrane permeability to calcium
• Marked contraction of trematode, then paralysis
• Used in trematode and cestode infections, drug of

choice in schistosomiasis
• Alternative to albendazole in systemic cysticercosis

(pork tapeworm)
• Contraindicated in ocular cysticercosis treat with

Albendazole
Intravitreal cysticercosis presenting as neovascular glaucoma, Dhanashree Ratra, Chekitaan Phogat, Maneesh Singh, Nikhil S Choudhari,
Scienceopen.com CC-BY 4.0
Trematodicidal Agents Praziquantel
Mechanism of action
• Increases membrane permeability to calcium
• Marked contraction of trematode, then paralysis
Toxicity
• Headache, dizziness, drowsiness
Cestodicidal Agents Niclosamide
Mechanism of action
• Uncouples oxidative phosphorylation, causing
paralysis
• Activates ATPases in tapeworms
• Alternative drug in beef, pork, fish tapeworms
• Not useful in systemic cysticercosis

(pork tapeworm cysts)
• Ova/larva are not killed by Niclosamide, use
Albendazole in the cyst form of pork tapeworm

Cestodicidal Agents Niclosamide
Toxicity
• Gastrointestinal distress
• Headache
• Rash
• Fever

The President returns from a first trip to Cuba in 50 years. He presents with
fever, dehydration, and nausea. A blood smear shows P. Falciparum
schizonts.
The following drugs are schizonticides except:
A. Chloroquine
B. Dihydroartemisinin
C. Quinine
D. Halofantrine
E. Sulfonamides

The President returns from a first trip to Cuba in 50 years. He presents with
fever, dehydration, and nausea. A blood smear shows P. Falciparum
schizonts.
The following drugs are schizonticides except:
A. Chloroquine
B. Dihydroartemisinin
C. Quinine
D. Halofantrine
E. Sulfonamides

Which drug would be effective in treating amebiasis in the liver?
A. Diloxanide furoate
B. Iodoquinol
C. Paromomycin
D. Metronidazole

B. Iodoquinol
C. Paromomycin
D. Metronidazole

B. Iodoquinol
The principle behind amebicidal therapy is understanding where each drug
works. The first three drugs are luminal amebicides; they stay in the lumen
C. Paromomycin
of the gut and work very well if the infestation is at the luminal surface.
Once the organism
D. Metronidazole becomes systemic, metronidazole would be a logical
choice, as it is activated by anaerobes and very effective in hepatic tissue.

While on mission with Medecins sans Frontières® (Doctors Without Borders®),
you see a young boy with a strange lump in his retina. It is a small cyst with a
hard centre.

hard centre. What would be the appropriate treatment?
A. Niclosamide
B. Praziquantel
C. Mebendazole
D. Albendazole
hard centre. What would be the appropriate treatment?
A. Niclosamide
B. Praziquantel
C. Mebendazole
D. Albendazole
you see a young boy with a strange lump in his retina. It is a small cyst
with a hard centre. What would be the appropriate treatment?
The image is the typical presentation of retinal cysticercosis, the larval

stage of pork tapeworm.
A. Niclosamide
Niclosamide does not kill pork tapeworm in this stage; it only kills it in the
cestode stage.
B. Praziquantel
Praziquantel should
C. Mebendazole never be used in ocular cysticercosis because the
destruction can cause permanent ocular lesions.
Mebendazole
D. Albendazoleis not systemically absorbed to any great degree and is
not a good choice
Albendazole is the drug of choice in this situation.
This document is a property of: Anubhav Mishra
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Pharmacology

With Dr. Pravin J. Shukle

Anubhav Mishra, anmishra013@gmail.com

Antiprotozoal agents Antihelminthic agents

Antimalarial agents Nematodes

Anubhav Mishra, anmishra013@gmail.com

Mechanism of action blood schizonticide

• Intracellular heme is toxic to the parasite.

• P. falciparum can also develop a transporter

• Coded by the pfcrt gene

Ute Frevert and Margaret Shear, https://commons.wikimedia.org/wiki/File:Malaria.jpg, CC-BY 2,5

Side effects at low doses

Artesunate, artemether, dihydroartemisinin

• Will work against multidrug resistant

Anubhav Mishra, anmishra013@gmail.com

Ute Frevert and Margaret Shear, https://commons.wikimedia.org/wiki/File:Malaria.jpg, CC-BY 2,5

Ute Frevert and Margaret Shear, https://commons.wikimedia.org/wiki/File:Malaria.jpg, CC-BY 2,5

Ute Frevert and Margaret Shear, https://commons.wikimedia.org/wiki/File:Malaria.jpg, CC-BY 2,5

Tissue schizonticide and gametocide

Anubhav Mishra, anmishra013@gmail.com

• Gastrointestinal distress, headaches

Anubhav Mishra, anmishra013@gmail.com

Anubhav Mishra, anmishra013@gmail.com

• Used for chemoprophylaxis for travellers

Anubhav Mishra, anmishra013@gmail.com

Inexpensive; used extensively in 3rd world

Anubhav Mishra, anmishra013@gmail.com

Anubhav Mishra, anmishra013@gmail.com

Anubhav Mishra, anmishra013@gmail.com

Anubhav Mishra, anmishra013@gmail.com

Consult local guidelines

Ute Frevert and Margaret Shear, https://commons.wikimedia.org/wiki/File:Malaria.jpg, CC-BY 2,5

• Mefloquine remains first choice in areas

• In areas with multidrug-resistant malaria

(atovaquone plus proguanil)

• Primaquine used in terminal prophylaxis

Ute Frevert and Margaret Shear, https://commons.wikimedia.org/wiki/File:Malaria.jpg, CC-BY 2,5

Tissue amebicides act on organisms in the tissue and liver.

Luminal amebicides act on organisms in the bowel wall and liver.

Anubhav Mishra, anmishra013@gmail.com

Toxicity (severe toxicity common)

• Drug of choice in severe intestinal wall disease and hepatic abscess

Anubhav Mishra, anmishra013@gmail.com

• Converted in the gut to diloxanide freebase

• The freebase form is an amebicide through an

• Drug of choice in asymptomatic amebiasis

• Used in mild intestinal disease in combination

• Toxic effects are mild and rare

• Used in mild to severe infections

• Toxic effects are mild and common

In overdose; systemic absorption can occur:

• Skin reactions due to iodine toxicity

• Neurotoxicity: peripheral neuropathy, visual dysfunction

• May be superior to diloxanide in

• Used in combination with tetracyclines

• Toxicity risk proportional to renal function

Image: Centres for disease control

Has activity against multiple protozoans:

• Giardia lamblia, Cryptosporidium parvum

• Metronidazole resistant strains of protozoa

Image: Centres for disease control

Disease form Drug(s) of choice Alternative drug(s)

Mild to moderate intestinal Metronidazole plus Tinidazole or tetracycline or