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20. ANTI-PARASITIC DRUGS

Pr Nermine Bouchi
Pharmacology

Faculty of Pharmacy
4th year – S2
 Outline
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 Introduction

 Anthelmintic drugs

 Antiprotozoan drugs

 Chemotherapy of malaria
 Introduction
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Parasites

Protozoa Metazoa

Worms = helminths Arthropoda

Nematoda = Plathelminths
round worms = flat worms
Vers ronds Vers plats

Cestoda =
Trematoda= Tapeworms
Flukes
Vers solitaires
 Modes of Transmission of parasitic
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diseases
Four main mechanisms for parasitic transfer:
 Ingestion of eggs from the fecal material of an infected
individual
 Ascaris lumbricoides
 The larva of the parasite can burrow into the skin of a
person
 Schistosomes
 The larva of the parasite can move from person to person
through an insect vector
 Trypanosomes
 Plasmodia
 Sexual transmission
 Trichomonas vaginalis
5 Anthelminthic agents
 Introduction
6

 Nematoda, trematoda & cestoda

 Adults are parasites of humans

 Immature forms = larva  different distribution in human organism than adult forms
 Immature forms invade humans via the skin or GI tract and evolve into well-differentiated adult worms with
characteristic tissue distributions.

 May require another host to complete their life cycle

 Anthelminthic drugs
 Different spectrum of activity : different types of worms ; adulticidal versus larvicidal ; ovicidal properties
 Mechanisms :
 Drugs act either
 locally within the gut lumen to cause expulsion of worms from the GI tract,
 or systemically against helminths residing outside the GI tract.
 inhibiting parasite metabolism or causing muscle paralysis
 High selective toxicity  usually safe and effective
 Best activity is against GI worms
 Least efficacy on many tissue-dwelling helminths
 Resistance occurs
 Anthelminthic drugs
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Nematoda Trematoda Cestoda

Benzimidazoles
Diethylcarbamazine DEC
Ivermectin
Pyrantel
Praziquantel
Niclosamide
 Benzimidazoles
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 Mebendazole (MBZ) VERMOX

 Albendazole (ABZ) ZENTEL

 Widely used because

 Wide margin of safety
 Wide helminthic spectrum of activity :
 Nematoda : enterobiasis, ascariasis, trichuriasis, and hookworm,
lymphatic filaria
 Trematoda (no therapeutic use)
 Cestoda : hydatid cystic disease due to Echinococcus granulosus,
neurocysticercosis caused by larval forms of Taenia solium
 Efficacy against immature stages
 Ovicidal properties
 Anti-Giardia , Trichomonas vaginalis (ABZ)
 Benzimidazoles : Pharmacodynamics
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 BZA bind β- tubulin, preventing its

dimerization with a-tubulin and
inhibiting the polymerization of
tubulin dimers into microtubules

 Other changes
 Inhibition of mitochondrial fumarate
reductase
 Reduced glucose transport
 Uncoupling of oxidative
phosphorylation

 Selective toxicity: BZA have a

higher affinity for nematode tubulin
at the normal temperature range
 Benzimidazoles : PK
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 PK
 MBZ & ABZ poorly soluble in aqueous solution  poor
absorption
 MBZ  low oral bioavailability (poor absorption + hepatic first
pass effect)
 ABZ  absorption is enhanced by the presence of fatty foods
 ABZ  ABZ sulfoxide = active metabolite widely distributed
(liver and intestine)

 Adverse effects
 Excellent safety profiles
 Mainly mild GI symptoms : abdominal pain, diarrhea, nausea,
and vomiting
 High doses MBZ  alopecia, reversible neutropenia,
agranulocytosis, and hypospermia
 High doses ABZ  liver dysfunction, hematologic toxicity
 Ivermectin
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 Broad-spectrum activity
 Endectocide
 Endocide : internal parasites : Nematodes
 Adult and immature stages
 Ectocide:
external parasites : insects, acarines
 No activity on trematodes, cestodes or protozoa
 No ovicidal activity

 Uses
 Strongyloidiasis, onchocerciasis, and cutaneous larva
migrans
 Alternative of DEC in loiasis
 Treatment of scabies (gale)
 Ivermectin : mechanism of action
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 Cause hyperpolarization of parasites nerve or muscle cells by binding

Selectively and with high affinity to glutamate-activated Cl- channels (GluCl)
With less affinity to GABA-gated Cl- channels

 This results in flaccid paralysis of the affected parasites, followed by their death
or expulsion
Paralysis of the pharyngeal pump :  nutrient ingestion
Paralysis of somatic musculature :  in the ability to remain in the site
 Ivermectin
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 Selective toxicity
 Affinity for invertebrate GABA receptors is about ~100-fold higher than
mammalian receptors
 GABA receptors are protected by BBB and Ivermectin is Pgp substrate
 PK
 Well absorbed from the gut
 Undergoes hepatic biotransformation (CYP3A4)
 Substrate of Pgp  excluded from CNS
 Excreted in the feces
 Low systemic clearance  long terminal t1/2 (~57 hours in adults)

 Adverse effects
 Well tolerated and produces few adverse effects.
 Uncommonly it causes constipation, diarrhea, dizziness, vertigo, or sedation.
 Filarial infections  reaction to dying microfilariae
 O. volvulus infections  mild itching and swollen, tender lymph nodes
 Piperazine : VERMIFUGE
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 Mode of action

 Highly effective against ascaris

lumbricoides and enterobius vermicularis.
Safe during pregnancy
 Praziquantel
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 Mechanism of action
 Induces an influx of Ca2+ across the tegument causing muscle
contraction and spastic paralysis.
 Causes tegumental damage (tegument vacuolization) that
 Makes it more easily attacked by proteolytic enzymes.
 Exposes worm antigens enabling host immune cells to attack the worm
 Efficacy
 Excellent against a wide spectrum of adult and larval cestodes 
drug of choice in adult tapeworm infections / alternative of ABZ in
cysticercosis
 Excellent against Schistosome trematodes  treatment of choice of
schistosomiasis, a disease that can affect a wide range of organs,
including the skin, liver, spleen, intestinal and urinary tracts, lungs,
brain, and spinal cord.
 Drug of choice in liver fluke (Clonorchis sinensis), the lung fluke
(Paragonimus westermani),
 No antinematodal activity
16

 Mechanism of action
 Induces an influx of Ca2+ across the tegument causing muscle
contraction and spastic paralysis.
 Causes tegumental damage (tegument vacuolization) that
 Makes it more easily attacked by proteolytic enzymes.
 Exposes worm antigens enabling host immune cells to attack the worm
 Praziquantel
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 PK
 Orally effective
 widely distributed and enters the CNS
 Extensive first-pass metabolism to many inactive
metabolites  excreted in the urine.

 Adverse effects
 Transient and dose-related  abdominal discomfort,
dizziness, drowsiness, and headache
 Consequence of parasite killing and antigen release 
fever, pruritus, urticaria, rashes, arthralgia, and myalgia
 Niclosamide TAENIASAN
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 Second-choice drug to praziquantel for treating human

intestinal infections with Taenia saginata, Diphyllobothrium
latum, Hymenolepis nana, and most other cestodes

 Mechanism of action
 Interference with glucose absorption
 Uncoupling of oxidative phosphorylation  energy deficiency 
death of parasite  digestion of scolex and segments

 Niclosamide poses a risk to people infected with T. solium

because ova released from drug-damaged gravid worms
develop into larvae that can cause cysticercosis
 Safe during pregnancy
19 Antiprotozoal drugs
 Antiprotozoal drugs
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Sarcomastigophora Apicomplexa

Amoebiasis Giardiasis Trichomoniasis Leishmaniasis Toxoplasmosis

Nitroimidazoles Miltefosine Pyrimethamine

Sulfadiazine
AG : paromomycin Folinic acid

Nitazoxanide AmphoB Spiramycin

Chloroquine Pentavalent Clindamycin

antimonials Azithromycin
Clarithromycin
Atovaquone
 Infection by Entamoeba histolytica occurs
by ingestion of mature cysts (1) in fecally
contaminated food, water, or hands.
Excystation (2) occurs in the small intestine
and trophozoites (3) are released, which
migrate to the large intestine. The
trophozoites multiply by binary fission and
produce cysts (4) , which are passed in the
feces. Because of the protection conferred
by their walls, the cysts can survive days to
weeks in the external environment and are
responsible for transmission. (Trophozoites
can also be passed in diarrheal stools, but
are rapidly destroyed once outside the
body, and if ingested would not survive
exposure to the gastric environment.)
In many cases, the trophozoites remain
confined to the intestinal lumen (A: non-
invasive infection) of individuals who are
thus asymptomatic carriers and cysts
passers. In some patients the trophozoites
invade the intestinal mucosa (B: intestinal
disease), or, through the bloodstream,
extraintestinal sites such as the liver, brain,
and lungs (C: extra-intestinal disease),
21 with resultant pathologic manifestations.
 Amebiasis clinical forms
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 Asymptomatic intestinal infection : carriers passing cyst

 Mild to moderate intestinal disease: non dysentery

colitis

 Severe intestinal infection : amebic dysentery

 Systemic symptoms due to invasive stage

 Liver abscess
 Ameboma: localized granulomatous lesion of colon
 Brain abscess
 Lung abscess
 Treatment of amebiasis
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Agents

Luminal Mixed Systemic

Antibiotics
Tetracyclines
Nitazoxanide Nitroimidazole Chloroquine
Paromomycin
Erythromycin

Asymptomatic amebiasis All forms of the Systemic forms

Intestinal disease disease of the disease
 Nitroimidazoles
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 Metronidazole FLAGYL
 Tinidazole FASIGYN
 Spectrum of activity:
 Anaerobic protozoa (Giardia, Trichomonads, Entmoeba,
Trypanosoma, Balantidium)
 Acts on trophozoites , no effect on cysts
 Anaerobic bacteria (Bacteroides, Clostridium, Helicobacter &
Campylobacter)
 Helminths : the nematode Dracunculus medinensis

 Metronidazole versus tinidazole

 Duration of action : TNZ>MNZ
 Toxicity: TNZ<MNZ
 Potency : TNZ = MNZ
 TNZ active against metronidazole-resistant strains of T. vaginalis.
 Nitroimidazoles Metronidazole is a prodrug;
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Anaerobic organisms express pyruvate-
O2  reductive ferredoxin oxidoreductase, an enzyme
activation of MTZ not found in mammalian cells, which is
and  recycling of involved in energy production, carbon
the activated drug recycling, and other metabolic functions .
prodrug it donates electrons to metronidazole
Reductive activation by
 O2
susceptible organisms to form
Pyruvate- highly reactive nitro radical
ferredoxin anions (dérivés nitrés
oxidoreductase toxiques) that kill these
organisms by radical-
mediated mechanisms that
target DNA and possibly
other vital biomolecules.
Metronidazole is catalytically
recycled; loss of the active
metabolite's electron regenerates
the parent compound.
 Nitroimidazoles
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 PK
 Metronidazole : Oral (complete absorption), IV , intravaginal, and topical
administration
 Well distributed into body tissues and fluids, including vaginal secretions, seminal fluid,
saliva, breast milk, and CSF. (reaches abcesses and is active in presence of pus)
 Metabolized in the liver (t1/2 ~8 hours)  active metabolite (50% activity of metronidazole
; t1/2 ~12 hours)
 Excreted primarily by the kidneys (the urine may appear dark red or reddish brown)
 Tinidazole : longer duration of action (t1/2 ~13 hours) & metabolized by CYP3A4

 Adverse effects:
 Usually well tolerated
 GI : metallic taste, nausea, vomiting, dry mouth, abdominal discomfort
 Neurotoxicity at high doses :
 CNS : headache, Dizziness, vertigo, encephalopathy, convulsions, ataxia
 Peripheral neuropathy : numbness or paresthesias
 Disulfiram-like effect  abdominal distress, nausea, vomiting, flushing, headache,
tachycardia if taken with alcohol
 Temporary neutropenia (reversible after D/C)
 Mutagenic and carcinogenic (bacteria/ rodents)
 Nitroimidazoles
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 Clinical uses
 Drug of choice in
 Amebiasis : intestinal and extra-intestinal forms
 Trichomoniasis, and giardiasis
 Serious infections owing to susceptible anaerobic bacteria, e.g.,
Bacteroides, Clostridium, Fusobacterium, and Helicobacter
 Pseudomembranous colitis (Clostridium difficile)
 Ulcerative gingivitis

 Contraindications / precautions:
 Pregnancy and nursing women.
 Alcohol intake
 CNS diseases
 Severe hepatic disease
 Severe renal disease
 Giardiasis and Trichomoniasis
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Giardiasis
 Flagellated protozoan:
Giardia intestinalis
 Ingestion of cyst form of the
parasite from contaminated
water or food
 Treatment
 Metronidazole : 5 days
treatment
 Tinidazole : single dose
 Paromomycin : pregnant
women
 Nitazoxanide
Trichomoniasis
 Flagellated Protozoan:
Trichomonas vaginalis
 Sexually transmitted disease :
protozoan inhabits the
urogenital tract:
 vaginitis in women
 urethritis in men
 Treatment
 Metronidazole : drug of choice
 Tinidazole : better tolerated ,
used at higher doses to treat
metronidazole resistant T.
vaginalis
 Toxoplasmosis
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 Zoonotic infection caused by the obligate intracellular protozoan

Toxoplasma gondii
 Cat = definitive host
 Immunocompetent subject  self-limiting illness in 90%  no
treatment required
 Immunocompromised patient  encephalitis treated by
 Pyrimethamine & sulfadiazine (+leucovorin)  toxicity due to
sulfadiazine  sulfadiazine may be substituted by clindamycin
 BACTRIM or pyrimethamine + azithromycin / clarithromycin / dapsone
 less toxic & less effective than pyrimethamine+ sulfadiazine

 Congenital toxoplasmosis
 Spiramycin concentrates in placenta treat toxoplasmosis in
pregnancy prevent transmission to the fetus
 If fetal toxoplasmosis detected  pyrimethamine, sulfadiazine, and
folinic acid (only after the first 12-14 weeks of pregnancy)
30 Chemotherapy of malaria
 Malaria
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 Four species of Plasmodium cause malaria:

 Plasmodium falciparum : mortelle
 Plasmodium malariae :nn mortelle , rechutes après 20ans
 Plasmodium ovale ;nn mortelle ,rechutes après 4à5ans
 Plasmodium vivax :

 Most cases of malaria are caused by P. falciparum or P.

vivax.

 The disease is
 Spread via the bites of female Anopheles mosquitoes
 Primarily found in tropical and subtropical areas
 More severe with P. falciparum
 Sporozoïte = trophozoïte

10 days
20 days

Merozoïte = schizozoïte

2 days

= schizont
Ma

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CHEMOTHERAPY OF MALARIA
 
EXOERYTHROYTIC STAGE I
(4 spp)
ASEXUAL ERYTHROCYTIC
Exoerythrocytic stage II: STAGE
hypnozoites (dormant form)
VIVAX, OVALE Trophozoites Schizonts
s
EXOERYTHROYTIC STAGE I
Last 1 week

ASEXUAL ERYTHROCYTIC STAGE Merozoites

=
Clinical manifestations
Last 48h to 72h gametocytes
 Les antiparasitaires
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 1 – chez l’homme :
 l’anophèle femelle ( vecteur ) ,  2 – cycle chez l’anophèle :
infeste l’homme en lui injectant le
parasite sous forme de sporozoite ;  lorsqu’un moustique pique
 celui-ci , migre par le sang vers les un sujet infesté , il ingère les
cellules du FOIE
 il pénètre dans l’hépatocyte , s’y gamétocytes mâles et
divise en donnant naissance à des femelles qui se transforment
mérozoites :stade exoerythrocytaire
 en éclatant, la cellule du foie les en gamètes ,
libère dans le sang , les mérozoites
pénètrent dans les globules rouges  après fécondation , l’oeuf
et s’y multiplient:Stade se transforme en sporozoite
erythrocytaire asexué
 ces derniers éclatent et infectent de
dans les glandes salivaires
nouveaux globules rouges du moustique
 parallèlement , dans le sang des  un nouveau cycle peut
cellules sexuées mâles et femelles (
gamétocytes ) se différencient commencer ,
Stade sexué
 Malaria : the disease
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 After the initial exoerythrocytic stage,

 P. falciparum and P. malariae are no longer found in the liver.
 P. vivax and P. ovale can maintain a quiescent hepatocyte
infection as a dormant form of the parasite known as the
hypnozoite  can reinitiate symptomatic disease long after
the initial symptoms of malaria are recognized and treated.

 Erythrocytic forms cannot reestablish infection of

hepatocytes

 The asexual erythrocytic stages of malarial parasites

are responsible for the clinical manifestations of
malaria
 Antimalarial agents
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Insecticides &
gametocytocidal agents
 Antimalarial agents
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Impossible to prevent infection because

no drug can kill sporozoites
 Antimalarial agents
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Used most commonly to eradicate the intrahepatic

hypnozoites of P. vivax and P. ovale that are
responsible for relapsing infections e.g. primaquine
 Antimalarial agents
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Action is directed against the asexual blood stages responsible for disease.
These drugs will treat, or prevent, clinically symptomatic malaria
 Drugs active against primary & latent
(hypnozoites) liver stages

Drugs active against asexual blood stages &

primary liver stages : Atovaquone, Proguanil

Drugs active against asexual blood stages :

Artemisinins, Chloroquine, Mefloquine,
Quinine, Pyrimethamine, Sulfadoxine,
Tetracyclines
When used as chemoprophylaxis, these drugs must
continue to be taken for several weeks after
exposure, until parasites complete their
intrahepatic stage of development and become
susceptible to therapy

Drugs active against gametocytes

40
 Quinolines and related compounds
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 Chloroquine : NIVAQUINE
 Amodiaquine
 Quinine
 Mefloquine
 Primaquine

 Quinine = first drug used nearly 400 years ago

 Quinolines : Mechanism of action
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 Plasmodium develops, multiplies and transforms by
utilizing hemoglobin of human erythrocytes as food
 Free Heme is toxic to the parasite Ingestion of the host Hb into the
 It converts heme rapidly into free radicals and iron- food vacuole of malarial parasite
bound heme (ferriprotoporphyrin IX) as highly reactive
by-products  polymerized by haem polymerase into
insoluble and ineffective pigment known as Hemozoin,
or the malariant pigment , which is non-lethal and non-
toxic to plasmodium
Degradation of host Hb
 Quinolines , weak bases, concentrate in the highly
acidic digestive vacuoles of susceptible Plasmodium,  Release of free soluble haem
bind to heme  prevents biocrystallization of heme in
to Hemozoin , by inhibiting haem polymerase. and production of FP IX
 Failure to inactivate heme or even enhanced toxicity of Quinolines Haem
drug-heme complexes is thought to kill the parasites via polymerase
 Oxidative damage to membranes,
 Digestive proteases, Haemozoin
 Other critical biomolecules
 Chloroquine : therapeutic uses
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 Most widely used antimalarial agent

 Acute attack of malaria

 Highly effective schizonticidal agent for all species
 Agent of choice for acute attacks of malaria caused by P. vivax, P. ovale, and P.
malariae
 No activity against primary or latent liver stages primaquine added for
radical cure
 Moderate gametocytocidal activity for the four main species

 Chemoprophylaxis of malaria
 Dose: 500 mg weekly. begin 1-2 week before departure & continue for 4
weeks after leaving the endemic area

 Hepatic amebiasis / abscess

 Rheumatoid diseases : rheumatoid arthritis, systemic lupus erythematosus, …

 Chloroquine : adverse effects
44

 Safe in pregnancy and young children

 Minimal adverse effects in chemoprophylaxis

 Oral therapy for acute attack

 GI upset, headache, visual disturbances, urticaria, and pruritis (in dark skinned
persons)
 Discoloration of nail beds and mucous membranes

 Therapeutic or high doses are administered too rapidly by parenteral

routes :
 Cardiotoxicity : hypotension, cardiac arrhythmias, and eventual cardiac arrest
 CNS toxicity : Confusion, convulsions, and coma

 High daily doses for treatment of rheumatoid diseases

 Retinopathy (drug accumulation in melanin containing tissues ) and ototoxicity
 Myopathy, cardiopathy, and peripheral neuropathy
 Artemisinin and derivatives
45

 Artemisinin (qinghaosu) = active ingredient of

Artemisia annua, a plant used in traditional Chinese
medicine for over two millennia.
 Potent activity against multidrug-resistant P. falciparum
 Derivatives of artemisinin called dihydroartemisinin,
artemether and artesunate have improved potency
against the erythrocytic stages of malaria and
improved bioavailability
 Artemesinins have the most potent and most rapid
action of current drugs against P. falciparum malaria 
standard of treatment for this infection worldwide
 Atovaquone + Proguanil
46

!Mechanism of action
 Atovaquone :
 Highly active against P. falciparum asexual blood stage parasites
 Effective against liver stages of P. falciparum but not against P. vivax
liver stage hypnozoites
 Selectively inhibits mitochondria electron transport in plasmodia and
collapse the mitochondrial membrane potential
 Proguanil : Prodrug  cycloguanil  selective inhibitor of the
bifunctional plasmodial dihydrofolate reductase-thymidylate
synthetase that is crucial for parasite de novo purine and
pyrimidine synthesis
 Therapeutic uses (Atovaquone+ proguanil)
 Treatment of uncomplicated P. falciparum malaria
 Treatment of multi-drug resistant P. falciparum malaria
 Standard agent for malaria chemoprophylaxis  discontinued 1 week
after leaving the endemic area because both components are active
against liver stage parasites