ANTIPROTOZOAL AGENTS Flashcards
This disease are highly prevalent in tropical third world countries
Antiprotozoal Agents
The common protozoal diseases:
-malaria
-amebiasis
-giardiasis
-trichomoniasis, toxoplasmosis & as a direct consequence of the AIDS
epidemic, pneumocystis carinii pneumonia
Entamoeba
histolytica
Amebiasis
Balantidium coli
Balantidiasis
Giardia lamblia
Giardiasis
Cryptosporidium
spp
Cryptosporidiosis
Trichomonas vaginalis
Trichomoniasis
Genital infection
Trichomoniasis
Pneumocystis carinii
(opportunistic pathogen)
Pneumocystis carinii
pneumonia
Best known for causing blindness in neonates
Toxoplasmosis
Leishmania donovani
Lieshmaniasis
2-methyl-5-nitroimidazole-1-ethanol
Metronidazole (Flagyl)
-Most useful of a group of antiprotozoal nitroimidazole derivatives
-First marketed for topical tx Trichomonas vaginalis vaginitis; effective
orally against both acute & carrier states of disease
-Possess amebicidal activity; effective against both intestinal & hepatic
amebiasis
-Also use in the tx for giardiasis & balantidiasi
Metronidazole (Flagyl)
Because of its bactericidal action, it has become an important agent
for treatment of serious infections (septicemia, pneumonia,
peritonitis, pelvic infections, abscesses, meningitis) caused by anaerobic bacteria
Metronidazole
Effective against obligate anaerobic bacteria but ineffective against
facultative anaerobes or obligate aerobes
Metronidazole
Despite its low water solubility, it is well absorbed following oral administration
Metronidazole
Is administeres parenterally only via slow infusion
Metronidazole
are unsuitable for IV administration
because of their extreme acidity
Metronidazole
-Possessed amebicidal activity in vitro
-Treatment of asymptomatic carriers of E. Histolytica
-Administered orally only as 500 mg tablets
Diloxanide Furoate
For acute & chronic intestinal amebiasis but not effective in extraintestinal
disease
Lodoquinol
Relatively high incidence of neuropathy occurs, so it should not be used
routinely for traveler’s diarrhea
Lodoquinol
-Obtained by separation from extracts of ipecac
Exert direct amebicidal action on various forms of E. Histolytica
-Protoplasmic poisons that inhibit protein synthesis in protozoal &
mammalian cells by preventing protein elongation
-Used only in combination w/ other agents because their effect in intestinal
amebiasis is solely symptomatic & cure rate only 10%-15%
-Toxic effect limit its usefulness
Emetine & Dehydroemetine
Causes high frequency of GI distress (nausea & diarrhea), cardiovascular
effects (hypotension & arrhythmia) & neuromuscular effects (pain &
weakness)
Emetine & Dehydroemetine
Lower incidence of cardiotoxicity w/ dehydroemetine
Emetine & Dehydroemetine
-Treatment of pneumonia caused by opportunistic pathogenic protozoan P.
Carinii, a frequent secondary invader associated w/ AIDS
-Administered by slow IV infusion or by deep IM injection for PCP
-Aerosol form – used by inhalation for prevention of PCP in high-risk patients
infected w/ HIV
-Both inhalant & parenteral dosage forms are sterile lyophilized powders that
must be made up as sterile aqueous solutions prior to use.
-Sterile water for injection must be used to reconstitute the aerosol, to avoid
precipitation of pentamidine salt
Pentamidine Isethionate
Cough & bronchospasm
Inhalation
Hypertension & hypoglycemia
Injection
-Prophylaxis and treatment of African trypanosomiasis
-Also for treating visceral leishmaniasis
-Prophylactic agent – rapidly disappears from plasma after IV injection and
is distributed to tissues, where it is stored for a long period.
Pentamidine Isethionate (NebuPent®)
-Highly lipophilic, water-insoluble analog of ubiquinone 6, an essential
component of mitochondrial electron transport chain in microorganisms
-Act as an antimetabolite for ubiquinone, thus interfere w/ function of
electron transport enzymes
-Originally developed as antimalarial drug but Plasmodium falciparum
developed rapid tolerance to its action
Atovaquone (Mepron)
-Recommended alternative to TMP-SMX for tx & prophylaxis of PCP in
patients intolerant to this combination
-Effective in eradicating T. Gondii in preclinical animal studies
-Slow & incomplete oral absorption because of low water solubility of drug
-Aqueous suspensions have better absorption than tablets
-Food (esp. high fat content) increases absorption
Atovaquone
Half life of Atovaquone is
62 to 80 hours
Side effects of Atovaquone
GI intolerance
-Treatment of West African sleeping sickness (Trypanosoma brucei / gambiense)
-Indicated for meningoencephalitic stage of disease
-Myelosuppressive drug that causes high incidences of anemia, leukopenia,
thrombocytopenia
-Monitor CBC during course of therapy
-Irreversible inactivation of ornithine decarboxylase by eflornithine is accompanied
by decarboxylation & release of fluoride ion from inhibitor, suggesting enzymecatalyzed activation of inhibitor
-Administered either IV or orally
-Penetration into CSF is facilitated by inflammation of meninges
Elfornithine
-In addition to their antibacterial & antifungal properties, also have
antiprotozoal activity w/c led to discovery of particular nitrofurans w/
antitrypanosomal activity
-Effective against T. cruzi (South American)
-Only clinically proven treatment for both acute and chronic forms of disease
-Administered orally
-Oral bioavailability is high but first-pass metabolism occurs
- Half-life: 2-4 hrs
-High incidence of n&v, abdominal pain & anorexia
Nifurtimox
-Nitroimidazole derivative
-Treament of Chagas disease
-Effectiveness similar to that of nifurtimox
-Therapy w/ oral benznidazole requires several weeks
-A/E: peripheral neuropathy, bone marrow depression, allergic-type
reactions
Benznidazole (Radanil®, Rochagan®
-Prepared by reduction of corresponding pentavalent arsanilate to the trivalent
arsenoxide followed by reaction of latter w/ BAL
-DOC for treatment of later stages of both forms of African trypanosomiasis
-Advantage: excellent penetration into CNS, thus effective against
meningoencephalitic forms of T. gambiense & T. Rhodesiense
-Trivalent arsenicals tend to be more toxic to host than corresponding
pentavalent compounds
-Shares toxic properties of other arsenicals, so its use must be monitored for
signs of arsenic toxicity
Melarsopol
-Pentavalent antimonial compound
- Treatment of various forms of leishmaniasis
-10% aqueous solution used for either IM or IV injection has pH of
approximately 5.5
-Low therapeutic index, thus monitor carefully for signs of heavy metal
poisoning
- Antileishmanial action requires its reduction to trivalent form, w/c is
believed to inhibit phosphofructokinase in parasite
Sodium Stibogluconate
-2,3-Dimercapto-1-propanol, BAL, dithioglycerol
- Developed by British during WWII as antidote for “Lewisite”, hence the
name British anti-Lewisite - Effective topically & systematically as antidote for poisoning caused by
arsenic, antimony, mercury, gold & lead
-Antidotal properties are associated w/ property of heavy metals to react
w/ sulfhydryl groups in proteins & interfere w/ their normal function
- Topically as ointment or IM as 5% or 10% sol’n in peanut oil
Dimercaprol
-High-molecular-weight bisurea derivative containing 6 sulfonic acid groups as
their sodium salts
- Developed in Germany after WWI as byproduct of research efforts directed
toward development of potential antiparasitic agents from dyestuffs
-Treatment of early cases of trypanosomiasis
- Long-term prophylactic agent (effectiveness after single IV injection maintained
up to 3 months) - Tissue penetration of drug does not occur bec. of its high molecular weight &
highly ionic character. - Thus, injected dose remains in plasma for very long period
-Prophylaxis of onchocerciasis
Suramin Sodium
