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7/27/2019 16 Anti Protozoal Drugs Lecture9 (0ct10)
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Anti-protozoal drugs
(trypanosomiasis, leishmaniasis, toxo etc)
PHCL-L3-Ant iMicro- lecture9
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Leishmanicidal drugs
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Leishmanicidal drugs
Cutaneous leishmania
Sodium stibogluconate, antimoniate,
pentamidine, topical paromomycin, Miltefosine
Visceral leishmania
Sodium stibogluconate, liposomalamphotericine, Miltefosine
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SODIUM STIBOGLUCONATE
Mechanism: inhibits glycolysis & Fatty acid-oxidation
ATP/GTP (inglycosomes)
It is administered i.m or i.v
Uses:Leishmaniasis (L. brazi l ienses, mexicana,donovoni, tropica)
Side Effects: Cardiac arrhythmia ,nephrotoxicity and pancreatitis &
Rapid emergence of resistance
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Lipid Amphotericin BIn 1997 the FDA approved liposomal
amphotericin B (Ambisome) for the treatment
of leishmaniasis
Less toxic than the antifungal amphotericin BAmphotericin complexes with ergosterol
precursors in the cell membrane, forming pores
that allow ions to enter the cell
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Leishmanicidal drugs between 1985 and 2005
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Trypanosomicidal drugs
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Trypanosomicidal drugs
Human Africa trypanosomiasis
Hemolymphatic stage
Pentamidine, suramin
Central nervous system stage
Melarsoprol, eflornithine
Chagas DiseaseNifurtimox and Benznidazole
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eflornithine
Indications:
Sleeping sicknesscaused by Trypanosoma brucie gambiense
MOA:
inhibits the enzyme ornithine decarboxylase An ornithine analogue that inhibits the enzyme ornithine
decarboxylase, the first enzyme in the synthesis of polyamines
These polyamines are essential for cell division, cellulardifferentiation, and in the protection against oxidative stress
Conversion of ornithine putrescine (polyamine)
Regulates DNA Synthesis
Adjust dosage as a function of creatinine clearance
IV use only agent, monitor for hematological problems
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Cl-+H3N
NH2
CF3
CO2H
Eflornithine HCl - Ornidyl
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Melarsoprol
Has been used to treat trypanomiasis since1947
Melarsoprol is a prodrug that is metabolizedinto melarsen oxide
Inhibits the many enzymes, including the
trypanothione reductase Can have severe side effects, including
death in 5% of patients
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N
N
NHN
H2N
H2N
As
S
S
CH2
CH
CH2OH
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Nifurtimox
Mechanism:
It acts by generating superoxide and hydrogen peroxideradicals toxic as they lack catalase.
Orally well absorbed
Side Effects: Allergic hypersens
GI distress
Weakness
Use: Used in the treatment of Trypanosoma cruzi infection(Chagas disease)
effective against both trypomastigote & amastigote stages
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SURAMIN
Synthesized in 1916 as a product of the German dye industry
Sulfonic acid and structurally related to dyes
A highly negatively charged compound- does not cross the BBB
Mechanism of action : It acts by inhibiting enzymes of energy metabolism including glycerol
phosphate dehydrogenasefor trypanocidal activity
Uses: old world trypanosomiasisT. gambiense, rhodesiense
Pharmacokinetics: ineffective for CNS inf
Side Effects:
N, malaise, fatigue (some a/w parasitic destruction) Shock, renal failure in some
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HNOC
NH
SO3H
HO 3S
SO3H
CO
NH CO
2X
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Melarsoprol
Trivalent arsenical
MOA
The drug acts by reacting with SH groupsof various enzymes
Uses
to treattrypanosoma infections with CNSinvolvement.
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Pentamidine Active against:
Trypanosoma ,leshmaniasis , pneumocystis carinii
MOA Aromatic diamine synthesized in the late 1930s Inhibits synthesis of parasitic DNA by blocking thymidine
synthase Also, Pentamidine interfere with synthesis of RNA
Administered IV or aerosol Pharmacokinetics:
Poor oral bioavailability so used by aerosol or IV Metabolism: ? Excretion: urine
Adverse effects Nephrotoxicity , Urticaria Pancreatitis Leukopenia Thrombocytopenia
O O
NH2
NH
NH2
NH HOSO2OH
SO2OH
OH
Pentamidine isethionate - Pentam, Pentacarinat, NebuPent
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Trypanosomicidal drugs between 1985 and 2005
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Others
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Toxoplamosis
Treatment
Pyrimethamine-sulphdiazine
Parenteral pentamidine
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Trichomoniasis
Treatment:
metronidazole
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