16 anti protozoal drugs lecture9 (0ct10)

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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16 anti protozoal drugs lecture9 (0ct10)

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