Anti-parasite pharm => Ch 52

Question 1

What are the enzymes not found in host’s cells?

Answer 1

Dihydropteroate synthase;
Pyruvate-ferredoxin oxidoreductase
Nucleoside phosphotransferases
Trypanothione reductase

Question 2

What parasites use dihydropteroate synthase? Why do they use it?

Answer 2

Sporozoans => Plasmodium, Toxoplasma, Eimeria

lack ability to use exogenous folate

Question 3

What Drug class works against DHPS? How?

Answer 3

Sulfonamides => antimetabolites of PABA to inhibit dihydrofolate reductase

Question 4

What is Fansidar? Use?

Answer 4

Combo of sulfadoxine & pyrimethamine for chloroquine resistant Plasmodium falciparum malaria

Question 5

What parasites use PFO? Why do they use it?

Answer 5

some anaerobic protozoans (trichomonad, entamoeba) due to lack of mitochondria but need to produce acetyl CoA & H+ via electron transport

Question 6

Other than PFO making acetyl CoA, what else is it responsible for?

Answer 6

Transferring electrons from pyruvate to nitro groups of nitroimidazoles

Question 7

What is primary nitroimidazole and how does it work?

Answer 7

Metronidazole

forms cytotoxic products to inn growth by binding to parasite’s proteins & DNA

Question 8

What provides metronidazole with its safety & effectiveness against amebiasis & trichomoniasis?

Answer 8

selective toxicity => exploits biochem & physio differences bw parasite & host

Question 9

What Rx is used to take advantage of Giardia lamblia & Cryptosporidium parvum?

Answer 9

Nitazoxanide inhibits PFO pathway

Question 10

What is the purine salvage pathway in protozoan parasites? Why is it critical?

Answer 10

organisms unable to synthesize purine nucleotides de novo

Question 11

What disease and what mechanism do allopurinol riboside, formycin B, & thiopurinol riboside share?

Answer 11

Leishmania
purine nucleoside phosphotransferase (transfers phosphate to 5’ of purine nucleosides) but also phosphorylates purine nucleoside analog

Question 12

Triphosphate derivates of what Rx may be incorporated into nucleic acids or may inhibit enzymes in purine metabolism?

Answer 12

allopurinol riboside
formycin B
thiopurinol riboside

Question 13

Toxicity of allopurinol riboside, formycin B, & thiopurinol riboside?

Answer 13

low bc mammalian cells lack salvage enzyme

Question 14

What role does trypanothione reductase play in life of kinetoplastidans?

Answer 14

central role in maintaining reduced state of intracellular thiols & essential for survival of parasites

Question 15

What molecule does Trypanothione relate to in mammals?

Answer 15

glutathione

Question 16

What Rx inhibits Trypanothione reductase? What disease is it used in?

Answer 16

Nifurtimox for Chagas’ disease

Question 17

What are the 3 mechanisms involving enzymes indispensable to parasites?

Answer 17

Purine phosphoribosyl transferases (PPPR)
Ornithine decarboxylase (OD)
Glycolytic enzymes (Gly-en)

Question 18

What is key enzyme in Leishmania, Schistosoma, & Trypanosoma?

Answer 18

HGPRTase

Question 19

What is a good substrate for PPPR?

Answer 19

Allopurinol for certain parasites but not for mammalian enzyme

Question 20

MOA of allopurinol?

Answer 20

metabolized to ribotide, which is incorporated after phosphorylation into RNA forms that interfere w/ normal growth

Question 21

Purine salvage in Giardia depends critically on what?

Answer 21

adenine phosphoribosyl-transferase & guanine phosphoribosylttransferase

Question 22

What is the function of ornithine decarboxylase?

Answer 22

controls formation of polyamine, putrescine and appears more critical for growth of certain parasites.

Question 23

What is the action of the substrate against Trypanosoma, Plasmodium & giardia species?

Answer 23

Eflornithine is suicide substrate of ornithine decarboxylase w/ anti parasitic activity

Question 24

How does Eflornithine work against T. gambiense in African trypansomiasis?

Answer 24

irreversible inhibitory action of eflornithine transforms organism into non dividing form that can be eliminated by host immune system

Question 25

What enzyme can be inhibited by what Rx in the bloodstream form of African trypanosome T. brucei?

Answer 25

G-3-P oxidase can be inhibited by salicylhydroxamic acid leading parasite into anaerobic state

Question 26

Biogenesis of glycosides may be target for anti parasitic Rx. What Rx would do this and its MOA?

Answer 26

Suramin (large polar molecule) binds to glycolytic enzyme & prevent incorporation of enzymes into glycosome

Question 27

What are the 6 mechanisms involving biochem functions common to host & parasite? (more susceptible in parasite)

Answer 27

``` Dihydrofolate reductase Thiamin transporter Mitochondrial electron transporter Microtubules NeuroTx & muscle contractino Lanosterol demethylase ```

Question 28

What enzyme is a target of ABx & CTX and the parasites - Plasmodium, Toxoplasma, Eimeria? What Rx is associated?

Answer 28

DHFR is inhibited by Pyrimethamine

Question 29

Which parasite species has some resistant strains to pyrimethamine? How?

Answer 29

P. falciparum uses point mutations in gene coding for DHFR to make it less susceptible

Question 30

What biochem function is the primary energy sours of coccidia? How can this be utilized for Rx? What Rx?

Answer 30

Carb metabolism thus needs thiamin transport for energy so can be inhibited. Amprolium leads to thiamin deficiency in coccidia & low toxicity in hosts

Question 31

What mechanism is utilized for anticoccidial effects to interact w/ respiratory chain specific for Eimeria species? Is it just this species?

Answer 31

Mitochondrial electron transporter via 4-Hydroxyquinolone Rx Only disrupts mitochondrial respiration in Eimeria (no others)

Question 32

What is a Rx of hydroxyquinoline that Tx Pneumocystis carinii infections? its MOA?

Answer 32

Atovaquone primarily binds to cytochrome bc1 complex where a drug binding site is present in cytochrome b

Question 33

What accounts for the selective toxicity of benzimadazole drugs? What is an Rx?

Answer 33

structural features of alpha-tubulins in helminths so they bind to microtubules to block transport processes Mebendazole

Question 34

What are the Rx and how do anti parasitic effects stem from nicotinic agonist drugs?

Answer 34

levamisole, pyrantel pamoate acts in nematodes to lead to neuromuscular transmission leading to muscle contraction

Question 35

What is the MOA of piperazine?

Answer 35

GABA receptor agonist in nematodes leading to flaccid paralysis

Question 36

MOA of milbemycins & avermectins?

Answer 36

promote release of neuroTx & increase binding to post junctional receptors by actions of GABA

Question 37

Do milbemycins & avermectins cross BBB? toxicity

Answer 37

NO and relatively nontoxic

Question 38

MOA of praziquantel

Answer 38

antischistosomal & anti tapeworm agent that stimulates Ca+ entry into muscles of these parasites & causes unphysiologic contraction

Question 39

What parasites contain ergosterol as principal sterol in plasma membranes? What Rx class takes advantage of this and its MOA?

Answer 39

T. cruzi & Leishmania Azoles inhibit CYP450 dependent C-14-alpha demethylation of lanosterol in the ergosterol biosynthetic pathway to inhibit growth of T cruzi & Leishamnia

Question 40

What is best Tx for cutaneous leishmaniasis?

Answer 40

Fluconazole