ID Exam 3: Harrold Drugs to Treat Parasitic Infections

amebiasis, giardiasis

Drugs used for ___/____

-tinadazole

-nitazoxanide

-paromomycin

reactive oxygen species

Tinidazole

-MOA: The nitro group undergoes oxidation/reduction reactions to generate ___ ___ ___ (specifically superoxide, hydrogen peroxide, and hydroxide radicals)

Anaerobes

Explain why Tinidazole is more selective for Giardia sp. than it is for human cells.

- ____ (such as Giardia sp.) reduce the nitro group much more efficiently than do human cells. Thus, the ROS are selectively generated in Giardia lamblia.

alcohol

Co-administration of what substance will cause a drug interaction with tinidazole?

-co-administration of ___ will cause severe nausea and vomiting

free radicals

Nitazoxanide

-While similar in structure to tinidazole, it does not produce __ ___

hydrolysis, reduction

Nitazoxanide is a prodrug that produces 2 active metabolites:

-undergoes ester ____ to form a phenolic hydroxylic group

-undergoes ____ of the nitro group to form a hydroxylamine.

oxidoreductase

Nitazoxanide MOA

-the 2 active metabolites block the parasitic enzyme pyruvate:ferredoxin _____

acetyl CoA

pyruvate:ferredoxin oxidoreductase: reversibly converts pyruvate to ___ ___

bioenergetics

Inhibition of pyruvate:ferredoxin oxidoreductase disrupts the ___ of the parasitic cell (i.e., it is not able to correctly produce energy or products it needs)

freezes, nonsense

Paromomycin

-an aminoglycoside

-MOA is to binds to the 30S ribosome and ___ the initiation complex by not allowing f-Met-tRNA to bind. It also can lead to the production of “___” proteins in the bacteria.

helminthiasis

drugs used for ___:

-benzimidazoles

-ivermectin

-praiquantel

recognize

helminthiasis:

-diseases caused by parasitic worm infections

-in most instances, the human host immune defenses do not ___ these pathogens

albendazole, triclabendazole, mebendazole

benzimidazoles

1. ___

2. ___

3. ___

fumarate reductase, cap

Albenazole and Mebendazole MOA

1) inhibit ___ ___

2) bind to tubulin and ___ the association end

oxidative phosphorylation

Albenazole and Mebendazole MOA 1

The enzyme fumarate reductase is required for ___ ___

electrons

Albenazole and Mebendazole MOA 1

Inhibition of fumarate reductase prevents the transfer of ____ from NADH in Complex I

energy, mobilization

Albenazole and Mebendazole MOA 1

by inhibiting the transfer of electrons from NADH in Complex I:

1. decreases the ___ supply for the parasite

2. decreases the ___ of the parasite and ultimately leads to the death of the parasite

tubulin, polymerization

Albenazole and Mebendazole MOA 2

bind to ___ in helminths and prevent the ____ of tubulin into microtubules.

capping, length

Albenazole and Mebendazole MOA 2

prevent the polymerization of tubulin into microtubules by ____ the association end of tubulin and allow the dissociation to continue. This causes a net loss of microtubule ____

mitosis

Albenazole and Mebendazole MOA 2

-by capping the association end, these drugs prevent ____

prodrug

Triclabendazole

-___ metabolized to active metabolite by CYP1A2

tegument

Triclabendazole

-both drug and active metabolite are absorbed by the ____ (outer covering of the parasite)

potential, motility, surface membrane

MOA-When Triclabendazole is absorbed by the tegument:

1. decreases resting membrane ___

2. inhibits tubulin function as well as protein/enzyme synthesis. the inhibition is associated with inhibition of ___ and disruption of the ___ ___

microflaria

Ivermectin MOA

1. decreases motility of ____ (early stage of life cycle of parasitic nematodes)

cytotoxic, adhere

by decreasing the motility of microflaria, Ivermectin allows ___ cells of the host to ___ to the parasite

chloride, GABA

Ivermectin MOA

2. increases ___ influx or acts as ___ agonist

hyperpolarization, muscle paralysis

Ivermectin increases Cl- influx or acts as GABA agonist to cause ___ and ___ ___

produced/released

Ivermectin MOA

3. Causes the degeneration of microfilariae in utero resulting in a reduction of microfilariae ____/___ to prevent chance of reinfection

allergic, inflammatory

Ivermectin ADEs

-There is an ___ and ___ response that the patient experiences due to the death of the microfilarie and the release of the parasitic cell contents

corticosteroid, antihistamine

How can the adverse effects of Ivermectin be limited?

-administer with a ___, an ___, and/or another anti-inflammatory drug to help minimize these reactions

parasite

Praziquantel MOA

-The mechanism of action of praziquantel depends on the ___

muscle contractions, paralysis

Praziquantel MOA

For helminths, praziquantel causes ___ ___ and ___ because of an influx of calcium.

antigens

Praziquantel MOA

For intravascular worms, praziquantel damages the worm tegument (i.e., the outer body covering) and exposes ____ in the helminths that lead to an immune response to kill/remove the parasite.

lice

drugs used for ___:

-permethrin

-abametapir

sodium influx

Permethrin MOA

-binds to the sodium channel and inhibits ___ ___ through nerve cell membrane channels in parasites

repolarization, paralysis, death

Permethrin MOA

-inhibiting sodium influx results in delayed ___, ___, and ___ of the head lice.

metalloproteinase

Abametapir MOA

-a _____ inhibitor.

egg, survival

Abametapir MOA

-Inhibition of metalloproteinase decreases ___ development and the ___ of the lice.

3A4, 2B6, 1A2

Abametapir

-inhibits CYP__, CYP___, and CYP___

2 weeks

Abametapir

-AVOID administration of drugs that are substrates for CYP3A4, CYP2B6, or CYP1A2 within ___ ___ after application of abametapir

discomfort

Identify one common adverse effect for Permethrin and Abametapir?

-Both drugs are administered topically as either creams or lotions. The most common

adverse effect involves local ___ at the application site.

malaria

drugs used for ___:

-quinolines

-atovaquone + proguanil

-artesunate

amino acid

Why is hemoglobin important for plasmodium sp. (species that causes malaria)?

Answer: Hemoglobin is a transport protein. Plasmodium sp. breaks down this protein to

provide it with ___ ___

heme

What part of hemoglobin is toxic to Plasmodium species?

non-toxic

plasmodium species are able to metabolize heme and produce a ___-___ polymer known as hemozoin

pi-pi

Quinoline MOA

-All quinolines contain the bicyclic quinoline ring that forms __-___ stacking bonds with the porphyrin nucleus

hemazoin

Quinoline MOA

-the π-π stacking bonds prevent the further polymerization of hemoglobin to ____ (non-toxic)

-this inhibition exposes the toxic heme to the Plasmodium leading to the death of the

organism.

efflux, metabolism

Quinolines Mechanism of Resistance

1. development of a gene that encodes for a transmembrane transporter that increases ____ of the drug

2. an increased ___ due to enhanced cytochrome P450 activity.

cardiac rythym

Quinolines ADEs

-serious side effect includes disturbances in ___ ___

QT

Quinolines Drug Interactions

-All of these drugs are metabolized by CYP450 oxidation (so induction/inhibition of this enzyme will change levels)

-since drugs in this class can cause ___ elongations, additive effects can occur with other drugs that alter these levels

3A4, 2D6

Quinolines- 2 metabolizing enzymes to know

quinine → CYP___

chloroquinine → CYP___

resistance

Why must Atovaquine and Proguanil be used in combination?

-The parasite, plasmodium falciparum, exhibits a high incidence of ____ to both atovaquone and proguanil if they are used as single agents for the treatment of malaria. The

combination has been shown to provide synergistic antimalarial activity

respiratory, coenzyme Q

Atovaquine MOA

-selectively inhibits plasmodium mitochondrial ___ chain at Complex III due to its structural similarity to ___ ____

ATP synthesis

Atovaquine MOA

-by inhibiting the mitochondrial respiratory chain at Complex III, atovaquine prevents ___ __

cycloguanil

Proguenil

-a prodrug converted to ___

2C19

Proguenil

-converted to cycloguanil by CYP___

2C19

Proguenil Drug Interactions

-will have a drug interaction with any other drug that inhibits CYP___ because this will block the conversion/activation of proguanil to cycloguanil

dihydrofolate reductase, selective

Proguenil

-inhibits ___ ____resulting in the inhibition of DNA synthesis and the depletion of folate cofactors.

-___ for the plasmodium version of this enzyme (as compared to the human version)

iron

The MOA of artesunate involves ___ and the production of toxic carbon and oxygen atoms.

heme

In the mechanism of artesunate, what is the iron source?

radicals

artesunate MOA

-The normal digestion of heme in the digestive vacuole provides a source of Fe2+ which reacts with the peroxide group of artesunate to produce lethal carbon ____.

heart

What is the most serious adverse drug reaction seen with artesunate?

-Artesunate can cause first-degree ___ block.