EXAM #4: ANTI-PARASITIC DRUGS Flashcards
What are the obstacles to treating parasitic organisms?
1) Eukaryotic
2) Nearly identical cellular machinery
Thus, there are limited drug targets and a high degree of toxicity.
What are the the three major targets for antiparasitic chemotherapy?
1) Enzymes only in the parasite
2) Enzymes or processes found in BOTH the host/ parasite but INDESPENSIBLE to the parasite
3) Enzymes that are the same in both host and parasite but with limited toxicity to host
What is an example of an enzyme found only in parasites that is targeted by antiparasitic drugs?
PFOR
List the intestinal/ luminal parasites.
- Giardiasis
- Amebiasis
- Trichmonoiasis
What causes Amebiasis?
Entamoeba histolytica
What are the two forms of Entamoeba histolytica and Giardia?
- Trophozite form that infects gut and disseminates to other tissue
- Dormant cyst
What drug is used to treat the intestinal parasites?
Metronidazole
What is PFOR?
Pyruvate: ferrodoxin oxidoreductase
*Found only in parasites
What is the MOA of Metronidazole?
- Pro-drug that enters cell and is reduced by PFOR to its active form
- Reduced Metronidazole produces reactive intermediates that disrupt DNA/proteins
What adverse effects are associated with Metronidazole?
1) Metallic taste
2) Disulfram-like effect
Thus, patients should avoid alcohol
If you’re treating a patient for Trichomoniasis with Metronidazole, what do you need to remember?
Trichomoniasis is a STD–need to treat the partner too
What form of Amebiasis is Metronidazole good at treating?
Trophozoites that have left the gut
Does NOT do a good job treating the cyst form
What drugs are used to follow-up Metronidazole treatment in Amebiasis?
1) Iodoquinol OR
2) Paromomycin
Now Paromomycin is more commonly used–less toxicity and shorter treatment course
What is Halogenated hydroxyquinoline good at treating?
BOTH forms of Entameba histolytica in the LUMEN
What is Paromomycin good at treating?
BOTH forms of Entameba histolytica in the LUMEN
What are the major opportunistic parasitic infections of AIDS patients and the immunocompromised?
1) Cryptosporidium parvum
2) Pneumocystis jiroveci
3) Toxoplasma gondii
What disease is caused by Cryptosporidium parvum?
Cryptosporidiosis–profuse watery diarrhea
- Self-limiting in adults
- Can be fatal in immunosuppressed
How is Cryptosporidiosis treated?
Nitazoxanide
What is the MOA of Nitazoxanide?
Inhibition of PFOR that disrupts energy metabolism in the parasite
In addition to Cryptosporidiosis, what else can Nitazoxanide treat?
Giardiasis
How are Pneumocystis jirovecii and Toxoplasma gondii treated?
Inhibitors of folate synthesis
- TMP-SMX
- Pyrimethamine-Sulfadiazine
What is the MOA of Sulfonamides?
PABA analog that inhibit DIHYDROPTEROATE SYNTHASE
What is the MOA of Diaminopyrmidines?
Inhibitors of DHFR that prevent formation of tetrahydrofolate
What is the major adverse effect seen with Sulfonamides?
Rash
What is an adverse effects seen with Pyrimethamine-Sulfadiazine treatment?
- Folic acid deficiency
- Can cause megaloblastic anemia
Note that this is used for Toxoplasmosis
How can folate deficiency in Pyrimethamine-Sulfadiazine treatment be treated?
Leucovorin rescue
What is the MOA of resistance to the folate synthesis inhibitors?
Point mutations in the enzyme targets
What drug is used to treat the hepatic stage of Malaria infection?
Primaquine
What is the major target of most of the Malaria drugs?
RBC cycle of replication
What the MOA of Chloroquine?
Unclear- maybe interferes parasite ability to detoxify metabolites
Where is Chloroquine used today?
West of the panama canal?
What is the mechanism of Chloroquine resistance?
Drug export pumps
What is the MOA of quinine?
- May interfere with Hb degradation and cause accumulation of toxic metabolites
- May complex with parasite DNA to prevent replication
What do you need to remember about Quinine?
Poor TI–associated with:
1) Cinchonism
2) Hypoglycemia
How is Quinine used to treat Malaria?
- NOT for prophylaxis b/c of toxicity
- Used IV if positive diagnosis
How is Mefloquine used to treat Malaria?
Prophylaxis
What adverse effects are associated with Mefloquine?
Severe neuropsychiatric reactions
What is the MOA of Primaquine?
- Prodrug
- Interferes with electron transports
- May inhibit pyrimidine synthesis
What do you need to remember about Primaquine?
ONLY DRUG available for liver/hypnozoite form
What species of malaria are associated with a liver form?
P. vivax
P. ovale
What toxicity is seen with Primaquine?
If taken by a patient with G6PD, can lead to hemolysis
*Thus, screen for G6PD before administering
What is Malarone good for treating?
P. falciparum
Good for treatment and for prophylaxis
What is Malarone?
Combination of Atoaquone and Proguanil
What is the MOA of Proguanil?
Inhibits DHFR
What is the MOA of Doxycycline?
Inhibits plasmodium protein synthesis
How is Doxycycline used to treat Malaria?
Prophylaxis
What are the major side effects of Doxycycline?
- Photosensitivity dermatitis
- Staining of teeth in kids
What patient populations is Doxycycline contraindicated in?
1) Children
2) Pregnant women
What is Artemisinin derived from?
Chinese wormwood
What is the clinical utility of Artemisinin?
Effective treatment for multi-drug resistant strains of P. falciparum
What is the general MOA of the antihelminthic drugs?
1) Inhibit mitosis of the parasite
2) Cause muscle paralysis of the parasite (allows the organism to be passed more easily)
List the Benzimidazoles.
Albendazole
Mebendazole
Thiabendazole
Which of the Benzimidazoles has the greatest toxicity? Why?
Thiabendazole–more easily absorbed into system circulation than the others
How are the Benzimidazoles normally given?
Orally on an empty stomach
What toxicities are associated with Thiabendazole?
CNS disturbances–delerium and hallucinations
In what patient populations are the Benzimidazoles contraindicated?
Pregnant women
What infections are Albendazole and Mebendazole used to treat?
Ascariasis
Pinworm
Hookworm
Whipworm
*Note that this is done with a SINGLE dose
What is Thiabendazole used to treat?
1) Topical preparation for cutaneous larval migrans
2) Strongyloidiasis (2nd line)
What is the MOA of Ivermectin?
Causes muscle paralysis in parasites BUT not in humans
What is Ivermectin the drug of choice for?
1) Strongyloidiasis
2) Tissue dwelling nematodes including:
- O. volvulus (river blindness)
- Loa loa (eye worm)
- W. bancrofti (elephantiasis)
(Thiabendazole is second line for Strongyloidiasis)
What is the MOA of Pyrantal Pamoate?
Depolarizing neuromuscular blockade
What is Pyrantal Pamoate the drug of choice for?
Pinworm
Note that only 2 doses are needed
What do you need to remember about Pinworm infections?
Treat the ENTIRE household
What drug is used to treat Tapeworm and Fluke infections?
Praziquantel
What is the MOA of Praziquantel?
- Increased the Ca++ permeability of the cuticle covering these worms
- Causes depolarizing neuromuscular blockade/ paralysis
