Antiparasitics

Question 1

Prevalence in U.S.A.:

Answer 1

1. Helminth infections: >1 million per year
2. Toxocara (from dogs, cats) roundworms: 14% of population
3. Malaria: 2000 endemic cases per year
4. Amebiasis: 3–5% of population
5. Giardia: 2–10% of population
6. Trichomonas vaginalis: ~3 million/year

• Infection associated with poor economic
  conditions

Question 2

Approaches To Antiparasitic Chemotherapy:

Answer 2

1. Selective Chemotherapy
2. “Cure” vs. “Control”
   
   • Can agent(s) be found to eradicate all stages of parasite in host

Question 3

Nematodes (Roundworms) Infections (10):

Answer 3

1. Ascaris lumbricoides (common roundworm)
2. Strongyloides stercoralis (threadworm)
3. Enterobius vermicularis (pinworm)
4. Necator americanus (hookworm)
5. Dracunculus medinensis (guinea worm)
6. Trichuris trichiura (whipworm)
7. Trichinella spiralis (trichinosis)
8. Toxocara canis (canine ascarid)
9. Ancylostoma braziliense (dog hookworm)
10. Wuchereria bancrofti, Loa loa, Onchocerca volvulus (filariasis)

Question 4

Chemotherapy for Nematode (Roundworm) Infections (4):

Answer 4

1. Mebendazole (Vermox®)
2. Albendazole (Albenza®)
3. Thiabendazole (Mintezol®)
4. Pyrantel pamoate (Antiminth®, Pin-X®)

Question 5

Mebendazole:

• Mechanism:
• Use:
• Absorption/Excretion:

Answer 5

• Mechanism:
  
  • ​selective damage to cytoplasmic microtubules
  • immobilizes and kills parasite
• Use:
  
  • ​effective for many intestinal roundworms
  • kills some ova
• Absorption/Excretion:
  
  • ​low systemic bioavailability = low systemic toxicity

Question 6

Albendazole:

• Mechanism:
• Use:
• Side Effects:

Answer 6

• Mechanism:
  
  • ​same as mebendazole
  • except liver quickly converts it to albendazole sulfoxide which is an active metabolite with good systemic distribution
• Use:
  
  • ​Echinococcus
    
    • 1st choice
    • hydatid cyst disease, actually a cestode
  • neurocysticercosis due to Taenia solium
  • cutaneous larval migrans
  • active against many intestinal roundworms but not a labeled indication
• Side Effects:
  
  • ​elevated hepatic enzymes
  • abdominal pain, nausea, vomiting, headache

Question 7

Thiabendazole:

• Mechanism:
• Use:
• Administration:
• ​Side Effects:

Answer 7

• Mechanism:
  
  • ​Hookworms: probably affects energy metabolism via inhibition of mitochondrial
    fumarate reductase
  • Strongyloides: inhibits assembly of parasitic microtubules
• Use:
  
  • strongyloidiasis
  • cutaneous larva migrans
  • alternate agent for other roundworm infections
• Administration:
  
  • ​oral or topical (if cutaneous larval migrans limited)
• Side Effects:
  
  • ​anorexia, nausea, vomiting, dizziness

Question 8

Pyrantel pamoate:

• Mechanism
• Use
• Side Effects

Answer 8

• Mechanism:
  
  • ​depolarizing neuromuscular blocker
  • causing spastic paralysis of worm
• Use:
  
  • ​hookworm, pinworm, and roundworm
• Side Effects:
  
  • ​not effective against Trichuris (whipworm)

Question 9

Trematode (Fluke) Infections:

Answer 9

1. Intestinal:
   
   • Fasciolopsis buski
2. Blood:
   
   • Schistosoma haematobium
   • S. japonicum
   • S. mansoni
3. Lung:
   
   • Paragonimus westermani
4. Liver:
   
   • Clonorchis sinensis
   • Fasciola hepatica

Question 10

Chemotherapy of Trematode (Fluke) Infections:

Answer 10

Praziquantel (Biltricide®)

Question 11

Praziquantel:

• Mechanism
• Use
• Side Effects

Answer 11

• Mechanism:
  
  • ​increases cell membrane permeability to calcium
  • resulting in marked muscle contraction
• Use:
  
  • ​drug of choice for all species of Schistosoma
  • some activity against other trematodes
    
    • e.g. Chlonorchis, Paragonimus, Opisthorchis
  • good activity against many cestodes
• Side Effects:
  
  • ​abdominal discomfort, nausea

Question 12

Cestodes (Tapeworms) Infections (5):

Answer 12

1. Taenia saginata (beef)
2. Diphyllobothrium latum (fish)
3. Taenia solium (pork)
4. Hymenolepsis nana (dwarf tapeworm)
5. Echinococcus granulosus, E. multilocularis (hydatid cysts)

Question 13

Chemotherapy of Cestodes (Tapeworms) Infections (3):

• Use:

Answer 13

1. Praziquantel (Biltricide®):
   
   • Use:
     
     • for Taenia solium (pork tapeworm)
     • will prevent neurocysticercosis
     • good activity against many cestodes
2. Albendazole
   
   • Use:
     
     • treat neurocysticercosis
3. Paromomycin Sulfate (Humatin®)
   
   • Use:
     
     • good activity against many cestodes

Question 14

Malaria Life Cycle:

Answer 14

1. Sporozoites in mosquito salivary gland are injected into human blood
2. Exoerythrocytic stage—
   
   • sporozoites multiply in liver ⇒ tissue schizonts
3. Escape from liver into bloodstream as merozoites
   
   • ​​begins the erythrocytic stage
   • merozoites invade red blood cells
   • multiply in them to form blood schizonts
4. Infected erythrocytes eventually rupture
   
   • releasing a new crop of merozoites
   • this erythrocytic cycle may be repeated several times
5. During the erythrocytic stage:
   
   • gametocytes (sexual stage) form
   • are released into the blood stream
   • where they may be taken up by a mosquito

Question 15

Classification of antimalarials based on life cycle stage (4):

Answer 15

1. tissue schizonticides:
   
   • eliminate latent liver hypnozoites
   • e.g. primaquine
2. blood schizonticides (suppressive agents):
   
   • act on blood schizonts
   • e.g. chloroquine, mefloquine, quinine
3. gametocides:
   
   • kill gametocytes in blood
   • e.g. primaquine for P. falciparum, chloroquine for P. vivax, malariae, ovale
4. sporonticidal agents:
   
   • render gametocytes noninfective in mosquito
   • e.g. pyrimethamine

Question 16

Antimalarial Drugs (6):

Answer 16

1. Chloroquine (Aralen®)
2. Mefloquine (Lariam®)
3. Atovaquone + Proguanil (Malarone™)(2000)
4. Quinine
5. Doxycycline (Atridox™, Doryx®, Doxy®, others)
6. Primaquine

Question 17

• *Chloroquine** (Aralen®):
• *Mechanism**

Answer 17

• blood schizonticide
• selectively toxic to parasite because parasitized erythrocytes concentrate the drug (>25-fold)
• only intraerythrocytic trophozoites that are actively degrading hemoglobin are chloroquine-susceptible
  
  • polymerize potentially toxic free heme into unreactive hemozoin
• chloroquine inhibits this heme polymerization
  
  • ​heme accumulates to toxic levels

Question 18

Chloroquine:

• **Use: **
• Side Effects:

Answer 18

• Use:
  
  • prevent attacks of all 4 species of malaria
  • eradicate P. malariae and chloroquine-sensitive P. falciparum
  • will not effect a complete cure of P. vivax or ovale
    
    • must give primaquine
• Side Effects:
  
  • visual impairment

Question 19

Mefloquine:

• Mechanism:
• Use:

Answer 19

• Mechanism:
  
  • not proven, but probably similar to chloroquine
  • blood schizonticide for P. falciparum and P. vivax
  • resistance can develop rapidly
• Use:
  
  • treatment of chloroquine-resistant and multidrug-resistant P. falciparum and P. vivax
  • used as prophylaxis in areas where organisms are resistant to chloroquine

Question 20

Atovaquone + Proguanil (Malarone™):

Mechanism

Answer 20

1. Atovaquone
   
   • ​​selectively inhibits malarial mitochondrial electron transport (cytochrome bc1 complex)
   • ultimate effect is disruption of protozoal
     pyrimidine synthesis
2. Proguanil
   
   • ​​prodrug
   • inhibits malarial dihydrofolate reductase and ultimately pyrimidine synthesis

Question 21

Atovaquone + Proguanil:

• Use:
• Side Effects:​​

Answer 21

• Use:
  
  • ​prevention and treatment of chloroquine- resistant P. falciparum
• Side Effects:
  
  • ​nausea, diarrhea, vomiting, rash

Question 22

Quinine:

• Mechanism:
• Use:
• Side Effects:

Answer 22

• Mechanism:
  
  • ​similar to chloroquine
  • blood schizonticide against all four malarial parasites
• **Use: **
  
  • ​agent of choice for severe acute attacks
  • treatment of chloroquine-resistant P. falciparum (alternate choice)
• Side Effects:
  
  • cinchonism: headache, visual disturbance, dizziness, tinnitus
  • gastric irritation, nausea, vomiting
  • cardiac effects similar to quinidine

Question 23

Doxycycline (Atridox™, Doryx®, Doxy®, others):

• Mechnaism:
• Use:​​

Answer 23

• Mechanism:
  
  • ​decrease malarial protein synthesisanddepress dihydroorotate dehydrogenaseactivity, therebyinterfering with pyrimidine synthesis
• Use:
  
  • multidrug-resistant P. falciparum

Question 24

Primaquine:

• Use:
• Side Effects:

Answer 24

• Use:
  
  • ​radical cure or terminal prophylaxis of P. vivax and P. ovale because it will kill dormant liver schizonts
  • should be used in conjunction with blood schizonticide
  • in combination with clindamycin to treat Pneumocystis jiroveci (carinii) pneumonia in AIDS patients
• Side Effects:
  
  • ​hemolytic reactions in those with G6PD deficiency

Question 25

What Causes Amebic Dysentery?

Answer 25

Entamoeba histolytica

Question 26

**Drugs that Treat Ambesias (3):**

Answer 26

1. **Metronidazole** 2. **Iodoquinol** 3. **Paromomycin**

Question 27

How are Amebic Drugs Classified?

Answer 27

**Site of Action** 1. **Tissue Amebicides** * eliminate organisms primarily in bowel wall, liver, and other extraintestinal tissues * **metronidazole** * needed for **symptomatic infections** 2. **​Luminal amebicides** * **​**​used alone for **asymptomatic infections** * **given with tissue amebicide for symptomatic infections** * **iodoquinol, paromomycin sulfate**

Question 28

**Metronidazole:** **Use**

Answer 28

**tissue amebicide** for mild to severe **symptomatic infections** of **E. histolytica**

Question 29

**Paromomycin Sulfate** (Aminosidine; Humatin®)**:** * **Mechanism:** * **Use:** * **Side Effects:**

Answer 29

* **Mechanism:** * ​aminoglycoside-like, **inhibiting protein synthesis** * **Use:** * ​**luminal amebicide** * **Side Effects:** * **​**diarrhea, nausea, vomiting, epigastric pain

Question 30

**Iodoquinol** (diiodohydroxyquin)(Yodoxin®; Diquinol, Yodoquinol)**:** * **Mechanism:** * **Use:** * **Side Effects:**

Answer 30

* **Mechanism:** * **luminal amebicide** * **Use:** * in **combination with metronidazole** for mild to severe infections of E. histolytica * **Side Effects:** * diarrhea and other gastrointestinal symptoms * contraindicated for those hypersensitive to iodine-containing preparations

Question 31

**Chemotherapy for Other Protozoal Diseases (4):**

Answer 31

1. Metronidazole (Flagyl®) 2. Atovaquone (Mepron®) 3. Paromomycin Sulfate 4. Nitazoxanide

Question 32

What other protozoa can **metronidazole** be used for?

Answer 32

**Drug of choice for:** 1. Giardia lamblia * most common intestinal protozoal infection in U.S. 2. Trichomonas vaginalis

Question 33

**Atovaquone** (Mepron®)**:** * **Mechanism:** * **Use:** * **Side Effects:**

Answer 33

* **Mechanism:** * **selective inhibitor of protozoal mitochondrial electron transport** * ultimate effect is **disruption of protozoal pyrimidine synthesis** * **Use:** * **alternate prophylaxis** or treatment for mild/moderate **Pneumocystis jiroveci (carinii)** in AIDS patients intolerant of TMP/SMX * **Side Effects:** * nausea, diarrhea, vomiting; rash

Question 34

**Nitazoxanide** (Alinia®)**:** * **Mechanism:** * **Use:** * **Side Effects:**

Answer 34

* **Mechanism:** * ​**inhibits pyruvate:ferredoxin oxidoreductase** which is required for **anaerobic energy metabolism** * **Use:** * Giardia lamblia * Cryptosporidium parvum * **Side Effects:** * ​abdominal pain, diarrhea, nausea

Question 35

What are the drugs used to treat **Pneumocystis jorveci (carnii)** in AIDS patients (4)?

Answer 35

1. **Trimethoprim + sulfamethoxazole (TMP-SMX)** 2. **Clindamycin + primaquine** 3. **Atovaquone** 4. **Dapsone**