Antiprotozoal Drugs Flashcards
What does P. falciparum infect?
RBCs of all ages
What does P. vivax infect?
Reticulocytes
What 2 forms of plasmodium cause relapsing malaria?
P. vivax and ovale
What causes relapsing malaria?
The hypnozoite form of the parasite resides in the liver and is then released to cause a relapse
What is the Malaria parasite life cycle?
- Sporozoite injected by mosquito and goes to liver 2. Merozoite formed in liver 3.(Hypnozoite formed in P. vivax and ovale) 4. Merozoite invades, divides, ruptures RBCs, reinvade 5. Sexual stage produced by gametocytes which is taken up by mosquito
What drugs kill the sporozoites?
There are no drugs to kill sporozoites. You cannot prevent infection
What are the exoerythrocytic schizonticides?
Primaquine, Atovaquone, and Artemisinins
What are the Erythrocytic Schizonticides?
Chloroquine, Mefloquine, Artemisinins, Quinine, Doxycycline (Tetra), and Clindamycin
Dosing Regimen: Chloroquine and Hydroxychloroquine Sulfate
Start 1-2 wks prior and continue 4 wks post (Used Sensitive Areas)
Dosing Regimen: Atovaquone + Proguanil
Start 1-2 d prior and continue 7 d post (All Areas)
Dosing Regimen: Mefloquine
Start >2 wks pre and continue 4 weeks post (Mefloquine sensitive areas
Dosing Regimen: Primaquine
Start 1-2 d pre till 7 ds post (in P. vivax areas)
Dosing Regimen: Doxy
Start 1-2 d pre and continue 4 wks post (All areas)
What is the treatment of choice for uncomplicated malaria caused by P. vivax or ovale that is chloroquine sensitive?
Chloroquine or Hydroxychloroquine PLUS Primaquine
What does Primaquine fight?
It conquers the hypnozoite stages in the liver
What is the treatment of choice for uncomplicated malaria caused by P. vivax or ovale that is chloroquine resistant?
1) Quinine Sulfate + doxycycline or Tetracycline + Primaquine 2) Atovaquone + Proguanil + Primaquine 3) Mefloquine + Primaquine
What is the treatment of choice for uncomplicated malaria from P. malariae or knowlesi?
Chloroquine or Hydroxychloroquine
What is the treatment regimen for complicated/severe malaria?
IV Quinidine gluconate + Doxy or Tetra or Clindamycin
What do you need to monitor with the severe malaria (Quinidine gluconate IV + Doxy) Regimen?
- Blood Pressure, 2. Cardiac Function, 3. Blood Glucose
What is another option for treatment of severe malaria?
Artesunate if quinidine gluconate is not available or not tolerated
What is the active group of Artemisinin?
Endoperoxide bridge is the active group and Fundamental to the drug’s function
What does Artemisinin fight against?
It is a rapid blood schizonticide, but does not affect liver stages. It is good for all species
What is the most successful Artemisinin Combination Therapy?
Pair Artemisinin (Short t1/2) with a longer t1/2 drug. Artemisinin provides rapid knockdown and other drugs gets remaining parasites
What are some common combinations with Artemisinin?
Artemether + Lumefantrine, Artesunate + mefloquine, Dihydroartemisinin + Piperaquine
What is the mechanism of action of the 4-substituted quinolines?
They are thought to accumulate in the food vacuole and inhibit heme polymerization
Why is it advantageous to block heme polymerization when fighting malaria parasites?
The parasites ingest Hbg from the host RBCs. The free heme is toxic so the parasite polymerizes it into hemozoin which is non-toxic. If you prevent this, then you maintain toxic heme in the cells.
Why do the pharmakokinetics of Chloroquine make it the drug of choice as an antimalarial?
- It is formulated for oral use and is well absorbed. 2. It has a very large Vd so it is slowly released from tissues. 3. Initial t1/2 = 3-5 d; Terminal t1/2 = 1-2 mos
What is the mechanism of Chloroqine resistance?
- Mechanism: Mutations in PfCRT1 which causes a reduced accumulation of chloroquine in the food vacuoles; 2. Mechansim: over-expression of PfMDR1 transporter
When is Chloroquine contraindicated?
Pts. with psoriasis or porphyria, Retina or visual field abnormalities, Myopathies
What should pts not take along with Chloroquine?
Antidiarrheal agent Kaolin and Calcium/Mg containing Antacids
Name other Chloroquine-related Compounds.
Mefloquine, Lumefantrine, Piperaquine, Amodiaquine, Halofantrine, Tafenoquine
What stage of malaria parasites do Quinine/Quinidine fight?
Blood Schiztosome
Quinine/Quinidine can be used for what species of Plasmodium?
All species, but is a 1st line alternate for P. falciparum
What are the differences in P. falciparum treatment w/ Quinine in severe vs. uncomplicated infection?
Severe = IV and Uncomplicated = P.O.
What is the generic name of Lariam?
Mefloquine
What is Mefloquine good to fight against?
Erythrocytic forms of P. falciparum and vivax
What are some adverse effects of Mefloquine?
Neuropsychiatric toxicity!
What is the probable mechanism of Primaquine?
Probably Involves ROS
What is the structural name of Primaquine?
It is an 8-aminoquinoline
What does Primaqine treat?
The hypnozoites (liver stages) of P. vivax and P. ovale; and gametocidal for all 4 malaria parasites
What is the only drug against Hypnozoites?
Primaquine
When is Primaquine contraindicated?
G6PDH Deficiency - Can cause hemolytic anemia
Why is Primaquine contraindicated in pregnancy?
The Fetus is G6PDH deficient
What are the Antifolate drugs for malaria?
Pyrimethaime & Proguanil
What is Fansidar?
It is a combination of Sulfadoxine and Pyrimethamine
What stage of malaria parasites does Fansidar fight?
It is a slow acting erythrocytic schozonticide
What is the Mechanism of Action of Pyrimethamine?
Inhibits plasmodia DHR-reductase
Why is Pyrimethamine so effective as a drug?
It inhibits the parasite’s DHF-reductase enzyme and this enzyme turns over much slower than the human enzyme so it cannot replace the enzyme as quickly
Name 2 other diseases where antifolates have proven effective?
Toxoplasmosis and Pneumocystis
What is the 1st line therapy for Toxoplasmosis?
Pyrimethamine + Sulfadiazine (Clindamycin can replace)
What is the 1st line therapy for Pneumocystis infection?
Trimethoprim+Sulfamethoxazole
Why is the use of single antifolates not recommended?
Resistance develops easily
What is Malarone?
It is a combination of proguanil and atavaquone
What is the MOA of Atavaquone?
It disrupts mitochondrial e- transport
What antibiotics are good schizonticides?
Tetracycline, Doxycycline, and clindamycin
Why can antibiotics be used to fight malaria parasites?
They target componenets of the apicoplast?
What is the apicoplast?
It is a plant-like organelle that carries out biochemical processes in the protozoan
When is Doxycycline used?
As chemoprophylaxsis in areas w/ high resistance to mefloquine
What is a good drug for anaerobic parasites?
Metronidazole
What is Metronidazole the drug of choice for?
Entamoeba histolytica, giardiasis, and trichomoniasis
What does Metronidazole kill?
Trophs not cysts
What is the significant clinical link between Metronidazole and alcohol?
Metronidazole inhibits Acetaldehyde dehydrogenase thus mimicking antabuse and causing alcohol sickness
What is Iodoquinol?
It is a luminal amebicide with low bioavailability. It kills trophozoites
Where does Iodoquinol act?
In the GI lumen
How do you treat amebic dysentery?
Use Iodoquinol in combination w/ metronidazole
When is Pentamidine used?
To treat West African Trypanosomiasis, and second line of defense in visceral leishmania and pneumocystosis
What is the MOA for Pentamidine?
Unknown, but accumulates preferentially in the parasite
What does Nifurtimox treat?
T. cruzi infection; only decreases the acute phase of the disease
What does Miltefosine treat?
1st oral anti-leishmanial drug.
How long is the treatment course with Miltefosine and what are the results?
28 day course yields near 100% cure rate
Can Miltefosine be used in pregnancy?
No, it is teratogenic
What do you use to treat the Early Stages of West African Trypanosoma brusei (Sleeping Sickness)
Pentamidine
What do you use to treat Late Stages of West African Trypanosoma brusei?
Eflornithine
What do you use to treat the Early Stages of East African Trypanosoma brusei infection?
Suramin
What do you use to treat Late stages of East African Trypanosoma brusei infections?
Melarsoprol
