Flashcards in Antimalarial Drugs: Inhibitors of Folate Synthesis Deck (21):
These cards will review inhibitors of folate synthesis. What are the drugs?
Used generally in combination regimens:
--pyrimethamine, proguanil, sulfadoxine
What are the clinical applications of inhibitors of folate synthesis?
Chemoprophylaxis: only in combo. Proguanil + chloroquine = no longer recommended
Intermittent Preventive Therapy: high risk patients receive intermittent therapy regardless of infection status
Tx of chloroquine-resistant falciparum malaria: pyrimethamine-sulfadoxine commonly used. Do not use for severe malaria
What are the antimalarial action of folate synthesis inhibitors?
Pyrimethamine + Proguanil:
--act slowly against erythrocytic forms of all malaria species
--some activity against hepatic forms
-weakly active against erythrocytic schizonts
What is the MOA of pyrimethamine + proguanil?
Inhibit plasmodial dihydrofolate reductase
What is the MOA of sulfonamides?
Inhibit dihydropteroate synthase
What are the PK and resistance for Folate synthesis inhibitors?
--relatively common for P. falciparum
What are the AE for Folate synthesis inhibitors?
Well tolerated (GI problems, rashes)
Proguanil (mouth ulcers, alopecia =rare)
Pyrimethamine-Sulfadoxine (erythema multiforme, steven johnson syndrome, toxic epidermal necrolysis)
Sulfadoxine (hematologic, GI, CNS, dermatologic and renal toxicity)
Pyrimethamine-sulfadoxine = safe
The next drug used in malaria is Doxycycline, what are some features?
Active against erythocytic schizonts of all human malaria parasites
Not active against liver stage
--used to complete treatment for severe falciparum malaria (given along with quinine) after initial tx with quinine, quinidine or artesunate.
--chemoprophylaxis against most forms: must be taken daily
What are the AE for Doxy?
Discoloration and hypoplasia of teeth, stunting of growth
Fatal hepatotoxicity (in pregnancy)
Do not use in pregos or children under 8
The next antimalarial drug is Artemisinin, what are some features?
Aretesunate: oral, IV, IM and rectal
Artemether: oral, IM. and rectal
Coartem: artemether + lumefantrine
What are the clinical applications for Artemisinin?
Tx of severe falciparum malaria (given IV)
No effect on hepatic stages
Should not be used as single agent to protect against resistance
What is the MOA and PK of artemisinin?
--appears to act by binding iron, breaking down peroxide bridges leading to generation of free radicals that damage parasite proteins
--very short half life
--if used alone, artesunate must be administered 5-7 days
What are the AE of Artemisinin?
Overall remarkably safe
Very high doses (neurotoxicity, QT prolongation)
More evidence for use in 2nd and 3rd trimesters of pregnancy
In 1st trimester can be used for tx of severe malaria
There are three other antimalarials that can be used.
1. Clindamycin: can be used as an alternative to doxy
2. Halofantrine: effective against erythrocytic stages of all parasites. Use is limited by irregular absorption and cardiac toxicity. Teratogenic
3. Lumefantrine: effective against erythrocytic stages of all parasites. only available as fixed dose combination with artemether. causes minor QT prolongation. well tolerated
These next set of cards are just review cards. For uncomplicated malaria what do you treat P. falciparum and P. malariae with?
P. Falciparum: if no resistance ----- chloroquine or hydroxychloroquine
--if resistance: atovaquone-proguanil (malarone) ; aretmether-lumefantrine (Co-artem) ; quinine + doxy or Mefloquine
P. Malariae: all regions
--chloroquine or hydroxychloroquine
For uncomplicated malaria what do you treat P. vivax or P. ovale with?
P. Vivax or P. Ovale: if no resistance ---- cholorquine + primaquine or hydroxychloroquine + primaquine
--if resistance --- Quinine + doxy + primaquine or Atovaquone-proguanil + primaquine or Mefloquine + Primaquine
For Uncomplicated Malaria in pregos?
P. Vivax, P. Ovale, P. Falciparum or P. malariae:
--Chloroquine sensitive then used chloroquine or hydrochloroquine
--chloroquine resistance P. Falciparum then used Mefloquine or Quinine + clindamycin
--chloroquine- resistant P. Vivax use Mefloquine
For all species of malaria what is the recommended drugs for severe malaria?
Resistance: all regions
--Quinidine + doxy or clinda (can progress to oral quinine + doxy)
--Artesunate followed by atovaquone-proguanil, clinda or mefloquine
For all species of malaria what is used for severe malaria in pregos?
1st trimester: Quinidine or Artesunate
2nd and 3rd trimester: First option is artesunate and second option is artemether
Finally for malarial chemoprophylaxis what are the drugs?
Chloroquine sensitive: chloroquine
Chloroquine resistant: mefloquine, doxy or primaquine