Antimalarial Drugs: Inhibitors of Folate Synthesis

Question 1

These cards will review inhibitors of folate synthesis. What are the drugs?

Answer 1

Used generally in combination regimens:

–pyrimethamine, proguanil, sulfadoxine

Question 2

What are the clinical applications of inhibitors of folate synthesis?

Answer 2

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

Question 3

What are the antimalarial action of folate synthesis inhibitors?

Answer 3

Pyrimethamine + Proguanil:
–act slowly against erythrocytic forms of all malaria species
Proguanil:
–some activity against hepatic forms
Sulfonamides:
-weakly active against erythrocytic schizonts

Question 4

What is the MOA of pyrimethamine + proguanil?

Answer 4

Inhibit plasmodial dihydrofolate reductase

Question 5

What is the MOA of sulfonamides?

Answer 5

Inhibit dihydropteroate synthase

Question 6

What are the PK and resistance for Folate synthesis inhibitors?

Answer 6

PK
–oral
Resistance
–relatively common for P. falciparum

Question 7

What are the AE for Folate synthesis inhibitors?

Answer 7

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)
Pregos:
Proguanil: safe
Pyrimethamine-sulfadoxine = safe

Question 8

The next drug used in malaria is Doxycycline, what are some features?

Answer 8

Active against erythocytic schizonts of all human malaria parasites
Not active against liver stage
Clinical applications:
–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

Question 9

What are the AE for Doxy?

Answer 9

Photosensitivity
Discoloration and hypoplasia of teeth, stunting of growth
Fatal hepatotoxicity (in pregnancy)
Do not use in pregos or children under 8

Question 10

The next antimalarial drug is Artemisinin, what are some features?

Answer 10

Aretesunate: oral, IV, IM and rectal
Artemether: oral, IM. and rectal
Dihydroartemisinin: oral
Coartem: artemether + lumefantrine

Question 11

What are the clinical applications for Artemisinin?

Answer 11

Tx of severe falciparum malaria (given IV)
No effect on hepatic stages
Should not be used as single agent to protect against resistance

Question 12

What is the MOA and PK of artemisinin?

Answer 12

MOA:
–appears to act by binding iron, breaking down peroxide bridges leading to generation of free radicals that damage parasite proteins
PK:
–very short half life
–if used alone, artesunate must be administered 5-7 days

Question 13

What are the AE of Artemisinin?

Answer 13

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

Question 14

There are three other antimalarials that can be used.

Answer 14

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

Question 15

These next set of cards are just review cards. For uncomplicated malaria what do you treat P. falciparum and P. malariae with?

Answer 15

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

Question 16

For uncomplicated malaria what do you treat P. vivax or P. ovale with?

Answer 16

P. Vivax or P. Ovale: if no resistance —- cholorquine + primaquine or hydroxychloroquine + primaquine
P. Vivax
–if resistance — Quinine + doxy + primaquine or Atovaquone-proguanil + primaquine or Mefloquine + Primaquine

Question 17

For Uncomplicated Malaria in pregos?

Answer 17

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

Question 18

For all species of malaria what is the recommended drugs for severe malaria?

Answer 18

Resistance: all regions
IV drugs:
–Quinidine + doxy or clinda (can progress to oral quinine + doxy)
–Artesunate followed by atovaquone-proguanil, clinda or mefloquine

Question 19

For all species of malaria what is used for severe malaria in pregos?

Answer 19

All species
All regions
1st trimester: Quinidine or Artesunate
2nd and 3rd trimester: First option is artesunate and second option is artemether

Question 20

Finally for malarial chemoprophylaxis what are the drugs?

Answer 20

Chloroquine sensitive: chloroquine

Chloroquine resistant: mefloquine, doxy or primaquine

Question 21

For malarial chemoprophylaxis in pregos?

Answer 21

Chloroquine sensitive: chloroquine

Chloroquine resistant: mefloquine