DDT 23 - Therapeutic Strategies in treatment and prophylaxis of malaria

Question 1

chemoprophylaxis

Answer 1

prevention of transmitting diseases using chemicals

Question 2

targets of anti-malarial drugs

Answer 2

Tissue schizonticides
Blood schizonticides - intra-erythrocytic targets
gametocytocides
sporontocides

Question 3

what would make the ideal anti malarial drug

Answer 3

potent activity against all plasmodium species
oral bioavailability (accessible and readily given)
rapid speed of action
strong and safe profile for kids and pregnant women
low cost
focus on exo-erythrocytic activity

Question 4

quinine is from what species

Answer 4

cinchona

A 4-quinoline methanol

Question 5

when has quinine been used and when has it been isolated

Answer 5

used since 1600s

isolated in 1820

Question 6

side effects of quinine

Answer 6

curare effect,
myocardial depression,
vasodilation
hemolytic anemia

Question 7

what rings does quinine have

Answer 7

quinoline ring

quinuclidine ring

Question 8

derivatives of quinine/ 4 aminoquinolines

Answer 8

Chloroquine 
Hydroxychloroquine
Mefloquine
Amodiaquine
Halofantrine (a 9-phenanthrenemethanol)

Question 9

why would DNA intercalation not work to stop malaria

Answer 9

But concentration to inhibit DNA synthesis is > than that to inhibit parasite growth….

Question 10

fault in weak base hypothesis for anti malarial drugs

Answer 10

Aminoquinolines are weak bases
Accumulate in lysosomes (pH 4.8-5.2)
Raising of pH in lysosome impairs haemoglobin digestion?

Question 11

FPIX hypothesis

Answer 11

Plasmodium digests host haemoglobin
Hemozoin is the waste product
Hemozoin contains Ferriprotoporphyrin IX (FPIX)
Free FPIX is TOXIC so is normally bound
Drug-FPIX complex retains toxicity → cell death

Question 12

Pyrimethamine

Answer 12

inhibits plasmodial dihydrofolate reductase

Question 13

Sulfadoxine

Answer 13

inhibits dihydropteroate synthase

Question 14

Pyrimethamine-Sulfadoxine

Answer 14

Developed for prevention and treatment of chloroquine-resistant malaria
Sometimes used for Intermittent Preventive Treatment (IPT) to reduce malaria in vulnerable populations like infants and pregnant women

Question 15

name 3 8-aminoquinolines

Answer 15

Prototype drug Pamaquine (1926)
Primaquine later marketed
tafenoquine

Question 16

how does 8 aminoquinolines work

Answer 16

Active vs. tissue and hepatic stages

Gametocidal

Question 17

why is 8 aminoquinolines not given long term

Answer 17

Not given long term to avoid toxicity and resistance

Question 18

mechanism of action of 8 aminoquinolines

Answer 18

Interference with the cell redox system

→ oxidative stress → cell death

Question 19

aim of tafenoquine

Answer 19

to provide longer-acting, more potent and less toxic agent than primaquine

Question 20

what is tafenoquine highly effective in

Answer 20

radical cure of relapsing * malaria

causal prophylaxis of P. vivax* and P. falciparum infections with protective efficacies of ≥ 90%

Question 21

Artemisinins are isolated from what

Answer 21

isolated from TCM - a plant

Question 22

what feature does Artemisinins have

Answer 22

endoperoxide - oxide within a ring

Question 23

what types of malaria is artemisinins used for

Answer 23

Active in resistant & cerebral malaria
Cornerstone of ACT
little toxicity

Question 24

artemisinin splitting

Answer 24

artemisinin
           I
          V
semi-synthetics/active 
metabolites
            I
           V
ethers(lipid soluble) and esters(water soluble)

Question 25

5 WHO malaria recommendations for treatment of malaria

Answer 25

3 days ACT with
Artemether & Lumefantrine
Artesunate & Amodiaquine
Artesunate & Mefloquine
Dihydroartemisinin & Piperaquine
Artesunate & Sulfadoxine/Pyrimethamine

Question 26

lumefantrine is a derivative of

Answer 26

halofantrine

Question 27

features of lumefantrine

Answer 27

Aryl amino alcohol

Note lipophilic substituents

Question 28

what other drug is used in combination with lumefantrine to treat what kind of malaria

Answer 28

in combination with Artemether in falciparum malaria

Question 29

drug treatment options for pregnant women with malaria

Answer 29

Quinine (esp. I)
Clindamycin
Artemisinins (II & III)

Question 30

preventative drug/prophylaxis for pregnant women

Answer 30

mefloquine

Question 31

2 types of malarial prophylaxis

Answer 31

Suppressive

Causal

Question 32

ways to prevent infection of malaria for travellers

Answer 32

Travellers entering endemic areas need cover
Expert advice essential
Generally 1 week before and up to 4 after
Protection against bites is also vital
Post travel illness must mean consideration of possibility of malaria

Question 33

preventative drugs used for travellers

Answer 33

Malarone® (atovaquone-proguanil)
Doxycycline
Mefloquine

Question 34

atovaquone

Answer 34

A lipophilic hydroxynaphthoquinone

Question 35

purpose of atovaquone

Answer 35

Inhibits electron transport in mitochondria

Impairs pyrimidine synthesis

Question 36

what is atovaquone used with

Answer 36

Synergistic with Proguanil (Malarone

Question 37

what makes doxycycline effective

Answer 37

effective in malaria due to the presence of a plastid-like organelle, the so‐called apicoplast

Question 38

what hinders doxycycline

Answer 38

Tetracyclines active but slow-acting

Question 39

how does doxycycline stop malaria

Answer 39

Inhibition of the prokaryote‐like RNA
Doxycycline best due to fat solubility
Good tissue distribution

Question 40

ways people can prevent mosquito bites

Answer 40

wear trousers, socks, long sleeve shirts
insect repellent - pregnancy and kids
ned nets w/ insecticide