DDT 23 - Therapeutic Strategies in treatment and prophylaxis of malaria Flashcards
chemoprophylaxis
prevention of transmitting diseases using chemicals
targets of anti-malarial drugs
Tissue schizonticides
Blood schizonticides - intra-erythrocytic targets
gametocytocides
sporontocides
what would make the ideal anti malarial drug
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
quinine is from what species
cinchona
A 4-quinoline methanol
when has quinine been used and when has it been isolated
used since 1600s
isolated in 1820
side effects of quinine
curare effect,
myocardial depression,
vasodilation
hemolytic anemia
what rings does quinine have
quinoline ring
quinuclidine ring
derivatives of quinine/ 4 aminoquinolines
Chloroquine Hydroxychloroquine Mefloquine Amodiaquine Halofantrine (a 9-phenanthrenemethanol)
why would DNA intercalation not work to stop malaria
But concentration to inhibit DNA synthesis is > than that to inhibit parasite growth….
fault in weak base hypothesis for anti malarial drugs
Aminoquinolines are weak bases
Accumulate in lysosomes (pH 4.8-5.2)
Raising of pH in lysosome impairs haemoglobin digestion?
FPIX hypothesis
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
Pyrimethamine
inhibits plasmodial dihydrofolate reductase
Sulfadoxine
inhibits dihydropteroate synthase
Pyrimethamine-Sulfadoxine
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
name 3 8-aminoquinolines
Prototype drug Pamaquine (1926)
Primaquine later marketed
tafenoquine
how does 8 aminoquinolines work
Active vs. tissue and hepatic stages
Gametocidal
why is 8 aminoquinolines not given long term
Not given long term to avoid toxicity and resistance
mechanism of action of 8 aminoquinolines
Interference with the cell redox system
→ oxidative stress → cell death
aim of tafenoquine
to provide longer-acting, more potent and less toxic agent than primaquine
what is tafenoquine highly effective in
radical cure of relapsing * malaria
causal prophylaxis of P. vivax* and P. falciparum infections with protective efficacies of ≥ 90%
Artemisinins are isolated from what
isolated from TCM - a plant
what feature does Artemisinins have
endoperoxide - oxide within a ring
what types of malaria is artemisinins used for
Active in resistant & cerebral malaria
Cornerstone of ACT
little toxicity
artemisinin splitting
artemisinin
I
V
semi-synthetics/active
metabolites
I
V
ethers(lipid soluble) and esters(water soluble)5 WHO malaria recommendations for treatment of malaria
3 days ACT with
Artemether & Lumefantrine
Artesunate & Amodiaquine
Artesunate & Mefloquine
Dihydroartemisinin & Piperaquine
Artesunate & Sulfadoxine/Pyrimethamine
lumefantrine is a derivative of
halofantrine
features of lumefantrine
Aryl amino alcohol
Note lipophilic substituents
what other drug is used in combination with lumefantrine to treat what kind of malaria
in combination with Artemether in falciparum malaria
drug treatment options for pregnant women with malaria
Quinine (esp. I)
Clindamycin
Artemisinins (II & III)
preventative drug/prophylaxis for pregnant women
mefloquine
2 types of malarial prophylaxis
Suppressive
Causal
ways to prevent infection of malaria for travellers
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
preventative drugs used for travellers
Malarone® (atovaquone-proguanil)
Doxycycline
Mefloquine
atovaquone
A lipophilic hydroxynaphthoquinone
purpose of atovaquone
Inhibits electron transport in mitochondria
Impairs pyrimidine synthesis
what is atovaquone used with
Synergistic with Proguanil (Malarone
what makes doxycycline effective
effective in malaria due to the presence of a plastid-like organelle, the so‐called apicoplast
what hinders doxycycline
Tetracyclines active but slow-acting
how does doxycycline stop malaria
Inhibition of the prokaryote‐like RNA
Doxycycline best due to fat solubility
Good tissue distribution
ways people can prevent mosquito bites
wear trousers, socks, long sleeve shirts
insect repellent - pregnancy and kids
ned nets w/ insecticide
