Anti-Malaria Drugs Flashcards
What is the first line treatment for Malaria? what is a contraindication for it?
Artemisinin combination therapy
except during first trimester pregnancy
what drugs are effective against malarial gametocytes?
Artemisinins
Primaquine
What anti-malaria drugs are active against hypnozoites?
Primaquine
which anti-malaria drug is associated with stevens johnson syndrome?
sulfadoxine
given as a combination - pyrimethamine-sulfadoxine
high resistance
what are the short acting anti-malarial drugs?
artesunate and other artemisinins, quinine
Chloroquine
oral, not for long term use (culumative doses are toxic)
active against erythrocytic states of all plasmodium species - concentrates in parasitic food vacuoles and inhibits heme polymerization
p. falciparum is resistant worldwide
can be used for propholaxis - start 2 weeks prior and continue for 4 weeks after
treatment - loading dose plus 3 over 48 hours
radical cure - add primaquine
safe in pregnancy
adverse effects of chloroquine
at prophylactic doses - well tolerated - GI irritation, rash, headaches
high dose increase risk; pruritis, diarrhea, nausea, vomiting, headache, visual disturbances
high cumulative doses - cardiovascular, toxicity, ototoxicity, myopathy and peripheral neuropathy
what are the cautions for use of chloroquine?
Hepatic impairment, psoriasis, QTc interval prolongation, porphyria
drug interactions - decreased absorption is caused by antacids and kaolin-pectin antidiarrheals
when combined with drugs that:
QT internal prolongation
lower seizure threshold
heme agranulocytosis
inhbiits CYP2D6
chloroquine resistance
K76T PfCRT mutation - molecular marker
P-glycoprotein transporter (gene pfmdr1); pfmrp
Mefloquine
oral use, well absorbed, distributes to CNS, inactivated by CYP3A4
shorter half-life in children
chemopropholaxis - weekly dosing, 2 wks before and 4 wks after
treatment - combination with artesunate
works on blood schizonticides; mature schizonts and trophozoites, effective against p. falciparum and p. vivaxd
mefloquine resistance
Mechanism of Resistance: Associated with amplification of
pfmdr1
Mainland Southeast Asia
mefloquine AE’s and cautions
not for use in patients with:
major psychiatric illness
recovering form cerebral malaria
seizures - or predisposition, or with other drugs that lower seizure threshold
QT-interval prolongation - congenital or other drugs
caution in activities that require fine motor coordination
Quinine and Quinidine
quinine - oral
quinidine - IV - for severe infections, CYP2D6 inhibitor
Quinine excretion is doubled in acidic urine
proposed MOA - homozoin polymerization or intercalation in to DNA
increased α1-acid glycoprotein levels in severe disease - reducing free levels
not used for prophylaxis because short half life
quinine treats uncomlicated chloroquine-resistant f. malaria
quinidine - complicated faciparum
works on blood schizonticide - mature schizonts and trophozoites
Quinine and Quinidine Adverse Effects
Cardiotoxic - quinidine
Cinchonism
mild - headache; vasodilation; sweating; nausea; dizziness;
tinnitus; disturbance in visual, auditory, and color
perception; dysphoria
severe - abdominal pain; vomiting; diarrhea; deafness; blindness;
disturbances in cardiac rhythm
hypoglycemia - especially in severe malaria and pregnant patients
Blackwater fever - malarial anemia, Massive intravascular hemolysis, hemoglobinemia,
hemoglobinuria, anuria, renal failure, death. quinine treatment.
Thrombocytopenia - Drug-induced immune-mediated reaction
QTc interval prolongation
Quinine: serious cardiac dysrhythmia.
Quinidine: ventricular arrhythmia
safe in pregnancy
Quinine/Quinidine Drug Interactions
Digoxin - ↓ digoxin clearance via P-gp
Warfarin - Enhanced anticoagulant effects
Neuromuscular blockers - Enhance NM block, opposes achE inhibitors
Lumefantrine - increased risk of QT interval prolongation
delayed absorption of antacids
Primaquine
oral, metabolized by CYP3A4
strong inhibitor of CYP1A2
active - primary and latent hepatic stage, gametocytocidal
MOA - electrophilic intermediates that generate reactive oxygen species; active compounds interfere with mito electron transport in the parasite or alter it’s DNA
NOT EFFECTIVE FOR TREATMENT OF ACUTE MALARIAL EPISODES
prophylasix, Rx - uncomplicated p. vivax, p. ovale, gametocydale prevention of p. palciparum transmission
other use - pneumocystis penumonia
Primaquine - AEs and Contraindications
can cause hemolytic anemia in G6PD deficient patients
acutely ill pts predisposed to granulocytopenia - SLE or RA
with other hemolytic drugs
Pregnancy - fetal hemolysis if G6PD def
can cause GI distress
Methemoglobinemia: NADH methemoglobin reductase
deficiency - occurs when RBCs defense against oxidative stress becomes overwhelmed
Lumefantrine
Oral; CYP3A4
MOA - hemin-beta-hematin complex which decreased the formation of hemazoin. Inhibits plasmodial nucleic acid and protein synthesis
Schizonticide - erythrocytic stage
Treatment of uncomplicated malaria; 3-day course
mild QT interval prolongation
caution with CYP3A4 inducers and inhibitors; heart disorders
Atovaquone-Proguanil - kinetics and use
slow, erratic absorption with low bioavialablity
proguanil hepatic meta CYP2C19 to cycloguanil
once daily for chemopropholaxis
atovaquone - erythrocytic and promary hepatic stage - sensitive falciparum
proguanil - erythrocytic stage of falciparum and vivax, primary hepatic
not effective for hypozoites, gametocytes or latent hepatic
Atovaquone-Proguanil - MOA
Atovaquone Binds cytochrome bc1 complex on inner mito membrane
> collapses the parasite mitochondrial
membrane potential
Proguanil - Accentuates mitochondrial membrane-potential-collapsing action of atovaquone
sulfadoxine-Pyrimethamine
long half life has increased resistance
oral , protein bound, widely distributed
sulfadoxine - renal exc unchanged; Competitive inhibitor of dihydropteroate synthase
Pyrimethamine: Competitive inhibitor of P. falciparum DHFR
resistance by point mutations - widespread resistance
sulfadoxine adverse effects
mild GI upset, severe skin rashes - erythema multiform, stevens-johnson syndrome, toxic epidermal necrolysis
Artemisinin
Artemisinin, Dihydroartemisinin, Artemether, Artesunate
oral, IM, IV, rectal - distributes to CNS
useful for cerebral malaria
hepatic metabolism - CYP2B6, 2C19, 3A4
binding globulin protein, heme iron catalyzes cleavage of artemisinin endoperoxide bridge, rearrangement to carbon-centered free radical, alkylation and damage of parasite macromolecules
Artemisinin - activity
asexual erythrocytic stages of chloroquine-sensitive and chloroquine-resistance all
plasmodia spp
Gametocytocidal activity
Leishmania
major, Toxoplasma gondii and Schistosoma
