Anti-Malaria Drugs

Question 1

What is the first line treatment for Malaria? what is a contraindication for it?

Answer 1

Artemisinin combination therapy

except during first trimester pregnancy

Question 2

what drugs are effective against malarial gametocytes?

Answer 2

Artemisinins

Primaquine

Question 3

What anti-malaria drugs are active against hypnozoites?

Answer 3

Primaquine

Question 4

which anti-malaria drug is associated with stevens johnson syndrome?

Answer 4

sulfadoxine

given as a combination - pyrimethamine-sulfadoxine

high resistance

Question 5

what are the short acting anti-malarial drugs?

Answer 5

artesunate and other artemisinins, quinine

Question 6

Chloroquine

Answer 6

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

Question 7

adverse effects of chloroquine

Answer 7

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

Question 8

what are the cautions for use of chloroquine?

Answer 8

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

Question 9

chloroquine resistance

Answer 9

K76T PfCRT mutation - molecular marker

P-glycoprotein transporter (gene pfmdr1); pfmrp

Question 10

Mefloquine

Answer 10

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

Question 11

mefloquine resistance

Answer 11

Mechanism of Resistance: Associated with amplification of
pfmdr1

Mainland Southeast Asia

Question 12

mefloquine AE’s and cautions

Answer 12

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

Question 13

Quinine and Quinidine

Answer 13

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

Question 14

Quinine and Quinidine Adverse Effects

Answer 14

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

Question 15

Quinine/Quinidine Drug Interactions

Answer 15

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

Question 16

Primaquine

Answer 16

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

Question 17

Primaquine - AEs and Contraindications

Answer 17

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

Question 18

Lumefantrine

Answer 18

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

Question 19

Atovaquone-Proguanil - kinetics and use

Answer 19

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

Question 20

Atovaquone-Proguanil - MOA

Answer 20

Atovaquone Binds cytochrome bc1 complex on inner mito membrane
> collapses the parasite mitochondrial
membrane potential

Proguanil - Accentuates mitochondrial membrane-potential-collapsing action of atovaquone

Question 21

sulfadoxine-Pyrimethamine

Answer 21

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

Question 22

sulfadoxine adverse effects

Answer 22

mild GI upset, severe skin rashes - erythema multiform, stevens-johnson syndrome, toxic epidermal necrolysis

Question 23

Artemisinin

Answer 23

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

Question 24

Artemisinin - activity

Answer 24

asexual erythrocytic stages of chloroquine-sensitive and chloroquine-resistance all
plasmodia spp

Gametocytocidal activity

Leishmania
major, Toxoplasma gondii and Schistosoma

Question 25

artemisinin - resistance

Answer 25

Greater Mekong subregion

Point mutation in the K13 gene → ↓ susceptibility

Down-regulation of metabolic activity in ring stages
→…→ reduced activation of artemisinin drugs

Question 26

artemisinin - Rx

Answer 26

only used in combination with longer-acting antimalarials – prevent emergence of resistance

first line - except first trimester pregnancy

severe malaria - IV bolus or IM doses, tranfers to oral within 4 hours of last dose

uncomlicated - coartem (lumefantrine) 3 day regimen

primaquine on day 1 to reduce gametocyte

Question 27

artemisinin - side effects

Answer 27

Most common: nausea, vomiting, diarrhea, and dizziness

heme - reversible neutropenia, anemia, acute hemolysis

transient increase in serum transaminases - hepatic

blackwater fever - artesunate IV, delayed onset (weeks), may be severe.

Question 28

Doxycycline, Clindamycin

Answer 28

antibiotics with antimalarial activity

Blood stage: Slow-acting schizonticides

mechanism - impair expression of apicoplast gene causing abnormal cell division and death of progeny

Doxycycline: Short-term prophylaxis in chloroquinine resistant areas and treatment of uncomplicated or severe malaria

clinamycin - alternative to doxycycline in children younger than 8 and pregnant women

not effective as monotherpy - slow acting

Question 29

Doxycycline, Clindamycin - adverse effects

Answer 29

doxycycline - GI upset, yeast infections, photosensitivity
contraindicated in children younger than 8 and pregnant women

clindamycin - diarrhea and skin rash, particularly HIV infected patients
pseudomembranous colitis - c. dif

Question 30

sulfadoxine-Pyrimethamine: because of it’s widespread resistance it is not only recommended for what use?

Answer 30

Intermittent Preventive Therapy

pregnancy - 4 doses from 2nd trimeseter out

infants - 10 wks, 14 wks and 9 mons

<5 - full course of amodiaquine and SP in rainy season

Question 31

which anti malaria drugs prolong QT interval?

Answer 31

chloroquine 
mefloquine 
quinine 
quinidine
lumefantrine - mild

Question 32

which antimalaria drugs cause Black Water Fever?

Answer 32

quinine

artemisinin - artesunate