AntiMalarials

Question 1

What are symptoms of complicated malaria?

Answer 1

prostration (general weakness), impaired consciousness, convulsions, renal injury, hypoglycemia, jaundice, pulmonary stress

Question 2

most dangerous, most severe (can cause anemia and cerebral malaria, even death); drug resistance
P. malariae: milder disease

Answer 2

p. falciparum

Question 3

mild dormant relapse of maalaria

Answer 3

p. ovale and vivax

Question 4

What is life cycle of malaria?

Answer 4

Sporozoites when in the blood. Once in the liver stage (exo erythrocytic or merozoite): targeted with tissue schizonticides to prevent disease.
Human blood stage (erythrocytic schizogony): targeted with blood schizonticides as well to terminate clinical attacks.
Gametocyte stage: targeted with gametocides to prevent transmission
Human liver dormant stages (Hypnozoites can form in P. ovale and P. vivax infections): targeted with primaquine or tafenoquine to prevent relapse

Question 5

What’s mechanism of action of chloroquine?

Answer 5

human heme is toxic to the malaria parasites, so to protect itself it makes heme into hemozoin via polymerization. Chloroquine prevents this polymerization causing lysis parasite and RBC

Question 6

How does parasite resist chloroquine?

Answer 6

mutation of drug transporter protein

Question 7

What are indications of chloroquine?

Answer 7

given orally because has long t1/2, treats uncomplicated malaria, serves as chemoprophylaxis for travel and safe for pregnancy and children

Question 8

What are ADRs of chloroquine?

Answer 8

Low dose: transient pruritus (common); GI irritation, headache, blurring of vision.

High doses: Severe skin reactions; neuropathies, psychosis, hemolysis, irreversible retinal and auditory damage, Myocardial depression

Im or iv can cause severe hypotension and respiratory/cardiac arrest, should be avoided

Question 9

What is MOA and pharmacokinetics of Quinine?

Answer 9

unknown MOA, but good against blood schizonticide and P. Vivax/ovale. short t1/2

Question 10

What are clinical indications of quinine?

Answer 10

Parenteral for severe falciparum malaria, but i.v. Artesunate is now preferred;
Oral for Chloroquine-resistant falciparum: combine with doxycycline or, in children, clindamycin to reduce duration and toxicity.

Question 11

What are ADRs and contraindications of quinine?

Answer 11

1)Cinchonism: auditory probs, reversible; 2) Hematotoxic effects: hemolysis (especially with G6PD deficiency)
3) Severe hypotension and QT prolongation
4) Blackwater fever (intavascular hemolysis)
5) Hypersensitivity reactions and hypoglycemia
Quinine should not be given concurrently with mefloquine;

Question 12

What’s PK and indications to use mefloquine?

Answer 12

long half life so oral. Is used as first line drug for prophylaxis. Indicated for uncomplicate falciparum

Question 13

ADRs of mefloquine?

Answer 13

Contraindicated in patients with epilepsy, psychiatric disorders, arrhythmias, cardiac conduction defects;
Not coadminister with quinine or quinidine due to potential cardiac arrest;

Question 14

What is mechanism of action of artemisinin?

Answer 14

accumulate in parasite food vacuoles to release toxic free radicals in blood schizoticides. Only effective against quinine resistant. Most rapid acting anti malarial

Question 15

What are indications for artemisinin?

Answer 15

Not used as monotherapy; 1st line for chloroquine or quinine-resistant malaria for uncomplicated, multidrug-resistant falciparum malaria in all endemic areas; E.g. Coartem (artemether-lumefantrine);
Severe malaria: I.v. Artesunate or rectally Artesunate and artemether

Question 16

What are ADRs of artemisinin?

Answer 16

GI discomfort is the most common;
rare: neutropenia, anemia, delayed hemolysis, elevated liver enzymes, allergic reactions

Question 17

What’s mechanism of action of Primaquine/Tafenoquine?

Answer 17

may acts as cellular oxidants and interferes ETC;
active against hepatic, hypnozoites, and gametocytic of all human malaria parasites

Question 18

true or false: tafenoquine has longer t1/2 than primaquine

Answer 18

true

Question 19

What are clinical indications of primaquine/tafenoquine?

Answer 19

Clinical Indication: Drug withheld until confirming G6PD status

1. Therapy of acute Vivax and Ovale Malaria with conjunction with a blood schizonticide, e.g., chloroquine first; then primaquine for 14 days or single dose of Tafenoquine
2. prophylaxis of Vivax and Ovale Malaria
3. Chemoprophylaxis of malaria
4. Gametocidal action to decrease transmission

Question 20

What are ADRs and contraindications of primaquine/tafenoquine?

Answer 20

Hemolytic anemia or methemoglobinemia (cyanosis) in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency

May cause GI discomfort, headache, and rare hematotoxic effects and cardiac arrhythmias

Avoided in patients with potential myelosuppression, G6PD deficiency, and pregnancy

Question 21

What’s mechanism of action of atovaquone?

Answer 21

disrupt mitochondrial electron transport to reduce ATP and pyrimidine biosynthesis in plasmodia;
active against tissue and erythrocytic schizonts;

Question 22

What is pharmacokinetic activity of atovaquone?

Answer 22

Only given orally; highly protein-bound; absorption is increased by fatty food; Half-life about 2-3 days

Question 23

What are indications and ADRs of atovaquone?

Answer 23

Clinical Indications: Good for children >5Kg; not for pregnancy
Atovaquone–proguanil Combination (Malarone): highly effective/synergistic for treating and chemoprophylaxis of falciparum malaria ( but more expensive than mefloquine or doxycycline)

Adverse effects: well tolerated
GI discomfort, headache, insomnia, and rash with higher dosage.

Question 24

What is mechanism of action of antifolates: pyrimethamine, proguanil,sulfadoxine?

Answer 24

inhibits dihydropteroate synthase (e.g., Sulfadoxine) or dihydrofolate reductases blood schizonticide; Proguanil also inhibits hepatic form

Question 25

What is PK of antifolates: pyrimethamine, proguanil, sulfadoxine?

Answer 25

Oral; Proguanil has a shorter half-life (12–16 h) than other drugs

Question 26

What are clinical indications of antifolates: pyrimethamine, proguanil, sulfadoxine?

Answer 26

Chemoprophylaxis for chloroquine-resistant: Proguanil/atovaquone (Malarone)
Treatment of falciparum malaria: sulfadoxine-pyrimethamine

Question 27

What are ADRs of antifolates: pyrimethamine, proguanil, sulfadoxine?

Answer 27

1. Sulfanomides: GI discomfort, skin rashes; Higher doses rarely cause hematologic, GI, CNS, skin, renal toxicity
2. Proguanil: Mouth ulcers and alopecia
3. Pyrimethamine (high dose): folic acid deficiency, megaloblastic anemia due to bone marrow suppression (Leucovorin reverse )

Question 28

What are indications of protein synthesis inhibitors: doxycycline, tetracyline, and clindamycin?

Answer 28

Chemoprophylactic drug in multi- resistance area (Southeast Asia): Doxycycline
Treatment of chloroquine-resistant P. falciparum: Doxycycline combined with Artesunate or quinine;
Clindamycin replaces doxycycline in children and pregnant women

Question 29

ADRs of protein synthesis inhibitors

Answer 29

Doxycycline/tetracycline: photosensitivity, tooth discoloration in children, and vaginal candidiasis; GI discomfort; esophagitis
Clindamycin: antibiotic-associated diarrhea and colitis caused by Clostridium difficile.