Lecture 70 - Anti-malarial drugs

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Antimalarial drugs

4-aminoquinolines (chloroquine and amodiaquine), 8-aminoquinoline (primaquine), quinoline methanols (quinine, quinidine, mefolquine), and folate antagonists (pyrimethamine, prouanil, and Fansidar).


the two members of this class are chloroquine and amodiquine. Amodiquine has same action as cholorquine but use has declined due to agranulocytosis (side effect).


the most commonly used 4-aminoquinoline. Has activity against erythrocytic forms of P faciparum and P vivax. Treatment of choice for sensitive malarial parasites. Accumulates in infected RBCs and acts by [1] inhibiting NA synthesis, [2] inhibiting lysosome enzymes, and [3] forming complexes with iron that cause cell lysis. Some parasites show resistance which is not well understood. The drug is rapidly absorbed from GI tract, widely distrubted, and has a long half-life. Toxicities: headache, visual and GI disturbances, itching.

Spectrum and therapeutic effect of cholorquine

a derivative of 4-aminoquinoline. Effective against asexual erythrocytic forms of P falciparum and P vivax, and against gametocytes of P vivax. It is not active against liver stage parasites. The drug of choice for the treatment of malaria. Administration during an acute malarial attack rapidly controls parasitemia and symptoms. Completely cures SENSITIVE strains of P falciarum, but cannot cure P vivax or P ovale.

Mechanism of cholorquine

the schizontocidal effect of this drug is not fully understood. This drug is preferentially accumulated in parasitized erthryocytes. [1] drug interacts with DNA and inhibits nucleic acid synthesis. [2] drug concentrates in lysosome and may inhibit acid hydrolyses in digestive vacuoles. [3] forms chloroquine-ferriprotoporphyrin IX complex from plasmodial digestion of hemoglobin and this complex causes lysis of parasite membrane.

Resistance to chloroquine

three types for this 4-aminoquinoline derivative. [R1] Initial therapy successful but recrudescence 2-4 wks later. [R2] initial clinical improvement, but parasitemia still present at subclinical level and recrudescence is more immediate. [R3] No response to therapy. Mechanism not understood. Could be due to induction or up-reglation of P-gp efflux pump or mutation in drug uptake transporter.

Pharmacokinetics or choloroquine

this 4-aminoquinoline drug is absorbed rapidly through the GI tract, is widely distributed, and slowly excreted by kidney. 70% is excreted unmetabolized. Bind to tissue and slow release leads to a long half-life (~4 days), which is allows for once weekly dosing of prophylaxis.

Toxicity of choloquine

main adverse effects of this 4-aminoquinoline are headache, visual disturbances, GI disturbances, and pruritus (itching). Effects are reversible with termination of therapy. Can cause hemolytic anemia in certain patients and is contraindicated for patients with psoriasis and porphyria because might precipitate an attack.


an antimalarial drug that was originally a Chinese herbal medication. Active against all 4 plasmodium spp. Degrades heme to free Fe, reduces peroxide bond in the drug, yields high-valent iron-oxo species that produce free oxygen radicals. May have some neurotoxicity. Now available in U.S.


an 8-aminoquinoline. Mehcanism: binds to DNA, may also enter and damage plasmodial mitochondria. Effective against exo-erythrocytic forms of P vivax; gametocytocidal activity against all 4 Plamodium spp; drug of choice for liver forms of P vivax and P ovale. Drug is well absorbed from GI tract, is widely dristrubted and quickly metabolized and excreted. Drug is generally well tolerated but can cause cramps, mild anemia, cyanosis, and leukocytosis. CAN CAUSE HEMOLYTIC ANEMIA in patients with a G6PD defieicny (x-linked).

Primaquine mechanism and spectrum

mechanism of this 8-aminoquinoline is uncertain. Bind to DNA, may also enter plasmodial mitochondria and cause swelling. This drug is effective against exo-erythrocytic forms of P vivax; exerts gametocytocidal activity against all four species; and is the drug of hoice for treatment of dormant liver forms of P vivax and P ovale.

Primaquine pharmacokinetics and toxicity

this 8-aminoquinoline is rapidly absorbed, widely distributed, quickly metabolized and renally excreted. Recommended doeses are well tolerated. Large doses produce cramps, mild anemia, cynanosis, and leukocytosis. CAN CAUSE HEMOTLYIC ANEMIA in male patients with G6PD deficiency (x-linked). Drug has toxic metabolite that increase the amount of oxidized glutathione (GSSG) which cannot be reduced when G6PD is low- cell membrane is damaged and cell lysis.

Quinoline methanols

quinine and its isomer quinidine. Mefloquine is a synthetic derivative related to quinine. These are anti-malarial agents. Quinidine is also an antiarrhythmic agent.


the oldest quinoline methanol. Used for over 350 years, synthesized in 1944. Suppressive effect; mechanism unknown. Used against erythocytic forms but not liver forms of Plasmodium spp. Some gametocytocidal acitivty against P vivax and P malariae. Valuable in tx of multiresistant strains of P falciparum. Absorbed via GI tract, metabolized by hydroxylation and excreted in urine. Short half-life. Toxicity: cinchonism (tinnitus, headache, nausea, dizziness, flushing, and blurred vision).

Quinine mechanism and spectrum

this suppressive quinoline methanol works by an unknown mechanism. It is effective against erythrocytics forms but not against the liver forms of the Plasmodium spp. It has some gametocytocidal activity against P vivax and P malariae. Valuable in the treatment of resistant strains of P falciparum. Resistance to this drug is uncommon.

Quinine pharmacokinetics and toxicity

this drug is absorbed well from the GI tract, metabolized by hydroxylation, and then renally excreted. It has a short half-life, thus given 3x per day. Toxicity: cinchonism (tinnitus, headache, nausea, dizziness, flushing, blurred vision). Other side effects: cardiac depressant, resp rate changes, stimulates uterine contractions, may stimulate insulin release (hypoglycemia), and hemolytic anemia (exp with G6PD deficiency).


a synthetic quinoline methanol that is effective against cloroquine-resistanct P falciparum. Recommended for malaria prophylaxis in region with known choloroquine-resistant strains. Very long half-life.

Folate antagonists

a class of anti-malarial drugs including pyrimethamine (a 2,4-diaminopyrimidine related to trimethoprim; sometimes combined with dapsone, a sulfa drug), proguanil (a biguanide derivative pro-drug; cycloguanil is the active form), and Fansidar (sulfadoxine + pyrimethamine).

Folate antagonists mechanism and spectrum

these anti-malarial drugs inhibit dihydrofolate reductase (DHFR) in the parasite. Selectively toxic to parasite due to high binding affinity for enzyme. Folic acid is a necessary co-factor in parasite macromolecule synthesis. Drugs are effective against erythrocytic forms of all 4 Plasmodium spp. Proguanil has activity against liver forms. Fansidar is particularly effective against choloroquine-resistant P falciparum. Resistance may be observed with elevated DHFR or altered binding affinity for the drug

Folate antagonists pharmacokinetics and toxicity

this class is well absorbed form the GI tract. Half-life differs by drug (pyrimethamine 4 days, proguanil 16 hrs), and dictates dosing for prophylaxis. The sulfadoxine in Fansidar has a half-life of 170 hrs. Drugs in this class are well tolerated, but Fansidar may cause rare cutaneous reactions and is thus no longer recommended for prophylaxis.

First line TB drugs

isoniazid, ethambutol, pyrazinamide, rifampin, streptomycin.

Second line TB drugs

ciprofloxacin, moxifloxacin, p-aminosalicylic acid.


a first line TB antibiotic. Its acid metabolite is a mimic of nicotinic acid. It is bactericidal against replicating organisms and bacteriostatic against non-replicating organisms. Interfer with cell wall synthesis, so bacilli lose their acid-fast property. Isonicotinic may be incorporated into NAD+ inhibiting its co-factor functions. Can be administered orally or by IV, is well distributed to all tissure including CSF, does not bind serum proteins, and half-life is 1-3 hours. Most drug undergoes acetylation and is excreted in urine within 24 hours.

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