What microorganism causes Malaria?
What is the primary form of Plasmodium in Asia?
Plasmodium vivax. Causes Benign tertian malaria
What is the primary form of Plasmodium in Africa?
Plasmodium falciparum. Malignant tertian malaria (most severe type, fatal)
What is the major group that Plasmodium is placed in?
What is the Plasmodium life cycle?
Mosquito bites human. Young Plasmodium transferred to human and travels to liver where it develops further (tissue schizont). Final liver stage (merozoite) is released, infects RBCs. Development is completed in RBCs, where they then lyse and release infectious Merozoites (which can infect more RBCs or re-infect liver cells). Some of the released forms develop into gametes
What is the primary focus of therapy for anti-malarial agents?
RBCs. Agents that target this step are called Schizonticides
What do Quinines require?
An intact quinoline ring and the secondary alcohol are required. The R groups can be varied; a specific chain is not required
What is the main 4-Aminoquinoline?
What does the structure of Chloroquine (4-Aminoquinoline) look like?
1) Secondary amine at C4. 2) Tertiary amine at terminus of C4 amino side chain. 3) Chlorine at C7. 4) C-C chain length in side chain (4 C's between the N's)
What is the main 9-Aminoacridine used?
What does the structure of Quinacrine (9-Aminoacridine) look like?
1) Structurally related to 4-Aminoquinolines (has a third ring). 2) More toxic, hence not used
What is the main 8-Aminoquinoline used?
What does the structure of Primaquine (8-Aminoquinoline) look like?
1) Secondary amine at C8. 2) Primary, secondary or tertiary amine at terminus of C8 side chain. 3) Methoxy at C6. 4) C-C chain length in side chain can vary
What is a major theory on how 4-Aminoquinolines work?
Plasmodium "digests" hemoglobin to obtain energy. The process results in the release ofheme, which is toxic. Plasmodium polymerize heme, which de-toxifies it (Polymerized form is called "hemozoin"). Chloroquine (and related 4-aminoquinolines) inhibit heme polymerization by binding directly to heme. Heme accumulates, preventing parasite development
What is a new theory on how Aminoquinolines work?
Chloroquine and primaquine bind tightly to the RBC enzyme quinone reductase, and inhibit its activity. Quinone reductase reduces oxidative stress; when it's inhibited, oxidative stress increases, to which Plasmodium are especially sensitive
What is 4-Aminoquinoline sensitivity like?
Heme polymerase enzyme unique to Plasmodium. Aminoquinolines are concentrated in parasite's food vacuole (entry as N-deprotonated forms, but gain H in the acidic food vacuole which restricts exit)
What is 4-Aminoquinoline resistance like?
Resistance is common. Resistant strains frequently increase efflux (sometimes can be overcome by Ca channel blockers). Resistance associated with mutations in the PfCRT gene (encodes Chloroquine transporter, that regulates drug accumulation levels). K76T mutation: either blocks uptake, or increases export
What are the general characteristics of Artemisinins?
Rapid action, no evidence of significant side effects. Provides a new, effective option for "drug-resistant" or severe strains of Plasmodium
What is this a structure of?
What is the MOA of Artemisinins?
1) Iron-catalyzed cleavage of the endoperoxide bond. 2) Rearrangement to form carbon-based free radicals. 3) Destruction of biopolymers - e.g. proteins, RNA, DNA. Recent studies specifically pinpoint SERCA Ca-pump PfATP6 as target. 5) Information implicates heme (required for hemoglobin formation in RBCs) in generation of reactive intermediates (this may be because heme contains iron, and can act through the pathway shown)
What are the SAR features of Artemisinins?
1) Activity requires endoperoxide (heme digestion releases Fe that catalyzes activation/conversion). 2) Modification of keto in naturally-occurring form increases potency (primary variant that is currently used: artemether). 3) Artesunate: succinate derivative, increased water solubility
What is Halofantrine?
Phenanthrene methanols have some anti-malarial activity. Progenitor of lumefantrine. Not recommended d/t erratic activity, potenially lethal cardiotoxicity
What is Lumefantrine and Coartem (Riamet)?
Lumefantrine is a superior "derivative" of halofantrine. Used in combination with artemether in the formulation called Coartem (Riamet) (Novartis). Interferes with heme polymerase
What drug is currently the WHO recommended malaria treatment for areas where significant chloroquine resistance occurs?
Lumefantrine and Coartem (Riamet) (Novartis)
What is Mefloquine?
1) Structurally similar to Quinine (Quinolone ring, secondary alcohol at C4, side chain extends into complex ring). 2) No rationale for the CF3. Initially very effective, now many strains are resistant
What are some anti-malarial agents that affect folic acid synthesis?
Sulfonamides and sulfones. Pyrimidines (Pyrimethamine). Combination of sulfadoxine with pyrimethamine (Fansidar) significantly increases efficacy. Biguanides (Cycloguanil, Proguanil (frequently used prodrug form)
What is Atovaquone?
Lipophilic compound similar to ubiquinone. Interferes with mitochondrial functions involving ubiquinone (cytochrome c reductase mutations lead to resistance). Useful in drug-resistant malaria. Combination with Proguanil (Malarone) significantly increases efficacy
How do Tetracycline and Doxycycline attack Malaria?
Inhibit protein translocation by interfereing with the Apicoplast