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63 Cards in this Set
- Front
- Back
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Describe what happens during malarial pathogenesis
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Destruction of erythrocytes
Liberation of parasites and erythrocyte material (Hemozoin) into circulation Host reaction to these events |
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Why is P. falciparum so virulent?
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It causes RBCs to become "sticky" by expressing ptns on their surface
Can stick to the spleen so it won't be flushed out of the system |
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What do these sticky cell walls do?
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They adhere to each other and the lining of the capillaries
->Can starve tissues, especially the brain, of O2 |
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What is special about the P. vivax and P. ovale species?
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They can recur
-->Stages remain in the liver |
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to be named (of things)
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называ'ться (impf.)
(называ' -ется, -ются) |
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What are the clinical features of malaria?
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-Acute febril attacks (Malaria paroxysms)
-Manifestations and severity depens on species and host status -Recrudescences or relapses can occur over months or years -Can develop severe complications (especially P. falcip.) |
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What is malaria paroxysm?
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Periodic episodes of fever alternating with symptomless periods
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to try
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стараться/по-
(стара' -юсь, стара -ешься, -ются) |
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What are the prodomal symptoms of malaria? (before malaria gets to the RBCs, while its going to the liver)
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End of incubation perios
2-3 days before 1st febrile attack Includes: malaise, fatigue, headache, muscle pain, nausea (flu-like symptoms) Can range from mild-severe |
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What is a febrile attack?
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Malarial Paroxysm
Periodic febrile episodes alternating with symptom-free periods Initially fever may be irregular before dev'p periodicity May be accompanied by splenomegaly, hepatomegaly (slight jaundice), anemia Parasites all become synchronized so they invade and burst out all at the same time |
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What is malaria paroxysm associated with?
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Synchrony of merezoite release
Temperature is normal and patient feels well between paroxysms |
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Which species undergo tertian malaria?
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P. vivax and ovale
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Which species undergoes quaternary malaria?
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P.malariae
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What kind of a cycle does P. falciparum undergoe?
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Different, because the fever can last 24 hours or be a continuous fever
Sometimes the fever can break |
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What are the different types of anti-malaria therapies?
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Causal prophylaxis
Suppressive prophylaxis Treatment hterapy Curative therapy Anti-relapse treatment |
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What is causal prophylaxis?
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Prevent infection (i.e target liver stage)
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What is suppressive prophylaxis?
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Prevent clinical disease
Blood schizontocides |
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What is treatment therapy?
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Clinical cure
Relieve symptoms Eliminate blood stae parasites |
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What is curative therapy?
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Radical cure
Eliminates parasites without regard to symptoms |
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What is anti-relapse treatment?
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Eliminate hypnozoites
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What is chemoprophylaxis?
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Recommmended for transient visits to endemic areas
Choice of drug depends on risk of malaria and degree of resistance in that area Many non-toxic drugs of limited resistance: chloroquine, pyrimethamine Presumptive treatment used in conjunction with prophylaxis: carry Fansidar, mefloquinee, quinine |
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What's the problem with chemoprophylaxis and malaria?
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A lot of resistance .: should not give it before going to the country
there are a lot of areas where you don't need it, just take the meds at their hospitals |
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What is drug resistance?
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Genetically transmitted loss of sensitivity in (parasite) population previously sensitive to the same drug
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Why can parasites so easily become drug resistant?
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Parasites in the blood are haploid
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What was the first malaria drug developed?
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Quinine
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What kind of drug is quinine?
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Treatment drug, not prophylaxis
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What's the problem with studying lab strains of malaria?
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Might not compare with field strains
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Why is it important to understand drug resistance?
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Only have a limited number of anti-parasite cmpds commercially available
Takes a long time to develop new drugs No guarantee of vaccines in near future |
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What are characteristics of a good drug?
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Cheap
Easy to produce Easy to obtain Affects only the parasite Parasites do not easily become resistant Little or no side-effects |
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What are mechanisms of drug resistance?
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**Improper dosage and length of treatment
-Mutations in target gene (pt mutation in target enz) Dec drug accumulation in an organelle (including efflux) Drug inactivation |
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What is a good drug targer?
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Mitochondrion
Apicoplast --> Ppl don't have these organelles, so best to targe them -Can also target digestive vacuole, Hz, cytosol etc |
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Describe the apicoplast
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Derived from algae
Important for research Only thing the makes us different from parasites |
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Describe the digestive vacuole
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Needs to take up Hb
Releases heme which is very toxic |
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What drugs do we think work on the digestive vacuole?
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Chloroquine (We know this one works)
Quinine Mefloquine |
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Why is chloroquine an important drug to make?
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Very cheap, only costs a few cents
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Describe quinine
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Toxic plant alkaloid
from bark of Cinchona tree in South America Used to treat malaria 350 years ago Introduced it in Europe later Longest lasting effective malaria drug |
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When and who 1st isolated quinine?
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1819 by Runge
1820 by Pelletier and Caventou It is still extracted from the bark of Cinchona tree, since synthetic ones are too expensive |
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What is the mode of action of quinine?
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porbably the same as chloroquinine
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What is Mefloquine?
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Lariam
-synthetic analogue of quinine -4-quinoline-methanol derivative Was a good prophylactic cuz of its long half-life Now widespread resistance to it |
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Describe chloroquine?
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Resochin
-Synthetically manufactured product -Belongs to 4-amino quinolines class USed for prophylaxis and treatment Most malaria strains are resistant to CQ |
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What does CQ do?
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inhibits heme deteoxification
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How is heme detoxified?
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By biomineralization
Heme lyses mbs Hydrolases relased into parasite cytoplasm Parasite dies |
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What is Hz?
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Heme polymers form insoluble malarial pigment
--> Parasite always has Hz crystals in food vacuole, degraded |
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Where has CQ resistance spread?
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SE Asia, Africa, South America
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What are the proposed models of CQ resistance?
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1) Loss of CQ importer
2) Acquisition of a heme binding ptn 3) Changes in vacuolar pH 4) Have different transporters: PGFI (brings in CQ) and PFCRT (we know it plays a role iin resistance) |
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Which is most likely correct?
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The fourth mechanism with the different transporters
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Are parasites resistant to CQ more or less fit than those that are sensitive to it?
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LESS fit to CQ
CQ sensitive parasites eventually become the main parasite in the region |
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What is pyrimethamine/sulfadoxine?
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Fansidar
-Acts by interfering with folate metabolism (folate antagonist) Resistance widespread (pt mutations in enz) No longer recommended |
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Where does sulfadoxine work?
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On DHPS (dihydropteroate synthase)
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Where does pyrimethamine work?
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On DHFR: dihydrofoloate reductase
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What do these block?
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Block DNA and ptn synthesis
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Why aren't these drugs used anymore?
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Cuz 1 mutation in the parasite folate path and the drugs wouldn't work
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Describe atovaquon/proguanil
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Malarone
Drug combo from 1998 95% effective in otherwise drug resistant P. falciparum Largely free from undesirable side effects Very expensive Resistant strains started in 1992 Proguanil is an antifolate |
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What does Atovaquon do?
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Inhibits e- transport and collapses mitochondrial mb potential
Acts against ubiquinol-cyt C oxidoreductase (complex III) |
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What is Artemisinin?
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From China
Used as a blood schizonticide with other agents Many synthetic analogs of it: artesunate and artemether Appears to undergo an iron-catalysed decomposition into free radicals, antimalrial effect via free-radical ddamage: alkylation of plasmodial ptns |
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What are the drugs vs blood schizontocied?
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Chloroquine, quinine, quinidine, mefloquine
Halofantrine, sulfonamides, tetracyclines, atovaquone, artemisinin |
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What are the drugs vs tissue schizontocide?
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Primaquine, proguanil, pyrimethamine
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What are the drugs vs gametocidal?
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Primaquine
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What are the drugs vs hypnozoitocidal?
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Primaquine
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Why drug combos?
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Combination treatment is the parallel use of 2 or 3 antimalarial agents in the form of free or fixed combos
The individual antimalarial agents used in combo therapy should have beneficial interaction that enhances the efficacy og medication or speeds up clinical response or both |
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What strain mostly uses combo drugs as treatment?
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Falciparum is the main domain of combo therpay, mostly because of drug resistance dev'p
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Why are there so few effective anti-parasitic drugs?
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omly 3 new ones in past 20 years
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How do major anti-parasitic drugs work?
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Many block critical metabolic paths
Best are parasite specific Others target parasite specific organelles |
