WEEK 10 - Antiparasitics Flashcards
What are protozoans
- Eukaryotes (= similar to mammalian cells)
- NOT bacterial (prokaryotic) - Are small, unicellular organisms that cause parasitic diseases
- NOT all are parasitic, can cause other disease
What disease is caused by protozoan parasites
Inc. 4 diseases: cause, transmission and treatment
- Trypanosomiasis
- CAUSE: T.brcei
- TRANSMISSION: tsete fly
- TREATMENT: sodium stibogluconate
- Chagas Disease
- CAUSE: t.cruzei
- TRANSMISSION: triatomine bugs
- TREATMENT: benznidazole - Leishmaniasis
- CAUSE:
- TRANSMISSION: sandflies
- TREATMENT: sodium stibogluconate, amphotericin B, paromycin - Malaria
- CAUSE: Plasmodium species
- e.g. P.falciuparum, P.vivax, P.malariae
- TRANSMISSION:
- TREATMENT
- DISEASE BURDEN: highest (compared to other diseases)
- esp. in child <5
Malaria Prevelance
- Most deaths are in sub-saharan africa
- children <5 are at greater risk - Incidence is highest in east asia, south america and central Africa
- Mortality rate has been steadily increasing from 1980 till 2005
- began to ↓ due to control measures, new drug combos etc.
- ↓ until 2019
- From 2019 there has been an ↑ - Has over 210 million cases worldwide
What are the challenges with Malaria treatment and how to beat Malaria
CHALLENGES:
- Early stages of the human infected-parasitic stage can remain dormant in hepatocytes for years
- Dormant hepatocytes cane be reactivated without having to be bitten again by mosquito
- Dormant cells make it difficult to eradicate malaria completely
SOLUTIONS:
- Kill mosquitos
- ↓ no of mosquitos = ↓ ability to infect human host
- inc. insecticides ~ ISSUE insecticide resistant anopheles mosquitos emerging
- Use mosquito nets covered in insecticides
- Change mosquito lifecycle
- introduce genetically-modified mosquitos that give rise in sexually incompetet mosquitos
- blocks life cycle + ↓ population
List the main classes of drugs used to treat / prevent malaria
5 classes
- Quinine
- 4-aminoquinolines
- Anti-folates
- Atovaquone
- Artemisin
NOTE:
ALL anti-malarials are basic, amine compound
- as organelle responsible for heme breakdown in plasmodium parasite vacuole is acidic
- compound is in protonted state = important for drug distribution in vacuole
ALL started before going to high risk area (as PROPHYLAXIS)
What is the MoA for Quinolines (Quinine & Mefloquine)
DO NOT NEED TO MEMORISE STRUCTURE (just know features related to action)
Effective AGAINST BLOOD STAGE but NOT the LIVER stage
- ↓ levels of infection in patients with blood active disease
MoA:
- Prevents breakdown of heme by parasite
- parasite try detoxifiying heme
- Heme becomes toxic to parasite + causes malaria parasite to die inside RBC
Quinine:
- 1st anti-malarial discovered, natural compound
- alkaloid molecule
- has SHORT half-life = NOT EFFECTIVE treatment
- Basic, amine compound
Mefloquinine:
- analogue of quinine (chemically synthesised)
- has LONG half life (2-4 weeks)
- due to ADDITION of LIPOPHILIC CHLORINATED group
- added group ↓ metabolism + ↑ vol. of distribution
- more EFFECTIVE + can be administered before travel
- Basic, amine compound
What is the MoA for 4-aminoquinolines
DO NOT NEED TO MEMORISE STRUCTURE (just know features related to action)
Active AGAINST BLOOD STAGE of disease
MoA:
- Concentrate in the acidc vacuole of plasmodium parasite + PREVENT HEME detoxification / breakdown
STRUCTURE:
- Basic amine compounds = able to be in acidic plasmodium vacoule
- LONG half-life (2-4 weeks)
= allows less frequent dosing
NOTE:
Inc. including chloroquine, amodiaquine and piperaquine
What is the MoA for antifolates
DO NOT NEED TO MEMORISE STRUCTURE (just know features related to action)
Active AGAINST BLOOD STAGE of infection
MoA:
- Target dihydrofolate reductase
- Folate metabolism is required for DNA synthesis = good TARGET
- antifolates PREVENT FOLATE SYNTHESIS = prevents synthesis of DNA = CELLS are UNABLE to DIVIDE / replicate
Sulfadoxine:
- bind to dihyropteroate synthease inihibting conversion of PABA
Pyrimethamine:
- inhibits conversion of dihydrofolic acid into tetrahydrofolic acid
Proguanil:
- a prodrug ~ metabolised by CYP450 into cycloguanil (more stable)
- OH group is hydroxylated
- cycloguanil inhibits dihydrofolate reductase
STRUCTURE:
- All antifolates resemble folate molecule (competitive inhibitor)
- MUST have selectivity for malarial emzyme or can be toxic to human folate synthesis
NOTE:
Inc. Pyrimethamine, Proguanil, Sulfadoxine
- given combination therapy of Sulfadoxine-Pyrimethamine as they act on diff. stages of folate metabolism = MORE EFEFCTIVE
What is the MoA for Atovaquone
DO NOT NEED TO MEMORISE STRUCTURE (just know features related to action)
MoA:
- Inhibits electron transport chain of parasite = metabolic toxin to parasitic cells
- REDOX reaction
- e- transport chain is how cells generate ATP from glucose
STRCUTRE:
- Basic, amine compound
- LONG half-life = long duration of drug exposure
- lipophilic compound
NOTE:
- Used in COMBO with proguanil (anti-folate)
What is the MoA for Artemisinin
DO NOT NEED TO MEMORISE STRUCTURE (just know features related to action)
STRCUTRE:
- Basic, amine compound
