Antiparasitics- malaria and other protozoan diseases

what are protozoans

• eukaryotes

• cells are similar to mammalian cells

• unicellular with a size range of 1-500um (mostly 10-50)

• over 45000 species of which 10000 are parasitic to higher organisms

what is amoebic dysentery

• soil or water borne

• cause up to 110000 deaths per year

• poor sanitation is the root cause

• can be treated with metronidazole and related drugs

wha is trypanosomiasis

• african sleeping sickness

• T.brucei transmitted by the tsetse fly

• WHO eradication programme nearing success

• treated with sodium stibogluconate

sodium stibogluconate

• complex salt of toxic metal

what is chagas disease

• american trypanosomiasis

• central and south america

• T.cruzei is transmitted by triatomine bugs

• benznidazole is the usual treatment

what is leishmaniasis

• transmitted by insect bite (sandflies)

• 20 species of leishmania

• trypanosome causes the illness

• occurs in the tropics and sub-tropic regions of africa, america etc

• treated with sodium stibugluconate, amphotericin B, paromycin and/or miltefosine

what causes malaria

• plasmodium species

• P.falciparum

• P.vivax

• P.ovale

• P.malariae

• P.falciparum (most severe)

where are the most deaths of malaria

• sub-saharan africa

• children under 5 at risk

• cost = 12 billion per year

how is malaria contracted

• parasite has a sexual phase in the anopheles mosquito

• when the mosquito bites a human, parasitic sporozoites are released into the blood stream

• within 30 minutes are absorbed into hepatocytes (liver)

• malaria reproduces within mosquito

what is the life cycle of malaria

• replication occurs in liver cells

• liver cells burst, releasing merozoites which infect erythrocytes

• in P.vivax and p.ovale a latent form can also be formed

• this leads to relapses weeks and years after infection

• further replication and differentiation occurs in RBC

• gametes which can infect mosquitos are produced

• so are further merozoites which can infect other erythrocytes

malaria symptoms

• severe chills

• high fever and sweating

• often headache, muscle pain, vomiting

• falciparum malaria can lead to coma, convulsions and death

• symptoms variable = lab diagnosis is essential, lab tests will reveal the parasite and also destruction of RBC

what are the strategies for beating malaria

• kill mosquitos

• marsh drying and insecticides (chlorophenothane)

• mosquito nets

why is strategies of beating malaria failing

• decreased use of DDT

• insecticide-resistant anopheles emergence

what is quinine

• isolated from cinchona bark

• effective against the blood stages but not against liver stages

• good for blood active disease

• short half life

• detoxifies haem

what was the second major class of drugs discovered

• 4-aminoquinolines

• chloroquine

• amodiaquine

• piperaquine

• thought to concentrate in the acidic vacuole of the parasite and prevent heme detoxification

what is folate metabolism

• basis of DNA synthesis

• good drug target for many diseases

• lots of enzymes require building blocks of DNA

what does pyrimethamine target

• dihydrofolate reductase (same as trimethoprim and methotrexate)

• prevents the conversion of dihydrofolic acid into tetrahydrofolic acid

• acts on the blood form of the disease and is used in prophylaxis

• structure resembles folate molecule they’re competing with

what is mefloquine

• analogue of quinine with much longer half life

• makes it useful in prevention of disease as it can be administered before travel to high risk areas

• 2 chiral centres

• used in same orientation to each other (racemic mixture)

• primary MOA - prevention of haem intoxication, prevent haem being broken down by malaria

where do 4-aminoquinolones concentrate

• in the acidic vacuole of the parasite and prevent heme detoxification

what are sulphonamides

• structural analogues of p-aminobenzoic acid

MOA of sulphonamides

• bind to dihyropteroate synthetase

• inhibit incorporation of p-aminobenzoic acid into dihydropteroic acid

antifolates MOA

• prevents DNA synthesis so cells can no longer divide

• block initial enzymatic process

why are sulfadoxine-pyrimethamine a good combo?

• both anti folate drugs that act on different stages of folate metabolism

• they’re not competing for the same enzyme so more effective than single agent

• lower risk of toxicity so good for infants and pregnant women

what is proguanil

• antifolate (prodrug)

• metabolized to cycloguanil which acts on dihydrofolate reductase

how is proguanil converted into cycloguanil

• prodrug activation mediated by CYP450 oxidation followed by a spontaneous reaction sequence

MOA of atovaquone

• redox active compound inhibits electron transport chain of parasite (ATP forms glucose) so metabolic toxins for these cells

• specific for malaria

• more expensive

• less SE

• used with proguanil in malarone for prophylaxis

artemisinin structure

• endoperoxide = peroxide buried inside molecule

artemisinin MOA

• potent against blood form of the parasite

• linked or parasite heme-mediated formation of free radicals

• able to kill the parasite in most stages of its life cycle

artemisinin characteristics

• short acting so administered with long er acting drugs like lumefantrine

strategies for malaria prophylaxis

• avoid being bitten by using long sleeves and trousers after dark in areas of risk

• use a mosquito net

• spray houses with insecticides

• use prophylaxis if travelling to high risk areas

examples of aryl-amino alcohols

• quinine

• mefloquine

MOA of aryl-amino alcohols and 4-aminoquinolines

• thought to act by concentrating in acidic vacuole and preventing hemoglobin breakdown

examples of 4-aminoquinolines

• chloroquine

• amodiaquine

• piperaquine

examples of antifolates

• sulfadoxine

• pyrimethamine

• proguanil

MOA of antifolates

• prevent nucleotide biosynthesis

• folate biology also essential in host cells, selectivity for parasite enzymes is essential

• proguanil is a prodrug that is activated by CYP450s

examples of endoperoxides

• artemisinin

• artemether

MOA of endoperoxides

• thought to be activated by heme to form toxic radical species

• often used in combination with longer acting drugs like lumefantrine

examples of naphthoquinones

• atovaquone

key points for vaccines (R21/Matrix-M)

• recently approved based on very positive clinical trial results

• very effective but <100% protection