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58832
Malria: diagnosis, treatment and prevention
Description
Microbiology Mind Map on Malria: diagnosis, treatment and prevention, created by maisie_oj on 27/04/2013.
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microbiology
microbiology
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maisie_oj
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Resource summary
Malria: diagnosis, treatment and prevention
Diagnosis
Microscopy
thin or thick blood films
Can tell four species apart
Antigen
Cannot distinguish between all types of malaria
Serves as a rapid diagnostic tool
PCR
Expensive
Treatment
Quinine-based drugs
Act within the food vacuole
Quinine
1st treatment available for malaria
Natural medicine
Peruvian mexicans chewed the bark of the Cinchona plant to treat malaria
Earkly 1600's it was used by the catholic missionaries (called it "Jesuit's powder")
Purified in 1817 - Pelletier and Caventou
First pharmaceutical agent = 4-methanol quinolone
Could cause cinchonism
Blurred vision, nausea, vomitting, imparied hearing and dizziness
Active against RBC stage malaria
Effective against chloroquine-resistant malaria
Found in tonic water
Pharmacokinetics
Absorption
Oral
Distribution
70% is bound to protein
Elimination
Redily metabolised in liver (~80%)
Metabolites inactive
20% in urine
Half life of ~18hrs
Chloroquine
4-aminoquninolone
Artificial analogue of quinine
Developed in 1940's
Cheap, stable and no serious side effects
Active against RBC stages
Used extensively in 60's and 70's (during erradication campaign)
Lead to massive levels of resistance
e.g. in Vietnam etc.
No other anti-malarial has come close
Pharmacokinetcs
Absorption
Oral
Distribution
50-60% protein bound
Elimination
Partially metabolised in liver in to active de-ethylated metabolites
Excreted in urine unchanged (45%) - but slowly
Half life = 1-2 months
MOA of Qunine and Chloroquine
e.g. during ring-stage
Parasite trophozoite requires haemoglobin (Hb) to survive
Hb taken up by cytosome (endocytosis) uptake -> transport vesicles - > fuse with food vacuole
Hb in food vacuole
Hb broken down to release amino acids (released into cytoplasm) and haematin (kept in food vacuole)
AA's used by cell
Haematin (toxic to parasite) is crystallised to form haemozoin (inert, non-reactive)
Two haematin molecules dimerised with a propionate group of one haematin interacting with the Fe ion of a second (this de-toxfies the Fe)
These dimers form crystalline structures with other dimers -> haemozoin
Seen as the second solid structure during the ring phase (the other one is the nucleus)
Dimer = 4-beta haematin
Fe(3+) ion of haematin can generate free radicals
Quinine and chloroquine accumulate in the food vacuole
Prevent the formation of haemozoin crystals -> haematin builds up, generates free radicals and kills the parasite
In the 60's chloroquine was heralded as a major success
However chloroquine resistance was observed as early as 1959 in SE Asia and S. America
Since then chloroquine resistance has spread to all endemic areas (1957 - spread through asia and oceana, 1959-60 spread through S. America)
In 1978 resistance from Asia spread throughout sub saharan africa
Resistance now common
Molecular basis for resistance
chloeroquine resistance develops slowly
Spectrum (low-high) resistance seen
Suggestions mechanism of resistance is complex
Resistance at target level (unlikely)
Target is haematin (synthesised by host - Hb)
Cannot be altered by parasite)
Resistance at drug level (likely)
Less chloroqunine retained in parasite
Either; reduced uptake or drug efflux
In low-medium resistant strains
Mutations detected (by PCR and sequencing) in parasite protein PfCRT (P. falciparum chloroquine resistance transporter)
PfCRT is found in the membrane of the food vacuole
Features 10 transmembrane domains
Resistance-conferring mutatin (K76T) is localised in a region of the protein involved in substrate selectivity
Mutation: K76T is a key diagnostic tool for resistance detection
In non-resistant strains food-vacuolar chloroquine is positively charged (protonated) due to the low pH
The lysine (K) residue at position 76 features a positive side chain which physically repels the chloroquine molecule - preventing its escape)
Hence its accumulation to x20,000 the level of the plasma chloroquine concentration
The mutation of K to threonine (T) at position 76 means that chloroquine is removed from the food vacuole as threonine has an uncharged side chain
Chloroquine is eliminated from the food vacuole via PfCRT (efflux pump)
In higher resistance strains
Feature additional mutaiotns to K76T in PfCRT
Resistance can be enhanced by a mutation in a second gene PfMDR (P.falciparum multi druig resistance)
PfMDR is an ABC (ATP-binding casette) transporter - group of membrane transporter proteins
MDRs in other organisms function to export hydrphobic drugs and indirectly regulate ionic gradients
MDRs are responsible for drug resistance in cancer cells
The Ca(2+) channel blocker verapamil (which reverses resistance of mammalian cells to anti-cancer cells) reverses chloroquine resistance
PfMDR contains 12 transmembrane domains (TMDs)
ATP interacting loops
PfMDR (like the PfCRT) is located in the membrane of the food vacuole
There are several known mutations unique to different geographical resistant strains
E.g. N86Y (Africa); S1034C, N1042D and D1246Y (S. America)
ALL RESISTANT STRAINS FEATURE K76T!!!
The acidity of the food vacuole causes chloroquine to accumulate (due to protination -> become charged) to x20,000 the plasma [chloroquine]
Mefloquine
Used in cases of chloroquine-resistant malaria
Absorption
Oral
Distribution
Can cross the BBB (cerebral malaria)
Side effects
Experienced in 1:10,000 patients (psychological effects, seizures, motor and CNS problems
MOA is unknonw
In food vacuole like other quinines?
Resistance newly emerging (SE Asia) - different mechanism to chloroquine
Molecular basis of mefloquine resistance
Requires wild type PfMDR1
Mutation in PfMDR actually causes mefloquine sensitivity
Mutation associated with overexpression of wild type PfMDR
Can remove mefloquine faster from the food vacuole
So mefloquine resistance occurs by a different method to chloroquine resistance
Amplification of PfMDR (mefloquine)
Mutataion in PfMDR (chloroquine)
Non-quinolone-based drugs
Sulfadoxine-pyrimethamine combinational therapy
Second-line treatment in chloroquine resistance (after mefloquine)
Active against the asexual cycle merozoite -> trophozoite -> merozoite
Side effects
(Rare) death from drug-induce dermatological conditions (toxic epidermal necrolysis; or Steven-Johnson syndrome (SJS)
Many milder side effects: rash, photosensitivity, blood disorders (aplastic anaeamia, agranulocytosis), liver/lung damage
Absorption
Single oral dose (3 tablets for adults)
Distribution
90% is protein-bound
both cross the placental barrier and pass into the breast milk
Pyrimethamine concentrates in blood cells (red and white) and crosses into the CNS fluids
Elimination
<5% of each drug is metabolised
both excreted in urine (long half lives - both >100 hrs)
MOA
Targets multiple enzymes of the folate synthesis pathway
Drugs act synergistically (complimentary)
Reduce folate levels -> folate is essential for nucleotide (DNA) synthesis and metabolism of certain amino acids
Humans lack components of this pathway and therefore rely on the diet for folate
Sulfadoxine
Type 1 anti-folate
para-aminobenzioc acid (PABA) analogue
Necessary in folate synthesis
Target: Dihydropteroate synthase (DHPS) - missing in humans
Competitive inhibition
In Plasmodium, DHPS is part of a bifunctional enzyme with dihydroptero pyrophosphokinase = PPPK-DHPS
Pyrimethamine
Type 2 anti-folate
Pyrimidine containing compound
Target: Dihydrofolate reductase (DHFR) - present in humans
Competitive inhibition
Pyrimethamine binds x7,000 more strongly to DHFR than dihydro folate (natural substrate)
In Plasmodium DHFR is in copmplex with another enzyme thymidylate synthase (TS)
Resistance
Basis of resistance due to difference in activity (pyrimethamine is more active than sulfadoxine)
Due to point mutations in their respective enzymes
Firstly in DHFR-TS (only DHFR domain affected)
Then in PPPK-DHPS (only DHPS domain affected)
After four mutations in DHFR (above) - A437G; and K540E cause sulfadoxine resistance
Diagnostic mutation = S108N (always present in resistant strains)
causes 100 fold increase in resistance
Secondary mutations cause increased resistance (e.g. N51I; C59R; I164L)
Atovaquone
Part of a combinational therapy (with proguanil - another Type 2 antifolate inhibitor [targets DHFR])
Active against liver and RBC stages
Casual prophylaxis (taken 1 day before travel)
Pharmacokinetics
Absorption
Oral (standard malarone tablet)
Distribution
99% binds to serum albumin (extremely lipophilic)
Elimination
Not metabolised (slowly excreted in faeces, little in urine - half life = 48-72hrs)
Side effects
Very few
Trade name = Malarone
MOA
Analogue of ubiquinone
Ubiquinone: shuttles electrons from complexes 1 and 2 of the oxidative phosphorylation pathway to complex 3 (cytochrome b)
Atovaquone inhibts the passing of electrons to (reduction of) complex 3 in the ETC
Inhibits proton gradient production -> ATP production
Resistance
Can only arise through a point mutation (Y268N or Y268S) in the gene encoding cytochrome b
Resistance is rare when using Malarone combinational therapy - first case reported in 2002
Tyrosine (Y) is a bulky hydrophilic amino acid that interacts with the hydrophobic atovaquone
Substitution to a less bulky asparagine (N) or serine (S) causes a loss of drug binding ability
Doxycycline
Absorption
Oral
Distribution
90% drug in plasma
Elimination
Not metabolised
Excreted in urine/faeces
Half life = 18hrs
MOA
Site of action is the apicoplast (prokaryote remenant that resembles a chloroplast - non-photosynthetic)
Inhibits cell growth by inhibiting translation in the apicoplast
Stops cell growth - doesnt kill
Broad spectrum antibiotic
Used as prophylaxis
Active against asexual cycle
Resistance not yet reported
Artemisinin
From leaves of Artemesia annua
Problem with supply
Not enough plant material can be grown for demmand
Made from a series of isoprene units with a peroxide bond
Pharmacokinetics poorly understood (oral bioavailability is poor)
Synthetic compounds (Artesunsate) produced with increased H2O solubility - can be injected
Active against ring stage
Used against MDR malaria
Evidence of resistance in Cambodia already
The way forward?
Artemisinin combinational therapy with...
Amodiaquine
Active against all forms of malaria (falciparum, vivax, ovale, malariae)
Active against chloroquine resistant strains
>20 million cases of malaria treated as of (2009)
...Mefloquine
Reduced mefloquine side effects
WHO advise use for uncomplicated falciparum infection
Not cosidered suitable for first line treatment in African malaria
MOA
Uknown whether one or multiple drug targets(?)
Inhibiton of food vacuole cysteine protease activity
Damage to parasite's ETC in the mitochondria
Irreversible inhibition with an ATPase (PfATP6) that pumps Ca(2+) from the cytoplasm into the ER
Three points of malarial chemotherapy
stage to target
Sporozoite
Liver schizont
Merozoite
Trophozoite (ring stage)
RBC schizont
In host
Liver
Blood
Species
P. falciparum
P. vivax
P. ovale
P. malariae
Anatomy of the infected RBC
RBC
Parasite (cytoplasm)
Site of action for sulfadoxine-pyrimethamine (combinational therapy)
Digestive (food) vacuole
The food vacuole is the site of action for quinine-base drugs
Nucleus
Mitochondrion
Atovaquone targets the mitochonrion
Apicoplast
Apicoplast: target for doxycycline
Cytosome uptake of haemoglobin
Prevention
Insecticide sprays - control of adult and larval stages
Particularly around breeding grounds (still water)
Ecological considerations
Mosquito nets
Contain insecticide
Cheap and insecticide is "contained"
Prophylactic treatment
Control of mosquito population (introduction of sterile males)
Drainage and removal of breeding grounds
Ecological considerations
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