Antimalarial Drugs Flashcards
(40 cards)
How many fatalities from malaria are caused by P. falciparum?
- 90% of fatalities are from P. falciparum
- 75% of infections are with P. falciparum
What factors are considered in drug design in how to target the parasite, P. falciparum?
Selective toxicity:
Exploit metabolic differences between host and parasite.
- Unique target in parasite
> Unique pathway or expression profile - Discriminate between host and parasite targets:
> Molecular differences
> Location
> Access - Target more important to parasite:
> Secondary or redundant to man - Greater drug accumulation by parasite:
> E.g. role of BBB in man, vs. FV (food vacuole) in parasite - Drug activation by parasite
> E.g. pro-drug
How is treatment determined for P. falciparum? What is the process?
- Pretreatment
> 72 hours prior to arrival in hospital; take bloods, culture parasites and determine drug sensitivity - Drug resistance vs. drug compliance vs. dosage errors:
> Measure drug levels in blood samples HPLC (high-performance liquid chromatography)
> Molecular characterisation of identified markers that are associated w/resistance - Mechanisms of treatment and resistance
> Guidance; WHO
> Reviews; Olliaro 2001
What modes of action are there to treat P. falciparum, and their corresponding drugs?
Folate antagonists; hypnozoite/liver stage)
- Proguanil hydrochloride
Antimitochondrial; hypnozoite/liver stage)
- Atovaquone
Antibiotic; both stages
- Doxycycline (prophylaxis AND treatment)
Parasitic food vacuole; Schizont + RBCs (Schizonticides, Intra-erythrocytics, Quinolones) - Quinine (quinidine) - Chloroquine - Mefloquine (Larium) - Sesquiterpene lactone - Natural product
What agents are used in the treatment of acute, uncomplicated P. falciparum, and the prophylaxis of?
Malarone (combination of:)
- Atovaquone
- Proguanil hydrochloride
How does atovaquone work?
- Naphthoquinone class
- Effective against sporozoites (sporelike-stage inoculated into humans)
> Often used in children w/sickle cell disease
> CQ resistant (Chloroquine-resistant) and MDR (Multiple Drug Resistant) strains of P. falciparum and P. vivax
How does atovaquone work?
Analogue of ubiquinone:
- In mitochondrial electron transport chain (ETC)
- Blocking ATP-synthesis and mitochondrial function
- Interacts w/cytochrome bc1 complex (Complex III) of ETC
- Binding to ubiquinol oxidation pocket of cyto bc1 complex
Why does the ubiquinone analogue atovaquone have low mammalian toxicity?
- Drug target is mitochondria
- Specificity for parasite by structural features of its Complex III; ubiquinone binding sites divergent from those of other species
- 1000x more potent at malarial than mammalian Complex III
What is the caveat with targeting malarial mitochondria as per atavaquone?
Erythrocytic stages do not use mitochondria for energy:
- Maybe less susceptible; but mainly used in hypnozoites/sporozoite, hence prophylaxis
- May relate to branch chain respiration of parasite
- Resistance can arise due to point mutations in bc1 complex ubiquinol binding pocket
How does proguanil work?
- Chloroguanide class
- Effective against sporozoites
> Prophylaxis
> Often used in children w/sickle cell disease
> Combination therapy w/atovaquone (Malarone)
Two proposed mechanisms:
- Antifolate
- Synergistic w/atovaquone; impair respiration of parasite?
How does the antifolate activity of proguanil come about?
Proguanil is a pro-drug:
- Converted to cycloguanil (CYP450)
- Inhibits DHFR (dihydrofolate reductase), which normally catalyses formation of THF from DHF, required for purine base (DNA) synthesis, and some AA synthesis.
> Thus inhibits cell proliferation (cycle), cell growth
Parasite has high rate of replication; folate synthesis required by rapidly proliferating cells
Humans cannot synthesise folate de novo; dietary intake
Thus lack of effect of drug in man (and greater affinity for malarial DHFR), and parasite cannot utilise exogenous folate to synthesise
What does the theory of proguanil’s mode of action being synergistic w/atovaquone propose?
- Proguanil is a pro-drug
- But with humans with CYP450 polymorphism who cannot convert it to its active metabolite (cycloguanil), it still works, even on cycloguanil-resistant [point mutation in DHFR] parasites (when given w/atovaquone)
- Proguanil has alternative target to DHFR too; does not act to affect mitochondria alone
Why is atovaquone (Malarone combi) used for P. falciparum prophylaxis?
Active against liver stages; sporozoites
Why is parasite death slower w/atovaquone therapy than with Artemisinin or Chloroquine?
- Delay due to acting on late trophozoites?
- Lipophilic and slow uptake; leads to development of parasite resistance
- Humans and mammals insensitive to drug; different bc1 complex
»> General property of mitochondrial-acting antimalarials
How is Malarone (Atovaquone + Proguanil) to be taken in malaria prophylaxis?
- 1-2 days before entering endemic area, continue for 1 week after leaving
- Adult and child over 40kg; 1 tablet OD
What are the CIs for Malarone?
Cautions:
- N&V (reduced absorption of atovaquone?)
- Diarrhoea
S/Es (many):
- Dizziness
- Depression
- Insomnia
CI:
- Breast-feeding women
- Use of machinery; effects on psychomotor performance (hands)
- Many drug-drug interactions e.g. ‘those that act on’ CYP450 (Artemisinin, moclobemide, tetracyclines, warfarin)
What is quinine? What stage does it act on? (16:45)
- First effective Western treatment for malaria
- Natural product of the Cinchona tree
- Used until 1940s; advent of chloroquine
»> Acts on erythrocyctic (RBC) stage
What are the analogues of quinine (the OG from the Cinchona tree) that are used today as antimalarials?
- Chloroquine (contains Cl)
- Mefloquine (contains Fl)
How do quinoline-containing compounds (e.g. Chloroquine/Mefloquine) work?
- Weak bases; accumulate in the acidic food (digestive) vacuole of parasite
> Impairs action of food vacuole
> Prevents hemozoin production
> Haem toxic; lytic (acts on membrane), ROS production; oxidising parasitic proteins.
What is the mechanism of base trapping in the food vacuole w/quinoline analogues?
- pH 4.5 in food vacuole
- Chloroquine; pKa = 8.1;
- Mefloquine; pKa = 8.7 (accumulates less well; more is ionised at physiological pH 7.4)
> E.g. 90% NH+ at physiological pH
> But then 99.8% NH+ (ionisation) at lysosomal pH 4.6; drug trapped inside food vacuole
How can P. falciparum develop resistance against quinoline-containing compounds?
Multiple genes:
Decreased drug accumulation in food vacuole:
- Accelerated drug efflux
> Expression of ATP-dependent P-glycoprotein in FVM (food vacuole membrane)
> PfMDR1 & PfMDR2 (P. falciparum Multiple Drug Resistant); code for Pgh1 protein expressed in FV membrane
- PfMDR1 imparts mefloquine resistance (MQ); CQ resistance is unclear, but there is reduced uptake.
> PfCRT gene product; Chloroquine Resistant Transporter
- Anion channel expressed in FVM; pumps out CQ
- Perfect correlation w/CQ resistance
- Transfection confers CQ resistance
When is Mefloquine (Larium) used for anti-malarial therapy?
- Use in prophylaxis; where high risk of CQ-resistant P. falciparum (country specific)
- Not for general treatment otherwise; P. falciparum resistance, better tolerated alternatives for non-P. falciparum
What ADR is Mefloquine associated with?
Potentially serious neuropsychiatric reaction:
- High affinity in the brain for 5-HT2A receptors; partial 5-HT2A agonist, full 5-HT2C agonist:
> Insomnia, anxiety, psychosis, depression, suicidal ideation, suicide.
- A2A antagonist too
- ADR can persist up to several months post-treatment; long half-life (due to lipophilicity)
»> BUT, not everyone experiences these S/Es…
What are the pros of CQ (chloroquine) use?
- Not associated w/potentially serious neuropsychiatric reaction (as MQ is; CQ does not bind readily to NT receptors in CNS)
- Recommended for use for treatment of non-P. falciparum:
> P. vivax, P. ovale
> Due to little resistance
> 3 day oral dosage
