Anti-Malarial Drugs (Paul Smith) Flashcards
Which stages of Plasmodium falciparum life cycle can we target with drugs?
Insecticides / repellants
Hepatic stage
Schizont stage
Gametocyte stage
How can drugs target malaria?
Exploit metabolic differences between host and parasite
= selective toxicity
Molecular differences, location, access
Greater accumulation in parasite compared to man
Drug activated by parasite
What is the benefit to culturing parasites?
Determine drug sensitivity
Which drugs target hypnozoites?
Folate antagnoists: porguanil hydrochloride
Antimitochondrial
What antibiotic drugs are used for prophylaxis and treatment?
Doxycycline
Which drugs target the parasitic food vacuole?
Schizontocydes
Intra-erythrocytic
Quinolines; chloroquine, quinidine, mefloquine, sesquiterpine lactone, natural product.
What stage of the plasmodium life cycle do folate inhibitors and anti-mitochondrials target?
Hepatic stages
Which stage of the plasmodium life cycle is attacked by quinolines?
Blood stages
What is Malarone used in the treatment of?
Uncomplicated actue falciparum and prophylaxis.
How does atavaquone work?
Effective against sporozoites, it is an analgoue of ubiquinone and so blocks its usual role in mitochondrial ETC. Blocking ATP synthesis and mitochondrial function.
It interacts with the cytochrome bc1 complex III of the ETC.
Where does atavoquone bind?
Binds to the ubiquinol oxidation pocket of cyto bc1 complex
How does atavoquone have low mammalian toxicity?
Mitochondria of Apicomplexan parasites are the target
Specificity of the parasite by structural features of its complex III
Is atavoquone effective at erythrocytic stage of malaria?
No because they do not use mitochondria for energy so less susceptible
When can resistance to atavaquone develop?
Point mutations in bc1 ubiquinol binding pocket
How does proguanil work?
Pro-drug for chlorguanide
Effective against sporozoites
Prophylatic treatment
Two proposed mechanisms: antifolate
synergistic action with atavaquone
What can proguanil be used in combination with?
Atavoquone
What is proguanil metabolised to in vitro?
Cycloguanil
Inhibits DHFR which catalyses the formation of dihydrofolate to tetrahydrofolate required for purine base synthesis and some amino acid synthesis
Inhibits cell proliferation and growth in parasite
How is proguanil converted to cycloguanil?
CYP450
How does proguanil not affect man?
Humans cannot synthesise folate de novo
When is proguanil ineffective in man?
Humans with a polymorphism in P450 cannot convert to cycloguanil
But the proguanil still works; even in cycloguanil resitant patients; point mutation DHFR. This suggests that proguanil has an additional target to DHFR; does not act on mitochondria alone.
What makes atovaquone effective prophylactically ?
Active in liver, sporozoite phase
What is a general principle re mitochondrial acting antimalarials?
Parasite death slower
Lipophillic and slow uptake (can sometimes lead to resistance).
What is the dose regimen of Malarone?
1-2 days before endemic area, duration and for 1 week afterwards
What is Malarone?
Atovaquane and proguanil
What are the contra-indications for malarone?
Cautions: nausea, diarrhoea, vomiting (reduced absorption)
Dizziness, depression, insomnia
Women breast feeding; not suitable
Many drug interactions that act on CYP450
Artemisin, moclobeminde, tetracycline, warfarin etc
What stage of the malarial cycle does quinine work on?
Red blood cells - erythrocyte stage
What are the clinically used quinine derivatives?
Chloroquine and mefloquine
How do quinoline containing compounds work?
Weak bases accumulate in acidic digestive (food) vacuole of the parasite
CQ Pka = 8.1
MQ Pka = 8.7
Chloroquine accumulates less well
They impair the action of the food vacuole and interact with haem disposal.
Preventing hemozoin formation
Haem is toxic, causes lysis and ROS production which is ultimately toxic to the parasite.
How can Quinoline resistance arise?
Multiple genes can lead to resistance that is presented as reduction in drug accumulation or as accelerated efflux.
Expression of ATP-dependent P-glycoprotein in FV membrane.
Pf-MDR1 and Pf-MDR2 confer resistance; MDR1 imparts MQ resistance
What is caused by the Pf-CRT gene?
CRT - Chloroquine Resistant Transporter
Anion channel expressed in the FV membrane that has a perfect correlation to Chloroquine resistance.
When can Mefloquine (Larium) be used?
Prophylactic where high risk of CQ resistant falciparum malaria (country specific)
Rarely used for treatment due to P. falciparum resistance and the availability of better tolerated alternatives for other non P. falciparum strains.
What is the scandal / concern associated with Larium?
Mefloquine - serious neuropsychiatric reaction; insomnia psychosis anxiety depression suicidal ideation and suicide
High affinity in the brain a 5-HT2a receptors
Adverse reactions may last after treatment for several months.
What are the benefits to Chloroquine?
Not associated with serious neuropsychiatric side effects and do not readily bind to NT receptors in the CNS
Recommended for treatment of non P falciparum e.g. vivax or ovale
Little resistance
3 days oral dosage
What are the disadvantages of Chloroquine?
P falciparum resistance
Contraindications :
Glucose-6-phosphate dehydrogenase deficiency exacerbates adverse effects
High volume of distribution; lipid soluble, adipose tissue
Toxic if overdosed due to accumulation effect
Retinal toxicity in accumulation; blurred vision and blindness
What is Chloroquine used for?
Prophylaxis in countries with low risk of CQ resistant falciparum
Rarely used for treatment due to falciparum resistance
Recommended for non falciparum treatment
When is Quinine used?
Widely used and effective
Initially used in pregnancy
Hw does Quinine work?
Base trapping mechanism in food vacuole
What are the risks associated with Quinine?
Overdose
Hypoglycemia / hyperinsulinemia
Directly stimulates insulin secretion and acts like sulphonylureas
What is concomitantly administered with Quinine?
Doxycycline 200 mg daily
What class of drug is Doxycycline and when is it used?
Used for prophylaxis
Tetracycline antibiotic
Mode of action too delayed for treatment purposes but can be used with Quinine for ensuring eradication
How does Doxycycline work?
Impairs progeny (offspring/daughters) of apicoplast genes
What is an Apicoplast?
Non photosynthetic plastid (organelle stores pigment) Found in most Apicomplexa including malaria parasites
Vital to parasite survival
When is Doxycycline used?
Prophylaxis - 1-2 days before entering endemic area
Treatment with Quinine but not in pregnancy
How can resistance to Doxycyline arise?
Mutations in target gene/protein (reduced selectivity)
Increased production of target
Decreased accumulation of drug i.e. increased efflux or inactivation of drug
Genetic polymorphisms; evolve and confer resistance under drug pressure
Unichemotherapy often leads to rapid selection of resistant mutants
Cross resistance as agents impart resistance to other similar acting drugs
What are the logistical and economical issues with malaria vaccines?
Who? Sufficient for herd immunity, which population?
Delivery? Multiple innoculations needed
Costs - affordability
Why can’t a vaccine be made for malaria?
Not a virus, active protozoa with active antigenic variation
What is the current gold standard treatment for malaria?
ACT - Artemisin-based combination therapies; fixed dose of 3.
What are the new targets of malarial drugs?
Enzymes structurally specific to Plasmodium
