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B33VPI > Anti-Malarial Drugs (Paul Smith) > Flashcards

Anti-Malarial Drugs (Paul Smith) Flashcards

1
Q

Which stages of Plasmodium falciparum life cycle can we target with drugs?

A

Insecticides / repellants
Hepatic stage
Schizont stage
Gametocyte stage

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2
Q

How can drugs target malaria?

A

Exploit metabolic differences between host and parasite
= selective toxicity
Molecular differences, location, access
Greater accumulation in parasite compared to man
Drug activated by parasite

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3
Q

What is the benefit to culturing parasites?

A

Determine drug sensitivity

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4
Q

Which drugs target hypnozoites?

A

Folate antagnoists: porguanil hydrochloride

Antimitochondrial

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5
Q

What antibiotic drugs are used for prophylaxis and treatment?

A

Doxycycline

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6
Q

Which drugs target the parasitic food vacuole?

A

Schizontocydes
Intra-erythrocytic
Quinolines; chloroquine, quinidine, mefloquine, sesquiterpine lactone, natural product.

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7
Q

What stage of the plasmodium life cycle do folate inhibitors and anti-mitochondrials target?

A

Hepatic stages

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8
Q

Which stage of the plasmodium life cycle is attacked by quinolines?

A

Blood stages

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9
Q

What is Malarone used in the treatment of?

A

Uncomplicated actue falciparum and prophylaxis.

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10
Q

How does atavaquone work?

A

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.

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11
Q

Where does atavoquone bind?

A

Binds to the ubiquinol oxidation pocket of cyto bc1 complex

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12
Q

How does atavoquone have low mammalian toxicity?

A

Mitochondria of Apicomplexan parasites are the target

Specificity of the parasite by structural features of its complex III

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13
Q

Is atavoquone effective at erythrocytic stage of malaria?

A

No because they do not use mitochondria for energy so less susceptible

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14
Q

When can resistance to atavaquone develop?

A

Point mutations in bc1 ubiquinol binding pocket

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15
Q

How does proguanil work?

A

Pro-drug for chlorguanide
Effective against sporozoites
Prophylatic treatment

Two proposed mechanisms: antifolate
synergistic action with atavaquone

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16
Q

What can proguanil be used in combination with?

A

Atavoquone

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17
Q

What is proguanil metabolised to in vitro?

A

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

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18
Q

How is proguanil converted to cycloguanil?

A

CYP450

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19
Q

How does proguanil not affect man?

A

Humans cannot synthesise folate de novo

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20
Q

When is proguanil ineffective in man?

A

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.

21
Q

What makes atovaquone effective prophylactically ?

A

Active in liver, sporozoite phase

22
Q

What is a general principle re mitochondrial acting antimalarials?

A

Parasite death slower

Lipophillic and slow uptake (can sometimes lead to resistance).

23
Q

What is the dose regimen of Malarone?

A

1-2 days before endemic area, duration and for 1 week afterwards

24
Q

What is Malarone?

A

Atovaquane and proguanil

25
Q

What are the contra-indications for malarone?

A

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

26
Q

What stage of the malarial cycle does quinine work on?

A

Red blood cells - erythrocyte stage

27
Q

What are the clinically used quinine derivatives?

A

Chloroquine and mefloquine

28
Q

How do quinoline containing compounds work?

A

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.

29
Q

How can Quinoline resistance arise?

A

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

30
Q

What is caused by the Pf-CRT gene?

A

CRT - Chloroquine Resistant Transporter

Anion channel expressed in the FV membrane that has a perfect correlation to Chloroquine resistance.

31
Q

When can Mefloquine (Larium) be used?

A

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.

32
Q

What is the scandal / concern associated with Larium?

A

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.

33
Q

What are the benefits to Chloroquine?

A

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

34
Q

What are the disadvantages of Chloroquine?

A

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

35
Q

What is Chloroquine used for?

A

Prophylaxis in countries with low risk of CQ resistant falciparum
Rarely used for treatment due to falciparum resistance
Recommended for non falciparum treatment

36
Q

When is Quinine used?

A

Widely used and effective

Initially used in pregnancy

37
Q

Hw does Quinine work?

A

Base trapping mechanism in food vacuole

38
Q

What are the risks associated with Quinine?

A

Overdose
Hypoglycemia / hyperinsulinemia
Directly stimulates insulin secretion and acts like sulphonylureas

39
Q

What is concomitantly administered with Quinine?

A

Doxycycline 200 mg daily

40
Q

What class of drug is Doxycycline and when is it used?

A

Used for prophylaxis
Tetracycline antibiotic

Mode of action too delayed for treatment purposes but can be used with Quinine for ensuring eradication

41
Q

How does Doxycycline work?

A

Impairs progeny (offspring/daughters) of apicoplast genes

42
Q

What is an Apicoplast?

A

Non photosynthetic plastid (organelle stores pigment) Found in most Apicomplexa including malaria parasites
Vital to parasite survival

43
Q

When is Doxycycline used?

A

Prophylaxis - 1-2 days before entering endemic area

Treatment with Quinine but not in pregnancy

44
Q

How can resistance to Doxycyline arise?

A

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

45
Q

What are the logistical and economical issues with malaria vaccines?

A

Who? Sufficient for herd immunity, which population?
Delivery? Multiple innoculations needed
Costs - affordability

46
Q

Why can’t a vaccine be made for malaria?

A

Not a virus, active protozoa with active antigenic variation

47
Q

What is the current gold standard treatment for malaria?

A

ACT - Artemisin-based combination therapies; fixed dose of 3.

48
Q

What are the new targets of malarial drugs?

A

Enzymes structurally specific to Plasmodium

B33VPI (16 decks)

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