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*B33VPI - Pharmacology & Therapeutics > Antimalarial Drugs > Flashcards

Antimalarial Drugs Flashcards

1
Q

How many fatalities from malaria are caused by P. falciparum?

A
  • 90% of fatalities are from P. falciparum

- 75% of infections are with P. falciparum

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2
Q

What factors are considered in drug design in how to target the parasite, P. falciparum?

A

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
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3
Q

How is treatment determined for P. falciparum? What is the process?

A
  • 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
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4
Q

What modes of action are there to treat P. falciparum, and their corresponding drugs?

A

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
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5
Q

What agents are used in the treatment of acute, uncomplicated P. falciparum, and the prophylaxis of?

A

Malarone (combination of:)

  • Atovaquone
  • Proguanil hydrochloride
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6
Q

How does atovaquone work?

A
  • 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
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7
Q

How does atovaquone work?

A

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
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8
Q

Why does the ubiquinone analogue atovaquone have low mammalian toxicity?

A
  • 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
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9
Q

What is the caveat with targeting malarial mitochondria as per atavaquone?

A

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
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10
Q

How does proguanil work?

A
  • 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?
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11
Q

How does the antifolate activity of proguanil come about?

A

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

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12
Q

What does the theory of proguanil’s mode of action being synergistic w/atovaquone propose?

A
  • 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
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13
Q

Why is atovaquone (Malarone combi) used for P. falciparum prophylaxis?

A

Active against liver stages; sporozoites

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14
Q

Why is parasite death slower w/atovaquone therapy than with Artemisinin or Chloroquine?

A
  • 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
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15
Q

How is Malarone (Atovaquone + Proguanil) to be taken in malaria prophylaxis?

A
  • 1-2 days before entering endemic area, continue for 1 week after leaving
  • Adult and child over 40kg; 1 tablet OD
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16
Q

What are the CIs for Malarone?

A

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)
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17
Q

What is quinine? What stage does it act on? (16:45)

A
  • First effective Western treatment for malaria
  • Natural product of the Cinchona tree
  • Used until 1940s; advent of chloroquine
    »> Acts on erythrocyctic (RBC) stage
18
Q

What are the analogues of quinine (the OG from the Cinchona tree) that are used today as antimalarials?

A
  • Chloroquine (contains Cl)

- Mefloquine (contains Fl)

19
Q

How do quinoline-containing compounds (e.g. Chloroquine/Mefloquine) work?

A
  • 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.
20
Q

What is the mechanism of base trapping in the food vacuole w/quinoline analogues?

A
  • 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
21
Q

How can P. falciparum develop resistance against quinoline-containing compounds?

A

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
22
Q

When is Mefloquine (Larium) used for anti-malarial therapy?

A
  • 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
23
Q

What ADR is Mefloquine associated with?

A

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…

24
Q

What are the pros of CQ (chloroquine) use?

A
  • 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
25
Q

What are the cons of CQ (chloroquine) use?

A
  • P. falciparum resistance (thus mostly used for P. vivax, P. ovale)
  • CIs; glucose-6-phosphate dehydrogenase deficiency
  • High Vd (volume of distribution):
    > Lipid soluble, Log P = 3.0, enters adipose tissue
    > But Log D at pH 7.4 = 1
    > Potentially base-trapped in cells
  • Toxic in overdose; accumulates in other acidic vacuoles
  • Retinal toxicity; accumulation may cause blurred vision and even blindness.
26
Q

When is CQ (chloroquine) used in antimalarial therapy?

A
  • Prophylaxis; where risk of CQ-resistant P. falciparum is low (country-specific)
  • RARELY used for treatment; P. falciparum resistance
    > However, not associated w/potentially serious neuropsychiatric reaction
    > Thus recommended in treatment of non-P. falciparum malaria; P. vivax, P. ovale.
27
Q

Where is quinine’s (OG) place in antimalarial treatment?

A
  • Widely used and effective
    > PO Quinine Sulphate 600mg every 8 hours for 5-7 days
    > Ensure complete eradication/ addition of doxycycline 200mg OD (simultaneously or sequentially; quinine not 100% effective as sole agent)
  • Initially used in pregnancy
  • Base trapping in food vacuole
28
Q

What occurs in quinine overdose?

A

Hypoglycaemia:
> Hyperinsulinemia can result in coma + death
- Directly stimulates insulin secretion
- Acts like sulphonylureas

29
Q

What is doxycycline, and where is its place in antimalarial treatment?

A
  • Tetracyclic antibiotic

- Prophylaxis NOT treatment of malaria (apart from in combination w/quinine)

30
Q

What is doxycycline only used in malarial prophylaxis, and not the treatment of?

A
  • Mode of action TOO DELAYED for treatment

But can be used in conjunction w/quinine to ensure eradication

31
Q

How does doxycycline work?

A

Impairs progeny (replication) of the apicoplast (plastid thing) genes; results in abnormal cell division

32
Q

What is the apicoplast, and which therapeutic agent targets it?

A
  • Non-photosynthetic plastid; organelle stores pigment
  • Found in most Apicomplexa, includes malaria parasites
  • Vital to parasite survival:
    > Lipid metabolism
    > Host cell invasion

> > > Doxycycline impairs progeny of apicoplast genes

33
Q

What are the dosage instructions for doxycycline for the prophylaxis and the treatment of malaria respectively?

A

Prophylaxis:
- 1-2 days before entering endemic area (esp. high risk areas)

Treatment:
- Only when WITH quinine
- Over 12 y/o; 200 mg OD for 7 days
»> NOT in pregnancy; impair teeth and skeletal development

34
Q

What are the various mechanisms of drug resistance?

A

Combination of:
- Mutations in target gene/protein
> Decrease selectivity

  • Increased production of target
  • Decreased accumulation of drug
    > Increased efflux of drug
    > Inactivation of drug
  • Parasites w/mutation or genetic polymorphisms
    > Eneole and confer resistance under drug pressure
    > Unichemotherapy often leads to rapid selection of resistant mutations
    > Simultaneous resistance (to several drugs that are used simultaneously)
    (treat w/combination therapy)
  • Cross-resistance (CQ/MQ)
    > Resistance to agent imparts resistance to other similar acting drugs
    > Also indicates common mode of action
35
Q

Why is there no viable, approved malaria vaccine on the market?

A
  • Malaria is a protozoa (unlike viruses)
    »> Which malaria?
    »> Active antigenic variation; there are > 50 variants of the var allele (would need > 50 types of vaccine)
  • Limited protection; even for those vaccines currently trialled e.g. Mosquirix; only 55% protection in children, 33% in infants, as well as adjuvant risks.
36
Q

What are the logistical and financial problems with a malaria vaccine?

A

Whom:

  • Sufficient for herd immunity (cost)
  • Which population communities?

Delivery:
- Multiple inoculation (4 - 6 doses)

Costs:
- Affordability

37
Q

What is an example of a new antimalarial therapy?

Why is it preferable?

A

Artemisinin-based combination therapies (ACT)
- Current GOLD STANDARD
- Fixed dose (3)
> Limiting number of doses improves compliance, and cheaper too.
> Gives prophylactic protection; long plasma half-life duration (hence fewer doses too; > 1 week plasma lifetime)

38
Q

How does ACT work?

A

Artemisinin-based combination therapies (ACT):

  • Reduces parasite load by 10,000 over 48 hour life cycle
  • To ensure eradication, activity over 3-4 life cycles
  • Plasma lifetime: > 1 week
39
Q

What are the aims of new antimalarial therapy?

A

Eradication

  • Prevention of transmission
  • Screen (treat) whole population whether infected or not

New targets
- Enzymes structurally specific to Plasmodium

Natural products

  • Herbal (traditional medicines)
  • Fungal
40
Q

How are the different antimalarials availible classed?

A

Casual Prophylaxis:
- Destroys parasites in liver, prevents RBC invasion
> Malarone

Suppressive Prophylaxis
- Suppresses RBC phase
> Chloroquine, mefloquine proguanil, doxycycline (NOT quinine)

Clinical cure:

  • Erythrocyte schizonticides
  • Terminate malarial fever
  • Slow acting, low efficacy:
    > Proguanil
  • Fast acting, high efficacy
    > Quinolines, artemisinin (hence gold standard)

*B33VPI - Pharmacology & Therapeutics (3 decks)

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