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PH3502-Chemotherapy and selective toxcitiy > Lec 10- Anti-Malarial agents > Flashcards

Lec 10- Anti-Malarial agents Flashcards

1
Q

Malaria facts

A
  • Plasmodium falciparum, Vivax, Malariae and ovale cause malaria
  • In 2015, malaria caused an estimated 429,000 deaths
  • Anopheles mosquito vector
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2
Q

Malaria- From the WHO malaria factsheet- updated April 2017

A
  • In 2015, 91 countries and areas had ongoing malaria transmission
  • Malaria is preventable and curable and increased efforts are dramatically reducing the malaria burden in many places
  • Between 2010-15, malaria incidence among populations at risk (the rate of new cases) fell by 21% globally. In the same period malaria mortality rates among populations at risk fell by 29% globally among all age groups, and by 35% among children U5
  • The WHO african region carries a disproportionately high share of the global malaria burden. In 2015, the region was home to 90% of malaria cases and 92% of malaria deaths
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3
Q

Imported malaria cases and deaths, UK: 1996-2014

A
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4
Q

Life cycle of the malarial parasite

A
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5
Q

Anti-malarial agents

A
  • Chloroquine- is used for the prophylaxis of malaria in areas of the world where the risk of chloroquine-resistant falciparum malaria is still low
  • Mefloquine- is used for the prophylaxis of malaria in areas of the world where there is a high risk of chloroquine-resistant falciparum malaria
  • Primaquine- is used to eliminate the liver stages of P.vivax or P.ovale following chloroquine treatment
  • Proguanil- is used (usually with chloroquine, but occasionally alone) for the prophylaxis of malaria
  • Pyrimethamine- should not be used alone, but is used with sulfadoxine (in Fansidar)
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6
Q

Chloroquine

A
  • Used for the prophylaxis of malaria in areas of the world where the risk of chloroquine-resistant falciparum malaria is still low
  • Easy synthesis that has cheap materials
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7
Q

Chloroquine- mechanism

A
  • After passive diffusion, chloroquine becomes trapped in the acidic parasitic digestive vacuole in the protonated form
  • Chloroquine caps hemozoin molecules to prevent further biocrystallization of haem => Haem build-up
  • Chloroquine binds to haem to form a complex that is highly toxic to the cell and distrupts membrane function
  • Toxic concentrations of haem and the complex => cell lysis => Parasite cell autodigestion
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8
Q

Mechanisms of some anti-malarials

A
  • Chloroquine, Mefloquine, Primaquine, Quinine, Iumefantrine
  • Interfere with the haem disposal mechanisms in infected erythrocytes (Plasmodia need to de-toxify haem)
  • Notice the many chiral centres
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9
Q

Lariam (mefloquine) can cause serious mental problems

A
  • Some people who take Lariam have sudden serious mental problems
    • Severe anxiety
    • Paranoia
    • Hallucinations
    • Depresison
    • Feeling restless
    • Unusual behaviour
    • Feeling confused
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10
Q

Proguanil

A
  • A biguanide derivative that is converted to an active metabolite cycloguanil
  • The latter inhibits parasitic dihydrofolate reductase enzyme => Blocks biosynthesis of purines and pyrimidines, which are essential for DNA synthesis and cell multiplication
  • It is thought that proguanil itself may act on another target that dihydrofolate reductase- this disrupts DNA synthesis
    • Enough of a difference between a parasite and human DHFR that it doesn’t affect ours
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11
Q

Proguanil- Problem

A
  • Variable metabolism in the liver by cytochrome P450 isoenzymes of proguanil to cycloguanil (PM/EM/IM)
  • => Clinical importance in poor metabolizers such as the Asian and African populations at risk of malaria infection as they may not achieve adequate therapeutic levels of the active compound, cycloquanil, even after multiple doses
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12
Q

Pyrimethamine

A
  • Commonly used as an adjunct in the treatment of uncomplicated, chloroquine resistant, P.falciparum malaria
  • It is a folic acid antagonist and inhibits the dihydrofolate reductase of plasmodia => blocks the biosynthesis of purines and pyrimidines
  • These are essential for DNA synthesis and cell multiplication
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13
Q

Artemisinin

A
  • Artemisinin has been used in China for at least 1000 years
    *
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14
Q

Artemisinin and analogues- Artemether

A
  • A prodrug for dihydroartemisinin
  • Artemether and lumefantrine combination therapy
  • Artemether is metabolised into the active metabolite dihydroartemisinin. It works against the erythrocytic stages of P.falciparum by inhibiting nucelic acid and protein synthesis
  • Mechanism: Interaction with heme or ferrous ions, in the parasite food vacuole => cytotoxic radical species
  • Artemether has a rapid onset of action and is rapidly cleared from the body (rapid symptomatic relief by reducing the number of malarial parasites)
  • Lumefantrine has a much longer half life and is believed to clear residual parasites
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15
Q

Atovaquone

A
  • Highly lipophillic
  • Acts by selectively affecting mitochondrial electron transport and parallel processes such as ATP and pyrimidine biosynthesis
  • Does not cause myelosuppression (important for patients who have undergone bone marrow transplantation)
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16
Q

Several different mechanism

A
  • Interference with the harm disposal mechanism- 4 different mechs
  • Inhibition of parasitic dihydrofolate reductase
  • Free radical formation and alkylation
  • Interfering with parasitic mitochondrial electron transport
  • Important because of drug resistance
17
Q

Drug resistance

A
  • Artemisinin resistance extends across much of Myanmar
  • We recordered P.falciparum parasites carrying K13-propeller mutations at high prevalence next to the north western border with India
  • Appropriate therapeutic regimens should be tested urgently and implemented comprehensively if spread of artemisinin resitance to other regions is to be avoided
18
Q

From the WHO malaria factsheet-

A
  • In recent years, parasite resistance to artemisinin has been detected in 5 countries of the greater Mekong sub-region
    • Cambodia
    • Lao People’s democratic republic
    • Myanmar
    • Thailand
    • Vietnam
  • Studies have confirmed that artemisinin resistance has emerged independently in many areas of this sub-region
  • Artemisinin resistance has not been contained
  • The pace at which the geographical extent of artemisinin resistance is spreading is faster than the rate at which control and elimination measures are being developed and instituted, or new drugs being introduced
  • A vigorous international effort to contain this enormous threat is needed
19
Q

Treatment stratergy

A
  • If the infective species is Not known, or if the infection is mixed, initial treatment should be as for falciparum malaria with
  • Qunine, Mefloquine, Proguanil
  • OR Artemether with Lumefantrine
    *
20
Q

Falciparum malaria

A
  • Falciparum malaria (malignant malaria) is caused by P.falciparum
  • In most parts of the world P.falciparum is now resistant to chloroquine which should not therefore be given for treatment
  • Quinine, Mefloquine, Proguanil with Atovaquone
  • Or Artemether with Lumefantrine
  • Specialist advice should be sought in difficult cases since new artemisinin drugs such as artesunate and artemether may be available for ‘named-patient use’
21
Q

Benign (recurring) Malarias

A
  • Usually caused by P.vivax and less commonly P.Ovale and P.malaria
  • Chloroquine is the drug of choice for the treatment of benign malaria (but resistance becoming widespread)
  • Chloroquine alone is adequate for P.malariae infections but in the case of P.vivax and P.ovale, a radical cure (to destroy parasites in the liver and this prevent relapse) is required. This is achieved with primaquine
22
Q

Prophylaxis against malaria- Protection against bites

A
  • Personal protection against being bitten is very important. Mosiquito nets impregnated with permethrin provide the most effective barrier protection against insects; coils, mats and vaporised insecticides are also useful
  • Diethyltoluamide (DEET)- in lotions, sprays or roll-on formulations is safe and effective when applied to the skin but the protective effect only lasts for a few hours. Long sleeves and trousers worn after dusk also provide protection
23
Q

Prophylaxis against malaria- Length of prophylaxis

A
  • Mefloquine- one week (preferably 2-3 weeks) before travel into an endemic area (or if not possible at earliest opportunity up to 1 or 2 days before travel). continue for 4 weeks after returining
  • Atovaquone/Proguanil- Prophylaxis should be started 1-2 days before travel. Continued for 1 week after returning
24
Q

For the future

A
  • Genome sequences determined for host (humans), vector (mosquito) and parasite (plasmodium)
  • => Identify selective targets
  • => Design, synthesise, test new agents
25
Q

TYPES OF MOLECULAR INTERACTIONS WE NEED TO KNOW

A
  • Acid-Base= COOH <=> NH
  • Hydrogen bonding- OH <=> OH
  • Van der Waals (hydrophobic)- C <=> C
  • Aromatic- Aromatic (hydrophobic)- Face <=> Face interaction or Face <=> Edge (T)
  • Water
  • Metal

PH3502-Chemotherapy and selective toxcitiy (21 decks)

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