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    Anti-Malerials Materials

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    raj royel
    Malaria is caused by plasmodium parasites transmitted via mosquito bites. It affects over 200 million people annually. The document outlines the life cycle of the malaria parasite, which involves sexual reproduction in mosquitoes and asexual reproduction in humans. It then describes various classes of antimalarial drugs that target different parasite stages, such as blood schizonticides that treat acute infections and chemoprophylaxis drugs that prevent infection. Several important antimalarial drugs are discussed in detail, including chloroquine, which concentrated in red blood cells and inhibits heme detoxification in plasmodium, though resistance has developed.

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    Anti-Malerials Materials

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    raj royel
    125 views13 pages
    Malaria is caused by plasmodium parasites transmitted via mosquito bites. It affects over 200 million people annually. The document outlines the life cycle of the malaria parasite, which involves sexual reproduction in mosquitoes and asexual reproduction in humans. It then describes various classes of antimalarial drugs that target different parasite stages, such as blood schizonticides that treat acute infections and chemoprophylaxis drugs that prevent infection. Several important antimalarial drugs are discussed in detail, including chloroquine, which concentrated in red blood cells and inhibits heme detoxification in plasmodium, though resistance has developed.

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    Malaria is caused by plasmodium parasites transmitted via mosquito bites. It affects over 200 million people annually. The document outlines the life cycle of the malaria parasite, which involves sexual reproduction in mosquitoes and asexual reproduction in humans. It then describes various classes of antimalarial drugs that target different parasite stages, such as blood schizonticides that treat acute infections and chemoprophylaxis drugs that prevent infection. Several important antimalarial drugs are discussed in detail, including chloroquine, which concentrated in red blood cells and inhibits heme detoxification in plasmodium, though resistance has developed.

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    125 views13 pages

    Anti-Malerials Materials

    Uploaded by

    raj royel
    Malaria is caused by plasmodium parasites transmitted via mosquito bites. It affects over 200 million people annually. The document outlines the life cycle of the malaria parasite, which involves sexual reproduction in mosquitoes and asexual reproduction in humans. It then describes various classes of antimalarial drugs that target different parasite stages, such as blood schizonticides that treat acute infections and chemoprophylaxis drugs that prevent infection. Several important antimalarial drugs are discussed in detail, including chloroquine, which concentrated in red blood cells and inhibits heme detoxification in plasmodium, though resistance has developed.

    Copyright:

    © All Rights Reserved
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    of 13

    BASICS OF MALARIA

    • Malaria: ‘Mal’ + ‘Aria’ = Bad or Poisonous air.


    • Malaria is a mosquito-borne infectious disease affecting humans and other animals
    caused by parasitic protozoans (a group of single-celled microorganisms) belonging to
    the Plasmodium type.
    • Main four species of plasmodia infect humans:
    o Plasmodium vivex
    o Plasmodium falciparum
    o Plasmodium ovale
    o Plasmodium malariae
    • P.falciparum infection can lead to capillary obstruction and death if treatment is not
    instituted promptly. P.vivex causes milder form of the disease. P.malariae is common to
    many tropical regions, but P.ovale is rarely encountered.
    • Malaria causes symptoms that typically include fever, tiredness, vomiting,
    and headaches. In severe cases it can cause yellow skin, seizures, coma, or death.
    Symptoms usually begin ten to fifteen days after being bitten.
    • The insect vectors are the female anopheles female mosquito which breeds in stagnant
    water.
    • According to World Health Organization (WHO), Malaria is a significant public health
    problem in more than 90 countries inhabited by some 2400 million people (about 40%
    of the world’s population).
    • The disease causes an estimated 300 million acute illness acute illness each year and at
    least 1 million deaths.
    • More than 90% of these occur in sub-Saharan Africa, and it is estimated that the disease
    kills an African child every 30 seconds. Even those who survive may suffer lasting mental
    impairment.

    ANTI-MALARIAL AGENTS – JINAL ADHIYA – M.PHARM (PHARMACOLOGY) 1


    LIFE CYCLE OF MALARIAL PARASITE

    Figure-1: Life cycle of malarial parasite with different stages

    • The mosquito, not the human, is the definitive host for plasmodia, and it has been said
    that the only function of human is to enable the parasite to infect more mosquitoes so
    that further sexual recombination occur.
    • The life cycle of the parasite consist of a sexual cycle, which take place in female
    anopheles mosquito, and an asexual cycle, which occurs in humans.
    • When an infected mosquito bites, it injects plasmodium sporozoites into the blood
    stream. The sporozoites migrate through the blood to the liver, where they form cyst-like
    structures contains thousands of merozoites.
    • Schizonts (the pre-erythrocytic stage), which liberate merozoites: these infect red blood
    cells, forming motile trophozoites, using haemoglobin as a nutrient, which after

    ANTI-MALARIAL AGENTS – JINAL ADHIYA – M.PHARM (PHARMACOLOGY) 2


    development, release another batch of erythrocyte-infecting merozoites , causing fever,
    this constitutes the erythrocyte cycle.
    • Dormant hypnozoites, which may liberate merozoites later (the exoerythrocytic stage)
    • Eventually, the infected cell ruptures, releasing heam and merozoites that can enter other
    erythrocyte.
    • Alternatively, released merozoites can become gametocytes, which are picked up by
    mosquitoes from the blood they ingest, the cycle thus begins again. The gametocyte
    becomes sporozoites in the insect

    Figure-2: The life cycle of malarial parasite (P.falsiparum) showing the sites of action
    of anti malarial drugs

    ANTI-MALARIAL AGENTS – JINAL ADHIYA – M.PHARM (PHARMACOLOGY) 3


    ADVANCED THERAPY FOR MALARIA:

    • The best way to deal with Malaria is to avoid the disease in the first place by mosquito
    bites.
    • Some drugs can be used prophylactically to prevent malaria, while others are directed
    towards treating acute attacks.
    • In general, Malarial drugs are classified in terms of the action against the different stages
    of life cycle of the parasite.
    1) Blood Schizonticidal agents
    • Blood schizonticidal agents are used to treat acute attacks, they are also known as drugs
    that produce a ‘suppressive’ or ‘clinical’ cure.
    • They act on the erythrocytic forms of the plasmodium
    • Drugs :
    o Quinoline-methanols: (Quinine, Mefloquine)
    o 4-aminoquinolones: (Chloroquine)
    o Phenanthrene: (Halofantrine)
    o Interfere with folate synthasis: (Pyrimethamine, Proguanil)
    o Hydroxy naphthoquinone compound: (Atovaquone)
    o Compounds derived from quinghaosu: (Artemether, Artesunate, Arteflene)
    2) Chemoprophylaxis
    • Drugs used for chemoprophylaxis block the link between exoerythrocytic stage and
    erythrocytic stage, Thus, prevent the development of malarial attacks
    • Prevention of infection by killing of sporozoites on entry into the host.
    • Drugs :
    o Chloroquine, Mefloquine Proguanil, pyrimethamine, Dapsone and Doxycycline
    3) Curative-suppressive therapy
    • Useful after observing malarial symptomes
    • Drugs :
    o Chloroquine, Quinine, Artether, Atovaquone, Lumifantrine

    ANTI-MALARIAL AGENTS – JINAL ADHIYA – M.PHARM (PHARMACOLOGY) 4


    4) Radical cure therapy
    • These agents affect a ‘radical’ (striking root of infection) cure by acting on the parasites
    in the liver. They destroy gametocytes, thus reduce the spread of infection.
    • Only 8-aminoquinolones have this action.
    • Drugs :
    o Primaquine, tafenoquine
    5) Folate antagonists
    • They inhibit Dihydrofolate reductase.
    • Drugs :
    o Pyrimethamine, Proguanil, Sulfadoxine, Dapsone
    6) Gameticidals
    • These drugs destroy the sexual forms of the parasite in the blood and thereby prevent
    transmission of the infection to the mosquito.
    • Chloroquine and quinine have gametocytocidal activity against P. vivax and P. malariae,
    but not against P. falciparum. Primaquine has gametocytocidal activity against all
    plasmodia, including P. falciparum.
    • Drugs :
    o Artemisinin, Primaquine, Trimethoprim, Chloroquine
    7) Sporonticidals
    • These drug prevent development of oocysts in the mosquito and thus ablate the
    transmission
    • Drugs :
    o Dihydrofolate reductase Primaquine, Chloroguanide,
    8) Curcumin-Artemisinin Combination Therapy
    • Artemisinin and curcumin show an additive interaction in killing Plasmodium falciparum
    in culture.
    • curcumin isolated from the roots of Curcuma longa (turmeric) has antimalarial activity
    preventing recrudescence due to artemisinin

    ANTI-MALARIAL AGENTS – JINAL ADHIYA – M.PHARM (PHARMACOLOGY) 5


    • In vivo, 3 oral doses of curcumin following a single injection of ALPHA AND BETA
    arteether
    • Artemisinin and curcumin (98% curcuminoid content)
    9) Aminoacyl-tRNA Synthetase Inhibitors
    • Drug : Mupirocin, Borrelidin
    • Mechanism of mupirocin inhibition. Mupirocin is a natural product of Pseudomonas
    fluorescens and is the only commercially available antibiotic that inhibits bacterial AaRS
    Borrelidin which is lethal to P. yoelii murine malaria.
    10)Proline‑tRNA synthetase Inibitors
    • Drug : Febrifugin, Halofiginone
    • It is Chinese herb derived molecule, which is highly efficient inhibitors of malarial
    parasite growth
    • It targets both asymptomatic liver stage and blood stages of plasmodium parasite.
    • THE cytoplasmic copy of ProRS gene from malarial parasite was identified as the specific
    target for these molecules.
    11)Malarial vaccines
    • P.falciparum genome vaccine
    • Blood stage vaccines: MSP1, AMA1, MSP3, GLURP
    • Pf RH5
    • RTS,S/AS01
    • Whole organism vaccine(Full length recombinant Plasmodium falciparum protein)
    • Transmission blocking vaccines
    12) Combination Therapy
    • Sulpha drugs: (Sulphadoxine + pyrimethamine)
    • Artemisinin + Lumifantrine (Chloroquine resistant Malaria)
    • Artemisinin + Chloroquine (To increase the effectiveness of therapy)
    • Biguanide derivatives: (Proguanil + Atovaquone mixture)
    13) Drugs obtained from natural sources and terpenoids
    o Artemisinin, Artemether, Arteether, Artesunate

    ANTI-MALARIAL AGENTS – JINAL ADHIYA – M.PHARM (PHARMACOLOGY) 6


    14) Cytokine based therapy
    • The relationship between host and parasite is determined largely by host cytokines
    and as more understanding of the role of cytokines is gained, the possibility of utilizing
    this for therapy is being studied.
    • Agents being considered include peptide antagonists at cytokine receptors, soluble
    cytokine receptors, anti-cytokine antibodies and mutant cytokines.
    • IL-2 has been shown to protect monkeys against malaria

    2.4 DETAILED NOTE ON SOME IMPORTANT ANTI-MALARIAL DRUGS:

    (1) CHLOROQUINE

    • Blood schizonticidal agent that is used to treat acute


    attacks, they are also known as drugs that produce a
    ‘suppressive’ or ‘clinical’ cure.
    • They act on the erythrocytic forms of the plasmodium.

    Mechanism:1 (Assumption):

    Figure-3: Famous formulation of


    chloroquine (Lariago-DS)

    ANTI-MALARIAL AGENTS – JINAL ADHIYA – M.PHARM (PHARMACOLOGY) 7


    Mechanism: 2 (Actual Mechanism):

    Resistance Mechanism:

    • Plasmodium falciparum is now resistance to chloroquine is most parts of the world.


    • Resistance appears to result from Effulx pump development and it efflux out the drug
    from the paracitic vesicle as a result of mutations in plasmodia transporter genes.

    Pharmacokinetic aspects:

    • Absorbed: After oral administration


    • Distribution: Concentrate in Erythrocyte, spleen, Kidney, Lungs also, penetrate CNS and
    travels through placenta.
    • Metabolism: Dealkylated by hepatic oxidase system.
    • Excretion: in urine (70% unchanged, 30% Metabolite)
    • Half life: 50 hours

    ANTI-MALARIAL AGENTS – JINAL ADHIYA – M.PHARM (PHARMACOLOGY) 8


    Therapeutic uses:

    • Anti-Malarial (Safest during pregnancy)


    • Rheumatoid arthritis
    • Amoebicidal agent
    • Quinine like effect: useful in arrythmia

    Adverse effect:

    • Nausea, Vomiting, Headache


    • Dizziness
    • Blurring vision
    • Fatal dysrhythmia (High dose)

    (2) QUININE

    • Quinine and its isomer Quinidine are blood Schizonticidal agent, useful for malarial strain
    that is resistant to Chloroquine.
    • Obtained from cinchona bark.

    Mechanism: 1 (Just like chloroquine)

    Also,

    ANTI-MALARIAL AGENTS – JINAL ADHIYA – M.PHARM (PHARMACOLOGY) 9


    Mechanism: 2

    Also,

    Mechanism: 3

    Also,

    Mechanism: 4

    ANTI-MALARIAL AGENTS – JINAL ADHIYA – M.PHARM (PHARMACOLOGY) 10


    Therapeutic uses:

    • Cerebral Malaria
    • Ecbolic agent

    Adverse effect:

    • Black water urine


    • Cinchonism (Ringing of Ear, Blurred vision, Headache)
    • Vertigo
    • Ototoxicity
    • Contraindicated in pregnancy (Ecbolic action, Premature baby birth/Abortion)

    (3) 8-AMINOQUINOLINES

    • The only 8-aminoquinoline licensed for current use Primaquine.


    • Etaquine and Tafenoquine are more active and slowly metabolised analogues of
    primaquine.
    • This class of drug is extended against liver hypnozoites and they can effect a radical cure
    of those form of malaria in which the parasites have a dormant stage in liver-P.vivex and
    P.ovale
    • It has a gametocidal action and it is most effective anti-Malarial drug for preventing
    transmission of the disease.

    Mechanism:

    ANTI-MALARIAL AGENTS – JINAL ADHIYA – M.PHARM (PHARMACOLOGY) 11


    Pharmacokinetic aspects:

    • Given orally and is well absorbed.


    • Its metabolism is rapid and very little drug is present in the body after 10-12 hours.
    • Half life is 3-6 hours,

    Adverse effect:

    • It causes haemolysis in individual with and X chromosome-linked genetic metabolic


    condition: G6PD deficiency (Glucose-6-phosphate dehydrogenase deficiency) in Red
    cells.
    • So, Red cells are not able to regenerate NADPH, Its concentration being reduced by
    oxidant metabolic derivative of primaquine.
    • As a result, Function of red cells are impaired and haemolysis occurred.

    (4) QINGHAOSU (ARTEMESININ) AND RELATED COMPOUNDS

    • The qinghaosu based compounds are derived from the herb qing hao, a tradition Chinese
    remedy for malaria.
    • Artemisinin, a poorly soluble chemical extract from Artemisia a fast acting blood
    Schizonticide effective in treating acute attack of malaria.
    • Artesunate, a water soluble derivative and synthetic analogues artemether and
    artether have higher activity and better absorbtion.
    • Artemisinin and derivative compounds are effective against multi drug resistant
    P.falciparum

    Mechanism:

    ANTI-MALARIAL AGENTS – JINAL ADHIYA – M.PHARM (PHARMACOLOGY) 12


    Adverse effect:

    • Transient Heart block


    • Decreasing in Neutrophil count
    • Episodes of fever
    • According to animal study, artemisinin shows cause unusual injury to brain stem.

    Combinations

    • Artemisinin + Lumifantrine (Chloroquine resistant malaria)


    • Artemisinin + Chloroquine (increase effectiveness of the therapy)
    • Never give combination of artemisinin with sulpha drug due to antagonistic action

    (5) FOLATE ANTAGONISTS

    • Folate antagonists inhibit Dihydrofolate reductase.


    • Pyrimethamine is having similar structure to trimethoprim
    • Abnormal folic acid formed. due to that Protein synthesis in parasite stop.
    • Drugs: Sulphamethoxazole, Sulfadoxime, proguanil, pyrimethamine, Dapsone

    Mechanism:

    ANTI-MALARIAL AGENTS – JINAL ADHIYA – M.PHARM (PHARMACOLOGY) 13

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