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Anti-Malarial drugs

Malaria
Protozoal disease
Plasmodium
infected female anopheles mosquito
WHO estimates
300-500 million cases year
> 1 million death

India- NVBDCP- 1.5 million confirmed cases


Types of Malarial Parasite
Plasmodium falciparum
Plasmodium vivax
Plasmodium malariae
Plasmodium ovale
Most of the serious complications and death
occur due to Plasmodium falciparum
Pathogenesis

5
Classification of Anti Malarial Agents: 1
Chemical Structure
4-Aminoquinolines : Chloroquine, Amodiaquine

8-Aminoquinoline: Primaquine, Bulaquine


Cinchona alkaloid : Quinine
Sesquiterpine lactones: Artesunate, Arteether, Artemether
Biguanides: Proguanil
Diaminopyrimidine : Pyremethamine
Quinoline methanol : Mefloquine
Sulfonamides : Sulfadoxine
Sulfamethopyrazine
Phenanthrene methanol : Halofantrine
Tetracycline: Doxycycline,
Acridine : Mepacrine
Naphthoquinone Atovaquone

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Life Cycle of the Malarial Parasite
Antimalarial Therapy
Causal prophylaxis
Suppressive prophylaxis
Clinical cure
Radical cure
Gametocidal
Classification- Stage of Parasite affected
Stage Drugs
Blood schizonticidal drugs Erythrocytic phase Chloroquine,
Terminates clinical illness Artemissin,
Quinine,
Atovaquone,

Tissue schizonticidal drugs Tissue form of plasmodium Primaquine,


Pyrimethamine
Proguanil
Tetracycline
Gametocidal drugs Destroy sexual forms of Primaquine
parasite Quinine
Prevent transmission to
mosquiotes
Hypnozoiticidal Destroy persistent liver Primaquine
stages of P vivax , P ovale
Chloroquine
Acts by :
concentrating in parasite food vacuoles,
preventing the polymerisation of the hemoglobin
breakdown product, heme, into hemozoin, and
thus eliciting parasite toxicity (plasma membrane
damage) due to the buildup of free heme.
Chloroquine, Quinine, Mefloquine.
Chloroquine
Oral absoption-Excellent
Partly metabolized in liver and slowly excreted in
urine
Adverse effects
-Cardiac depresssion
-CNS toxicity
-Retinal damage
Should not be coadministered with mefloquine,
amiodarone and other anti-arrythmics
Mefloquine
Oral absorption is good but quite slow
Highly plasma protein bound
Metabolised by liver and secreted in bile
Quinine & Quinidine
First-line therapies for falciparum malaria.

Oral administration.

Higher plasma levels and half-life in infected persons


than in healthy controls, but toxicity is not increased,
apparently because of increased protein binding.
MOA: is unknown, it may act like chloroquine
Adverse Effects

Cinchonism: Hypersensitivity reactions


Tinnitus, Hypoglycemia
Headache,
Too-rapid IV infusions :
Nausea,
Severe hypotension
Dizziness,
IV Quinidine : ECG
Flushing,

Visual Disturbances
abnormalities.
Black water fever
rare severe illness
marked hemolysis ,

hemoglobinuria
Proguanil & Pyrimethamine
Proguanil is cyclized in the body to a triazine
derivative(cycloguanil) which inhibits
plasmodial DHFRase.
Half life: 16-20hr
Pyrimethamine is a directly acting inhibitor of
plasmodium DHFRase.
High affinity for plasmodial enzyme(-2000 times
greater than for the mammalian enzyme)
Proguanil and Pyrimethamine
Sulfonamide-Pyrimethamine Combination

Supra-additive synergistic combination due to


sequential block.
Both components are slow acting, the
combination acts faster, so that it can be
employed as a clinical curative, particularly for
P.falciparum
By addition of sulfonamide, development of
resistance to pyrimethamine is retarded.
Sulfonamide-Pyrimethamine Combination
Primaquine
Radical cure
prevents relapse in P vivax and P ovale
malaria
Hemolytic anemias- G-6PD status should
be evaluated
Not given parenterally- causes hypotension
Contraindicated in Pregnancy and infants
MOA- unknown
Tetracyclines
None should be used as single agents because their action
is much slower than that of standard antimalarials.
Tetracycline : erythrocytic schizonts , but not active against
liver stages.
Doxycycline : falciparum malaria in conjunction with
quinine, allowing a shorter and better-tolerated course of
that drug, it has also become a standard
chemoprophylactic drug.
Artemisinin derivatives
Artemisinin: used orally.

Analogs are:
Artesunate (water-soluble; oral, IM, IV and rectally),

Artemether (lipid-soluble; oral, IM, and rectally),

Dihydroartemisinin (water-soluble; oral).


They are very rapidly acting blood schizonticides against
all human malaria parasites, no effect on hepatic stages.
Artemisinin derivatives
The parasite when it infects a RBC, it consumes Hb within its digestive vacuole,
liberating free heme, The iron in heme interacts with Artemisinin producing
reactive oxygen radicals which damage the parasite leading to its death
Or inhibition of a parasite calcium transporter.

Artemisinin-based combination therapy is now the standard for treatment


of uncomplicated falciparum malaria in nearly all areas endemic for falciparum
malaria.

A/E: GI disturbance, dizziness, neutropenia, anemia,

hemolysis, elevated liver enzymes, allergic reactions.


Halofantrine & Lumefantrine
Against erythrocytic (but not other) stages
of all four malaria species.
MOA: unknown.

A/E : GI disturbance, cough, rash, headache,


pruritus, and elevated liver enzymes, dose-
related prolongation of QT and PR intervals
Atovaquone
For treatment and prevention of malaria, administered orally.

MOA: disrupting mitochondrial electron transport and thus


interferes with ATP production.
It collapses plasmodial mitochondrial membrane
It is active against tissue and erythrocytic schizonts.

Proguanil potentiates its antimalarial action and prevents


emergence of resistance

A/E: GI disturbance, Fever, Rash, Headache