Chemotherapy of Malaria

Faraza Javed

Mphil Pharmacology

Malaria

Malaria is caused by various species of plasmodia, which are carried by the female anopheline mosquito.

Four species of Plasmodium typically cause human malaria.

Plasmodium falciparumP. vivaxP. malariaeP. ovale

A 5th species, P. knowlesi, is primarily a pathogen of monkeys, but has recently been recognized to cause illness, including severe disease, in humans in Asia.

Although all species may cause significant illness, P. falciparum is responsible for the majority of serious complications and death.

Pathophysiology

Sign & Symptoms

The signs and symptoms of malaria typically begin 8–25 days following infection.

Headache Fever Shivering Joint pain VomitingHemolytic anemia

According to WHO, if any of these symptoms are present, it is considered as complicated malaria.

Decreased ConsciousnessTwo or more convulsionsLow BP (less than 70mmHg)Circulatory ShockPulmonary odemaBlood glucose less than 40mg/dlKidney failure or Hb in urine

Diagnosis

Different diagnostic test are available. Microscopy Rapid diagnostic antigen test (RDT) PCR

Aims of TreatmentAims Causation Therapy Drugs

To alleviate symptoms

Symptoms are caused by blood

forms of the parasite

Blood schizonticidal

drugs

Chloroquine , quinine,

pyrimethamine/sulphadoxine , artemisinin

Chloroquine, sulphadoxine,

To prevent relapses

Relapses are due to hypnozoites of P. vivax / P. ovale

Tissue schizonticidal

drugs

Primaquine

To prevent spread

Spread is through the gametocytes

Gametocytocidal drugs

Primaquine for P. falciparum ,

Chloroquine for all othes.

Classification of Antimalarial Agents

Four Broad Groups Based on Mechanism of Action:

QuinolineArtemisininAntifolate Antibacterial

Quinoline Derivatives

Quinoline derivatives include Chloroquine, Amodiaquine, Quinine, Quinidine, Mefloquine, Primaquine, Lumefantrine, and Halofantrine. These drugs have activity against the erythrocytic stage of infection; Primaquine also kills intrahepatic forms and gametocytes.

MOA: Parasite digest the host cell hemoglobin to obtain essential amino acids and releases large amount of heme which is toxic to parasite. To protect itself parasite parasite polymerize the heme to non toxic hemozion. All Quinoline derivatives prevent this polymerization and result in the lysis of cell.

Chloroquine

Chloroquine, 4-aminoquinolines, has activity against the blood stages of Plasmodium ovale, P. malariae, and susceptible strains of P. vivax and P. falciparum.

Used in the treatment and chemoprophylaxis of maleria.

Mutations in the gene encoding the chloroquine resistance transporter protein (PfCRT), located in the food vacuole, are associated with chloroquine resistance both in vitro and in vivo.

Quinine and Quinidine

Quinine is a derivative from the bark of the South American Cinchona tree. In malaria-endemic regions it is the most commonly used parenteral antimalarial drug.

Quinidine is a stereoisomer of quinine available in parenteral formulation and is very effective for treatment of severe malaria.

Primaquine

The only 8-aminoquinoline in clinical use. It is largely used to prevent relapse of P. ovale

and P. vivax malaria by eliminating dormant hypnozoites, and it also has activity against the pre-erythrocytic stage and gametocytes of P. falciparum.

Primaquine is used as radical cure and chemoprophylaxis of infection with P.vivax and P.ovale.

Halofantrine Hydrochloride, a phenanthrene methanol, is effective against erythrocytic stages of all four human malaria species. Its mechanism of action is unknown.

Lumefantrine, an aryl alcohol related to Halofantrin, is available only as a fixed dose combination with artemether (Coartem) which is now 1st line therapy for uncomplicated falciparum malaria.

Adverse Effects:Choloroquine is usually well tolerated.Pruritis is common. Other side effects include

Nausea, Vomiting, Abdominal pain, Headache, Anorexia and Urticaria. Dosing after meal may reduce some effects.

Rare reactions include Hemolysis, Impaired hearing, Hypotension, agranulocytosis, Retinopathy and Peripheral Neuropathy.

Artemisinin

Artemisinin is a Sesquiterpine lactone extracted from herb called sweet wormwood.

Most important of these analogs are:ArtesunateArtemetherDihydroartemisinin

MOA: Its antimalarial action involves the production of free radicals within the plasmodium food vacuole, following cleavage of the drug's endoperoxide bridge by heme iron in parasitized erythrocytes. It is also believed to covalently bind to and damage specific malarial proteins.

Clinical Significance: Artemisinin monotherapy for uncomplicated

malaria treatment is now strongly discouraged. Combination therapy is now the standard for the treatment of uncomplicated falciparum malaria.

Artemisinin are also proving to have outstanding efficacy in the treatment of complicated falciparum malaria.

Artesunate and Artemether have also been effective in treatment of severe malaria when administered rectally, offering valuable treatment modality when parenteral therapy is not available.

Adverse Effects:No clinical toxicity seen in thousands of

people.Irreversible Neurotoxicity has been seen in

animals.Rare toxicities include Neutropenia,

Hemolysis and Allergic Reactions.

Antifolate Drugs

MOA: Inhibit DNA synthesis by inhibiting enzymes involved in folate metabolism.

Agents in this class are:PyrimethamineSulfadoxine

Clinical Significance: Fansidar, a fixed combination of

sulphonamide sulphadoxine (500mg/tab) and pyrimethamine (25mg/tab) is widely used in the treatment of malaria but resistance limits the efficacy of this combination in the treatment of malaria.

Antibiotics

A no. of antibiotics in addition to folate antagonist and sulfonamides are modestly active antimalarial.

MOA: Antibiotics that are bacterial protein synthesis inhibitors appears to act against malaria by inhibiting protein synthesis in Plasmodial prokaryote like organelle, the Apicoplast.

None of the antibiotic should be used as single agent in the treatment of malaria because their action is much slower than that of standard antimalarial.

Antibiotics used as antimalarial include:DoxycyclineClindamycinAzithromycin

Clinical Significance: Doxycycline is useful in combination therapy

with quinine for multiple-resistant organisms. Also useful for chemoprophylaxis in areas with multiresistant Plasmodium.

Clindamycin treats mild malaria and can work against quinoline-resistant strains.

Drug Resistant Malaria

Ability of parasite species to survive and/or multiply despite the administration or absorption of a drug given in doses equal to or higher than those usually recommended.

MDR Malaria: Resistance to 3 or more antimalarials of different chemical classes of which two are 4-aminquinoline and diaminopyridine.

Mechanism of Resistance

Efflux of drug by active pump mechanism.Decrease concentration of drug in vacuole.Crt-chloroquine resistant transporter and

mutation in Pfmdr transporter.Binding of chloroquine with hemoglobin

breakdown product to form toxic complexes prevented.

Treatment of Malaria

Uncomplicated Malaria

1. P.vivax:P.Vivax cases should be treated with

chloroquine for three days and Primaquine for 14 days.

Primaquine is used to prevent relapse but is contraindicated in pregnant women and individuals with G6PD deficiency.

• Artesunate + amodiaquine

• Artemether/lumefantrine

• Artesunate + SP

• Artesunate + mefloquine

ACTs

Combination Therapies Recommended by WHO

2. P. falciparum:P. Falciparum cases should be treated with ACT accompanied by single dose primaquine preferably on day 2.

FDC

3. Pregnant women with uncomplicated P. falciparum should be treated as follows:

1st Trimester: Quinine

2nd & 3rd Trimester: ACT

Primaquine is contraindicated in pregnant woman .

All mixed infections should be treated with ACT and Primaquine therapy for 14 days.

Severe Malaria

Administration of parenteral Artemisnin therapy.

After parenteral artemisinin therapy, patients will receive a full course of oral ACT for 3 days. OR

Combination of Quinine+Doxycycline

Development of Analogs of Existing Drugs

1. Pyronaridine

Related to chloroquine developed in china.

2. Tefanoquine

More active slowly metabolized analogue of primaquine, has advantage that it can be given on weekly basis.

3. Bulaquine Congener of primaquine developed in india Better tolerated in G6PD deficiency Comparable antirelapse activity when used for

5 days.

New Chemosensitizing Agent

Tricyclic Acridone molecules could make chloroquine resistant parasites susceptible to the drug again. This action is attributed to blocking the PfCRT pump protein, meaning that chloroquine can reach its target.

This new class of antimalarial drug have dual role that is reserve the malaria parasite resistance to existing drugs and also have an antimalarial action.

Vaccine for Malaria

RTS,S/ASO1 Vaccine Hybrid construct of the Hepatitis B surface

antigen fused with the recombinant antigen derived from part of circum sporozoite protein.

This vaccine is now in Phase III clinical trials. WHO has already taken the unusual step of

indicating that it would recommend this 1st malaria vaccine fore use in some African countries as early as 2015.

References

Katzung Pharmacology, 12th Edition. Lippincott Pharmacology, 6th Edition. Diagnosis and treatment of malaria by National vector borne

disease control programe, 2013. WHO global database on drug resistance 1996-2004. The National Antimalarial Drug Policy, 2010.