Antimalarial Agents Introduction Quiz

Malaria

• Malaria is a protozoan infection caused by Plasmodium parasites.
• It is transmitted exclusively by the bite of the female Anopheles mosquito.
• Malaria is one of the major killer diseases in the world, causing about 2-3 million deaths every year.
• It is endemic in the tropics and the subtropics, including Ghana, with 90% of deaths occurring in the sub-Saharan region.

Clinical Characteristics of Malaria

• Malaria is characterized clinically by paroxysms of severe chills, fever (38-40°C), profuse sweating, and recurring attacks of nausea and vomiting.
• These episodes occur at well-defined intervals determined by the life cycle of the invading parasite.
• When untreated, the disease often becomes chronic with repeated relapses.

Causative Agents

• The Plasmodium parasite is responsible for malarial infection.
• There are over 40 species of Plasmodium, but only four affect humans: P.vivax, P.ovale, P.malariae, and P.falciparum.

Life Cycle of Plasmodium Parasite

• The parasite has four possible sites for drug therapy:
  • Kill the sporozoites injected by the mosquito and/or prevent the sporozoites from entering the liver.
  • Kill the primary schizonts residing in hepatocytes and/or prevent them from becoming merozoites.
  • Kill the merozoites in the blood and/or prevent them from developing into gametocytes.
  • Kill the gametocytes before they can enter the mosquito and reproduce into zygotes.

Eradication

• Non-pharmacological methods:
  • Destruction of mosquitoes through good drainage, larvicides, insecticides, breeding of certain fish, and use of bacterial toxins.
  • Protection from mosquito bites through special clothing, repellants, and treated mosquito nets.

Requirements for an Ideal Antimalarial Drug

• Rapidly relieve symptoms of the disease.
• Be harmless to the patient and have no unpleasant side effects.
• Preferably destroy all stages of development of malaria parasites, including gametocytes.
• Be cheap and easy to administer.

Action of Antimalarial Drugs

• Classified based on the life cycle of the parasite:
  • Causal prophylactic drugs (e.g., Proguanil, Primaquine).
  • Schizonticidal drugs (e.g., Amodiaquine, Quinine, Artemisinin, Mefloquine).
  • Gametocidal drugs (e.g., Quinine, Primaquine).
  • Sporonticides (e.g., Pyrimethamine, Proguanil).

Classes of Antimalarials

• Naturally occurring antimalarials (e.g., quinine).
• 4-aminoquinolines (e.g., Amodiaquine).
• 8-aminoquinolines (e.g., Primaquine).
• 9-aminoacridines (e.g., mepacrine).
• Dihydrofolate reductase inhibitors (e.g., Pyrimethamine).
• Sulphonamides (e.g., sulphadoxine).
• Other antimalarials (e.g., antibiotics).

Naturally Occurring Antimalarials

• Quinine is a 6-methoxy-α-(5-vinyl-2-quinuclidinyl)-4-quinoline-methanol, mainly schizontocidal.
• Quinine is dibasic at the quinuclidine and the quinoline rings.
• Stereoisomer quinidine is schizonticidal but has a primary indication for cardiac arrhythmia.

Amodiaquine

• 4-(7-chloro-4-quinolylamino)-2-(dimethylaminomethyl)phenol.
• Used in combination with an artemisinin derivative to treat uncomplicated malaria.
• Has rapid schizontocidal effect and is also gametocytocidal against P.vivax and immature gametocytes of P.falciparum.

Mechanism of Action of Amodiaquine

• Very potent schizonticidal drug against erythrocytic stage of all four Plasmodium species.
• No effect on sporozoites or gametocytes.
• Weak base, concentrates in the parasite's lysosome, possibly by a parasite-specific drug-concentrating mechanism.
• Inhibits the enzyme that converts haem to harmless haemozoin, leading to a buildup of haem that kills the parasite by membranolytic action.
• Causes fragmentation of the parasite's RNA and intercalates in its DNA.

Mefloquine (Lariam)

• A quinine-type alcohol, belonging to the 4-quinolinemethanol group.
• May interfere with the transport of haemoglobin and other products of metabolism from the host to the parasite's food vacuole.
• Binds to hemozoin and the complex is toxic to the malaria parasite.

8-Aminoquinolines

• Examples: Primaquine, Pamaquine, Quinocides, Pentaquine, and Isopentaquine.

Primaquine SAR

• 6-methoxy substitution appears not essential for antimalarial activity.
• Introduction of 6-methyl group gives compound with complete loss of antimalarial activity.
• Addition or substitution on the quinoline nucleus tends to decrease both activity and toxicity.
• Reduction of the quinoline nucleus to 1,2,3,4-tetrahydro analogues gives compounds that retain antimalarial activity but with lower potency and toxicity.

Dihydrofolate Reductase Inhibitors

• Examples: 5-(3,4,5-Trimethoxybenzyl) pyrimidine2,4-diamine (Trimethoprim).
• Interfere with Plasmodial biosynthesis, leading to purine and pyrimidine synthesis.

Biguanides

• Examples: Proguanil, Halogen substitution at the para position increases the activity.
• Chlorproguanil has longer activity, and a second chlorine at the meta position increases activity but is more toxic.

Diaminopyrimidine Derivatives

• Examples: Pyrimethamine.

SAR for Diaminopyrimidine Derivatives

• For the highest antimalarial activity, the 2,4-diamino-pyrimidines require:
  • A strong lipophilic substituent such as phenyl group in the 5-position.
  • An alkyl group in the 6-position.
  • When the 6-ethyl group in pyrimethamine is replaced by H, methyl, propyl, butyl, NO2, or a halogen grouping, there is a marked loss of antimalarial activity.