Artemisinin Derivatives

ARTEMISININ DERIVATIVES

Artemisinin is the active principle of the plant Artemisia annua used in Chinese traditional medicine as ‘Quinghaosu’. It is a sesquiterpine lactone active against P. falciparum resistant to all other antimalarial drugs as well as sensitive strains. Potent and rapid blood schizontocide action is exerted eliciting quicker defervescence and parasitaemia clearance (<48 hr) than chloroquine or any other drug. In the erythrocytic schizogony cycle of the malarial parasite, artemisinins exert action on a wide range of stages—from ring forms to early schizonts; thus have the broadest time window of antimalarial action.

Artemisinin is poorly soluble in water as well as oil. Several derivatives have been produced, of which three are marketed in India: Artemether is soluble in oil, while Artesunate (sod.) is water soluble. Another compound Arteether has been developed in India. Artemisinins do not kill hypnozoites but have some action on falciparum gametes. The duration of action is short and recrudescence rate is high when they are used alone in short courses. Recrudescence depends upon the dose and duration of therapy as well as severity of disease. So far no resistance among P. falciparum patients to artemisinin has been noted, but can be developed in animal models.

Because artemisinins are short acting drugs, monotherapy needs to be extended beyond the disappearance of the parasites to prevent recrudescence. After 5 days treatment recrudescence rate is ~10%, while with a 3 day course it is ~50%. Recrudescence can be totally prevented by combining 3 day artesunate/artemether with a long-acting drug (see ACT later).

Mechanism Of Action of artemisinin is not definitely known. The endoperoxide bridge in its molecule appears to interact with haeme in the parasite. Iron-mediated cleavage of the bridge releases a highly reactive free radicals species that binds to membrane proteins, causes lipid peroxidation, damages endoplasmic reticulum, inhibits protein synthesis and ultimately results in lysis of the parasite.

Pharmacokinetics

Data on pharmacokinetics of artemisinin derivatives is limited and incomplete. Both artesunate and artemether are prodrugs.

Artesunate:  Its sodium salt is water-soluble and is administered by oral, i.m. or i.v. routes. After oral ingestion, absorption is incomplete but fast, reaching peak in <60 min. It is rapidly converted to the active metabolite dihydro-artemisinin (DHA) with a t½ of 30–60 min. The t½ of DHA is 2–4 hours. After repeated dosing, artesunate causes autoinduction of its own metabolism.

FALCIGO, FALCYNATE, ARTINATE 50 mg tab, 60 mg/ vial inj; LARINATE, ARNATE 50 mg tab.

Artemether:  It is lipid-soluble and is administered orally or i.m., but not i.v. Oral absorption is slower taking 2–4 hours, but is enhanced by food. It undergoes substantial first pass metabolism and is converted to DHA. Extensive metabolism by CYP3A4 yields a variable t½ of 3–10 hours.

PALUTHER, LARITHER, MALITHER, METHILEX 40 mg cap, 80 mg inj (in 1 ml arachis oil).

α/β Arteether:  This compound developed in India has been released for institutional use only, for i.m. administration in complicated/cerebral malaria. Because of its longer elimination t½ (23 hours), it is effective in a 3 day schedule with a recrudescence rate of 5%.

Dose: 150 mg i.m. daily for 3 days in adults.

EMAL, FALCY, RAPITHER 150 mg/2 ml amp (box of 3 amp).

[Note: The recent (2006) WHO Regional guidelines for South East Asia recommend a 5 day course of i.m. arteether (3.2 mg/kg on 1st day, followed by 1.6 mg/kg daily for the next 4 days), see box on p. 784].

Adverse Effects

Data from >10000 monitored patients shows that artesunate/artemether produce few adverse effects; most are mild: nausea, vomiting, abdominal pain, itching and drug fever. Abnormal bleeding, dark urine, ST segment changes, QT prolongation, first degree AV block, transient reticulopenia and leucopenia have been noted but subside when the patient improves or drug is stopped. Millions of patients have been treated so far without any serious neurological or other toxicity, but close monitoring of the patient is advocated. Intravenous artesunate is much safer than i.v. quinine.

Interactions Concurrent administration of artemisinin compounds with terfenadine, astemizole, antiarrhythmics, tricyclic antidepressants and phenothiazines may increase the risk of cardiac conduction defects.

Use

Oral artemisinins are indicated only for the treatment of uncomplicated chloroquine/ multidrug-resistant falciparum malaria. Parenterally they are used in severe and complicated falciparum malaria. There is no justification of using them for uncomplicated chloroquine or S/P sensitive falciparum malaria or for vivax malaria. Because of their short duration of action and availability of better tolerated/cheaper drugs, use of artemisinins for prophylaxis of malaria is irrational, and is not allowed.

Uncomplicated resistant falciparum malaria: Oral artemisinins are almost 100% effective, but recrudescence rates are high. In order to protect their powerful antimalarial activity and to reduce recrudescence rates, current recommendation is to use them only in combination with a longeracting drug (see box on p. 783 and ACT below). Their gametocidal action cuts down transmission and spread of resistant P. falciparum.

Severe and complicated falciparum malaria: Parenteral artemisinins are higly effective and are indicated irrespective of chloroquine-resistant status. Though i.v. quinine is still advocated as the 1st line drug in complicated/cerebral malaria, i.v. artesunate offers several advantages:

·          It causes faster parasite clearance than i.v. quinine.

·          It is safer and better tolerated than i.v. quinine.

·          Its dosing schedule is simpler.

·          Recent evidence indicates higher efficacy and lower mortality.

In a recent randomized trial* on 1461 severe/complicated falciparum malaria patients conducted in India, Indonesia, Myanmar and Bangladesh, mortality in artesunate treated patients was 15% compared to 22% in quinine recipients. Also artesunate produced fewer adverse effects.