Usage
Artesunate is an antimalarial drug used to treat severe Plasmodium falciparum malaria. It is also used in combination with other antimalarials (e.g., 8-aminoquinoline) to treat severe malaria caused by Plasmodium ovale or Plasmodium vivax. It belongs to the pharmacological class of artemisinins. Artesunate’s mechanism of action involves the production of free radicals within the parasite’s food vacuole, leading to parasite death.
Alternate Names
While “artesunate” is the internationally recognized generic name, there may be regional variations. Brand names vary depending on the manufacturer and country. Some examples include Zeromal AT and Akshnat.
How It Works
Pharmacodynamics: Artesunate interacts with heme iron within the malarial parasite, generating reactive oxygen species that damage parasite proteins and membranes, ultimately causing parasite death. It is effective against the asexual blood stages of Plasmodium species, including gametocytes (except those of P. falciparum).
Pharmacokinetics:
- Absorption: After intravenous (IV) administration, artesunate is rapidly hydrolyzed to dihydroartemisinin (DHA), its active metabolite. After intramuscular (IM) administration, absorption is also rapid and almost complete.
- Metabolism: Artesunate is rapidly converted to DHA by plasma esterases. DHA is further metabolized primarily via glucuronidation by UGT1A9 and other UGT isoenzymes.
- Elimination: DHA and its metabolites are mainly eliminated via hepatic excretion with a small amount of renal excretion.
Mode of Action: Artesunate’s endoperoxide bridge reacts with iron from the parasite’s ingested hemoglobin, generating free radicals that alkylate essential parasite proteins and damage its membranes. This mechanism of action targets the parasite’s food vacuole.
Receptor binding, enzyme inhibition, or neurotransmitter modulation: Artesunate’s primary mechanism is not through receptor binding, direct enzyme inhibition, or neurotransmitter modulation but rather through free radical generation in the parasite. However, DHA is a substrate of CYP2A6 and may interact with drugs metabolized by this enzyme, such as strong UGT inducers which reduce artesunate efficacy and strong UGT inhibitors which may increase DHA adverse reactions. DHA may also induce CYP3A4 and inhibit CYP1A2, so caution is advised when co-administering intravenous artesunate with substrates of these CYP enzymes, particularly those with narrow therapeutic windows.
Dosage
Standard Dosage
Adults: 2.4 mg/kg IV or IM administered at 0, 12, and 24 hours, followed by once daily dosing until the patient can tolerate oral antimalarial therapy.
Children: 2.4 mg/kg IV or IM (same as adult dose) administered at 0, 12, and 24 hours, followed by once daily dosing until the patient can tolerate oral antimalarial therapy. Children under 20 kg have shown to benefit from higher doses (3 mg/kg/dose) to ensure comparable drug exposure compared to adults.
Special Cases:
- Elderly Patients: No specific dose adjustments are explicitly outlined in the reviewed literature, but careful monitoring is recommended.
- Patients with Renal Impairment: Dosage adjustments are not typically required.
- Patients with Hepatic Dysfunction: Caution is advised but specific dose adjustments aren’t consistently defined. Close monitoring of liver function tests is crucial.
- Patients with Comorbid Conditions: Considerations for comorbid conditions such as cardiac or gastrointestinal disease should be made.
Clinical Use Cases
Dosing remains consistent (2.4 mg/kg at 0, 12, and 24 hours, then once daily) across clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations involving severe malaria.
Dosage Adjustments
Dosage adjustments may be needed based on factors like renal or hepatic dysfunction, but specific guidelines are limited. Monitor patients closely for adverse effects.
Side Effects
Common Side Effects:
- Nausea, vomiting
- Dizziness
- Headache
- Fever
- Anorexia
- Diarrhea
- Cough
- Rhinitis
Rare but Serious Side Effects:
- Anaphylaxis
- Post-artesunate delayed hemolysis (PADH)
- Hemolytic anemia
- Neutropenia
- Thrombocytopenia
- Acute renal failure
- Jaundice
- Neuropsychiatric reactions (including seizures, confusion, coma, and agitation)
- QT prolongation (at high doses)
- Allergic reactions (rash, urticaria, pruritus)
- Reversible neurologic changes
Long-Term Effects: PADH can occur weeks after treatment initiation.
Adverse Drug Reactions (ADR): Anaphylaxis, severe PADH, and acute renal failure are clinically significant ADRs that necessitate prompt medical intervention.
Contraindications
- Hypersensitivity to artesunate or other artemisinin derivatives.
- First trimester of pregnancy (unless the benefits outweigh the risks).
Drug Interactions
- CYP450 Interactions: DHA is metabolized by CYP2A6 and may interact with drugs that are substrates, inducers, or inhibitors of this enzyme. It can also affect the activity of other enzymes like UGT1A9 (substrate), CYP3A4 (inducer), CYP1A2 (inhibitor).
- UGT Interactions: Co-administration with strong UGT inhibitors (e.g., axitinib, vandetanib, imatinib, diclofenac) may increase DHA exposure, whereas UGT inducers (e.g., nevirapine, ritonavir, rifampicin, carbamazepine, phenytoin) can decrease DHA levels and reduce efficacy.
- Other Interactions: Interactions with other medications like mefloquine (increased risk of QT prolongation), isavuconazole and ketoconazole (decreased Artesunate metabolism), levobupivacaine and lidocaine (increased methemoglobinemia risk), and lumefantrine (increased QT prolongation risk) have been reported.
Pregnancy and Breastfeeding
- Pregnancy: Artesunate is generally avoided during the first trimester due to potential teratogenic effects in animals. It’s considered relatively safe during the second and third trimesters when the benefits outweigh the risks.
- Breastfeeding: Small amounts of artesunate are excreted in breast milk. While generally considered safe, withholding breastfeeding for 6 hours post-dose can minimize infant exposure.
Drug Profile Summary
- Mechanism of Action: Generates free radicals within the malarial parasite, leading to its death.
- Side Effects: Nausea, vomiting, dizziness, fever, anemia, PADH. Rarely: anaphylaxis, renal failure, neuropsychiatric reactions.
- Contraindications: Hypersensitivity, first trimester of pregnancy (relative).
- Drug Interactions: UGT inducers/inhibitors, CYP3A4 and CYP1A2 substrates, some antimalarials (e.g., mefloquine).
- Pregnancy & Breastfeeding: Generally avoided in the first trimester. Relatively safe in later trimesters and during breastfeeding.
- Dosage: 2.4 mg/kg IV/IM at 0, 12, and 24 hours, then once daily. Children under 20 kg benefit from 3 mg/kg/dose.
- Monitoring Parameters: Hemoglobin, reticulocyte count, haptoglobin, LDH, total bilirubin, liver and renal function tests.
Popular Combinations
Artesunate is often combined with other antimalarials like mefloquine, amodiaquine, sulfadoxine-pyrimethamine, lumefantrine, and piperaquine, for enhanced efficacy and to prevent resistance development.
Precautions
- General Precautions: Assess for allergies, hepatic/renal dysfunction, and cardiac history before administration.
- Specific Populations: Closely monitor pregnant women, breastfeeding mothers, children, and the elderly.
- Lifestyle Considerations: Alcohol, smoking, and diet do not significantly interact with artesunate, but concurrent use of some OTC and herbal medications warrants caution.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Artesunate?
A: The standard dosage is 2.4 mg/kg IV or IM given at 0, 12, and 24 hours, then daily until oral medication is tolerated. Children under 20 kg benefit from 3 mg/kg/dose.
Q2: What is the primary mechanism of action of Artesunate?
A: Artesunate generates free radicals within the malarial parasite, damaging its proteins and membranes.
Q3: Is Artesunate safe in pregnancy?
A: While generally avoided in the first trimester, it’s considered relatively safe during the second and third trimesters when the benefits outweigh the risks for severe malaria.
Q4: What are the most common side effects of Artesunate?
A: Nausea, vomiting, dizziness, fever, and headache are common side effects.
Q5: What is Post-artesunate delayed hemolysis (PADH)?
A: PADH is a rare but serious side effect characterized by a delayed drop in hemoglobin levels, occurring days to weeks after treatment initiation.
Q6: What are the significant drug interactions with Artesunate?
A: Artesunate interacts with drugs metabolized by or affecting CYP2A6, UGT1A9, CYP3A4, and CYP1A2. Co-administration with strong UGT inducers or inhibitors can alter DHA exposure and efficacy.
Q7: How should Artesunate be administered?
A: Artesunate should be administered as a slow IV bolus injection over 1-2 minutes or via IM injection.
Q8: Can Artesunate be used in children?
A: Yes, the pediatric dosage is the same as the adult dosage (2.4 mg/kg), although children under 20 kg may benefit from a 3 mg/kg/dose.
Q9: What monitoring parameters are essential for patients receiving Artesunate?
A: Monitor hemoglobin, reticulocytes, haptoglobin, LDH, and total bilirubin regularly, particularly for signs of PADH. Assess liver and renal function.
