Primaquine - Malaria

PRIMAQUINE

Primaquine is the drug of choice for the eradication of dormant liver forms of P vivax and P ovale and can also be used for chemo-prophylaxis against all malarial species.

Chemistry & Pharmacokinetics

Primaquine phosphate is a synthetic 8-aminoquinoline (Figure 52–2). The drug is well absorbed orally, reaching peak plasma levels in 1–2 hours. The plasma half-life is 3–8 hours. Primaquine is widely distributed to the tissues, but only a small amount is bound there. It is rapidly metabolized and excreted in the urine. Its three major metabolites appear to have less antimalarial activity but more potential for inducing hemolysis than the parent compound.

Antimalarial Action & Resistance

Primaquine is active against hepatic stages of all human malaria parasites. It is the only available agent active against the dormant hypnozoite stages of P vivax and P ovale. Primaquine is also gameto-cidal against the four human malaria species. Primaquine acts against erythrocytic stage parasites, but this activity is too weak to play an important role. The mechanism of antimalarial action is unknown.

Some strains of P vivax in New Guinea, Southeast Asia, Central and South America, and other areas are relatively resistant to primaquine. Liver forms of these strains may not be eradicated by a single standard treatment with primaquine and may require repeated therapy. Because of decreasing efficacy, the standard dos-age of primaquine for radical cure of P vivax infection was recently doubled to 30 mg base daily for 14 days.

Clinical Uses

A. Therapy (Radical Cure) of Acute Vivax and Ovale Malaria

Standard therapy for these infections includes chloroquine to eradi-cate erythrocytic forms and primaquine to eradicate liver hypnozo-ites and prevent a subsequent relapse. Chloroquine is given acutely, and therapy with primaquine is withheld until the G6PD status of the patient is known. If the G6PD level is normal, a 14-day course of primaquine is given. Prompt evaluation of the G6PD level is helpful, since primaquine appears to be most effective when insti-tuted before completion of dosing with chloroquine.

B. Terminal Prophylaxis of Vivax and Ovale Malaria

Standard chemoprophylaxis does not prevent a relapse of vivax or ovale malaria, because the hypnozoite forms of these parasites are not eradicated by chloroquine or other available blood schizonti-cide agents. To markedly diminish the likelihood of relapse, some authorities advocate the use of primaquine after the completion of travel to an endemic area.

C. Chemoprophylaxis of Malaria

Primaquine has been studied as a daily chemoprophylactic agent. Daily treatment with 30 mg (0.5 mg/kg) of base provided good levels of protection against falciparum and vivax malaria. However, potential toxicities of long-term use remain a concern, and pri-maquine is generally recommended for this purpose only when mefloquine, Malarone, and doxycycline cannot be used.

D. Gametocidal Action

A single dose of primaquine (45 mg base) can be used as a control measure to render P falciparum gametocytes noninfective to mos-quitoes. This therapy is of no clinical benefit to the patient but will disrupt transmission.

E. Pneumocystis jiroveci Infection

The combination of clindamycin and primaquine is an alternative regimen in the treatment of pneumocystosis, particularly mild to moderate disease. This regimen offers improved tolerance com-pared with high-dose trimethoprim-sulfamethoxazole or pentami-dine, although its efficacy against severe pneumocystis pneumonia is not well studied.

Adverse Effects

Primaquine in recommended doses is generally well tolerated. It infrequently causes nausea, epigastric pain, abdominal cramps, and headache, and these symptoms are more common with higher dosages and when the drug is taken on an empty stomach. More serious but rare adverse effects are leukopenia, agranulocytosis, leukocytosis, and cardiac arrhythmias. Standard doses of pri-maquine may cause hemolysis or methemoglobinemia (manifested by cyanosis), especially in persons with G6PD deficiency or other hereditary metabolic defects.

Contraindications & Cautions

Primaquine should be avoided in patients with a history of granu-locytopenia or methemoglobinemia, in those receiving potentially myelosuppressive drugs (eg, quinidine), and in those with disor-ders that commonly include myelosuppression. It is never given parenterally because it may induce marked hypotension.

Patients should be tested for G6PD deficiency before pri-maquine is prescribed. When a patient is deficient in G6PD, treat-ment strategies may consist of withholding therapy and treating subsequent relapses, if they occur, with chloroquine; treating patients with standard dosing, paying close attention to their hema-tologic status; or treating with weekly primaquine (45 mg base) for 8 weeks. G6PD-deficient individuals of Mediterranean and Asian ancestry are most likely to have severe deficiency, whereas those of African ancestry usually have a milder biochemical defect. This difference can be taken into consideration in choosing a treatment strategy. In any event, primaquine should be discontinued if there is evidence of hemolysis or anemia. Primaquine should be avoided in pregnancy because the fetus is relatively G6PD-deficient and thus at risk of hemolysis.