Definition
ChEBI: A N-substituted diamine that is pentane-1,4-diamine substituted by a 6-methoxyquinolin-8-yl group at N4 position. It is a drug used in the treatment of malaria and Pneumocystis pneumonia.
Brand name
Primaquine (Sanofi Aventis).
Antimicrobial activity
Primaquine is highly active against the hepatic stages of the
malaria life cycle, including the latent hypnozoite stage of P.
vivax. It has poor activity against erythrocytic stages of malaria
parasites, other than gametocytes. The isomers have similar
antiplasmodial activity but differ in toxicity. It exhibits activity
against Pneumocystis jirovecii and, in experimental models,
against Babesia spp. and the intracellular stages of Leishmania
spp. and Trypanosoma cruzi.
Acquired resistance
Failure rates of up to 35% have been reported in South East Asia
in patients treated with a standard course for P. vivax infections.
Pharmaceutical Applications
A synthetic 8-aminoquinoline, formulated as the diphosphate
for oral administration.
Mechanism of action
Moving the side chain from the fourth position of the quinoline ring to the eighth position
completely changes the compound’s spectrum of activity. Unlike the 4-substituted aminoquinolines, primaquine has practically no effect on erythrocyte forms of the malaria parasite. Its activity is limited to tissue forms of the parasite in mammals and in the mosquitoes
themselves. This makes primaquine an especially valuable drug, allowing radical recovery
and simultaneous prevention, which is usually not achieved by using erythrocyte drugs.
The place of action of primaquine is the mitochondria of the malarial parasite. It seems
likely that primaquine interferes in the process of electron transfer, causing damage to
mitochondrial enzymatic systems. This is expressed in the swelling and vacuolization of
the parasite’s mitochondria. Host mitochondria are not affected.
Pharmacokinetics
Oral absorption: >75%
Cmax 45 mg oral: 0.2 mg/L after 2–3 h
Plasma half-life: 4–10 h
Volume of distribution: 2 L/kg
Plasma protein binding: Extensive
Bioavailability is variable after oral administration. There is
extensive tissue distribution. About 60% of the dose is metabolized
to carboxyprimaquine, which can reach levels 50 times
that of the parent drug; this metabolite has a half-life of 16 h,
a low tissue distribution and is detectable at 120 h. Methoxy
and hydroxy metabolites are also detectable. Less than 4% of
the original dose is excreted unchanged in urine.
Clinical Use
Primaquine is an important antimalarial because it is
essentially the only drug effective against the liver (exoerythrocytic)
forms of the malarial parasite. The drug
also kills the gametocytes in all four species of human
malaria. Primaquine is relatively ineffective against the
asexual erythrocyte forms. Primaquine finds its greatest
use in providing a radical cure for P. vivax and P. ovale
malaria.
Clinical Use
Primaquine is the only 8-aminoquinolinecurrently in use for the treatment of malaria. It is not usedfor prophylaxis. Its spectrum of activity is one of the narrowestof the currently used antimalarial drugs being indicatedonly for exoerythrocytic P. vivax malaria. To treat endoerythrocytic P. vivax, chloroquineor a drug indicated for chloroquine-resistant P. vivax isused with primaquine. In addition to its approved indication,it is also active against the exoerythrocytic stages ofP. ovale and primary exoerythrocytic stages of P. falciparum.Primaquine also inhibits the gameocyte stage that eliminates the form required to infect themosquito carrier. In vitro and in vivo studies indicate thatthe stereochemistry at the asymmetric is not important forantimalarial activity. There appears to be less toxicity withthe levorotatory isomer, but this is dose dependent andmay not be that important at the doses used to treatexoerythrocytic P. vivax malaria.
Although structurally related to the cinchona alkaloids,the 8-aminoquinolines act by a different mechanism of action.Primaquine appears to disrupt the parasite’s mitochondria.The result is disruption of several processes includingmaturation into the subsequent forms. An advantage is destroyingexoerythrocytic forms before the parasite can infecterythrocytes. It is the latter step in the infectious process thatmakes malaria so debilitating.
Clinical Use
Radical cure of malaria caused by P. vivax or P. ovale
Mild or moderately severe infections with Pn. jirovecii (in combination with
clindamycin).
Because of its gametocytocidal properties, primaquine has
been used rarely in a single dose to prevent the spread of chloroquine-
resistant P. falciparum.
Synthesis
Primaquine, 8-[(4-amino-1-methylbutyryl)amino]-6-methoxyquinoline
(37.1.2.4), is made from 6-methoxy-8-nitroquinoline (37.1.2.1), which is synthesized in a
Skraup reaction from 4-methoxy-2-nitroaniline and glycerol in the presence of sulfuric
acid. The nitro group in this compound is reduced to make 6-methoxy-8-aminoquinoline
(37.1.2.2). Alkylating the amino group with 4-bromo-1-phthalimidopentane gives
8-[(4-phthalimido-1-methylbutyryl)amino]-6-methoxyquinoline (37.1.2.3), the hydrazinolysis of which removes the phthalimide protection, giving primaquine.
Veterinary Drugs and Treatments
Primaquine is considered the drug of choice for treating Babesia
felis in cats. Primaquine does not apparently “cure” the infection;
repeated courses of therapy may be necessary. It may be useful in
treating Hepatazoon canis in dogs or Plasmodium spp. in birds. In
humans, primaquine is used for treatment and prophylaxis for malaria
and treating Pneumocystis pneumonia.
