Pharmacology and mechanism of action
Proguanil (PG) was introduced as a prophylactic agent against malaria just after the Second World War. It is a pyrimidine derivative which is highly active against pre-erythrocytic forms of Plasmodium (P) falciparum making it suitable for casual prophylaxis. It is also effective in the erythrocytic phase (schizontocide) against all forms of malaria, but the action is too slow for the drug to be used for treatment. Proguanil prevents the formation of sporozoites in the mosquito, thus interfering with the spread of malaria
[1]. The drug acts through an active metabolite (cycloguanil). The mechanism of action is due to an inhibition of dihydropholate reductase
[2].
Like most other antimalarials, the efficacy of proguanil has been reduced by the development of resistence. Already during the 1950s and 60s P. falciparum resistance was reported from all endemic areas including Africa
[1]. In P. vivax and P. malariae, resistence seems less frequent but resistent strains have been reported in Malaysia, Indonesia, and Taiwan
[1]. Partial crossresistance occurs with other antifolates, particularly with pyrimethamine.
Indications
Proguanil is used in combination with chloroquine as chemoprophylaxis against falciparum malaria in areas with a low frequency of resistance, i.e. tropical Africa.
Side effects
Proguanil is well tolerated in recommended doses and severe side effects are not reported in persons with a normal kidney function
[3]. Several reports of mouth ulceration due to proguanil have, however, been reported
[4, 5], and mild epigastric discomfort may occur.
Contraindications and precautions
Dosage adjustments are necessary in patients with kidney failure
[6].
Interactions
Chloroquine may increase the risk of mouth ulceration with proguanil
[7].
Preparation
Available as proguanil hydrochloride: 100 mg hydrochloride equals 87 mg base.
• Paludrine® (Zeneca). Tablets 100 mg.
References
1. Black RH, Canfield CJ, Clyde DF, Peters W, Wernsdorfer WH (1986). Proguanil and proguanil analogues. In: Chemotherapy of Malaria, 2nd edn, edited by L.J.Bruce-Chwatt. (Geneva: World Health Organization), pp. 71–77, 110–111.
2. Ferone R, Burchall JJ, Hitchings GH (1969). Plasmodium berghei dihydrofolate reductase. Isolation properties and inhibition by antifolates. Mol Pharmacol, 5, 45–59.
3. Proguanil. Therapeutic Drugs, edited by Sir Colin Dollery (1991), (London: Churchill Livingstone), pp. P247–P251.
4. Mulley G (1974). Proguanil and mouth ulcers. Lancet, 2, 873.
5. Daniels AM (1986). Mouth ulceration associated with proguanil. Lancet, i, 269.
6. Boots M, Phillips M, Curtis JR (1982). Megaloblastic anaemia and pancytopenia due to proguanil in patients with chronic renal failure. Clin Nephrol, 18, 106–108.
7. Drysdale SF, Phillips-Howard PA, Behrens RH (1990). Proguanil, chloroquine, and mouth ulcers. Lancet, 355, 164.
Description
Chloroguanide is active with respect to exoerythrocyte and erythrocyte forms of
plasmodia. It is most beneficial for suppressive therapy. It is used for preventing malaria,
and it should be started 2 weeks before entering a malarial zone and should be taken
for 8 weeks. Synonyms of this drug are biguanide, bigunal, paludrine, proguanil, and
others.
Uses
Proguanil is medicaments; used in preparation of pyrrolecarboxamide derivatives as anti-malarial agents.
Indications
Chloroguanide hydrochloride (Paludrine) is activated
to a triazine metabolite, cycloguanil, which also interferes
with parasite folic acid synthesis. It is a dihydrofolate
reductase inhibitor that is used for the prophylaxis
of malaria caused by all susceptible strains of plasmodia.
Chloroguanide is rapidly absorbed from the gastrointestinal
tract. Peak plasma levels occur 2 to 4 hours
after oral administration, and the drug is excreted in the
urine with an elimination half-life of 12 to 21 hours. Its
side effects and spectrum of antimalarial activity are
quite similar to those of pyrimethamine.The conversion
of chloroguanide to the active metabolite is decreased
in pregnancy and also as a result of genetic polymorphism
in 3% of whites and Africans and 20% of Asians.
Definition
ChEBI: A biguanide compound which has isopropyl and p-chlorophenyl substituents on the terminal N atoms. A prophylactic antimalarial drug, it works by inhibiting the enzyme dihydrofolate reductase, which is involved in the reproduction of the malaria
parasites Plasmodium falciparum and P. vivax within the red blood cells.
brand name
Paludrine (Zeneca).
Antimicrobial activity
Proguanil has low antiplasmodial action, but useful activity is
attributable to the metabolite cycloguanil, which inhibits the
early erythrocytic stages of all four Plasmodium spp. that cause
human malaria and the primary hepatic stage of P. falciparum.
Proguanil acts synergistically with atovaquone and probably
enhances its effect on mitochondrial membrane charge.
Acquired resistance
Resistance of P. falciparum associated with point mutations
of dihydrofolate reductase has been reported worldwide.
Resistance in P. vivax and P. malariae has been reported in
South East Asia. Cross-resistance with pyrimethamine is not
absolute, because differential resistance can arise from different
point mutations on the dihydrofolate reductase gene.
Pharmaceutical Applications
A synthetic arylbiguanide, formulated as the hydrochloride
for oral use. It is slightly soluble in water.
Pharmacokinetics
Oral absorption: >90%
C
max 100 mg oral: 0.4 mg/L after 2–4 h
Plasma half-life: 10 h
Plasma protein binding: 75%
Oral absorption is slow. It is 75% protein bound and is concentrated
10- to 15-fold by erythrocytes. About 20% of the
drug is metabolized to dihydrotriazene derivatives, most
importantly cycloguanil,by hepatic cytochrome P
450 processes.
Cycloguanil is detectable 2 h after administration of
proguanil. High proportions of ‘non-metabolizers’ have been
identified in Japan and Kenya, indicating another source of
resistance. About 60% of the dose is excreted in the urine.
Clinical Use
Antimalarial prophylaxis (usually in combination with chloroquine)
Treatment and prophylaxis for drug-resistant falciparum malaria (in
combination with atovaquone)
Side effects
It is well tolerated at recommended doses. Gastrointestinal and
renal effects have been reported at doses exceeding 600 mg
per day.
Safety Profile
Poison by ingestion,
intravenous, and intraperitoneal routes.
Experimental reproductive effects. When
heated to decomposition it emits toxic
fumes of Cland NOx.
Synthesis
Chloroguanide, N1
-(4-chlorophenyl)-N5
-isopropylbiguanide (37.1.3.2),
is made from 4-chloroaniline and sodium dicyanoamide, the interaction of which results
in the formation of (4-chlorophenyl)dicyanodiamide (37.1.3.1). Reacting this with isopropylamine gives the desired chloroguanide.
In in vitro conditions, chloroguanide is not active, although in the organism it transforms
to an active dihydrotriazine compound.
