Proguanil drug

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proguanil atovaquone malaria

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Proguanil (Chloroguanide)

Drug Class & Chemistry

Proguanil is a biguanide antimalarial prodrug (also called chloroguanide). It is structurally distinct from quinoline-based antimalarials and acts as a precursor to its active metabolite, cycloguanil - a cyclic triazine structurally related to pyrimethamine.

Mechanism of Action

Proguanil's antimalarial activity is primarily due to cycloguanil, its active triazine metabolite:

DHFR inhibition: Cycloguanil selectively inhibits the bifunctional dihydrofolate reductase-thymidylate synthetase (DHFR-TS) of plasmodia. This blocks deoxythymidylate synthesis, depletes folate cofactors, and ultimately inhibits DNA replication and nucleic acid synthesis in the parasite.
Synergy with atovaquone: Proguanil itself (independent of cycloguanil) potentiates atovaquone's ability to collapse the mitochondrial membrane potential of P. falciparum. This mechanism does not require conversion to cycloguanil and is separate from DHFR inhibition.

The parent drug proguanil exerts an alternative, cycloguanil-independent antimalarial activity, though the exact molecular basis remains unknown. - Goodman & Gilman's, p. 1315

Spectrum of Activity

Parasite/Stage	Activity
P. falciparum liver stages (primary)	Active
P. falciparum asexual blood stages	Active
P. vivax acute infection	Active
P. vivax latent liver stages (hypnozoites)	Not active (relapses can occur)
Gametocytes	Not destroyed (but oocysts in mosquito gut fail to develop normally)

Pharmacokinetics (ADME)

Parameter	Details
Absorption	Slowly but adequately absorbed from the GI tract; enhanced with food
Tmax	~5 hours after a single oral dose
Protein binding	~75%
Distribution	Concentrates in red blood cells (~3x plasma level); does not accumulate appreciably in other tissues
Metabolism	Via CYP2C19 (CYP2C subfamily) to active cycloguanil and inactive 4-chlorophenyl biguanide
Elimination t½	~180-200 hours (or longer) for the parent drug; serum level falls to near zero within 24 hours - requires daily dosing
Excretion	40-60% of absorbed drug excreted in urine (as parent drug or metabolite)
Hepatic impairment	Drug levels increased; elimination impaired

Genetic polymorphism note: CYP2C19 is polymorphic:

~3% of Caucasians are poor metabolizers
~20% of Asians and Kenyans are poor metabolizers
Poor metabolizers have inadequate cycloguanil levels at standard dosing, which may reduce efficacy when proguanil is used as monotherapy

Clinical Uses

1. Atovaquone-Proguanil (Malarone) - Primary Use

The fixed-dose combination is the best tolerated option for prevention and treatment of chloroquine-resistant malaria.

Prophylaxis:

Begin 1-2 days before departure to a malaria-endemic area
Continue during exposure
Continue for 7 days after returning (shorter than doxycycline's 4 weeks)

Treatment of uncomplicated malaria:

Higher doses administered over a 3-day course
Effective against chloroquine-resistant P. falciparum and P. vivax
Travelers taking atovaquone-proguanil for prophylaxis should not use it to treat breakthrough malaria; use an alternative regimen

2. Proguanil + Chloroquine

Used for malaria prophylaxis in parts of Africa without widespread chloroquine-resistant P. falciparum
Proguanil alone (without atovaquone) is not available in the US but has been used in England and Europe

Resistance

Resistance to proguanil monotherapy develops rapidly in areas of exclusive use, driven by amino acid changes near the DHFR-binding site
Breakthrough infections can also result from deficient conversion to cycloguanil (poor metabolizers)
Resistance to the atovaquone-proguanil combination is uncommon unless the strain is already atovaquone-resistant
P. falciparum rapidly develops resistance to either atovaquone or proguanil as monotherapy

Adverse Effects

At prophylactic doses (200-300 mg/day): Generally well tolerated

Occasional nausea and diarrhea

At high doses (≥1 g/day):

Vomiting, abdominal pain, diarrhea
Hematuria, transient appearance of epithelial cells and casts in urine

Atovaquone-proguanil combination:

Abdominal pain, nausea, vomiting, diarrhea
Headache, pruritus, rash, anorexia, dizziness
Asymptomatic, transient elevation of liver enzymes (at treatment doses)

Safety in special populations:

Pregnancy: Safe for use during pregnancy
Folate supplementation: Women of childbearing age on atovaquone-proguanil should continue folate supplements (to prevent neural tube defects); there is no clinical evidence that folate reduces drug efficacy

Key Comparisons

Feature	Proguanil	Pyrimethamine	Atovaquone alone
Class	Biguanide prodrug	Diaminopyrimidine	Hydroxynaphthoquinone
Target	DHFR (via cycloguanil)	DHFR	Mitochondrial cytochrome bc1 complex
Dosing interval	Daily	Weekly	Daily (as monotherapy)
Resistance risk	Rapid with monotherapy	Rapid with monotherapy	Rapid with monotherapy
Use in combination	Atovaquone or chloroquine	Sulfadoxine (Fansidar)	Proguanil

Summary Points

Proguanil is a prodrug - converted to cycloguanil by hepatic CYP2C19
Primary mechanism: DHFR inhibition blocking folate/DNA synthesis in plasmodia
Unique synergism with atovaquone: collapses mitochondrial membrane potential (proguanil-dependent, cycloguanil-independent)
Must be dosed daily due to short duration of active drug levels
The combination atovaquone-proguanil (Malarone) is the preferred regimen for chloroquine-resistant malaria prophylaxis and is the best tolerated option
Safe in pregnancy; not active against P. vivax hypnozoites (relapses can occur)

Sources: Goodman & Gilman's Pharmacological Basis of Therapeutics; Harrison's Principles of Internal Medicine 22E; Lippincott Illustrated Reviews: Pharmacology; Goldman-Cecil Medicine

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