Usage
Proguanil is primarily prescribed for the prevention and treatment of malaria, specifically caused by Plasmodium falciparum. It belongs to the antimalarial pharmacological class. Proguanil acts as a dihydrofolate reductase inhibitor in the malaria parasite, disrupting its folate metabolism and consequently, DNA synthesis. Proguanil is a pro-drug which is metabolized to its active form, cycloguanil.
Alternate Names
- Chlorguanide
- Paludrine (brand name)
How It Works
Pharmacodynamics: Proguanil is a pro-drug metabolized to cycloguanil in the liver. Cycloguanil inhibits dihydrofolate reductase (DHFR) in the malaria parasite, a crucial enzyme in the folate pathway responsible for DNA synthesis. This inhibition interrupts parasite growth and multiplication, thus exerting antimalarial effects.
Pharmacokinetics:
- Absorption: Proguanil is well-absorbed orally, especially when taken with food.
- Metabolism: Primarily metabolized by CYP2C19 in the liver to its active metabolite, cycloguanil.
- Elimination: Both proguanil and cycloguanil are excreted primarily in the urine, with a half-life of approximately 12-25 hours for proguanil and 16-20 hours for cycloguanil.
Mode of Action: Cycloguanil’s primary mechanism of action is through the inhibition of DHFR, which disrupts the folate metabolic pathway crucial for pyrimidine biosynthesis, essential for DNA replication and cell division in the parasite.
Receptor binding, enzyme inhibition, or neurotransmitter modulation:
- Enzyme Inhibition: Dihydrofolate reductase (DHFR) inhibition in Plasmodium falciparum.
Elimination pathways: Primarily renal excretion of both proguanil and its active metabolite cycloguanil.
Dosage
Standard Dosage
Adults (for Prophylaxis): 200 mg daily (two 100 mg tablets).
Children (for Prophylaxis):
- Under 1 year: 25 mg daily.
- 1 to 4 years: 50 mg daily.
- 5 to 8 years: 100 mg daily.
- 9 to 14 years: 150 mg daily.
- Over 14 years: Adult dose (200mg) daily.
Special Cases:
- Elderly Patients: No dose adjustment generally necessary, but monitor for potential adverse effects.
- Patients with Renal Impairment: Caution advised in patients with severe renal impairment (creatinine clearance <30 mL/min); dose adjustment may be necessary.
- Patients with Hepatic Dysfunction: No dose adjustment is typically needed for mild to moderate impairment. Severe hepatic impairment may warrant precaution and potential dose adjustment.
Clinical Use Cases
Proguanil itself is not typically used in clinical settings such as intubation, surgical procedures, mechanical ventilation, ICU, or emergency situations like cardiac arrest. It is mainly used for malaria prophylaxis.
Dosage Adjustments
- Renal/hepatic dysfunction: As above
- Metabolic disorders/genetic polymorphisms: Monitor individuals with CYP2C19 polymorphisms.
Side Effects
Common Side Effects
- Nausea
- Vomiting
- Abdominal pain
- Headache
- Mouth ulcers
Rare but Serious Side Effects
- Severe skin reactions (e.g., Stevens-Johnson syndrome)
- Blood disorders (e.g., pancytopenia)
- Hepatotoxicity
Long-Term Effects Long-term use is generally safe, but potential adverse effects should be monitored.
Adverse Drug Reactions (ADR)
Contraindications
- Hypersensitivity to proguanil.
- Severe renal impairment (CrCl < 30 mL/min).
Drug Interactions
- Warfarin: Proguanil may increase the anticoagulant effect of warfarin.
- Metoclopramide: May decrease the efficacy of proguanil.
- Tetracyclines: May decrease the efficacy of proguanil.
- CYP2C19 inhibitors/inducers: May affect proguanil metabolism.
Pregnancy and Breastfeeding
- Pregnancy: It can be used during pregnancy if the benefits outweigh the risks, particularly if there are no suitable alternatives.
- Breastfeeding: Can be used during breastfeeding for infants weighing >5 kg. However, the infant will require separate malaria prophylaxis.
Drug Profile Summary
- Mechanism of Action: Inhibits dihydrofolate reductase in Plasmodium falciparum.
- Side Effects: Nausea, vomiting, abdominal pain, headache, mouth ulcers. Rare: Severe skin reactions, blood disorders, hepatotoxicity.
- Contraindications: Hypersensitivity, severe renal impairment.
- Drug Interactions: Warfarin, metoclopramide, tetracyclines, CYP2C19 inhibitors/inducers.
- Pregnancy & Breastfeeding: Generally safe if benefits outweigh risks. Infant requires independent prophylaxis.
- Dosage: Prophylaxis: Adults: 200 mg daily. Children: Weight/age-based dosing.
- Monitoring Parameters: Renal function, liver function tests, complete blood count (if long-term use), signs of adverse reactions.
Popular Combinations
- Atovaquone: The combination atovaquone/proguanil (Malarone) is frequently used for both malaria prophylaxis and treatment. They have synergistic effects and are highly effective against chloroquine-resistant malaria.
Precautions
- General Precautions: Renal/hepatic function assessment.
- Specific Populations: Pregnant/breastfeeding women: Assess risk-benefit. Children: Monitor weight/age-based dosing.
- Lifestyle Considerations: No specific lifestyle restrictions.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Proguanil for malaria prophylaxis?
A: Adults: 200 mg daily. Children: Dose varies by age and weight. See pediatric dosing guidelines.
Q2: Can Proguanil be used for the treatment of malaria?
A: Yes, although the atovaquone-proguanil combination is more commonly used for treatment than proguanil alone.
Q3: What is the mechanism of action of Proguanil?
A: It inhibits dihydrofolate reductase, crucial for the malaria parasite’s folate pathway.
Q4: What are the most common side effects of Proguanil?
A: Nausea, vomiting, abdominal pain, headache, and mouth ulcers.
Q5: Is Proguanil safe during pregnancy?
A: It can be used if the benefits outweigh the potential risks, especially in chloroquine-resistant areas and if no suitable alternatives exist.
Q6: Can Proguanil be used in patients with renal impairment?
A: Use with caution in patients with severe renal impairment. Dose adjustment might be required.
Q7: What are the known drug interactions with Proguanil?
A: Clinically significant interactions include warfarin, metoclopramide, and tetracyclines. Interactions with CYP2C19 inhibitors/inducers should also be considered.
Q8: What are the contraindications for Proguanil?
A: Hypersensitivity to the drug and severe renal impairment.
Q9: What is the difference between Proguanil and atovaquone/proguanil?
A: Proguanil can be used alone for malaria prophylaxis, but atovaquone/proguanil (Malarone) is more commonly used for both prophylaxis and treatment, offering enhanced efficacy.
Q10: How should Proguanil be administered?
A: Orally, preferably with food or a milky drink to enhance absorption.
