Introduction: Simultaneous development of technology is composed with environmental hazardous with heavy-metals and organic solvents and thus toxic catalysts/organic solvents must be replaced with biocatalysts and water. Urease is a hydrolase enzyme and urease-urea can be considered a safe source of toxic ammonia in synthesis of nifedipine. Nifedipine is an antihypertensive drug synthesized by four–component reaction of 2 mmol methyl acetoacetate, 2–nitro-benzaldehyde, and ammonia using catalysts and organic solvents. The object of this research is replacement of toxic ammonia with urease-urea and organic solvents with water and study of heavy-metals and organic-solvent inhibition of urease on the synthesis of nifedipine. Methods: In this experimental work, by controlling of yield and time of nifedipine synthesis via reaction of methyl acetoacetate, 2–nitro-benzaldehyde, and urease/urea in water, optimum urease/urea concentration, temperature, and pH for maximum yield were determined. Then, the effect of heavy-metal/organic solvent inhibitors on the production of ammonia and urease-catalyzed synthesis of nifedipine have been investigated. Results: Based on the yield of nifedipine, the activity of urease for ammonia production depends on parameters such as urease/urea amount, temperature, pH, and kind or concentration of inhibitors. The results accorded urease specificity for maximum dissociation of urea in experiment with 10 mg/mL urease, pH=7, and 70 C° in water, while heavy-metal ion/organic solvent inhibitory of urease showed trends of Hg2+>Ag+>Cu2+>Pb2+>Cd2+ and acetonitrile>chloroform>dichloromethane to reduce in ammonia concentration and nifedipine. Conclusion: Urease-urea makes a biocompatible source of ammonia for synthesis of anti–hypertension drug of nifedipine, while inhibitors such as heavy metal cations especially Hg2+, organic solvents, and sulfuric acid decrease the reaction rate. Biocompatibility, use of water and no organic solvent/catalyst, high yield and selectivity are advantages of this green method in comparison to previous reported methods.