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Folate antagonists
This document discusses the classification, mechanisms of action, antimicrobial spectrum, pharmacokinetics, and adverse effects of several classes of antifolate drugs including sulfonamides, trimethoprim, and cotrimoxazole. Sulfonamides are bacteriostatic inhibitors of bacterial folate synthesis that compete with PABA. Trimethoprim inhibits dihydrofolate reductase. Cotrimoxazole combines trimethoprim and a sulfonamide for broad-spectrum antibacterial activity through dual inhibition of folate synthesis. These drugs are absorbed orally, distributed widely, and excreted renally. Common adverse effects include hematologic and gastrointestinal issues.
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Folate antagonists
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- 2. ANTIFOLATE DRUGS CLASSIFICATION ANDPHARMACOKINETICS Sulfonamides The sulfonamides have a common chemical nucleus resembling p-aminobenzoic acid (PABA).
- 3. SULFONAMIDES ORALLY ABSORBABLE short acting sulfisoxazole, intermediate acting sulfamethoxazole, long acting sulfadoxine ORALLY NONABSORBABLE Sulfaguanidine, sulfasalazine weakly absorbed after oral administeration ,used for enteric fever TOPICAL Sulfadiazine is used in burns topically, Sulfacetamide in ophthalmic preparations
- 4. ANTIFOLATE DRUGS MECHANISMS OFACTION 1. Sulfonamides • The sulfonamides are bacteriostatic inhibitors of folic acid synthesis. • As antimetabolites of PABA, they are competitive inhibitors of dihydropteroate synthase. • The selective toxicity of sulfonamides results from the inability of mammalian cells to synthesize folic acid; they must use preformed folic acid that is present in the diet.
- 5. ANTIMETOBOLITE ANTIBIOTICS They inhibitthe folic acid synthesis p-Aminobenzoic acid (PABA) Dihydrofolic acid Tetrahydrofolic acid Purines DNA Dihydropteroate synthase Dihydrofolate reductase Sulfonamides (compete with PABA) Trimethoprim, pyrimethamine
- 7. ANTI-BACTERIAL SPECTRUM Against enterobacterspecies in UTIs Nocardia species Sulfadiazine + pyrimethamine= used for toxoplasmosis Sulfadoxine + pyrimethamine = as anti-malarial drug
- 8. RESISTANCE Bacteria thatobtain folate from environment Resistance may be due to plasmid transfer or mutation These involves following processes 1.Altered dihydropteroate synthetase 2. Decreased permeability 3.Enhanced production of PABA
- 9. PHARMACOKINETICS Well absorbedorally sulfasalazine is used as suppository for treatment of ulcerative colitis IV preparation are also available Usually not applied topically due to risk of allergic reaction But in burn units, creams of silver sulfadiazine or mafenide acetate used to inhibit sepsis
- 10. DISTRIBUTION Bound toserum albumin, depends on pKa value of drug Smaller pKa, greater the binding Distribute throughout the body including CSF Also cross placental barrier METABOLISM Acetylated and conjugated in liver Acetylated product is devoid of activity
- 11. EXCRETION Through glomerularfiltration dose adjustment in renally compromised patients ADRs Crystalluria/ stone formation in kidney that can be prevented by adequate hydration and alkalinization of urine Hypersensitivity; rashes, angioedema or stevens- johnson syndrome
- 12. Hematopoietic disturbances: 1.Hemolytic anemia 2. granulocytopenia 3. Aplastic anemia 4. Blood dyscrasias Kernicterus Billirubin in CNS of newborns as sulfa drugs displace them from serum albumin
- 14. Drug potentiation;warfarin and methotrexate levels increased due to displacement Contraindication Due to kernicterus, should be avoided in newborns and pregnant women
- 15. TRIMETHOPRIM Anti-bacterial spectrumsimilar to sulfonamides Mostly used in combination with sulfamethoxazole 20-50 folds more potent than sulfa drugs MOA Through inhibition of dihydrofolate reductase leading to decreased availability of tetrahydrofolate cofactor necessary for purine, pyrimidine synthesis
- 16. RESISTANCE Altered dihydrofolatereductase Efflux pump Decreased permeability
- 17. PHARMACOKINETICS Absorbed afteroral administration Widely distributed into body fluids and tissues Also penetration into CSF Undergoes O-demethylation metabolism 60-80 % excreted unchanged in urine
- 18. ADRS Folic aciddeficiency which includes megaloblastic anemia, leukopenia and granulocytopenia But these disorder can be reversed through adminitration of folinic acid which cant enter in bacteris
- 19. COTRIMOXAZOLE The combinationof trimethoprim with sulfamethoxazole, called cotrimoxazole shows greater antimicrobial activity than equivalent quantities of either drug used alone combination was selected because of the similarity in the half-lives and synergistic activity of the two drugs.
- 21. MECHANISM OF ACTION inhibition of two sequential steps in the synthesis of tetrahydrofolic acid Sulfamethoxazole inhibits the incorporation of PABA into dihydrofolic acid precursors, Trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate
- 22. ANTIBACTERIAL SPECTRUM Broaderspectrum of antibacterial action than the sulfa drugs effective in treating following infections UTIs RTIs Pneumocystis jiroveci pneumonia and ampicillin- chloramphenicol-resistant systemic salmonella infections.
- 23. MRSA socan be used for skin and soft tissue infections Also activity against Nocardia species
- 24. RESISTANCE Resistance is lessfrequently encountered than resistance to either of the drugs alone because simultaneous resistance to both drugs is required.
- 25. PHARMACOKINETICS Administration ofone part trimethoprim to five parts of the sulfa drug generally administered orally Intravenous administration to patients with severe pneumonia caused by P. jiroveci. Both agents distribute throughout the body.
- 26. Trimethoprim concentrates inthe relatively acidic environment Crosses BBB Both drugs and metabolites excreted in urine
- 27. ADVERSE DRUG REACTIONS Dermatologic:Reactions involving the skin are very common Gastrointestinal: Nausea, vomiting, as well as glossitis and stomatitis are not unusual. Hematologic: Megaloblastic anemia, leukopenia, and thrombocytopenia All these effects may be reversed by the concurrent administration of folinic acid
- 28. Patients infected withhuman immunodeficiency virus: Immuno-compromised patients with P. jiroveci pneumonia frequently show drug-induced fever, rashes, diarrhea, and/or pancytopenia. Drug interactions: Prolonged prothrombin time in combination with warfarin
- 29. The plasma half-lifeof phenytoin may be increased due to an inhibition of its metabolism. Methotrexate levels may rise due to displacement from albumin-binding sites by sulfamethoxazole.