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Semelhante a SULFONAMIDE: MECHANISM OF ACTION AND CLINICAL USES
Semelhante a SULFONAMIDE: MECHANISM OF ACTION AND CLINICAL USES (20)
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SULFONAMIDE: MECHANISM OF ACTION AND CLINICAL USES
- 1. -: PRESENTED BY :- ASSISTANT PROF. NATHANI ZEESHAN MUNAF (M.Pharm) DEPT. OF PHARMACOLOGY PROF. RAVINDRA NIKAM COLLEGE OF PHARMACY Morane – Gondur By-Pass Road, Near Punam Petrol Pump, Gondur, Tal. dist. Dhule- 424001 SULFONAMIDE 2/23/2021 Z.M.NATHANI 1
- 2. INDEX • Sulfonamide • Classification • MOA • Pharmacokinetics • Adverse effect • Cotrimoxazole 2/23/2021 Z.M.NATHANI 2
- 3. Sulfonamide is anti-bacterial medications; also called sulfa- related group of drugs. Sulfonamides derived from p-aminobeneznesulfonamide They are competitive inhibitors of p- amino benzoic acid in the folic acid metabolism cycle in the organisms Which are used to treat bacterial infection and some fungal infections. They are synthetic antibacterial agents where in all sorts of drug design strategies have been applied successfully. It was developed as life saving drugs called era of sulfa drugs. SULFONAMIDE 2/23/2021 Z.M.NATHANI 3
- 4. Sulfonamide was firstly noted as anti-bacterial in 1900’s by Gerhard Domagk; a Nobel Prize winner in 1939. In his attempt to save his daughter from streptococci killing infection, he observed that prontosil; a sulfonamide dye, is able to selectively restrain the infectious bacteria cells. In 1936, Ernest Fourneau found out prontosil pathway in human body. He discovered that this dye was a pro-drug. It, actually changes in human body to sulfanilamide which is the anti-bacterial active agent. HISTORY 2/23/2021 Z.M.NATHANI 4
- 5. his invention triggered the discoveries of other anti-bacterial members derived from this chemical group such as sulfapyridine in 1938 against pneumonia. sulfacetamide in 1941 against urinary tract infections. succinoylsulfathiazole in 1942 against gastrointestinal tract infections. Sulfathiazole was commonly used during World War II to cure soldier wounds’ infections. On the contrary, sulfanilamide was not very used due to its greater human toxicity. Later on, sulfisoxaide, sulfamethoxazole, sulfacetamide, mafenide and sulfadiazine silver were discovered, and those four agents are the sulfonamide anti-bacterial agents have been in the clinical use so far. 2/23/2021 Z.M.NATHANI 5
- 9. Prontosil Rubrum metabolization 2/23/2021 Z.M.NATHANI 9
- 11. Structure Analogue of PABA 2/23/2021 Z.M.NATHANI 11
- 15. Sulfonamides The sulfonamides are bacteriostatic inhibitors of folic acid synthesis. As antimetabolites of PABA, they are competitive inhibitors of dihydropteroate synthase. (It is an enzyme use for folic synthesis) 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. MOA 2/23/2021 Z.M.NATHANI 15
- 16. PABA The structure of Folic acid Folic acid, another form of which is known as folate, is one of the B vitamins. Folate is essential for the body to make DNA, RNA, and metabolize amino acids which are required for cell division. Humans cannot make folic acid, it is required from the diet. MOA ( Wood-Fields Theory) 2/23/2021 Z.M.NATHANI 16
- 26. Sulfamethoxazole was selected for combining with trimethoprim because both have nearly the same t½ (~ 10 hr). Optimal synergy in case of most organisms is exhibited at a concentration ratio of sulfamethoxazole 20 : trimethoprim 1, the MIC of each component may be reduced by 3–6 times. This ratio is obtained in the plasma when the two are given in a dose ratio of 5 : 1, because trimethoprim enters many tissues, has a larger volume of distribution than sulfamethoxazole and attains lower plasma concentration. However, the concentration ratio in many tissues is less than 20 : 1. Trimethoprim adequately crosses blood-brain barrier and placenta, while sulfamethoxazole has a poorer entry. Moreover, trimethoprim is more rapidly absorbed than sulfamethoxazole concentration ratios may vary with time. Trimethoprim is 40% plasma protein bound, while sulfamethoxazole is 65% bound. Trimethoprim is partly metabolized in liver and excreted in urine. Sulfamethoxazole 2/23/2021 Z.M.NATHANI 26
- 27. Trimethoprim It has been argued that in certain situations trimethoprim alone may be as effective as the combination, while majority of adverse effects are due to the sulfonamide. Thus, wherever shown effective, trimethoprim alone may be preferred. However, comparable efficacy of trimethoprim alone has been demonstrated only in: 1. Urinary tract infections: treatment of acute cases, suppressive treatment of chronic and recurrent cases— especially in females. 2. Prostatitis: Trimethoprim is concentrated in prostate, but not sulfonamide. Dose: 100–200 mg BD (children 6 mg/kg/day). Trimethoprim 2/23/2021 Z.M.NATHANI 27
- 29. Spectrum of Action 2/23/2021 Z.M.NATHANI 29
- 30. Resistance Bacteria are capable of acquiring resistance to trimethoprim mostly through mutational or plasmid mediated acquisition of a DHF Rase having lower affinity for the inhibitor. However, resistance to the combination has been slow to develop compared to either drug alone. Widespread use of the combination has resulted in reduced responsiveness of over 20% originally sensitive strains. Resistance 2/23/2021 Z.M.NATHANI 30
- 31. Preparations SEPTRAN, SEPMAX, BACTRIM, CIPLIN, ORIPRIM, SUPRISTOL, FORTRIM Trimethoprim Sulfamethoxazole 8 0 mg + 400 mg tab: 2 BD for 2 days then 1 BD. 160 mg + 800 mg tab: double strength (DS); 1 BD. 2 0 mg + 100 mg pediatric tab. 4 0 mg + 200 mg per 5 ml susp; infant 2.5 ml (not to be used in newborns), children 1–5 yr 5 ml, 6–12 year 10 ml (all BD). 160 mg + 800 mg per 3 ml for i.m. injection 12 hourly. (CIPLIN, ORIPRIM-IM) 8 0 mg + 400 mg per 5 ml for i.v. injection (WK-TRIM, ORIPRIM-IV) 10–15 ml BD. Cotrimazine It is a combination of trimethoprim with sulfadiazine. Its utility is similar to that of cotrimoxazole. Trimethoprim Sulfadiazine 90 mg + 410 mg: TRIGLOBE, ULTROX tab and per 10 ml susp.; 2 tab BD for 2 days, then 1 BD. 180 mg + 820 mg: TRIGLOBE FORTE, ULTROX DS tabs. Preparations 2/23/2021 Z.M.NATHANI 31
- 32. 1. Urinary Tract Infections Most acute uncomplicated infections respond rapidly. Single dose therapy with 4 tablets of cotrimoxazole has been recommended for acute cystitis. Courses of 3–10 days have been advised for lower and upper urinary tract infections, according to associated features. It is specially valuable for chronic and recurrent cases and in prostatitis, because trimethoprim is concentrated in prostate. 2. Respiratory Tract Infections Both upper and lower respiratory tract infections, including chronic bronchitis and faciomaxillary infections, otitis media caused by gram positive cocci and H. influenzae respond well. 3. Typhoid Initially cotrimoxazole was an effective alternative to chloramphenicol. However, in many areas resistant S. typhi have appeared, and now it is seldom used. Sensitive strains of S. typhi respond to one DS tab BD for 2 weeks. 4. Bacterial Diarrhoeas And Dysentery Cotrimoxazole may be used for severe and invasive infections by Campylobacter, E. coli, Shigella and Y. enterocolitica (see p. 661). Though response rate is lower than previously, and fluoroquinolones are more commonly used, it is effective in ampicillin resistant cases. 5. Pneumocystis jiroveci Pneumocystis jiroveci causes severe pneumonia in neutropenic and AIDS patients. Cotrimoxazole has prophylactic as well as therapeutic value, but high doses are needed. One DS tablet 4–6 times/day for 2–3 weeks may be curative, but adverse effects necessitate discontinuation in upto 20% cases. One DS tab. daily has been used for prophylaxis and is better tolerated. 6. Chancroid Cotrimoxazole (800 + 160 mg) BD for 7 days is a 3rd choice inexpensive alternative to ceftriaxone, erythromycin or ciprofloxacin. USES 2/23/2021 Z.M.NATHANI 32