Sulfonamides PDF

Therapeutic Classes Synthetic Antimicrobial Agents Synthetic antimicrobial agents are not modeled after any natural product, so they may not properly be termed “antibiotics.” Some synthetics are extremely effective for treatment of infections and are widely used. 1...

Therapeutic Classes Synthetic Antimicrobial Agents Synthetic antimicrobial agents are not modeled after any natural product, so they may not properly be termed “antibiotics.” Some synthetics are extremely effective for treatment of infections and are widely used. 1 Prof. Afaf AL Nadaf 11/3/2024  Sulfonamides Prontosil rubrum, (a red dye), was one of a series of dyes examined for that it might be taken up selectively by certain pathogenic bacteria and not by human cells The dye proved to be active in vivo against streptococcal infections in mice. but it was not active in vitro. The urine of prontosil rubrum–treated animals was bioactive in vitro. Fractionation led to identification of the active substance as: p-aminobenzenesulfonic acid amide (sulfanilamide), a colorless cleavage product formed by reductive liver metabolism of the administered dye. 2 Prof. Afaf AL Nadaf 11/3/2024  Bioactivation of Prontosil 3 Prof. Afaf AL Nadaf 11/3/2024  Mechanism of action 4 Prof. Afaf AL Nadaf 11/3/2024  Nomenclature of the Sulfonamides Sulfonamide is a generic term that denotes three different cases: 1.Antibacterials that are aniline-substituted sulfonamides(the“sulfanilamides”). 2.Prodrugs that react to generate active sulfanilamides (i.e.,sulfasalazine). O 3.Non aniline sulfonamides (mafenide acetate). O H3N O S NH2 O 5 Prof. Afaf AL Nadaf 11/3/2024 6 Prof. Afaf AL Nadaf 11/3/2024  Structure-activity relationships The functional group that differs in the two molecules is the carboxyl of PABA and the sulfonamide moiety of sulfanilamide The strongly electron-withdrawing character of the aromatic (-SO2 (group makes the nitrogen atom to which it is directly attached partially electropositive (so that this functional group is slightly acidic) The pKa of the carboxyl group of PABA is approximately 6.5 (replacement of one of the NH2 hydrogens by an electron-withdrawing heteroaromatic ring was not only consistent with antimicrobial activity but also greatly acidified the remaining hydrogen). 7 Prof. Afaf AL Nadaf 11/3/2024  Structure-activity relationships With suitable groups in place, the pKa is reduced to the same range as that of PABA itself The pKa of sulfisoxazole, one of the most popular of the sulfonamides in present use, is approximately 5.0. Crystalluria and resulted in kidney. The clinically useful sulfonamides vary in the heterocyclic aromatic substituents on the sulfonamide nitrogen 8 Prof. Afaf AL Nadaf 11/3/2024  Structure-activity relationships 9 Prof. Afaf AL Nadaf 11/3/2024  Pharmacokinetics The orally administered sulfonamides are well absorbed from the gastrointestinal (GI) tract, distributed fairly widely, and excreted by the kidney They are bound to plasma protein (sulfisoxazole, 30–70%, sulfamethoxazole, 70%) and, may displace other protein-bound drugs as well as bilirubin (neonatal jaundice in late term pregnancy). acetylation and glucuronidation. resistance (decreased sensitivity of dihydropteroate synthase or increased production of PABA). 10 Prof. Afaf AL Nadaf 11/3/2024  Therapeutic Applications Sulfisoxazole acetyl is tasteless, which accounts for its use in pediatric preparations. This is active against susceptible organisms that may include E. coli, Klebsiella sp., and Proteus sp. and Streptococcus pyogenes, Streptococcus pneumoniae ,and Haemophilus sp. The remaining sulfonamides are not used systemically. Sulfadiazine in the form of its silver salt is used topically for treatment of burns Sulfacetamide is used ophthalmically sulfasalazine is used in the treatment of ulcerative colitis and Crohn's disease Allergic reactions are the most common adverse effect and take the form of rash, photosensitivity, and drug fever. Less common problems are kidney and liver damage and hemolytic anemia. 11 Prof. Afaf AL Nadaf 11/3/2024 12 Prof. Afaf AL Nadaf 11/3/2024  Salfasalazine and its activation 13 Prof. Afaf AL Nadaf 11/3/2024 Topical: Mafenide Acetate: O 4-(Aminomethyl)benzene sulfonamide O acetate (Sulfamylon) H3N O is a homologue of the sulfanilamide molecule. S NH2 It is not a true sulfanilamide-type compound, O as it is not inhibited by PABA. Its antibacterial action involves a mechanism that differs from that of true sulfanilamide-type compounds. Silver Sulfadiazine (Silvadene) The salt is only slightly soluble and does not penetrate the cell wall but acts on the external cell structure. NH2 Ag O S N O N N 14 Prof. Afaf AL Nadaf 11/3/2024  Trimethoprim Mechanism of action A further step in the pathway leading from the pteroates to folic acid and on to DNA bases requires the enzyme dihydrofolate reductase. Exogenous folic acid must be reduced stepwise to dihydrofolic acid and then to tetrahydrofolic acid, an important cofactor essential for supplying a 1-carbon unit in thymidine biosynthesis and, ultimately, for DNA synthesis. The same enzyme also must reduce endogenously produced dihydrofolate. This inhibitor prevents tetrahydrofolic acid biosynthesis and results in bacteriostasis. Trimethoprim selectivity between bacterial and mammalian dihydrofolate reductases results from the subtle but significant architectural differences between these enzyme systems. 15 Prof. Afaf AL Nadaf 11/3/2024  - Co-trimoxazole is available in oral and intravenous preparations with the standard single-strength tablet containing 80 mg of trimethoprim combined with 400 mg of sulfamethoxazole. - It is an antibiotic used to treat a variety of bacterial infections. - It consists of one part trimethoprim to five parts sulfamethoxazole. - It is used for urinary tract infections, skin infections, travellers’ diarrhoea, respiratory tract infections, and cholera, among others. It may be used both to treat and prevent pneumocystis pneumonia in people with HIV/AIDS. 16 Prof. Afaf AL Nadaf 11/3/2024 17 Prof. Afaf AL Nadaf 11/3/2024  Therapeutic application Trimethoprim frequently is used as a single agent clinically for the oral treatment of uncomplicated urinary tract infections Combined with sulfamethoxazole, it is used for oral treatment of urinary tract infections, shigellosis, otitis media, traveler's diarrhea, methicillin-resistant Staphylococcus aureus and bronchitis Among the opportunistic pathogens that afflict patients with AIDS is the pneumonia-causing fungus Pneumocystis jiroveci. The combination of sulfamethoxazole-trimethoprim has proven to be useful and comparatively nontoxic for these patients The most frequent side effects of trimethoprim-sulfamethoxazole are rash, nausea, vomiting and severe drug related diarrhea 18 Prof. Afaf AL Nadaf 11/3/2024  Resistance Bacterial resistance to trimethoprim is increasingly common In pneumococcal infections, it can result from a single amino acid mutation (Ile-100 to Leu) in the dihydrofolate reductase enzyme Overexpression of dihydrofolate reductase by Staphylococcus aureus has been reported in resistant strains 19 Prof. Afaf AL Nadaf 11/3/2024