Pharmacology & Medicinal Chemistry III Lecture #11 - Sulfonamides and Trimethoprim PDF

Pharmacology & Medicinal Chemistry III Lecture #11 Sulfonamides and Trimethoprim Today’s Outline: I. Sulfonamides II. Trimethoprim Read for this lecture: Goodman and Gilman – Chapter 57 Poll everywhere PollEv.com/dominaa Or text: DOMINAA to 22333 Lea...

Pharmacology & Medicinal Chemistry III Lecture #11 Sulfonamides and Trimethoprim Today’s Outline: I. Sulfonamides II. Trimethoprim Read for this lecture: Goodman and Gilman – Chapter 57 Poll everywhere PollEv.com/dominaa Or text: DOMINAA to 22333 Learning Objectives for Sulfonamides and Trimethoprim Lecture By the end of this lecture, you should be able to… Identify selected drugs as Sulfonamides. Describe the mechanism of action of Sulfonamides and Trimethoprim. Describe the benefit of administering a Sulfonamide and Trimethoprim together. Describe the antibacterial spectrum for these medications. Describe common mechanisms of resistance for Sulfonamides and Trimethoprim. Identify adverse events associated with administration of these medications. Identify how Sulfonamides and Trimethoprim I. Sulfonamides  Sulfonamides – Structure ctural analogs of PABA (Para-AminoBenzoic Acid) gure 52.1 – Goodman and Gilman  Sulfonamides – Mechanism of Action  Competitive inhibitors  Compete with PABA for binding to the active site of _________________________  Considered ________________ Figure 12.6 - Foundation in Microbiology, 7th Sulfonamides – Mechanism of Action (Continued)  ________________ - Host cell immune defenses are critical to completely eradicate the pathogen.  Reversible - If the drug is removed and bacteria have not been destroyed, then bacterial growth may resume.  Susceptible bacteria cannot import folate from the environment.  Some bacteria and human cells utilize pre- formed folate from the environment (e.g. diet) and thus are not affected by Sulfonamides. Sulfonamides – Antibacterial Spectrum  Broad antibacterial spectrum: ________________ ________________________________ bacteria may be affected.  Examples of bacteria susceptible to Sulfonamides (assuming no acquired resistance): Staphylococcus aureus Streptococcus pneumoniae Gram negative enteric bacteria (e.g. E. coli) Haemophilus influenzae Listeria monocytogenes  Poor activity against anaerobic bacteria, Pseudomonas aeruginosa, and atypical bacteria. Sulfonamides – Bacterial Resistance  Resistance is increasingly a problem with Sulfonamides.  Resistance may be due to: - Mutations in dihydropteroate synthase leading to decreased affinity for Sulfonamides. - Decreased entry of Sulfonamides or increased efflux. - Acquisition of alternative metabolic pathway to produce dihydrofolic acid. - Increased production of___________________________ ________________  Sulfonamides – Therapeutic Uses  Use of Sulfonamides as a single therapy has become less common due to ________________ Sulfonamides – Three Groups Based on Pharmacological Properties CLASS SULFONAMIDE SERUM HALF- LIFE HOURS 1. Oral, Absorbed, and Sulfisoxazole 5–6 Excreted Rapidly ________________ 11 Sulfadiazine 10  Can be used to treat a variety of infections, including urinary tract infections  Sulfamethoxazole – Often administered with a fixed concentration of Trimethoprim. More information in the next section. Table 52-1, Goodman and Gilma Sulfonamides – Three Groups Based on Pharmacological Properties CLASS SULFONAMIDE SERUM HALF- LIFE HOURS 2. Oral, Non-absorbed – Sulfasalazine — Active in bowel lumen Sulfasalazine  A non-antibiotic Sulfonamide  Used in the treatment of rheumatoid arthritis, ulcerative colitis, enteritis, and other inflammatory bowel conditions due to anti-inflammatory affects. Some systemic absorption occurs. Table 52-1, Goodman and Gilma Sulfonamides – Three Groups Based on Pharmacological Properties CLASS SULFONAMIDE SERUM HALF- LIFE HOURS 3. Topical Sulfacetamide — Silver — sulfadiazine  Sulfacetamide – Used to treat bacterial conjunctivitis and as an adjunct therapy for chlamydia. ‐ Ophthalmic and topical formulations  Silver sulfadiazine – Used as a prophylaxis to prevent infection in burns. ‐ Topical Table 52-1, Goodman and Gilma ulfonamides – Highlighted Adverse Effect  Overall incidence is ~5%. Numerous and varied….Include: _____________________________ (Sulfa allergy) - Skin rash (most common, usually not severe) o Urticaria o Other forms of rash - Fever - Malaise - Stevens-Johnson Syndrome - Exfoliative dermatitis - Photosensitivity - Anayphylaxis Typically occurs after the first week of treatment, unless previously sensitized.  Sulfonamides – Highlighted Adverse Effects (Continued) Anorexia, nausea, vomiting ________________ (especially in dehydrated patients) – may lead to acute kidney failure. More common with Sulfamethoxazole and Sulfadiazine. Hemolytic anemia - in patients with glucose-6- phosphate dehydrogenase deficiency Aplastic anemia - Bone marrow suppression affecting all types of blood cells (rare, but serious; with higher doses) Hepatomegaly and liver necrosis (rare, but may be fatal) – Evidenced by jaundice and elevated hepatic enzymes in the serum  Sulfonamides – Highlighted Adverse Effects (Continued) Kernicterus – results from bilirubin displacement from albumin in the blood in perinatal infants, resulting in encephalopathy and brain damage - Infant may appear jaundiced - Avoid in infants less than 4 months - Avoid in pregnant women who are near term  Sulfonamides – Clearance  Sulfonamides are excreted by the ________________ ‐ Adjust dose for individuals with significant renal insufficiency (for systemic use).  Sulfonamides – Drug Interaction Sulfonamides inhibit CYP2C8 and CYP2C9 Warfarin - This potentiates the effects of warfarin and increasing the INR. - If possible, avoid administering Sulfonamides with Warfarin. II. Trimethoprim- sulfamethoxazole ethoprim Structure and Mechanism of Ac  Inhibits _____________________________  Highly selective for prokaryotic DHFR over mammalian DHFR.  Considered a folate antagonist  Available as a single agent or in combination + Pteridine oodman and Gilman, 11th ed. Figure 12.6 - Foundation in Microbiology, 7th  Trimethoprim and Sulfamethoxazole Combination Therapy Trimethoprim combined with Sulfamethoxazole (a Sulfonamide) - Synergistic effects Typically administered: 5 parts Sulfamethoxazole to 1 part Trimethoprim + Pteridine Figure 12.6 - Foundation in Microbiology, 7  Trimethoprim and Sulfamethoxazole – Antibacterial Spectrum and Resistance  Numerous Gram positive and Gram negative bacteria are sensitive to this combination.  Trimethoprim alone is bacteriostatic; however, when combined with Sulfamethoxazole, the effect may be bactericidal.  ________________ is rapidly increasing.  Trimethoprim and Sulfamethoxazole – Therapeutic Uses  ________________________________________________  Bacterial respiratory tract infections - Acute exacerbations of chronic bronchitis  Acute otitis media  Acute maxillary sinusitis  Gastrointestinal infections -Shigellosis - Typhoid fever - Acute diarrhea due to E. coli (although not recommend for E.coli O157:H7 due to increased risk for hemolytic-uremic syndrome, perhaps due to increased shiga toxin release).  ________________  Other infections  Trimethoprim and Sulfamethoxazole – Highlighted Adverse Effects Includes… Most involve skin conditions (rash) Glossitis – tongue become swollen and changes color Stomatitis – inflammation of the mucous lining of the mouth And others from the sulfanomide (in previous section)  Trimethoprim inhibits A. Synthesis of the bacterial cell wall. B. Production of folate by blocking dihydropteroate synthase. C. Production of amino acids, nucleotides, and ribonucleotides by blocking bacterial DHFR. D. The entry of sulfonamides into bacteria.