Basic Pharmacology Nucleic Acid Synthesis Inhibitors PDF

BASIC PHARMACOLOGY 09/08/2024 MOD 5: NUCLEIC ACID SYNTHESIS INHIBITORS...

BASIC PHARMACOLOGY 09/08/2024 MOD 5: NUCLEIC ACID SYNTHESIS INHIBITORS Charles C. Monsada, MD Trans Group/s: 8A I. ANTIFOLATE DRUGS ○ But rather they are actually being stimulated in their growth. A. SULFONAMIDES ○ Avoid giving sulfonamides in patients with Structurally like p-aminobenzoic acid (PABA) Rickettsiae infections. Sulfonamide-susceptible microorganisms like bacteria Poor activity against anaerobes cannot use exogenous folate but must synthesize it Pseudomonas aeruginosa: resistant to sulfonamides from p-aminobenzoic acid (PABA). 4. PHARMACOKINETICS 1. MECHANISM OF ACTION Oral, absorbable: absorbed from the stomach and Bacteriostatic: prevents normal bacterial utilization of small intestine, widely distributed to tissues and body PABA for the synthesis of folic acid → halt the formation fluids (including CSF). of the purine bases and nucleic acid synthesis. Oral, non-absorbable Topical 5. CLINICAL USE Used in combination with an inhibitor of dihydrofolate reductase (trimethoprim or pyrimethamine) → synergistic activity because of sequential inhibition of folate synthesis ○ Have additive effect → bactericidal effect Trimethoprim-Sulfamethoxazole (co-trimoxazole) — drug of choice for infection such as Pneumocystiis jirovecii pneumonia, toxoplasmosis and nocardiosis ○ May also be used in UTI, Listeriosis, and Shigellosis 6. ORAL ABSORBABLE AGENTS ORAL ABSORBABLE AGENTS Sulfisoxazole and UTI Sulfamethoxazole Sulfadiazine + First line therapy for Mechanism of Action of Antifolate Drugs. Pyrimethamine Acute Toxoplasmosis Sulfonamide: structural analogs of PABA that inhibit Sulfadoxine + specifically the DIHYDROPTEROATE SYNTHASE and Second line for malaria Pyrimethamine halt the folate production of microorganisms ○ Combined with trimethoprim and pyrimethamine. Trimethoprim and pyrimethamine: inhibitors of the 7. ORAL NONABSORBABLE AGENTS DIHYDROFOLATE REDUCTASE. Sulfasalazine (Salicylazosulfapyridine) — treatment Sulfonamide ONLY → bacteriostatic → halt the of inflammatory bowel disease growth of these microorganisms. Sulfonamide + trimethoprim → inhibit both 8. TOPICAL AGENTS dihydropteroate synthase and dihydrofolate reductase → synergistic effect → bactericidal. TOPICAL AGENTS 2. MECHANISM OF RESISTANCE Sodium Sulfacetamide Cause overproduction of PABA ophthalmic Bacterial conjunctivitis Cause overproduction of folic acid-synthesizing solution/ointment enzyme that has low affinity for sulfonamides Impair permeability to sulfonamides → microorganisms they will not be able to enter and leave Absorbed from burn sites, the cell → sulfonamides will not be able to exert its limited use due to inhibition Mafenide Acetate effect. of carbonic anhydrase → Metabolic Acidosis 3. COVERAGE Less toxic for prevention of Inhibit both gram-positive bacteria, gram-negative Silver Sulfadiazine burn wounds, may slow enteric bacteria, and some protozoa wound healing Rickettsiae are NOT inhibited by sulfonamides. Pharmacology - Mod # Topic Title 1 of 2 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  3. PHARMACOKINETICS 9. ADVERSE REACTIONS Well absorbed after oral administration Hypersensitivity Reactions: usually allergies Most have bioavailability between 80-90% Crystalluria: sulfonamides precipitate in urine at neutral Divalent cations such as calcium interfere with the or acidic pH absorption ○ Treated with sodium bicarbonate to alkalinize urine Wide distribution: low protein binding, high lipid Hematopoietic disturbance — hemolytic/ aplastic solubility anemia Longest half-life: Levofloxacin and Moxifloxacin ○ Hemolytic reactions in patients with G6PD Kernicterus in infants (if sulfonamide was taken near 4. MECHANISM OF RESISTANCE end of pregnancy) Altered target: one or more point mutations in Quinolone binding region or target enzyme II. DNA GYRASE INHIBITORS Change in permeability of the organism causing decreased accumulation primarily in the microorganism, A. FLUOROQUINOLONES or inside the cytoplasm of the organism Usually has the suffix “-floxacin” Ciprofloxacin, Norfloxacin, Levofloxacin, Ofloxacin, 5. CLINICAL USE Moxifloxacin, Enoxacin Urinary tract infections (Including P. aeruginosa) Bacterial diarrhea (caused by Shigella, Salmonella, 1. MECHANISM OF ACTION Toxigenic E. coli, and Campylobacter) Block bacterial DNA synthesis by inhibiting bacterial Respiratory tract infections topoisomerase Il (DNA gyrase) and topoisomerase ○ Acute bacterial bronchitis: Levofloxacin, IV prevents relaxation of positively supercoiled DNA → Sparfloxacin, Ofloxacin, Gatifloxacin, prevents normal DNA Replication Moxifloxacin Inhibition of topoisomerase IV → interfere with ○ Community Acquired Pneumonia separation of replicated chromosomal DNA into the Prostatitis: Levofloxacin respective daughter cells ○ Levofloxacin is the first-line drug for treating prostatitis 2. SPECTRUM OF ACTIVITY GIT infection: Norfloxacin, Ciprofloxacin Higher generations = more gram-positive effects. Skin, bone, soft tissue infection Lower generations = more gram-negative effects. 6. ADVERSE REACTIONS GIT upset: nausea, vomiting, diarrhea FLUOROQUINOLONES SPECTRUM OF ACTIVITY CNS manifestations: headache, dizziness, drowsiness, confusion, seizures, vertigo Nalidixic acid: Enterobacteriaceae Photosensitivity and skin reactions (e.g., rashes, 1st pruritus) Generation Narrow gram-negative coverage Connective tissue and teratogenicity: one of the most notable defects Class I (Norfloxacin – prototype), ○ Cartilage erosions → arthropathy (in elderly Enoxacin, Lomefloxacin patients) ○ Contraindicated in pregnant or breastfeeding Gram negative – excellent activity women (deposition in the connective tissue) Gram positive – good but limited ○ Reversible activity Others (seen in elderly patients): ○ QT prolongation ○ Myalgia, joint swelling 2nd ○ Tendonitis → tendon rupture Class II (Ciprofloxacin – prototype), Generation Ofloxacin Gram negative – excellent activity Gram positive – moderate-to-good activity Ciprofloxacin – Pseudomonas aeruginosa Levofloxacin (prototype), Clincafloxacin, Sparfloxacin, Gatifloxacin 3rd Gram positive – improved activity (S. Generation pneumoniae with coverage of atypical pathogens such as Chlamydia spp., Mycoplasma spp., etc.) Moxifloxacin (prototype) 4th Generation Gram positive – enhanced activity Anaerobic bacteria — good activity Pharmacology - Mod 5 🏠 Nucleic Acid and Folic Acid Synthesis Inhibitors 2 of 2 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.