12 Antifolates, Nitrofurantoin, Metronidazole Cupo Flashcards
What are Antifolates?
Sulfonamides. Dihydrofolate reductase inhibitors. Combination products
What are the different Sulfonamides used?
Sulfisoxazole. Sulfadiazine. Sulfamethoxazole. Sulfasalazine
What is the Dihydrofolate Reductase Inhibitor used?
Trimethoprim (Proloprim, Trimpex). Use as combination product
When is Trimethoprim used singularly?
In treatment of bacterial prostatitis (due to favorable penetration)
What is Trimethoprim/Sulfamethoxazole?
Bactrim (combination product). Available as fixed 1:5 ratio to provide therapeutic concentrations
What is Pediazole?
Erythromycin/Sulfamethoxazole combination
What is the MOA of sulfonamides?
Inhibits Dihydropteroate synthetase from making Dihydropteroic acid
What is the MOA of trimethoprim?
Inhibits Dihydrofolate reductase from making Tetrahydrofolic acid
How does the development of resistance occur?
Alteration to dihydropteroate synthetase –> lower affinity for the sulfonamide (E. coli). Increased production of an essential metabolite or drug (i.e. increased PABA with N. gonorrheae, S. aureus)
What is the absorption of Sulfonamides like?
Well absorbed from GI tract. Exception: Sulfasalazine; designed for local effects in bowel. Co-administration w/ food affects rate not extent
What is the distribution of sulfonamides like?
Pleural, peritoneal, synovial - about 50-80% of plasma. CNS - about 25-30% for sulfamethoxazole
Which sulfonamide is designed for local effects in bowel?
Sulfasalazine
What is the metabolism of Sulfonamides like?
In liver to inactive metabolites (N4 acetylation and glucuronidation)
What is the elimination of Sulfonamides like?
Via kidneys (GF; some tubular secretion). Renal excretion (SMX –> 10-30%, TMP 50-75%). Dose adjust for CrCl < 30ml/min by increasing interval (t1/2 ~ 10 hrs increases to ~10hrs)
What is the distribution of Trimethoprim like?
Well distributed in kidney, lung, sputum; also, bile, saliva. Prostatic tissue levels > 2-3x plasma levels. CSF ~40% of plasma levels
What is the metabolism of Trimethoprim like?
4 oxide/hydroxyl derivatives (not biologically active)
What is the elimination of Trimethoprim like?
About 60-80% excreted in urine via tubular secretion. Also biliary excretion
What is the DOC for Pneumocystis carinii?
TMP/SMX
What is the spectrum of activity like for TMP/SMX?
S. aureus, S. pneumoniae, S. pyogenes. L. monocytogenes. E. coli. H. influenzae. Klebsiella. P. mirabilis. S. maltophila. Nocardia asteroides. Shigella. Salmonella. Also, Pneumocystis carinii (DOC) and Toxoplasma gondii
What are the ADRs associated with TMP/SMX?
GI (N/V/D, anorexia). CNS (HA, confusion, dizziness, seizures). Dermatologic (generalized skin eruption). Hematologic (dose-related). Agranulocytosis. Hemolytic anemia. Aplastic anemia
What severe dermatologic reaction can occur in patients on TMP/SMX?
Erythema multiforme, SJS, TEN. Do not re-challenge if rash occurs in patient
What is TMP/SMX like for pregnancy?
Category C. AVOID in first and last trimester (may increase fetal blood levels of unconjugated bilirubin –> kernicterus)