How do sulfonamides work?
They are synthetic analogs of PABA that inhibit folate synthesis (folate antagonists)
They are antimetabolites that inhibit folate and folinate (tetrahydrofolate-trimethoprim);
We get folate from our diet because we're better than bacteria
Spectrum of sulfonamides and trimethoprim
Bacteriostatic against many GP and GN organisms
GPs: Strep pyogenes, Strep pneumoniae, Bacillus anthracis, actinomyces, Nocaridia
GNs: Proteus mirabilis, E. coli, Klebsiella, enterobacter, H. influenzae, H. ducreyi (chancroid)
Salmonella, shigella, calymmatobacterium (granuloma inguinale)
Typical sulfonamide indications
UTI, Toxoplasmosis, Malaria, Inflammatory Bowel Disease, Burn sepsis, inclusion conjunctivitis, trachoma, pneumonia, nocarditis
How long do oral sulfonamides work?
Short acting: 6-9hr t1/2 sulfisoxazole
Intermediate acting: 10-12hr t1/2 sulfamethoxazole and sulfadiazine
Sulfisoxazole indications
High water solubility; low renal toxicity; low incidence of crystalluria
UTIs
No longer a single agent
Sulfisoxazole acetyl + erythromycin (ESP) = drug for H. influenzae otitis media in children
Selfamethoxazole indications
Slower absorption and excretion than sulfisoxazole; Crystalluria common; no longer single agnet
Sulfamethoxazole + Trimethoprim (Bactrim, Septra) synergystic actions; called "SMX TMP"
Sulfadiazine indication
Accumulates in CSF; crustalluria common
Sulfadiazine + Pyrimethamine = synergistic compound for toxoplasmosis; give folinate suplement to avoid myelosuppression
Sulfasalazine (Azulfidine) indications
UC, granulomatous colitis, regional enteritis; poorly absorbed; degraded to sulfapyridine (activedrug) and 5-aminosalicylate (antinflammatory), which makes it good for IBD
Toxicity = hemolysis, agranulocytosis, rash
Sulfacetamide (Bleph-10, Ovace) indications
Topically for ocular infections
Topically for acne and susceptible bacterial skin infections
Silver sulfadiazine (Silvadene) indications
Topically for preventing bun infections; adverse rxn includes allergy, burning, itching
Resistance to sulfonamides
Due to plasmid transfer or random mutations
Cross-resistance among sulfonamides
Four mechanisms:
Altered dihydropteroate synthetase
Decreased permeability
Enzymatic inactivation
Increased synthesis of PABA (unique)
Administration, absorption, and distribution of sulfonamides
Most excellent oral bioavailability; Sulfasalizine not orally absorbed (used for chronic IBD); Silver sulfadiazine cream topically;
Well distributed in fluids; concentrate in urine; traverse placenta; enter breast milk; highly bound to albumin
Metabolism and excretion of sulfonamide
Acetylated in liver to inactive metabolites; able to precipitate causing crustalluria or kidney stones; sulfasalazine degraded to sulfapyridine and 5-aminosalycilate by intestinal microbes;
Parent drug and metabolites excreted by glomerular filtration; accumulate with decreased kidney function
Adverse effects to sulfonamides
Crystalluria and nephrotoxicity; prevent with lots of water
Hypersensitivity: drug fever, dermatitis, skin rash, Stevens-Johnson syndrome; cross-sensitivity to related drugs
Hemolytic anemia in pt. with G6P-DH deficiency
Kernicterus: newborns displace billirubin leading to it in CNS
Potentates certain drugs by displacing from albumin
What drugs are related to sulfonamides? Why do I care?
Acetazolamide, thiazide, furosemide, bumetanide, diazoxide, sulfonylurea hypoglycemic agents;
They can cause cross-allergenicity
What drugs are potentiated by sulfonamides
Tolbutamide, warfarin, bishydroxycoumarin, methotrexate
Displaced from albumin
Contraindications to sulfonamides
Newborns and infants less than 2 months old; pregnant females at term because of risk of kernicterus
How is trimethoprim formulated
Alone: Polytrim, Primsol
With sulfamethoxazole to give SMX-TMP "cotrimoxazole" (Bactrim, Septra); Also available with polymixin B for external eye infections
Spectrum and indications for trimethoprim
Similar to sulfamethoxazole, though 20 to 50X more potent; indic for UTI, bacterial prostatitis
Staph aureus, Staph epidermidis
Viridans Strep, Strep pneumoniae
H. influenzae
Pseudomonas aeruginosa
Pharmacokinetics of trimethoprim
Similar to sulfamethoxazole; higher levels in prostatic and vaginal fluids; demethylated in liver; drug and metabolite excreted in urine
Adverse effects of trimethoprim
Are the consequences of folate deficiency:
Megaloblastic anemia, Leukopenia, Granulocytopenia;
Can avoid with concurrent administration of folinic acid (leucovorin)
Mechanism of SMX-TMP
Synergistic: Sulfamethoxazole reduces production of folate from PABA;
Trimethoprim inhibits conversion of dihydrofolate to tetrahydrofolate (folinate)
Inhibit two sequential steps in folate synthesis
Indications for SMX-TMP
RTI (Strep pneumoniae, H. influenzae, M. catarrhalis)
1st line: otitis, sinusitis, pneumonia by H. influenzae and M. catarrhalis
Gastroenteritis (Salmonella, Shigella)
First line: enterobacter
UTI (E.coli, Proteus, Enterobacter, Klebsiella)
Prostate infection
Lymphogranuloma venerum by Chlamydia trachomatis
Brucellosis, Cholera, Calymmatobacterium granuloma inguinale, Legionella pneumophilia, Listeria (meningitis and bacteremia)
first line: Chancroid by H. ducreyi
DOC: nocardia pulmonary lesions and pneumocystis jiroveci pneumonia
Resistance to SMX-TMP
Less common that either alone; requires resistance to both;
S. pneumoniae most commonly resistant
Pharmacokinetics of SMX-TMP
Orally; can be I.V. with Pneumocystis jiroveci pneumonia or those unable to take orally; well distributed (both); trimethoprim in prostatic and vaginal fluids; both parent compounds and metabolites excreted in urine
Adverse effects to SMX-TMP
Derm: Hypersensitivity; may be severe in elderly
GI: Nausea, vomiting, stomatitis, glossitis
Heme: Hemolytic anemia in G6P-DH deficient pt. (SMX); Megaloblastic anemia and leukopenia by TMP but reversed by folinic acid supplement
HIV pt: Often hypersensitive when infected with Pneumocystis jiroveci, exhibit GI Sx and pancytopenia