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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

What are the oral sulfonamides

Sulfisoxazole, sulfamethoxazole, sulfadiazine

Sulfisoxazole indications

High water solubility; low renal toxicity; low incidence of crystalluria
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

What are the non-oral sulfonamides

Sulfasalazine; Sulfacetamide; Silver sulfadiazine

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

Trimethoprim mechanism

Inhibits dihydrofolate reductase; analog of dihydrofolate

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

Resistance to trimethoprim

Altered target site (dihydrofolate reductase) in GN bacteria

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

Spectrum of SMX-TMP

Broader than sulfonamides

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

Drug interactions with SMX-TMP

Warfarin: increased prothrombin time
May inhibit phentoin
SMX may increase methotrexate by displacing from albumin

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