Pharm Sulfa Drugs

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Single sulfona/mides

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Once single sulfas were the mainstay of chemotherapy but now less used in US because resistance is  common.

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Trimethoprimsulfamethoxazole is

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a synergistic combo that is very often used

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Pathogens are only susceptible

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if they require PABA to synthesize folic acid.

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All Sulfas are chemical congeners of

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PABA

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MECHANISM OF ACTION OF THE SULFONAMIDES
Most are
-Some inhibit indirectly by
-Single sulfas are bacteriostatic as they -Selective since

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competitive inhibitors of DHPS
-serving as an alternative substrate & exhausting the pteridine cofactor.
prevent new DNA synthesis.
-people use dietary folate & don’t require this path.

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The individual sulfonamides are rarely drugs of first choice with the exceptions cited below
-Has the shortest t½

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SULFISOXAZOLE
-Very soluble in water so unlikely to cause crystalluria
(5-6 hr)

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SULFISOXAZOLE
Ineffective for

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Sometimes used for Rx of uncomplicated UTIs because 10-20x concentrated in urine
Other drugs preferred for UTIs now (TMP-SMX, a quinolone, fosfomycin, ampicillin)
SMX acetyl + erythromycin for otitis media & upper resp. tract infections in children
CNS infections (low lipid sol)

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SULFADIAZINE (ORAL)
-Achieves highest concentration in
-limits its use
-Urine flow must be
-shoud use

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-CSF (30-80% of plasma)
Relatively rapidly absorbed & excreted T 1/2= 10hrs
Crystalluria
- brisk, alkaline
-Bicarbonate to reduces reabsorption

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SILVER SULFADIAZINE (SILVADENE): TOPICAL
-not useful

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Agent of choice for prevention of infections in 2nd & 3rd degree burn
Silver released is broad--
-spectrum agent x bacteria and fungi
Reduces colonization, encourages healing but
-against established deep infections
Used topically on burns with little toxicity but systemic absorption is poss.

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SULFASALAZINE (AZULFIDINE):
-Used for
-an active antiinflammatory inhibits cyclooxygenase)
-toxic

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POORLY ABSORBED

-Held in GI tract/bowel & excreted in feces
-inflammatory bowel disease (IBD), ulcerative colitis, regional enteritis
Sulfasalazine ▬▬▬► Sulfapyridine + 5-aminosalacylate
5AS (mesalamine) A comparable conc. of mesalamine in the colon cannot otherwise be obtained
-Can cause systemic toxic effects because of absorption of sulfapyridine

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SULFACETAMIDE

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Used for Rx of many sulfonamide-sensitive ophthalmic infections
An alternate for Rx of Chlamydia trachomatis
High concentrations (30%) aren’t irritating or allergenic & are of neutral pH
Readily penetrates ocular fluids, tissues

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DEVELOPMENT OF RESISTANCE TO SULFONAMIDES

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-Reduced sulfonamide uptake
-Alteration of drug binding site on dihydropteroate synthase can occur even during therapy
-Overproduction of PABA (competitive with drug at active site)

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PHARMACOKINETICS OF SULFONAMIDES

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Most are well absorbed orally (70-95%)
Most are widely distributed including into the CSF, fetus ( but sulfadiazine best for penetration of BBB)
Acetylation occurs in liver
inactivates &
decreases solubility
may be more readily excreted in the kidney
Elimination is by glomerular filtration with 10-20x concentration in urine

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URINARY TRACT TOXICITY

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-Crystals of sulfonamide & acetylated sulfonamide can cause renal damage
-Biggest problem is with sulfadiazine (Remember fluids, bicarbonate!)
-Must use reduced dosage (or cease use) if kidney function is impaired.

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hypersensitivity rxns

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Skin Rashes (2-3%) during 1st wk
Stevens-Johnson Syndrome
most serious rash (exfoliative)
most common with sulfadoxine (long-acting) but can occur with other sulfa drugs
Drug Fever (3%)
Photosensitivity

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MECHANISM OF TMP-SMX

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TMP [trimethoprim) competitively inhibits DHFR (dihydrofolate reductase)
SMX potentiates TMP by reducing [dihydroptoric ace that is availabe to compete with trimeth].
These combos are both bacteriocidal rather than bacteriostatic.

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MECHANISM OF TRIMETHOPRIM & PYRIMETHAMINE

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-Both competitively inhibit dihydrofolate reductase
-Both are superadditive with sulfas
-Both are bactericidal with sulfameth-oxazole
-Their selectivity is due to highly specific binding to bacterial/protozoal DHFR relative to the human DHFR (100,000/1).

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RX USES OF TMP-SMX - I

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-Treatment of choice or important alternate for 32 bacterial infections
-Gram-negative bacilli
-Actinomycetes
-Parasites
-Often used for oral Rx of uncomplicated UTIs
-Often used for Rx of otitis media in kids due to H. influenzae or Strep. pneumoniae
-Chronic bronchitis
-Shigellosis & Traveler's diarrhea, esp. in kids

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DRUG RESISTANCE TO TMP-SMX

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Much less common than against a single sulfonamide: only occurs via plasmid transfer.

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TOXICITY OF TMP-SMX

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AIDS patients: more frequent SEs including fever, rashes, leukopenia, & diarrhea.
-can produce anti-folate side effects lke anemia etc. can be prevented with folinic acid
-can cause cns effects like headache, depression, and hallucinations
-contra indicated in pt with renal malfunction

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pharmokinetics

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well absorbed orally with peak conc in 2 hr and t 1/2 = 11 hr; IV for serious infections.
-very lipid soluble and enters all body compartments.
-as with most sulfonamides, TMP crosses the placenta and achieves high urinary conc.