SULFONAMIDES

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SULFONAMIDES

• Recognized since 1932.
• In clinical usage since 1935.
• First compounds found to be effective
  antibacterial agents in safe dose ranges.
• Mainstay of therapy before penicillins.

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SULFONAMIDES

• Now largely superceded by antibiotics and
  trimethoprim-sulfamethoxazole.
• They continue to occupy a small place in therapy.

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Wheel of Bugs
Gram-negative
H. influenzae
Neissseria spp
E. Coli (coliforms)
Bacteroides spp
P. aeruginosa
Anaerobic
Clostridium spp
S. aureus
Streptococcus spp
Enterococcus spp
Gram-positive
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ANTIBACTERIAL ACTIVITY

• Bacteriostatic.
• Broad spectrum antibacterials

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FOLIC ACID BIOSYNTHESIS
DIHYDROPTERIDINE
2 ATP
PYROPHOSPHATE DERIVATIVE
Dihydropteroate Synthetase
2HN
COOH
DIHYDROPTEROIC ACID
Glutamic Acid
DIHYDROFOLIC ACID
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BLOOD
Body Fluids Tissues
CSF
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KERNICTERUS IN THE NEWBORN

• Results from displacement of bilirubin from
  plasma protein binding sites.
• Free bilirubin goes into the CNS.
• High concentrations in the brain cause
  kernicterus in the newborn.

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KERNICTERUS IN THE NEWBORN

• Displacement of bilirubin from plasma protein
  binding sites.

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METABOLISM
H
SO2N
R
Acetylated sulfonamides-inactive, toxic, and
less soluble
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EXCRETION

• They are excreted in the urine partly as the
  parent and partly as the metabolite.
• Some sulfonamides are very insoluble in the acid
  urine.

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EXCRETION

• Half life of the sulfonamides depends on renal
  function.
• Dosage should be modified or the sulfonamides
  should not be used in renal failure.

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SULFONAMIDE PREPARATIONS

• Rapidly absorbed and rapidly eliminated
  (prototype- sulfisoxazole).
• Poorly absorbed sulfonamides (sulfasalazine).
• Topical sulfonamides (sulfacetamide, silver
  sulfadiazine).
• Long-acting sulfonamides (sulfadoxine)

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THERAPEUTIC USES

• Parasitic diseases (combined with other
  antimicrobials)- malaria, toxoplasmosis, PCP.

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CONTRAINDICATIONS
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DRUG-DRUG INTERACTIONS

• Inhibit metabolism of some drugs.
• Displace certain drugs from plasma albumin.

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TRIMETHOPRIM-SULFAMETHOXAZOLE
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PABA
Pteridine
Dihydropteroate Synthetase
DIHYDROPTEROIC ACID
Dihydrofolate Synthetase
DIHYROFOLIC ACID
Dihydrofolate Reductase
TETRAHYDROFOLIC ACID
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COTRIMOXAZOLE

• Optimal ratio of the two drugs is 51 sulfa
  trimethoprim.

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Synergism
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ADVANTAGES

• Expanded number of organisms inhibited.
• Bactericidal .
• Decreased resistance.
• Decreased toxicity.

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THERAPEUTIC USES

• Urinary tract infections.
• Bacterial respiratory tract infections.
• Pneumocystis jirovicii (carinii) pneumonia (PCP)

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THERAPEUTIC USES
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hcd2.bupa.co.uk/.../ html
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PNEUMOCYSTIS PNEUMONIA (PCP)
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PNEUMOCYSTIS PNEUMONIA (PCP)
www.learningradiology.com/
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PNEUMOCYSTIS PNEUMONIA (PCP)

• The most common opportunistic infection in
  advanced AIDS (80 of AIDS patients have at least
  one episode).
• Now considered a fungus (P.jurovecii).
• Multiple infections are often present
  simultaneously with the PCP.

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PROPHYLAXIS

• Routine prophylaxis has been successful in
  improving survival.
• PCP prophylaxis is indicated if the patient has a
  CD4 T lymphocyte count lower than 200 cells/mm3,
  or has oral candidiasis regardless of the CD4
  count.

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TREATMENT OF PCP

• Early therapy is essential as success of therapy
  is related to severity of the disease at the time
  of initiation of therapy.

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TMP-SMX

• Treatment of choice.
• Oral form used for mild-moderate cases or after
  initial response to IV therapy and for
  prophylaxis.

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TMP-SMX

• Excellent tissue penetration.
• Produces a rapid clinical response.

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DRUG INTERACTIONS

• Same as with sulfonamides

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SULFONAMIDE SUMMARY
SULFONAMIDE THERAPEUTIC USE ADVERSE REACTIONS
Sulfisoxazole Sulf-acetamide Silver sulfadiazine UTIs Opthalmic Infs. Burn therapy GI, Hypersensitivity reactions, crystalluria
TMPSMX PCP, Respiratory Infs., UTIs Hypersensitivity reactions, Hematologic effects
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RESISTANCE

• Altered dihydropteroate synthetase.
• Decreased transport into the bacteria.
• Increased PABA synthesis.
• Cross-resistance among all sulfonamides.

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RESISTANCE

• Results from multiple mechansims.
• Altered dihydropteroate synthetase.
• Cross-resistance among all sulfonamides.

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PABA
Pteridine
Dihydropteroate Synthetase
DIHYDROPTEROIC ACID
Dihydrofolate Synthetase
DIHYROFOLIC ACID
Dihydrofolate Reductase
TETRAHYDROFOLIC ACID
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ADVERSE EFFECTS

• Hypersensitivity reactions -common
• allergic rashes
• photosensitivity
• drug fever
• Stevens-Johnson syndrome

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ADVERSE EFFECTS

• Urinary tract disturbances
• -formation of crystalline aggregates in urinary
  tract, hematuria and obstruction.
• DRINK ADEQUATE FLUIDS.
• Less likely with the newer more soluble
  sulfonamides.

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CRYSTALLINE AGGREGATES, HEMATURIA, OBSTRUCTION
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ADVERSE EFFECTS

• Headache, nausea, vomiting and diarrhea.
• Hematological effects -anemia, agranulocytosis.

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ADVERSE REACTIONS

• Dermatological reactions including skin rashes.
• GI (nausea and vomiting).

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HEMATOLOGICAL EFFECTS

• Leukopenia, thrombocytopenia and megaloblastosis.
• Most likely in patients with preexisting folate
  deficiency or in patients taking prolonged
  therapy.