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SULFONAMIDES

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ADVERSE EFFECTS Hypersensitivity reactions -common allergic rashes ... (sulfadoxine) THERAPEUTIC USES Parasitic diseases (combined with other antimicrobials ... – PowerPoint PPT presentation

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Title: SULFONAMIDES


1
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.

2
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  • Now largely superceded by antibiotics and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
5
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
7
BLOOD
Body Fluids Tissues
CSF
8
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.

13
EXCRETION
  • Half life of the sulfonamides depends on renal
    function.
  • Dosage should be modified or the sulfonamides
    should not be used in renal failure.

14
SULFONAMIDE PREPARATIONS
  • Rapidly absorbed and rapidly eliminated
    (prototype- sulfisoxazole).
  • Poorly absorbed sulfonamides (sulfasalazine).
  • Topical sulfonamides (sulfacetamide, silver
    sulfadiazine).
  • Long-acting sulfonamides (sulfadoxine)

15
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.

20
TRIMETHOPRIM-SULFAMETHOXAZOLE
21
PABA
Pteridine
Dihydropteroate Synthetase
DIHYDROPTEROIC ACID
Dihydrofolate Synthetase
DIHYROFOLIC ACID
Dihydrofolate Reductase
TETRAHYDROFOLIC ACID
22
COTRIMOXAZOLE
  • Optimal ratio of the two drugs is 51 sulfa
    trimethoprim.

23
Synergism
24
ADVANTAGES
  • Expanded number of organisms inhibited.
  • Bactericidal .
  • Decreased resistance.
  • Decreased toxicity.

25
THERAPEUTIC USES
  • Urinary tract infections.
  • Bacterial respiratory tract infections.
  • Pneumocystis jirovicii (carinii) pneumonia (PCP)

26
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/
31
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.

32
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.

33
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.

34
TMP-SMX
  • Treatment of choice.
  • Oral form used for mild-moderate cases or after
    initial response to IV therapy and for
    prophylaxis.

35
TMP-SMX
  • Excellent tissue penetration.
  • Produces a rapid clinical response.

36
DRUG INTERACTIONS
  • Same as with sulfonamides

37
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.

41
RESISTANCE
  • Results from multiple mechansims.
  • Altered dihydropteroate synthetase.
  • Cross-resistance among all sulfonamides.

42
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.

54
CRYSTALLINE AGGREGATES, HEMATURIA, OBSTRUCTION
55
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).

58
HEMATOLOGICAL EFFECTS
  • Leukopenia, thrombocytopenia and megaloblastosis.
  • Most likely in patients with preexisting folate
    deficiency or in patients taking prolonged
    therapy.
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