Title: SULFONAMIDES
1SULFONAMIDES
- 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.
2SULFONAMIDES
- Now largely superceded by antibiotics and
trimethoprim-sulfamethoxazole. - They continue to occupy a small place in therapy.
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4Wheel 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
5ANTIBACTERIAL ACTIVITY
- Bacteriostatic.
- Broad spectrum antibacterials
6FOLIC ACID BIOSYNTHESIS
DIHYDROPTERIDINE
2 ATP
PYROPHOSPHATE DERIVATIVE
Dihydropteroate Synthetase
2HN
COOH
DIHYDROPTEROIC ACID
Glutamic Acid
DIHYDROFOLIC ACID
7BLOOD
Body Fluids Tissues
CSF
8KERNICTERUS 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.
9KERNICTERUS IN THE NEWBORN
- Displacement of bilirubin from plasma protein
binding sites.
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11METABOLISM
H
SO2N
R
Acetylated sulfonamides-inactive, toxic, and
less soluble
12EXCRETION
- They are excreted in the urine partly as the
parent and partly as the metabolite. - Some sulfonamides are very insoluble in the acid
urine.
13EXCRETION
- Half life of the sulfonamides depends on renal
function. - Dosage should be modified or the sulfonamides
should not be used in renal failure.
14SULFONAMIDE PREPARATIONS
- Rapidly absorbed and rapidly eliminated
(prototype- sulfisoxazole). - Poorly absorbed sulfonamides (sulfasalazine).
- Topical sulfonamides (sulfacetamide, silver
sulfadiazine). - Long-acting sulfonamides (sulfadoxine)
15THERAPEUTIC USES
- Parasitic diseases (combined with other
antimicrobials)- malaria, toxoplasmosis, PCP.
16CONTRAINDICATIONS
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19 DRUG-DRUG INTERACTIONS
- Inhibit metabolism of some drugs.
- Displace certain drugs from plasma albumin.
20TRIMETHOPRIM-SULFAMETHOXAZOLE
21PABA
Pteridine
Dihydropteroate Synthetase
DIHYDROPTEROIC ACID
Dihydrofolate Synthetase
DIHYROFOLIC ACID
Dihydrofolate Reductase
TETRAHYDROFOLIC ACID
22COTRIMOXAZOLE
- Optimal ratio of the two drugs is 51 sulfa
trimethoprim.
23Synergism
24ADVANTAGES
- Expanded number of organisms inhibited.
- Bactericidal .
- Decreased resistance.
- Decreased toxicity.
25THERAPEUTIC USES
- Urinary tract infections.
- Bacterial respiratory tract infections.
- Pneumocystis jirovicii (carinii) pneumonia (PCP)
26THERAPEUTIC USES
27hcd2.bupa.co.uk/.../ html
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29PNEUMOCYSTIS PNEUMONIA (PCP)
30PNEUMOCYSTIS PNEUMONIA (PCP)
www.learningradiology.com/
31PNEUMOCYSTIS 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.
32PROPHYLAXIS
- 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.
33TREATMENT OF PCP
- Early therapy is essential as success of therapy
is related to severity of the disease at the time
of initiation of therapy.
34TMP-SMX
- Treatment of choice.
- Oral form used for mild-moderate cases or after
initial response to IV therapy and for
prophylaxis.
35TMP-SMX
- Excellent tissue penetration.
- Produces a rapid clinical response.
36DRUG INTERACTIONS
- Same as with sulfonamides
37SULFONAMIDE 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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40RESISTANCE
- Altered dihydropteroate synthetase.
- Decreased transport into the bacteria.
- Increased PABA synthesis.
- Cross-resistance among all sulfonamides.
41RESISTANCE
- Results from multiple mechansims.
- Altered dihydropteroate synthetase.
- Cross-resistance among all sulfonamides.
42PABA
Pteridine
Dihydropteroate Synthetase
DIHYDROPTEROIC ACID
Dihydrofolate Synthetase
DIHYROFOLIC ACID
Dihydrofolate Reductase
TETRAHYDROFOLIC ACID
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45ADVERSE EFFECTS
- Hypersensitivity reactions -common
- allergic rashes
- photosensitivity
- drug fever
- Stevens-Johnson syndrome
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53ADVERSE 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.
54CRYSTALLINE AGGREGATES, HEMATURIA, OBSTRUCTION
55ADVERSE EFFECTS
- Headache, nausea, vomiting and diarrhea.
- Hematological effects -anemia, agranulocytosis.
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57ADVERSE REACTIONS
- Dermatological reactions including skin rashes.
- GI (nausea and vomiting).
58HEMATOLOGICAL EFFECTS
- Leukopenia, thrombocytopenia and megaloblastosis.
- Most likely in patients with preexisting folate
deficiency or in patients taking prolonged
therapy.