sulfonamides(1)
DESCRIPTION
TRANSCRIPT
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.
SULFONAMIDES
Now largely superceded by antibiotics and trimethoprim-sulfamethoxazole.
They continue to occupy a small place in therapy.
Wheel of BugsGram-negative
Gram-positive
Ana
erob
ic
P. aeruginosa
H. influenzaeNeissseria spp
E. Coli(coliforms)
S. aureus
Streptococcus spp
Bacteroides spp
Clostridium spp
Enterococcus spp
2HN COOH
DIHYDROPTERIDINE
PYROPHOSPHATE DERIVATIVE
DIHYDROPTEROIC ACID
DIHYDROFOLIC ACID
FOLIC ACID BIOSYNTHESIS
Glutamic Acid
2 ATP
2HN SO2NH2
Dihydropteroate
Synthetase
BLOOD
Protein Bound
Metabolites
Free
Oral
X Topical Parenteral
CSFBody Fluids & Tissues
Kidney
Other-Sweat, Saliva, Prostatic fluid, Stool
KERNICTERUS IN THE NEWBORN Displacement of bilirubin from
plasma protein binding sites.
SO2N
METABOLISM
Acetylated sulfonamides-inactive, toxic, and less soluble
H
RNC3HC
O
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.
EXCRETION
Half life of the sulfonamides depends on renal function.
Dosage should be modified or the sulfonamides should not be used in renal failure.
SULFONAMIDE PREPARATIONS
Rapidly absorbed and rapidly eliminated (prototype- sulfisoxazole).
Poorly absorbed sulfonamides (sulfasalazine).
Topical sulfonamides (sulfacetamide, silver sulfadiazine).
Long-acting sulfonamides (sulfadoxine)
CONTRAINDICATIONS
DRUG-DRUG INTERACTIONS
Inhibit metabolism of some drugs.
Displace certain drugs from plasma albumin.
TRIMETHOPRIM-SULFAMETHOXAZOLE
2HN CH2
OCH3
OCH3
OCH3
80 mg TRIMETHOPRIM
O
2HN SO2NH
N CH3
400 mg SULFAMETHOXAZOLE
COTRIMOXAZOLE
Optimal ratio of the two drugs is 5:1 sulfa :trimethoprim.
Synergism
ADVANTAGES
Expanded number of organisms inhibited.
Bactericidal .
Decreased resistance.
Decreased toxicity.
THERAPEUTIC USES
PNEUMOCYSTIS PNEUMONIA (PCP)
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.
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.
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.
TMP-SMX
Treatment of choice.
Oral form used for mild-moderate cases or after initial response to IV therapy and for prophylaxis.
TMP-SMX
Excellent tissue penetration.
Produces a rapid clinical response.
DRUG INTERACTIONS
Same as with sulfonamides
other sulphonamides
Sulphonylureas (anti-diabetic agents)
Carbutamide
Acetohexamide
Chlorpropamide
Tolbutamide
Tolazamide
Glipizide
Gliclazide
Glibenclamide (glyburide)
Glibornuride
Gliquidone
Glisoxepide
Glyclopyramide
Glimepiride
Anticonvulsants Acetazolamide Ethoxzolamide Sultiame Zonisamide Dermatologicals Mafenide
Other Celecoxib (COX-2 inhibitor) Darunavir (Protease Inhibitor) Fosamprenavir (Protease Inhibitor) Tipranavir (Protease Inhibitor) Probenecid (PBN) Sotalol (Beta-blocker) Sulfasalazine (SSZ) Sumatriptan (SMT)
Diuretics Acetazolamide Bumetanide Chlorthalidone Clopamide Dorzolamide Furosemide Hydrochlorothiazide (HCT, HCTZ, HZT) Indapamide Mefruside Metolazone Xipamide
0
2
4
6
1 2 3 4 5 6 7 8 9Time of incubation (hrs)
Via
ble
org
anis
ms
control
sulfonamide
RESISTANCE
Results from multiple mechansims.
Altered dihydropteroate synthetase.
Cross-resistance among all sulfonamides.
PABA
DIHYDROPTEROIC ACID
DIHYROFOLIC ACID
TETRAHYDROFOLIC ACID
+ Pteridine
SULFONAMIDE
TRIMETHOPRIMDihydrofolate Reductase
Dihydrofolate Synthetase
Dihydropteroate Synthetase
ADVERSE EFFECTS
Hypersensitivity reactions -common allergic rashes photosensitivity drug fever Stevens-Johnson syndrome
hypersensitivity reaction to sulfa drugs are rash and hives. However, there are several life-threatening manifestations of hypersensitivity to sulfa drugs, including Stevens–Johnson syndrome, toxic epidermal necrolysis, agranulocytosis, hemolytic anemia, thrombocytopenia, and fulminant hepatic necrosis, among others.
CRYSTALLINE AGGREGATES, HEMATURIA, OBSTRUCTION
ADVERSE EFFECTS
Headache, nausea, vomiting and diarrhea.
Hematological effects -anemia, agranulocytosis.
ADVERSE REACTIONS
Dermatological reactions including skin rashes.
GI (nausea and vomiting).
