pharmacology of sulfonamides
DESCRIPTION
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Dr.U.P.RathnakarMD.DIH.PGDHM
www.scribd.com
ChemotherapyFolic Acid Antagonists [Sulfa & diaminopyrimidines]
And
Quinolones,
July 2010
Folic AcidAntagonists
Folate synthetase inhibitors[Sulfonamides]
Folate Reductase inhibitors[Diaminopyrimidines]
Dual inhibitors [Sequential blockade]
Classification of sulfonamides
1)Absorbed and excreted rapidly- eg.sulfadiazine
2)Absorbed very poorly when administered orally and hence are active in the bowel lumen, such as sulfasalazine;
3)Used mainly topically, such as sulfacetamide, mafenide, and silver sulfadiazine;
4)Absorbed rapidly but excreted slowly, sulfadoxine
Sulfonamides and PABA
SulfonamidesMOA
Dihydropteroic acid
Sequential blockade
SulfonamidesMOA………..
• Sulfonamide may be incorporated as folate• Only bacteria which synthesize FA are affected• Pus is rich in purine and thymidines• Sulfonamides ineffective in the presence of pus• Humans, -dietary folic acid, are not affected, • Bacteria that obtain folates from their environment
are naturally resistant to these drugs.
Resistance
• Acquired bacterial resistance to the sulfa drugs can arise Altered dihydropteroate synthetase, Decreased cellular permeability to sulfa drugs, or Enhanced production of the natural substrate, PABA.• Organisms resistant to one member of this drug family are resistant to
all.
Pharmacokinetics
• Absorption• Most -well absorbed via the small intestine• Topical –Sensitization
Pharmacokinetics
• Distribution
• Bound to serum albumin • Cross BBB even in the absence of
inflammation. • Pass the placental barrier and
enter fetal tissues.
Pharmacokinetics
• Metabolism: • Acetylated, in the liver.
• Excretion: • Products ppt in neutral or acidic media-Crystalluria• Eliminated by glomerular filtration. Therefore,
depressed kidney function causes accumulation of both the parent compounds and their metabolites.
• Also eliminated in breast milk.
Adverse effects
S-J-Syndrome
G-6PD defeciency
Displaces Bilurubin from binding sites
Kidney damage
DI and CI
• Displaces from binding sitesTolbutamideWarfarin Drug toxicityMethotrexate• Kernicterus-avoided in newborns and infants less
than 2 months and pregnant women. • Sulfonamides condense with formaldehyde, they
should not be given to patients receiving methenamine for UTIs
Antibacterial spectrum
• Bacteriostatic [Host defenses essential for eradication]
• Selected enterobacteria and Nocardia,• Almost never used alone an AMA in the treatment• Mostly used in combination• Or as a topical agent in prophylaxis
Sulfonamides uses
• Pneumocystis carinii-• Sulfamethaxozole Combined with trimethoprim (co-trimoxazole)• Toxoplasmosis-• Sulfadiazine +pyrimethamine • Drug-resistant malaria. • Sulfadoxine+pyrimethamine• Inflammatory bowel disease: • Sulfasalazine (sulfapyridine+ 5 ASA)• Rheumatoid arthritis: • Sulfasalazine (sulfapyridine+ 5 ASA)• And topical uses• [And all uses of co-trimoxazole]
Sulfonamides uses….
• TopicalPrevent infection- burns -Silver sulfadiazineFor eye infections -Sulfacetamide• Respiratory infections: use now confined to a
few special problems (e.g. infection with Nocardia).
SULFONAMIDES FOR TOPICAL USE
Sulfacetamide• Employed extensively for ophthalmic infections.
WHY?????? WHY?????? WHY??????• Its aqueous solubility is ~90 times that of sulfadiazine. • Very high aqueous concentrations are not irritating to the
eye • Penetrates readily into ocular fluids and tissues.• Sensitivity reactions to sulfacetamide are rare, but it
should not be used in patients with known sulfonamide hypersensitivity.
• Use: Ocular infections-Chlamydia
SULFONAMIDES FOR TOPICAL USE
Silver Sulfadiazine
• Inhibits the growth of nearly all pathogenic bacteria and fungi, including some species resistant to sulfonamides.
• Used topically to reduce microbial colonization and the incidence of infections in burn patients-Prophylactic-Pseudomonas
• It is not used to treat an established deep infection. • Silver is released slowly in concentrations that are selectively toxic
to microorganisms. • The plasma concentration of sulfadiazine may approach
therapeutic levels if a large surface area is involved.• Adverse reactions—burning, rash, and itching—are infrequent.
• Agents of choice for the prevention of burn infection.
SULFONAMIDES FOR TOPICAL USEMafenide
• Not typical sulfa[CH2 bet benzene & amino]• Used topically to prevent infections in burns-
Pseudomonas• Active in pus• Intense pain at sites of application, allergic
reactions, loss of fluid by evaporation from the burn surface,
• Metabolic acidosis secondary to inhibition of carbonic anhydrase.
LONG-ACTING SULFONAMIDES
• Sulfadoxine long t1/2 (7–9 days). • 500 mg sulfadoxine + 25 mg
pyrimethamine -prophylaxis and treatment of -resistant strains of Plasmodium falciparum
SULFONAMIDES FOR PROPHYLAXIS
• Prophylaxis of rheumatic fever -in patients who are hypersensitive to penicillin.
• Untoward responses usually occur during the first 8 weeks;
• Serious reactions after this time are rare. • W.B.C should be checked weekly during the
first 8 week• NOT ROUTINELY USED
Inhibitors of folate reduction
Pyrimethamine
Co-trimoxazole[Sequential blockade]
Trimethoprim
• Folate reductase inhibitor• Bacteriostatic• Rarely used alone• When sulfa CI• Prophylaxis-UTI• Combined with sulfamethoxazole
Pyrimethamine
• Antiprotozoal [Malaria and Toxoplasma]• MOA• Combined withSulfadoxine-Malaria-Sometimes a ‘Sulfone’Sulfadiazine-T.Gondii
Co-Trimoxazole
Co-TrimoxazoleFDC
Advantages
• Compliance• Synergism• Benefits add up• Counteracts ADE
Disadvantages
• Cost• CI for one component
Cotrimoxazole
• FDC• Combination of trimethoprim with
sulfamethoxazole[1:5]• Trimethoprim alone is also used• Spectrum of Trimethoprim –same as sulfa• Synergistic combination
Co-trimoxazoleMOA
Dihydropteroic acid
Sequential blockade
Why mammalian cells not affected by Co-trimoxole?
• Trimethoprim is a highly selective
inhibitor of dihydrofolate reductase of lower organisms;
• ~100,000 times more drug is required to
inhibit human reductase than the bacterial
Relative selectivity
PK
• The pharmacokinetic profiles of sulfamethoxazole and trimethoprim are closely but not perfectly matched
• TMP-absorbed faster• Trimethoprim greater aVD[More lipid soluble]
• Ideal ratio of Sulfa:Trimethoprim=20:1• FDC=5:1 [800mg:160mg]
Pharmacokinetics
• Trimethoprim concentrates in acidic prostatic and vaginal fluids-use of infections at these sites.
• Both parent drugs and their metabolites are excreted in the urine.
• Usual route-Oral
Co-TrimoxozoleSpectrum and Therapeutic applications
Adverse reactions to cotrimoxazole
Megaloblastic anemia,leukopenia, and thrombocytopeniaReversed by Folinic acid,
Margin of safety is lower if Patient is folate deficient
Preparations
• TabletsSulfamethoxazole:Trimethoprim=400mg:80mgSulfamethoxazole:Trimethoprim=800mg:160mg
Dose: 1-2 tablets[DS] BIDPneumocystis: Very high doses-5-10 tablets /day
Dose
• Uncomplicated Acute UTI: Single dose -2DS tab,
• Three days therapy preferred
• Chronic UTI- Small dose- 3-10 days
• Pneumocystis: Very high doses-5-10 tablets /day