Dr.U.P.RathnakarMD.DIH.PGDHM

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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