Chemotherapy

Folic Acid Antagonists [Sulfa & diaminopyrimidines] And Quinolones, July 2010

Folic Acid Antagonists

Folate synthetase inhibitors [Sulfonamides]

Folate Reductase inhibitors [Diaminopyrimidines] Dual inhibitors [Sequential blockade]

Classification of sulfonamides
1) Absorbed and excreted rapidlyeg.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

Sulfonamides MOA

Dihydropteroic acid
Sequential blockade

Sulfonamides MOA..
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
Kidney damage

S-J-Syndrome

G-6PD defeciency

Displaces Bilurubin from binding sites

DI and CI
Displaces from binding sites  Tolbutamide  Warfarin Drug toxicity  Methotrexate 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 cariniiSulfamethaxozole Combined with trimethoprim (co-trimoxazole) ToxoplasmosisSulfadiazine +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.
Topical Prevent infection- burns -Silver sulfadiazine For 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 reactionsburning, rash, and itchingare infrequent. Agents of choice for the prevention of burn infection

SULFONAMIDES FOR TOPICAL USE Mafenide

Not typical sulfa[CH2 bet benzene & amino] Used topically to prevent infections in burnsPseudomonas 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 (79 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

Co-trimoxazole [Sequential blockade]

Pyrimethamine

Trimethoprim
Folate reductase inhibitor Bacteriostatic Rarely used alone When sulfa CI Prophylaxis-UTI Combined with sulfamethoxazole

Pyrimethamine
Antiprotozoal [Malaria and Toxoplasma] MOA Combined with  Sulfadoxine-Malaria-Sometimes a Sulfone  Sulfadiazine-T.Gondii

Co-Trimoxazole

Co-Trimoxazole FDC
Advantages Disadvantages

Compliance Synergism Benefits add up Counteracts ADE

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-trimoxazole MOA

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-Trimoxozole Spectrum and Therapeutic applications

Adverse reactions to cotrimoxazole

Margin of safety is lower if Patient is folate deficient

Megaloblastic anemia, leukopenia, and thrombocytopenia Reversed by Folinic acid,

Preparations
Tablets  Sulfamethoxazole:Trimethoprim=400mg:80mg  Sulfamethoxazole:Trimethoprim=800mg:160mg

 Dose: 1-2 tablets[DS] BID  Pneumocystis: 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