Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSORDEPT. OF PHARMACOLOGYSSIMS & RC.

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They inhibit the folic acid synthesisp-Aminobenzoic acid (PABA)

Dihydrofolic acid

Tetrahydrofolic acid

Purines

DNA

Dihydropteroate synthase

Dihydrofolate reductase

Sulfonamides (compete with PABA)

Trimethoprim, pyrimethamine

generic name for derivatives of para-aminobenzene sulfonamide(sulfanilamide)

Analogues of PABABroad spectrumCompetitive inhibitors of dihydropteroatesynthase – needed for folic acid synthesis

Baceticidal in urine

Gerhard Domagk gets a Nobel for Medicine,1939.

Orally absorbable agentsShort acting agents T1/2-6-9 hrs-SULFACYTINE,SULFADIAZINE, SULFIZOXAZOLE and SULFAMETHIZOLEIntermediate acting-T1/2-10-12hrs-SULFAMETHOXAZOLE

SULFAMOXOLELong acting-SULFADOXINEOrally non-absorbable-SULFASALAZINE, BALASALAZINE,

OLASALAZINETopical agents- SILVER SULFADIAZINE, MAFENIDE,

SULFACITAMIDE

• The sulfonamides are bacteriostatic inhibitors of folic acidsynthesis.

• As antimetabolites of PABA, they are competitive inhibitors ofdihydropteroate synthase.

• The selective toxicity of sulfonamides results from the inabilityof mammalian cells to synthesize folic acid; they must usepreformed folic acid that is present in the diet.

Gram-positive and gram negative. Nocardia, chlamydia trachomatis, some protozoa.Invitro-Streptococcus pyogenes, Streptococcuspneumoniae, Haemophilus influenzae, Haemophilusducreyi, Nocardia, Actinomyces,

Absorbed from the stomach and small intestine→distributed widely to tissues and body fluids CNS,CSF, placenta, fetus

Hepatic metabolism → acetylated or glucuronidatedand excreted in the urine

Rate of excretion increases in alkaline urine.

Altered affinity of enzyme for drugDecreased permeability or active effluxNew pathway of folic acid synthesis

Production of a mutated dihydropteroate synthetase that hasreduced affinity for binding of sulfonamides. Resistance istransmitted among Gram-negative bacteria by plasmids.

Resistance in Staphylococcus aureus occurs as a result ofexcessive synthesis of PABA. Some resistant bacteria havereduced uptake of sulfonamides.

Bacteria which utilize exogenous folic acid are resistant tosulfonamides.

A rapidly increasing problem. However, it is lower withthe combination compared to agents used alone.

In a survey of children in Memphis Tennessee 29%isolates were penicillin resistant, and 25% of thesewere resistant to TMP-SMZ.

Emergence of TMP-SMZ resistant S.aureus andEnterobacteriaceae is a serious problem in AIDSpatients!

Mechanism of action:Sequential blocking of purine synthesis (synergism).Trimethoprim inhibits dihydrofolate reductase enzymeso inhibits tetrahydrofolic acid synthesisThe combination is bactericidal

PABA

DIHYDROPTEROIC ACID

DIHYROFOLIC ACID

TETRAHYDROFOLIC ACID

+ Pteridine

SULFONAMIDE

TRIMETHOPRIMDihydrofolate Reductase

Dihydrofolate Synthetase

DihydropteroateSynthetase

Synergism

Trimethoprim is a selective inhibitor of bacterialdihydrofolate reducate that prevents formation of theactive tetrahydro form of folic acid.It is a weak base and is trapped in acidic environments,reaching high concentrations in prostatic and vaginalfluids.A large fraction of trimethoprim is excreted unchanged inthe urine.The half-life of this drug is similar to that ofsulfamethoxazole (10—12 h).

A.TOPICAL1. Opthalmology- ocular infections

Sulfacetamide 10- 30%2. Ulcerative colitis

Sulfasalazine ( sulfapyridine+ 5- amino salicylate )-(orally, not absorbed )

3. Infected burnsMafenide acetate ( sulfamylon cream )Silver sulfadiazineEffective against p.aeruginosaLess effective against staphyllococci

B. ORALPneumocystis carinii pneumonia2. Nocardiosis3. Toxoplasmosis4. UTIs – limited cases5. RTIs ( H. influenza; S. pneumonia )6. Acute otitis media in children- L. cases7. Prostatitis8. Shigellosis9. Falciparum malaria ( sulfadoxine+ pyrimethamine )10. Rheumatoid arthritis-sulfasalazine11. Ulcerative colitis-sulfasalzine

2. Trimethoprim-sulfamethoxazole (TMP-SMX)is effective against P jiroveci pneumonia, shigellosis,

systemic salmonella infections, uti, prostatitis,respiratory pathogens pneumococcus, H.influenzae

andMoraxella catarrhalisTMP-SMX is also the drug of choice in nocardiosis, apossible backup drug for cholera, typhoid fever, andshigellosis, and has been used in the treatment ofinfections caused by methicillin-resistant staphylococciand Listeria monocytogenes.

Hypersensitivity reactionsN.V.D.Crystalluria, hematuria, renal obstruction.Allergic nephritisHaemolytic anaemia, aplastic anaemia,thrombocytopenia.Megaloblastic anemia , leukopenia & granulocytopenia( can be prevented by administration of folic acid )Kernicterus in new born

TrimethoprimTrimethoprim may cause the predictable adverseeffects of an antifolate drug, including megaloblasticanemia, leukopenia, and granulocytopenia.These effects are usually ameliorated by supplementaryfolinic acid.The combination of TMP-SMX may cause any of theadverse effects associated with the sulfonamides.AIDS patients given-SMX have a high incidence ofadverse effects, including fever, rashes, leukopenia

Competition with warfarin, hypoglycemic drugssulfonylureas, phenytoin and methoteraxate forplasma protein binding transiently increases theplasma levels of these drugsSulfonamides can displace bilirubin from plasmaproteins, with the risk of kernicterus in the neonate ifuse in the third trimester of pregnancy