4. Sulphonamides

They were the first AMAs effective against pyogenic bacterial infections

1. Sulfonamides BY Jagir R. Patel Assistant Professor

2. Sulfonamides They were the first AMAs effective against pyogenic bacterial infections Due to development of resistance the and availability of more safer drugs their current utility is limited Except used in combination with Trimethoprim as Cotrimoxazole or pyrimethamine

3. Classification Short acting : Sulfadiazine, sulfacetamide, Sulfadimidine, S ulfisoxazole Intermediate acting : Sulphamethaxazole, sulfadoxine, sulfamoxole Long acting: sulphamthoxypyridazine , sulfadimethoxine, sulphamthoxypyrazine Special purpose : sulfacetamide, sulfadiazine, sulfasalazine

4. Anti Bacterial spectrum The sulfonamides are broad-spectrum antimicrobial s effective against gram-positive and some gram negative organisms of the Enterobacteriaceae. G ood activity against Escherichia coli, M oderate activity against Proteus mirabilis and Enterobacter spp . Poor activity against in Proteus and Klebsiella spp. N o I nhibitory activity against Pseudomonas aeruginosa and Serratia spp. They are also effective against Chlamydia spp .,

5. Folate synthesis F olate (“dihydrofolate”, “FH2”, “folic acid”, “vitamin B9”) is a cofactor ( methyl-group donor ) in the synthesis of purines and pyrimidines used for DNA and RNA synthesis H umans are not able to synthesize folate themselves , and exclusively rely on absorption of folate from the GI tract Mammalian cells in contrast use folate receptors and folate carries in the plasma membrane to scavenge the intact vitamin which is fundamental difference b/w pathogen and mammalian cell which makes DHFR inhibitors an ideal target F olate is only active in the tetrahydrofolate (FH4) form , thus both humans and bacteria need to activate folate to utilize it synthesis and activation of folate is done in 3 steps

6. Mechanism of action

7. Cont… S ulfonamides are synthetic structural analogues of PABA and act by displacing PABA from its binding site on dihydropteroate synthetase, thus inhibiting bacterial synthesis of folate this leads to an inability of the bacteria to synthesize DNA and RNA and following inability for them to divide however , bacteria are still able to survive without dividing, thus sulfonamides are only bacteriostatic S ince humans do not synthesize their own folate, sulfonamides leave DNA and RNA synthesis in human cells untouched

8. R esistance B acteria may develop resistance to sulfonamides by plasmid transfer and/or chromosomal mutations - this resistance may occur by 3 separate mechanisms MECHANISM DESCRIPTION DECREASED UPTAKE Due to decreased permeability of the bacterial cell envelope to sulfonamides DECREASED AFFINITY Due to structural alterations of dihydropteroate synthetase (folate synthase enzymes) I NCREASED DISPLACEMENT Due to increased synthesis of PABA and adopt alternative pathway for folate synthesis

9. Sulphadiazine prototype SULFADIAZINE, sulphadoxine, sulfomethaxazole General information A dministered orally and/or IV , may cross the blood-brain barrier may cross the placental barrier Medical uses T reatment of cystitis due to escherichia and/or proteus Infection Treatment of chlamydia T rachoma lymphogranuloma due to chlamydia infection

10. Pharmacokinetics Absorption : completely absorbed from G.I.T. Plasma protein binding about 10 to 95% more the protein binding longer the action Distribution : wildly distributed plasma, CSF, and placenta Excretion : they are mainly excreted by the kidney through glomerular filtration Both renal tubular secretion and reabsorption occurs The lipid soluble members are reabsorbed hence long posses long action

11. Cont.… Side effects Headache, nausea and vomiting, hepatitis B one marrow depression : leading to thrombocytopenia G ranulocytopenia Methemoglobinemia, hemolytic anemia ( if glucose-6-phosphate deficiency ) kernicterus ( in infants ) U rolitihasis (“crystalluria ”) Due to poor solubility in the low pH of the renal tubules and following crystal formation) hypersensitivity reactions leading to skin rashes and/or A ngioedema

12. LONG-ACTING SULFONAMIDES SULFAMETHOXYDIAZINE Side effects Same as sulfadiazine, except for urolithiasis (due to higher solubility at low pH , Hypersensitivity reactions leading to skin rashes, angioedema and/or stevens johnson syndrome Drug- drug Interactions They inhibit the metabolism possibly display protein binding sites of phenytoin, tolbutamide, and warfarin Use: Rarely used alone In chronic UTI and Gum infection

13. Dihydrofolate reductase inhibitors D ihydrofolate reductase inhibitors are structural analogues of folate and act by competitively inhibiting dihydrofolate reductase . S ince humans need to activate folate as well, dihydrofolate reductase inhibitors also affect DNA and RNA synthesis in human cells (!) however, dihydrofolate reductase inhibitors have a much stronger affinity for bacterial dihydrofolate reductase , thus affecting human cells to a much smaller extent Mechanism of resistance : due to structural alterations of dihydrofolate reductase

14. Pyrimethamine General information Administered orally, may cross the blood-brain barrier Medical uses T reatment of malaria due to plasmodium falciparum and/or plasmodium malariae, & or plasmodium vivax, and plasmodium ovale infection Treatment of malaria due to plasmodium falciparum infection then administered in conjunction with mefloquine

15. Side effects nausea and vomiting, folate deficiency leading to, macrocytic hyperchromatic , anemia, leukocytopenia and/or thrombocytopenia Hypersensitivity reactions leading to skin rashes

16. Trimethoprim Medical uses T reatment of cystitis due to escherichia and/or prot eus Infection T reatment of pneumonia due to streptococcus and/or Haemophilus infection Mechanism and other side effects are same as pyrimethamine

17. combinations Pyrimethamine + Sulfadiazine General information this particular combination is chosen due to similar pharmacokinetics of the 2 active compounds administered orally and/or IV may cross the blood-brain barrier USE Toxoplasmosis due to toxoplasma infection M alaria due to plasmodium falciparum, malariae, vivax and ovale and/or with aminoquinoline

18. Cotrimoxazole The fixed dose combination ( 1:5 according to WHO) Trimethoprim + Sulamethoxazole = Cotrimoxazole Both drug interfere in same metabolic pathway produces sequential blockage The combination produces supra-additive effect Sufomethaxazole inhibits folate synthetase and trimethoprim inhibits folate reductase

19. Cont.… Both drugs match closely They have similar half life Optimum synergistic effect at (20:1 suphamethaxazole:trimethoprim) in plasma and tissues Advantage of combination : Individually both are bacteriostatic but combination is bactericidal Chances of bacterial resistance are reduced

20. Pharmacokinetics Oral and parenteral use: well absorbed orally Widely distributed in various organs and tissues including CSF and sputum Metabolized in liver excreted in urine Dose reduction is needed in case of renal insufficiency

21. Adverse effect Dermatologic : skin rash G.I.T .: nausea, vomiting Hematologic : megaloblastic anemia, leukopenia, thrombocytopenia Patients with HIV : rashes, drug induced fever, diarrhea Drug interactions: Trimethoprim + warfarin: prolonged prothrombin time Plasma half life of phenytoin increases

22. Cotrimoxazole uses UTI : due to grm –ve organism like E.coli , Proteus sp. Can be given for chronic recurrent UTI in women's Small doses thrice weakly for long term prophylaxis in recurrent UTI Male: for bacterial prostatitis as it is concentrated in prostatic tissue Bacterial Respiratory tract infections : Acute and chronic bronchitis due to H.influenza and S.Pneumoniae

23. Cont.. Bacterial diarrhoeas : due to Shigella, E.coli, and salmonella sp. Typhoid fever : it may also be effective with fluoroquinolones Chancroid: caused by H. Ducreyi Cotrimoxazole is equally effective compared to drug of choice Azithromycin