SULFONAMIDES

FOLIC ACID ANTAGONISTS

Coenzymes containing folic acid - required for the synthesis of purines and pyrimidines (precursors of RNA and DNA) and other compounds necessary for cellular growth and replication.

• In the absence of folic acid, cells cannot grow or divide.

FOLIC ACID ANTAGONISTS:1. The sulfonamides (sulfa drugs) inhibit the synthesis of

folic acid. 2. Trimethoprim - prevents the conversion of folic acid to

its active, coenzyme form (tetrahydrofolic acid)

2

SULFONAMIDES The antimicrobial containing a sulfonamido

(sulfanilamide, SO4NH2) group are called sulfonamides.

NH2 SO4-NH

• Structurally related to p-aminobenzoic acid (PABA).

This group is also present in other non-antibacterial compounds like

-Sulphonureas -Benzothiazids -Furosemide -Acetazolamide

3

CLASSIFICATION1. Orally absorbable agents Short acting(4-8hrs.)- Sulfadiazine, Sulfisoxazole, Sulfacytine, sulfamethizole

Intermidiate acting(8-12hrs.)- Sulfamethaxazole Sulfamoxole

Long acting(7days)- Sulfadoxine sulfamethopyrazine

2. Orally Non- absorbable agents Special purpose sulfonamides- Sulfasalazine (ulcerative colitis) Silver sulfadiazine Sulfacetamide Burn(topical) Mafenide 4

Antibacterial spectrum

Bacteriostatic action at low conc.

Strept.pyogens, staph. Aurius, H.influenzae, H.ducreyi, calymmatobacterium granulomatis, v.cholerae.

Gonococci, meningococci, pnumococci.

E.coli, shigella.

Chlamydia- trachoma, Lymphogranuloma venereum  inclusion conjunctivities.

Actinomyces, Nocardia & Toxoplasma 5

Folic acid synthesis

Dihydropteridine + PABA

Dihydropterate

Dihydrofolate

Tetrahydrofolate

DNA/RNA

Dihydropteroate synthetase

Dihydrofolate reductase

6

(+) Glutamate

Sulphonamides: inhibitors of folate synthesis

Pteridine + PABA

dihydrofolic acidsynthetase

dihydrofolic acid

dihydrofolic acidreductase

sulphonamides

trimethoprim

tetrahydrofolic acid

Purine and pyrimidine synthesis

7

Dihydropteroic acid synthetase

Dihydrofolate reductase

Mechanism of action

Folic acid - synthesized from PABA, pteridine, and glutamate.

All sulfonamides are analogues of PABA. Because of their structural similarity to PABA, SA compete with this substrate for the bacterial enzyme, dihydropteroate synthetase. They thus inhibit the synthesis of bacterial folic acid.

All sulfa drugs are bacteriostatic.

8

Resistance to sulfonamide Capable of developing resistance-

Gonococci, meningococci, staph. aurius, E. coli & shigella

As result of mutation or by plasmid mediated1. Alteration in the nature of folic acid synthetase

(decrease affinity).2. Decreased bacterial permeability or active efflux of

drug.3. An appearance of alternative pathway for PABA

synthesis.

9

Pharmacokinetics Absorbed rapidly from the GIT (except topically used ).

Peak plasma levels are achieved in 2-6hrs.

widely distributed and pass through BBB as well as placental barrier.

Metabolized as acetylated conjugates in liver.

Acetylated metabolites are inactive and low soluble in acidic urine, leads to ppt. of crystaluria and renal toxicity.

Excreted through the glomerular filtration in urine.

10

Individual sulfonamides:

1) Well absorbed orally, short-acting: Sulfadiazine, Sulfadimidine, Sulfisoxazole, Sulfamethoxazole

2) Well absorbed orally, long-acting: Sulfamethopyrazine

3) Poorly absorbed in GIT: Sulfasalazine

4) Used topically: Silver sulfadiazine

11

Adverse effects

Blood Hemolytic and aplastic anemia (G6PD def.)

Thrombocytopenia

Hypersensitivity Photosensitivity Exfoliative dermatitis Stevens-Johnsons.

Drug fever Eosinophilia. 12

Crystalluria and renal toxicity- Adequate intake of water By making urine alkaline

Kernicterus in neonates- Sulfonamides displace bilirubin from protein binding

sites. Free bilirubin gets diposited-toxic encephalopathy Avoided in neonates & pregnancy (last trimester)

GI - Nausea, vomiting, diarrhea, pancreatitis

13

CONTRAINDICATIONS

Pregnancy (full term)Newborn and infant (<2months)Patients on Methenamine, Tolbutamide,

oral anticoagulants.

14

SULFASALAZINE

Poorly absorbed through GIT Reserved for treatment of chronic inflammatory

bowel disease (e.g., Crohn disease or ulcerative colitis).

Intestinal flora split sulfasalazine into sulfapyridine and 5-aminosalicylate which exerts the anti-inflammatory effect..

SILVER SULFADIAZINEEffective in reducing burn-associated sepsis.

15

- USES- Lower respiratory tract infections Bone and joint infections Infectious diarrhea Urinary tract infections Skin infections- Burn cases-silver sulfadiazine topically. Sexually transmitted diseases- Chancroids due to H. ducreyi Lymphogranuloma venereum  Chloroquine resistant malaria

16

TRIMETHOPRIM

Inhibitor of bacterial dihydrofolate reductase.

Antibacterial spectrum similar to SA

• Mostly compounded with sulfamethoxazole = co-trimoxazole.

17

Folic acid synthesis inhibitors

pterdine + para-amino benzoic acid

dihydropterate

dihydrofolate

tetrahydrofolate

DNA/RNA

Trimethoprim

(Diaminopyrimidines)

Binding

Sulphamethoxazole

(Sulphonamides)

Structural analogues of PABA

Dihydropteroate synthetase

Dihydrofolate reductase

18

Mechanism of action

The active form of folate – tetrahydro derivative (formed by reduction of dihydrofolate by dihydrofolate reductase).

• This enzymatic reaction is inhibited by trimethoprim ----

• There occurs decreased availability of the tetrahydrofolate coenzymes required for purine, pyrimidine, and amino acid synthesis.

Other folate reductase inhibitors: Pyrimethamine (used with SA in parasitic infections)Methotrexate (in cancer chemotherapy).

19

Antibacterial spectrum

Spectrum - similar to sulfamethoxazole

• Trimethoprim is 20- 50 fold more potent than SA.

Resistance Presence of altered dihydrofolate reductase with

lower affinity for trimethoprim. Overproduction of the enzyme Decrease drug permeability.

20

Uses

1. Acute UTIs

2. Bacterial prostatitis

3. Bacterial vaginitis.

21

Pharmacokinetics

Similar to sulfamethoxazole.

But - it is a weak base - higher concentrations of Trimethoprim in relatively acidic prostatic and vaginal fluids.

It also penetrates the CSF.

It undergoes some O-demethylation, but mostly excreted unchanged through the kidney.

22

Adverse effects

Effects of folic acid deficiency (megaloblastic anemia, leukopenia, granulocytopenia - especially in pregnant women and pts with a poor diets)

The blood disorders . can be reversed by the simultaneous administration of folinic acid, which does not enter bacteria.

Nausea, vomiting, skin rashes

23

CO-TRIMOXAZOLE

Trimethoprim – mostly compounded with sulfamethoxazole.

This combination - co-trimoxazole - shows greater antimicrobial activity than equivalent quantities of either drug used alone.

Selected because of the similarity in the pharmacokinetics of the two drugs.

24

COTRIMOXAZOLE1. Sulfamethaxazole + trimethoprim = FDC

5:1= 400+80mg

DS 1Tab. BD T1/2=10-11 hrs.

ADV: Synergistic, Potent. Bactericidal

2. Sulfadoxine+Pyrimethamine- 20:1=500+25mg

Indication:chloro.resistant P. falciparum, toxoplasmosis

25

Mechanism of actionThe synergistic antimicrobial activity of co-trimoxazole –

Inhibition of 2 sequential steps in the synthesis of tetrahydrofolic acid.

Sulfamethoxazole inhibits the incorporation of PABA into folic acid.

Trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate.

More potent activity than sulfamethoxazole or Trimethoprim alone.

Doses of both drugs are 1/10 of those needed if drug were used alone.

26

Antibacterial spectrum

Broader spectrum than SA Uses:

1. Treating UTls

2. Respiratory tract infections

3. Pneumocystis pneumonia

4. Ampicillin- or chloramphenicol-resistant systemic salmonella infections.

27

Pharmacokinetics More lipid soluble than sulfamethoxazole - greater Vd.

Ratio: 20 parts sulfamethoxazole to 1 part trimethoprim – according to some authors considered optimal for the antibiotic effect.

Generally administered orally.

Trimethoprim concentrates in the relatively acidic milieu of prostatic and vaginal fluids - the use of the trimethoprim-sulfamethoxazole in infections at these sites.

Both parent drugs and their metabolites are excreted in the urine

28

Adverse effects Dermatological: Reactions involving the skin are very common and

may be severe in the elderly.

GIT: N, V, glossitis, stomatitis - not unusual.

Hematological: Megaloblastic anemia, leukopenia, thrombocytopenia

May be reserved by administration of folinic acid (it protects the pts and does not enter the microorganism).

Hemolytic anemia - in pts with G6PD deficiency due to the sulfamethoxazole.

Pneumocystis pneumonia - frequently drug-induced fever, rashes, diarrhea, and/or pancytopenia.

29