Folic acid and antifolate drugs or folate antagonists

Antifolates

1. FOLATE ANTAGONISTS
BASIS OF USE
1 FH
4 (active form) is needed for
synthesis of bacterial RNA / DNA/AA
duplication & cell growth
2 No FA or its conversion to FH
4
no binary fission
3 Bacteria cannot utilise readymade FH
4
or FA, It has to prepare it from PABA /
pteridine ( MAN : JUST OPPOSITE )

2. SULFONAMIDES
ANTIBACTERIAL SPECTRUM
•Nocardia
•Chlamydia T
•Few Enteric Bacteria
•Some Protozoans
No effect on Anerobes

3. Mechanism of Action

4. KINETICS
Good oral abs.
Good CSF entry & Good Fetal entry,
Variable Protein binding
Metabolism
Acetylation – Loss of AB. activity
But toxicity
retained ↓ solubility

Renal calculi & crystalluria

5. ADR
1Nephrotoxicity
> In acidic / neutral pH
To avoid
↑ H
2
O intake & alkalinize urine

2.Steven-Johnson-Syndrome
(Erythema multiformae)
Inflammation of skin and musocal
membrane.

6. 3.Hematological
•G6PD-def. – Hemolytic anemia
•Hypersensitivity reactions
Type II Bone marrow dep.

Type III Arthritis
Drug fever
Exfoliative
dermatitis

7. 4.Kernicterus :
Competes with bilirubin for
albumin binding
5.Drug interaction
displaces Protein bound drugs
oral anticoagulatns
methotrexate toxicity
oral hypoglycemics –
when given with methernamine
crystalluria results
( acidic pH )

8. Systemic Use:
A. Short acting (t½ -6h)
Sulfadiazine & Sulfisoxazole
< Pr. Binding  ↑ free drug conc
Useful in
Nocardiasis
Toxaplasmosis
Prophylaxis of rheumatic fever
(In case of Pn. Allergy)

9. B. Int. acting (t½ -11h)
Sulfamethoxazole
Sulfamoxole
(A Component of cotrimoxazole )
C. Long acting ( t½ -6 to 9 days)
Sulfadoxine (ADR-High)
Used in combination only
Malaria (prophylaxis)
Toxoplasmosis
P.carini pneumonia

10. LOCAL USE - POORLY ABSORBED
SULFASALAZINE

Colonic Bac
Sulfapyridine 5-Amino Salicylic Acid
Toxicity Beneficial effects
Haemopoitic Ulcerative colitis
disorders Regional enteritis
Hypersensitivity Granulomatous
colitis

11. Topical use – Eye
SULFACETAMIDE
1.very high conc. in aquous humour
2.non-irritating
3.30% solution has pH 7. 4
4.Good penetration into deeper
tissues
5. Sensitivity reactions are rare

12. Topical Use – Skin
Silver sulfadiazine
Active ingredient Silver & Sulfonamide
Both - antibacterial
Effective against
all pathogenic M.O. including fungi
↓ incidence of wound infections
↓ microbial colonization
Not useful for deep infection

13. MEFENIDE (Skin) BURNS
ABS: both G+ve and G-ve MOs
ADR
1. Superinfection with candida
2. Absorbed D & D.metabolite
(–) carbonic anhydrase 
metabolic acidosis
3. Allergic Reaction – common
4. Pain at the site of application
( So less popular )

14. Trimethoprim
•Resembles Folic acid in structure
•Selective inhibition of
Dihydrofolate reductase
↓
Folic Acid active FH
4

•Selective toxicity to MO & not to human
AFFINITY for Bac. DHFR >> Human DHFR
(50,000 times)

15. Not a sulfonamide
ABS
• same as sulfonamides
• bacterio static activity greater than
sulfamethoxazole
• Kinetics:
Well absorbed orally
Good entry into CSF, vaginal fluid
& tissues like prostate

16. USES:
UTI, RTI, Prostatitis, Vaginitis Cervicitis
(alone or in combination )
•Whenever TMP alone is effective it is
preferred for cotrimoxazole
ADR of sulfonamide – avoided
ADR : Megaloblastic anemia
To avoid give folinic acid

17. Cotrimoxazole
Trimethaprim + Sulphamethoxazole
1:5 oral dose = 1:20 plasma conc
( Peak Sequential block )
ABS:
1Facultative G-ve anerobes
2Enterobactericeal : E.coli, S.typhi,
Shigella
3G-ve cocci : N.meningitidis
N.gonorrhoea
4Pneumocytitis carinii

18. Advantages
•Static effect -– Cidal & Synergistic
•Spectrum widened
•Effective against both
Sulfa-resistant & TPM-resis. strains
emergence of resis. to both is LESS
•ADR due to sulfa < sulfa alone (↑dose)
•Cheaper than modern Abs
•Orally effective

19. ADR
1Bone marrow (rare):
Thrombocytopenia
Megaloblastic anemia
2Hemolysis – G6PD-def.
3Kernicterus in newborn
4Teratogenicity
5Nephrotoxicity

20. Indications
1RTI ( H.Inf. M catarrhalis, P.carinii Pn.
Nocardia -- Drug of choice)
2UTI: Acute uncomplicated
Recurrent UTI with prostatitis
3Acute Otitis Media
( M. catarrhalis / H. Inf.)
4Sinusitis
5GIT – Typhoid, Bacillary dysentery

21. Contraindications
a. New Born
b. Preg / lactating mother
c. G6PD- Diff
d. Hypersensitive
Preparation :1 : 5 ratio
Ideal TMP + SMZ
80 mg 400 Mg
Paediatrics 20 mg 100 mg

22. OTHER COMBINATIONS
Sulfadoxine + Pyrimethamine
( Pyrimethamine inhibits MP specific
Dihydrogolate reductase ) Sequential
block
Uses
1.Mefloquine / Chloroquine resis.
Plasmodium Falciparum MALARIA
2For Pneumocystitis Carinii pneumonia
3Toxoplasmosis