ANTIFOLATE DRUGS

ANTIFOLATE SULFONAMIDE TRIMETHOPRIM METRONIDAZOLE

DRUGS
OVERVIEW  Bacteriostatic - trimethoprim : - antiprotozoal drug
 Structure= p-aminobenzoic acid  inhibit bacterial dihydrofolic
(PABA) reductase 50000x
 Properties ≠ based on diff  efficienct > than mammal
substituent attached to amino / enzyme
amino group -pyremethamine :
 inhibit protozoa dihydrofolic
acid reductase> mammal
- trimethoprime- combination w
sulfonamide
 synergism-sequential blocking
-combined form-bactericidal
RESISTANCE  Mutation-overproduction of PABA  Reduced cell permeability
 Low-affinity-enzyme to  Overproduction dihyrofolate
sulfonamide reductase
 Impermeability to sulfonamide  Altered reductase-
MECHANISM  Block folic acid synthesis-  Anaerobes
reversible  Bacteriodes
OF ACTION  DNA production  Clostridium species

PABA
↓←sulfonamide (competitive inhb w
dyhydropteroate synthase)
dihydrofolic acid
↓
tetrahydfolic acid
↓
Purines
↓
DNA

ACT ON 1. Gram + bac

2. Gram – bac
3. Nocardia
4. Clamydia trachomatis
5. Some protozoa
6. Some enteric bact- E.coli,
Klebsiella, salmonella,
shigella, enterobacter

PHARMACO- 3 major group: - Oral, IV : trimethoprim + - Oral : good

- Oral absorbable sulfamethoxazole - Distribution : wide + CNS
KINETICS - Oral non-absorbable - Absorbtion : trimethoprim-well - ROUTE : IV, oral,suppository
- topical - Distribution : wide + CNS - METABOLISM: liver
- Excretion : kidney
IV sufonamide-rarely used xcept - Reduce dose in renal problem
sulfomethazole- trimethoprim - Concentrated in prostatic and
vaginal fluids
Absorbtion : stomoch, SI
Distribution : wide including CNS,
placenta, fetus
Metabolism : acetylation and
sulfonamide- in urine
Dose is reduced in renal failure

CLINICAL Oral absorbable  Oral trimethoprim: acute  Anaerobec, mixed

urinary tract infection intraabdominal infx
USED  Rarely use- single antibiotic  Trimethoprime-  Vaginitis (trachomas)
 Sulfisoxazole n sulfamethoxazole : sulfamethoxazole:  Antibiotics associated
UTI - P jiroveci pneumonia, enterocolitis
 Sulfadiazine + pyremathamine: shigellosis, salmonella  Brain abcess
toxoplasmosis - UTI, prostatitis  Amoebiasis
 Sulfadoxine- long acting ( - Mycobacteria  Giardiasis
↑protein binding n tubular - Respiratory tract  Trichomoniasis
absorbtion ) pathogen: pneumococus,
 Fansidar( sulfodoxine + HI, klebsiella
pyremethamine): malaria  IV trimethoprim-
ANTIFOLATE DRUGS

- Oral non-absorbable sulfamethazole:

- Severe pneumocystis
Sulfasalazine pneumonia
 Salicyl-azo-sulfapyridine: - Gram –ve bacterial sepsis
ulcerative colitis, enteritis, IBD - UTI
 Sulfasalazine: split by intestinal  Oral phyrimethamine +
microflora to sulfapyridine + 5 sulfonamide
aminosalicylate : anti- - Leishmaniasis
inflammatory - Toxoplasmosis
- Falcifarum malaria
(fansidar)
- topical
 Sodium sulfacetamide
ophthalmic solution or
ointment : bacteria
conjuntivitis, trachoma
 Silver sulfadiazine: burn
wound= prevent infectn

ADVERSE 1. fever, skin rashes, exfoliative 1. Antifolate effect: 1. nausea, dry mouth, metallic
dermatitis, photosensitivity, urticaria,  Megaloblastic anemia state in mouth
EFFECT 2. nausea, vomiting, dirrhea  Leucopenia, granulocytopenia 2. dirrhea
3. urinary tract problem 2. Sulfonamide- associated side effect 3. stomatitis
- sulfonamide precipitates in urine in combine drug: 4, pheripheral neuropathy w
- producing crystalluria, hematuria, n  Nausea, vomiting prolonged use
obsruction in acid urine  Fever 5. disulfram- like effect
-rx: alkalization of urine, adequate  Renal damage 6. seizure-rare- occur w IV
hydration  CNS disturbance
-nephrosis  AIDS patient >> prone to dvlp
-allergic nephritis adverse effect
4. Stevens- johnson syndrome
5. hematopoietic disturbances
- hemolytic
- aplastic anaemia
- thrombocytopenia
- leukemoid rxn
- Kernicterus in newborns
OTHER - stomatitis Drug2 interaction:
- conjunctivitis - ↑ warfarin effect
ADVERSE - arthritis - ↑ elimination when used
EFFFECT -hematopoeitic disturbances together
- polyarteritis nodosa - cimetidine ↓ plasma
- psychosis clearance
- lithium toxicity