Folate Synthesis Inhibtors Flashcards
What are the two actives in co-trimoxazole?
Sulphonamides and Trimethoprim
What is the MOA of sulfonamides?
- PABA and Pteridine (Dihydropteroate synthase)
- Dihydropteroic acid (Dihydrofolate synthase)
- Dihydrofolic acid (Dihydrofolate reductase)
- Tetrahydrofolic acid
What are some mechanisms of resistance?
Mutations
1. Lower affinity of dihydropteroate synthase enzyme for sulfonamide
2. Reduced bacterial cell permeability
3. Active efflux pump
4. Alternative pathway for essential metabolite synthesis
5. Enhanced production of essential metabolites or antagonists
What is the spectrum of activity?
Retained Potent Activity
Klebsiella granulomatis
Haemophilus ducreyi
Chlamydia trachomatis
Nocardia spp.
Actinomyces
Important Activity
Parasites
Fungi (Pneumocystis jiroveccii – Co-trimoxazole = DOC)
What are the gaps in the spectrum
Pseudomonas aeruginosa
Anaerobes
Enterococci
Resistant pathogens
Rickettsiae
Classify the sulfonamides
Oral Absorbable
1.Sulfamethoxazole
2. Sulfadoxine
Oral Non-absorbable
Sulfasalazine
Topical
1. Sulfacetamide
2. Silver Sulfadiazine
What the pharmacokinetics of the oral absorbable agents?
A - Well absorbed. Stomach and intestine
D - Widely distributed. Includes CNS, placenta, foetus, body fluids. Variable protein binding (20% - 90%)
M - Acetylation. Glucuronidation.
E - Active and inactive metabolites excreted in urine (glomerular filtration)
What type of killing does it exhibit?
Single Therapy usually Time-dependent
Combination (Co-trimoxazole) also has concentration-dependent effects
What are the clinical uses for oral absorbable agents?
PJP - Co-trimoxazole Drug of Choice
Nocardiosis - Co-trimoxazole drug of choice in some countries. Severe cases: + second agent
Toxoplasmosis
Sulfadiazine + pyrimethamine
What are expected adverse effects?
Allergic reactions - Fever
Skin rashes
Exfoliative dermatitis
Photosensitivity
Urticaria
Stevens-Johnson’s syndrome (rare).
UTI-
Crystalluria
Haematuria
Obstruction
Haematotoxicity -
Haemolytic anaemia
Granulocytopenia
Thrombocytopenia
Be cautious in patients with G6PD deficiencies
If taken near end of pregnancy, can cause kernicterus
What are some drug interactions?
Warfarin
Methotrexate
Bilirubin
What about trimethoprim?
Similar structure to folic acid
Reaches high concentrations in prostatic and vaginal fluids
Excreted mostly unchanged in urine
Resistance due mostly due to production of enzyme with low affinity for trimethoprim
Similar t1/2 to sulfamethoxazole
Thus co-formulated (i.e. co-trimoxazole)
Comparable adverse effects to sulfonamides
HIV positive patients have higher risk of adverse effects