Antimetabolites Flashcards
Antimetabolites drugs?
- Sulfonamides
- Trimethoprim
- Co-trimoxazole
Antimetabolites Pathway MOA?
- PABA is converted to dihydrofolate by the enzyme dihydropteroate synthetase
- Dihydrofolate is converted to tetrahydrofolate by dihydrofolate reductase
- Tetrahydrofolate is converted to synthesisof purines and then to DNA
Which enzymes do which antimetoabolites act on?
Sulfonamides-dihydropteroate synthetase enzyme
Trimethoprim-dihydrofolate
Sulfonamides parent drug?
Prontosil(parent drug)=Sulfanilamide(intialy produced) =Sulfonamides
Sulfonamides and PABA?
Structural analogues of PABA
Sulfonamides targets what type of bacteria?
Target both gram +ve and -ve bacteria
Sulfonamides MOA for bacteria?
Bacteriostatic cell division but does not kill
Sulfonamides and rickettsia?
Sulfonamides stimulate rickettsiae
What affects the effects of sulfonamides?
- Presence of pus
- Tissue Fluid
- PABA
Sulfonamides CI
-Pregnancy
Sulfonamides in clinical examples & their indications?
- Silver Sulfadiazine(topical)
I: Infected leg ulcers, pressure sores and burn wounds
- Sulfasalazine
-Spilt by intestinal microflora
Sulfapyridine + 5-aminosalicylaste
I: Rheumatoid arthrytis & colitis
- Oral absorbable
– Sulfamethoxazole- In combination with
trimethoprim (co-
trimoxazole)
- In combination with
Trimethoprim
-Bacteria MOA
-Spectrum
-MOA
-Bacteriostatic
-Broad Spectrum
-Inhibits dihydrofolate reductase
Co-trimoxazole?
A combination of sulfonamides and trimethroprim
Co-trimoxazole composition?
Combination of trimethoprim and sulfamethoxazole
Ratio: 1: 5
T: S
Co-trimoxazole bacteria MOA?
Bactericidal
Co-trimoxazole I?
For use in HIV patients
-Pneumocystis jirovecii pnemonia
-Toxoplasmosis & Isospora belli diarrhea
-Nocardiosis (treatment of choice)
Which condition does co-trimoxazole not treat and why?
Not used for rickettsiae ‘coz it causes rickettsiae
Co-trimoxazole CI?
Pregnant woman
Antimetabolites mechanisms of resistance-5?
- Overproduction of PABA
- Overproduction of dihydrofolate reductase
- Production of altered reductase with decreased drug binding
- Production of dihydropteroate synthetase with decreased affinity for sulfonamides
- Loss of permeability to both drugs
Sulfamethoxazole S/E-7?
-Kernicterus (Bilirubin displacement)-toxic encephalopathy
-Allergy: Rash, SJS, Drug fever
-Decreased efficacy of oral contraceptives
-Nausea, vomiting and headache
-Agranulocytosis & thrombocytopenia
-Precipitation of acetylated metabolites in the
urine (crystalluria) → drink lots of water and
make urine more alkaline
-Cross-sensitivity with other sulfanilamide
derivatives
Trimethoprim S/E-5?
-Tetraogenic
-Megaloblastic anemia
-Myelosuppression-Bone marrow depression
-Skin rashes, pruritis, glossitis, epigastric pain
-Reduced efficacy of combined oral conceptives
Co-trimoxazole S/E-4?
-Thrombocytopenia (when used with diuretics)
-Fever & Myelosuprresion (In AIDS patients)
-Megaloblastic anemia(long term use)
-Nausea, vomitting, skin rashes and anemia
Antimetabolites CI-4?
- Pregnancy
- Porphyria
- G6PD Deficiency
- Allergy
Which adverse effect is CI for antimetabolites and is rare for drugs to treat?
Porphyria
Action of antimetabolites?
- As antibiotics: inhibit DNA, RNA & protein
synthesis by blocking the folate pathway - Tetrahydrofolate leads to the synthesis of
nucleotides and ultimately DNA
Why are so many organisms resistant to Sulfonamide?
Due to widespread use=many organisms became resistant
Sulfonamide broad spectrum bacteria?
ANC
Actinomyces
Nocardia
Chlamydia trachomatis Plasmodia
Sulfonamide enteric bacteria?
KEESS
klebsiella
E coli
Enterobacter
salmonella
shigella
What are the line of treatment for sulfonamides and why?
Sulfonamides are NOT the drugs of 1st choice.
Reasons:
– Bacterial resistance → use of combinations &
more effective antibiotics
– Toxicity (hypersensitivity)
Sulfonamide Pharmacokinetics:
-Absorption
-Distribution
-Administration and least likely
-Protein binding and consequences
-Metabolism
-Excretion
-Absorption:
Well absorbed from the GIT
-Distribution:
Wide distribution to tissues and body fluids (incl. CNS, cerebrospinal fluid), placenta & foetus
-Administration and least likely:
Usually not topically administered → cause
allergic reactions
-Protein binding and consequences:
Protein binding (20 – 90%)=Increased protein binding and thus causes varying drug interactions
-Metabolism:
* Metabolised in the liver
-Excretion:
* Acetylated and glucuronidated before being
excreted in the urine
Sulfonamide DI-4?
Potentiate effects of:
1. Oral anticoagulants (warfarin)-Increased risk of bleeding
- Sulfonylureas (e.g. glibenclamide)-Increase hypoglycaemia in type 2 diabetes
- Phenytoin-Sulfonamide inhibit metabolism
- Methotrexate-can cause myelosuppression
Why should water be taken with Sulfonamide?
Precipitation of acetylated metabolites in the
urine (crystalluria) → drink lots of water and
make urine more alkaline
What do susceptible organisms require?
Extracellular PABA to form dihydrofolic acid and essential step in the production of nucleotide and nucleic acids
Sulfamethoxazole type of therapy
Never used in monotherapy because of the resistance. It is used in combination with trimethoprim (co-trimoxazole)
