Antimetabolites Flashcards
What is an Antimetabolite
its a structural analogue to an endogenous compound–> interferes with its role in cellular metabolism
Action of ANtimetabloites
inhibit DNA, RNA and Protein SYnthesis by blocking the folate pathway
What are Sulfonamides
are structural analogues of PABA (p-aminobenzoic acid) which is a precursor in bacterial folic acid synthesis
Organisms susceptible to Suphonamides require
extracellular PABA to form Dihydrofolic acid
Sulfonamides are effective against
Sensitive strains of Gram +ive and -ive bacteria
Bacteriostatic drugs
ARE NEVER 1st LINE DRUGS
Spectrum of Sulfonamides
Borad Spectrum
Some Enteric bacteria like E.coli and Salmonella
Rickettsiae
What do Sulfonamides not have an effect on
Mammalian cells
What is the name of the topical Sulfonamide
Silver Sulfadiazine
When is Topical Sulfonamide used
infected leg ulcers
pressure sores
burn wounds
What is the name of the Oral Absorbable Sulfonamide
Sulfamethoxazole
When is the oral Sulfonamide used
NEVER USED ON ITS OWN
in combination with Trimethoprim (co-trimoxazole)
MOA of Sulfonamide
Its a PABA analogue therefore it binds in its place to Dihydropteroate Synthetase
Resistance Mechanisms against Sulfonamides
- Overproduction of PABA
- Production of Dihydroggen Synthetase with low affininty for Sulfonamides–> bypasses it
- Loss of permeability to Sulfonamides
Absorption and Distribution of Sulfonamides
They are well absorbed from the GIT
Wide distribution to tissues and body fluids (including CNS, CSF), placenta and foetus
Which Admin method is not used for Sulfonamides
Topical admin as it causes allergic rxns
*ONLY used in one case
Metabolism of Sulfonamides
Extensively metabolized in the liver
They are Acetylated and Glucoronidated before being excreted in the urine
SEs of Sulfonamides
1.N,V,H
2.Precipitation of acetylated metabolites in urine–> Crystalluria: lots of water intake required to make urine more alkaline
3. Allergy: rash, SJS, drug fever
4. Cross-sensitivity with other Sulfanilamide derivatives
5. Danger of Kernicterus
6. Agranulocytosis and thrombocytopenia
7. Photosensitivity
8. Hepatotoxicity
9. Reduced efficacy of COC
Why are Kernicterus indicated as a SE for Sulfonamides
Bilirubin is pushed from their serum binding sits–> cross BBB and enter Brain nuclei–> cause Toxic Encaphalopathy
*must not be administered during Last 2 wks of pregnancy
DIs of Sulfonamides
Oral Anticoagulants (warfarin: decr. m)
Sulfonylureas (glibenclamide: decr M=hypo)
Phenytoin: inhibits its metabolism
Methotexate: decr excretion in urine
CIs of Sulfonamides
Babies in first 3wks of life: incr. risk of haemolysis and Kernicerus
Last trimester of pregnancy (last 2 wks)
Porphyria
G6PD deficiency
Allergy
What is Trimethoprim
Its a Broad spectrum Bacteriostatci that eventually inhibits DNA Synthesis
Uses of Trimethoprim
Acute uncomplicated UTIs
Prophylaxis of UTIs
Respiratory tract infections
Chronic Prostatitis
How is Trimethoprim used in SA
Used in combination with Sulfamethoxazole as Co-trimoxazole
MOA of Trimethoprim
-Inhibits the bacterial Dihydrofolate Reductase enzyme–> catalyses formation of Tetrahydrofolate form Dihydrofolate
-Inhibits synthesis of Nucleotides
-Inhibits DNA synthesis
Resistance Mechanisms against Trimethoprim
- Reduced cell permeability
- Overproduction of Dihydrofolate reductase
- Production of an ALtered Reductase with reduced drug binding
Absorption and Distribution of Trimethoprim
Rapidly absorbed
Widely distributed–> therapeutic levels in bile, CSF, Prostatic tissue, vaginal fluid
SEs of Trimethoprim
Teratogenic
Glossitis: frequently
Folate Deficiency anemia in people with low folate stores
Skin rashes, pruritus
Nausea, Epigastric Pain
Bone marrow depression: rare
Reduced efficacy of COC
Uses of Co-trimoxazole
Recommended for use in HIV patients
Prophylaxis and treatment of Pneumocystis Jirovecii Pneumonia
Prophylaxis of Toxoplasmosis and Isospora belli diarrhea
Treatment of choice for Nocardiosis
MOA of Co-trimoxazole
They interrupt the Synthetic pathway of Tetrahydrofolate in 2 ways:
1. inhibit Dihydropteroate Synthetase (sulfamethaoxazole)
2. inhibit Dihydrofolate Reductase (Trimethoprim)
Admin of Co-Trimoxazole
1:5 (T:S)–> synergistic
Orally
Large colume of distribution
What is the combined effect of Co-trimoxazole
Bactericidal
They are Bacteristatic individually
Advantages of Co-trimoxazole
Delays development of resistance against T
Synergistic action
Wider spectrum than T
Excretion of Co-trimoxazole
T: mostly unaltered via kidneys
S: Metabolized in Liver and rapidly excreted in the urine
SEs of Co-Trimoxazole
NV
Skin rashes+anemia
Long term use=folate shortage–> Megoblastic Anemia
Incr. AEs in elderly on DIRUETICS: Thrombocyropenia
Incr. AEs in AIDS patients=fever+ bone marrow depression
DIs of Co-Trimoxazole
- Digoxin levels may incr.
- Incr. risk of Thrombocytopenia
- Oral Contraceptive
- Incr. risk of hypoglycemia with oral antidiabetic agents
- May inhibit Phenytoin metabolism
- Concurrent use with Pyrimethamine: megoblastic anemia
- Rifampicin use leads to decr levels of Co-trimoxazole
- Warfarin: incr. bleeding risk
- Zidovudine: incr. toxicity risk
- Methotrexate: incr. toxicity risk
