Anti metabolites Flashcards
What are metabolites ?
A structural analogue to an endogenous compound , which interferes with the unction of the endogenous metabolites
What is the action of antimetabolites as antibiotics?
- Inhibites dna , rna and protein synthesis by blocking the folate pathway
- Tetrahydorfolate leads to the synthesis of purines and pyrimidines
What is a sequential blockage and give an example
The combined action of 2 drugs that inhibit sequential steps in a pathway of bacterial metabolism
eg. Co-Trimoxazole
{Trimethoprim and sulphonamide ( sulphamethoxazole)}
What are the characteristics of co-trimoxazole
1.It is a combination of trimethoprim and sulphanomide(sulphomethroxazole)
- It has a broad spectrum
- Administredd in a formulation of 5;1 (trimethoprim and sulphonamide )
- Individual drugd are bacteriostatic wgen when they are combined they work synergistically =bactericidal
Use and spectrum of co-trimoxazole
- Effectiveness is decreasing due to increase in resistance
- It is a recommended treatment for Aids patients
- Prophylaxis and treatment for pneumocystis jirovecii pneumonia
- Prophylaxis of toxoplamosis and isospora belli diarrhea
- Treatment choice dor corcardiosis
- Not used for Rickettsiae , stimulated by sulphonamides
What is the action mechanism of co-trimoxazole
Folate → A precursor in the synthesis of DNA and
RNA because it is an element is purines and pyrimidines in both mammals and bacteria of nucleic
• Mammals → acquire folate from diet
• Bacteria must synthesize it
• In bacteria PABA is used to synthesize folic acid
• Sulfamethoxazole→ structural analogs of
PABA and thus inhibit dihydropteroate synthetase →
dihydrofolate
Selectively toxic towards bacteria
Trimethoprim
Inhibits formation of tetrahydrofolic acid (tetrahydrofolate ) by inhibiting dihydrofolate reductase.
Inhibits the bacterial dihydrofolate
reductase enzyme (± 50 000 x more
sensitive) that catalyzes the formation of
tetrahydrofolate (FH4, the active form of
the vitamin) from dihydrofolate (FH2)
How can resistance be developed against co-trimoxazole
- Overproduction of PABA
- Production of dihydropteroate synthase
- Loss of permeability for both drugs ( trimethoprim and sulphonamide)
- Overproduction dihydrofolate reductase
- Production of an altered dihydrofolate reductase drug binding
What are the advantages of using co-trimoxazole
- Delays resistance to trimethoprim
- The synergistic action of trimethoprim and sulphonamid3
- Wider spectrum than trimethoprim
- development of resistance is lower than to individual drugs alone
What is the pharmacokinetics of co-trimoxazole
- It is well absorbed well orally
- Trimethoprim is well distributedin the tissue fluis (Vd = L) and sulponamides has a low Vd = 12L-18L
- hallf life : trimethoprim (8 - 11 hr) and sulphonamides ( 9 hrs )
- Protein binding of trimethoprim =44% and sulphonamides = 70%
- Trimethoprim mostly excreted unaltered via kidneys
- Sulphonamides(sulfamethoxazole ) is acetylated and glucoronidated in the liver before being excreted in the urine
Side effects of sulfamethoxazole
- Precepitation of acetylated metabolites in the urine ( crystalluria ) thus need to drink lots of water and make urine more alkaline
- Allergy : rash , Stevens Johnson syndrom and drug fever
Side effects of trimethoprim
- Skin rash , pruritus ,nausea ,epigastric pain
- Glossitis( common )
- Bone marrow depression (rare)
- Long term usage can result to folate deficiency causing megaloblastic anaemia
- Efficiency is reduced when orally taken with contraceptives’ pills
- Teratogenic
Drug interaction of co-trimoxazole with others
1.Digoxin levels increase metabolism
2.Thiazides increase risks of thrombocytopenia
3.Decrease efficiency when combined with oral contraceptives
4.May inhibit phenytoin
5.Increase of hypoglycemic effect with oral antibiotics drugs(glibenclamide)
6. Concurrent use with pyrimethamine →
megaloblastic anaemia
7.Rifampicin uses leads to decreased levels of co-trimoxazole
8.Warfarin increased bleedings
9.ZidovudineLead to increased risk of toxicity
10.Methotrexate increase metabolism
Contraindications
Pregnancy (Trimethoprim, Sulphonamide: last 2 weeks) 1. Porphyria 2. G6PD deficiency 3. Allergy
give examples of sulphonamide
Other sulphonamides Silver sulfadiazine (topical) • Treating infected leg ulcers, pressure sores & burn wounds Sulfasalazine • Split by intestinal microflora: • sulfapyridine + 5 aminosalicylate
