Antimetabolites Flashcards
What is the action of antimetabolites?
inhibit DNA, RNA and protein synthesis by blocking the folate pathway
What are sulfonamides a structural analogue of?
p-aminobenzoic acid (PABA)
T or F - Sulfonamides are bacteriocides?
False, they are bacteriostatic drugs that are broad spectrum (effective against gram positive and negative bacteria)
What are the broad spectrum uses of sulfonamides?
Actinomyces, Nocardia, Chlamydia trachomatis & Plasmodia
What are the enteric uses of sulfonamides?
E coli, klebsiella, salmonella, shingella & enterobacter
What is an absolute CI for Sulfonamides?
Tick bite fever. They stimulate RICKETTSIAE
What affects the antibacterial effect of Sulfonamides?
Pus, tissue fluid and PABA
T or F - Sulfonamides are first choice drugs?
False, there is a high degree of bacterial resistance (used in combination with other drugs) and they are toxic (hypersensitivity especially for topical admin). They are still commonly used in developing countries
What are the two examples of Sulfonamides?
Silver sulfadiazine (Topical) and Sulfamethoxazole (oral)
What are the indications for Silver Sulfadiazine?
Infected leg ulcers, pressure sores and burns
What is Sulfamethoxazole co-admin with?
Trimethoprim (co-trimoxazole)
What is the MOA of Sulfonamides?
decrease the formation of dihydrofolate (by PABA) by inhibiting dihydropteroate synthase)
What are the reasons for resistance to Sulfonamides?
- Overproduction of PABA
- Production of Dihydropteroate synthase with low affinity for sulfonamides
- loss of permeability to sulfonamides
How are Sulfonamides metabolised?
They are metabolised in the liver where they are glucuronidated and acetylated
T or F - Sulfonamides are well distributed?
True. They are well distributed and have a high protein binding
What are the side effects of Sulfonamides?
- N, V and headache
2.Crystalluria - Allergic rxns (SJS, rash)
- Cross sensitivity with other Sulfonamide derivatives
- Kernicterus (occurs in neonates suffering from jaundice)
- Cannot be administered in last two weeks of pregnancy
- Agranulocytosis & thrombocytopenia
- Photosensitivity
- Hepatotoxicity
- Reduce efficacy of contraceptive pill
Sulfonamides interact with warfarin, sulfonylureas (glibenclamide) and what other drugs?
Phenytoin and Methotrexate
What are the CI for Sulfonamides?
- Babies in the first few weeks of life
- Last trimester of pregnancy (last 2 weeks)
- Porphyria
- G6PD deficiency
- Allergy
What are the indications for Trimethoprim and what is it given in combination with?
Acute UTI, repiratory tract infections, chronic prostatitis
Used in combination with sulfamethoxazole as co-trimoxazole
What is the MOA of Trimethoprim?
Inhibits the bacterial enzyme dihydrofolate reductase to inhibit the production of tetrahydrofolate (active form) from dihydrofolate
What causes resistance of Trimethoprim?
- Reduced cell permeability
- Overproduction of dihydrofolate reductase
- Production of an altered reductase with reduced drug binding
T or F - Trimethoprim is poorly distributed?
False. It rapidly absorbed and widely distributed
What prolongs the half life of Trimethoprim?
Severe renal failure and neonates
T or F - Trimethoprim is metabolised extensively?
False. It is metabolsed 10-20% in the liver and excreted in urine as an unchanged drug and inactive metabolites
What are the side effects of Trimethoprim?
- Skin rashes, pruritus, N, epigastric pain, glossitis (frequent)
- Bone marrow depression (rare)
- Folate deficiency anaemia
- Reduced efficacy of oral contraceptive
- Tetratogenic
What are the indications for Trmethoprim + sulfonamide (co-trimoxazole)?
HIV patients
– Prophylaxis & treatment of Pneumocystis
jirovecii pneumonia
– Prophylaxis of toxoplasmosis & Isospora belli
diarrhea
– Treatment of choice for nocardiosis (pneumonia)
What is the MOA of co-trimoxazole?
Interrupts the synthetic pathway of tetrahydrofolate at two places:
1. Initially dihydropteroate synthase is inhibited (sulfametoxazole)
2. Dihydrofolate reductase is inhibited (trimethoprim)
What is the ratio of trimethoprim:sulfamethoxazole?
1:5
T or F - co-trimoxazole is bacteriostatic?
False. The combination is bacteriosidal
Why is co-trimoxazole advantageous?
Delays resistance to trimethroprim and provides a wider spectrum than trimethroprim
Which drug has a better volume of distribution, trimethoprim or sulfamethoxazole?
Trimethoprim
Which drug has a better protein binding, trimethoprim or sulfamethoxazole?
Sulfamethoxazole
How is co-trimoxazole excreted?
Trimethoprim is mostly excreted unaltered via the kidneys
Sulfamethoxazole is metabolised in the liver and excreted in the urine
What are the side effects of co-sulfamethoxazole?
- Nausea and vomiting, skin rashes and anaemia
- Long term use → folate shortage →
megaloblastic anaemia - Increased adverse effects in the elderly on
diuretics → thrombocytopenia - Increased adverse reactions in AIDS patients →
fever & bone marrow depression
What are the drug interactions for co-sulfamethoxazole?
- Digoxin levels may ↑
- ↑ risk of thrombocytopenia (thiazides)
- Oral contraceptives
- ↑ of hypoglycaemic effect with oral antidiabetic
agents - May inhibit phenytoin metabolism
- Concurrent use with pyrimethamine →
megaloblastic anaemia - Rifampicin use leads to ↓ levels of co-
trimoxazole - Warfarin → ↑ bleeding
- Zidovudine → ↑ risk of toxicity
- Methotrexate → ↑ risk of toxicity
