Mechanism of actions - Exam 2 Flashcards
Chloroquine
accumulates in food vacuole of plasmodium and prevents polymerization of the hemoglobin breakdown product heme into hemozoin
Heme is toxic to the parasite
Resistance can develop to this by having pumps to shuttle the drug out
Quinine
complexes with dsDNA to prevent strand separation, resulting in a block of DNA replication and transcription to RNA
NOTE: IUSM TEACHER SAYS THAT MECH UNKNOWN, BUT PROB SIMILAR TO CHLOROQUINE
Primaquine
orms quinoline-quinone metabolites, which are electron-transferring redox compounds that act as cellular oxidants — ROS
Antifolates
Ultimately inhibit the production of DNA/RNA synthesis
Sulfonamides
act as antimetabolites of PABA and block folic acid synthesis by inhibiting DIHYDROPTEROATE SYNTHESIS
Pyrimethamine
selective inhibitor of protozoan dihydrofolate reductase
Proguanil (part of malarone?)
bioactivated to cycloguanil which is a selective inhibitor of protozoan dihydrofolate reductase
Amodiaquine
component of malarone
disrupts mitochondrial electron transport in protozoa
Artemisinin and its derivatives
metabolized in the food vacuole of the parasite, forming toxic free radicals
Metronidazole and tinidazole
not definitively known - Katzung says it undergoes a reductive bioactivation of its nitrogroup by ferredoxin to form reactive cytotoxic products
METRONIDAZOLE INTERACTS WITH ALCOHOL IN THAT ACETALDEHYDE ACCUMULATES
Benzimidazole
–which drugs are in this class?
binds tubulin - inhibits the polymerization of microtubules
Albendazole
Mebendazole
Thiabendatzole
Ivermectin
Why this this selective?
intensified GABA-mediated neurotransmission; paralyzes microfilariae; faciliates microfiliare removal by RES via cytotoxic cells (allows them to adhere)
selective b/c it doesn’t cross BBB
Pyrantel pamoate
stimulates nicotinic receptors present in NMJ of nematodes - neuromuscular blocking agent; causes realease of Ach and inhibition of cholinesterase; worms are paralyzed and expelled
Praziquantel
increases membrane permeability to calcium, causing marked contraction initially and then paralysis of trematode and cestode muscles (…but IUSM teacher also said it is used for nematodes)
Penicillins
Beta-lactam antibiotics inhibit transpeptidases that “glue” the peptidoglycan strands together by cross-linking (transpeptidase that cross-links the peptidoglycan strands)
Katzung:
1. Binding of the drug to specific enzymes (penicillin-binding proteins) in bacterial cytoplasmic membrane 2. Inhibition of transpeptidation reaction that cross-links the linear peptidoglycan chain constituents of the cell wall 3. Activation of autolytic enzymes that cause lesions in the bacterial cell wall
Vancomycin
Inhibits Gram+ cell wall synthesis
binds to peptidyl side change D-ala-D-ala terminus in the peptidoglycan precursor (before cross-linking)
Note: similar result as with B-lactams, but different mechanisms
What drugs inhibit microbial protein synthesis?
- Chloramphenicol
- Tetracycline
- Macrolides
- Telithromycin
- Clindamycin
- Streptogramins
- Linezolid
Macrolides
inhibit protein synthesis by binding reversibly to the P site of the bacterial ribosome, thereby inhibiting translocation of peptidyl-tRNA from the A site to the P site (inhibit transpeptidation)
mainly invovles binding to 23S RNA, NOT the ribosomal protein
Aminoglycosides
KATZUNG: Bind to the 30S ribosome and interfere with protein synthesis in at least 3 ways
○ Block formation of the initiation complex
○ Cause misreading of the code on the mRNA template
○ Inhibit translocation
CUSHMAN: binds to 30 ribosomal subunit, specifically the 16S rRNA forming the A site
○ Interferes with formation of the initiation complex, blocks further translation, and elicits premature termination
○ Impairs proofreading function
○ Selection of wrong aminoacids during translation causes formation of “nonsense proteins”
Examples of aminoglycosides
Kanamycin A
Gentamycin
Streptomycin
Streptogramins
Quinupristin - binds to the ribosomal tunnel and causes blockage of the tunnel
Dalfopristin - directly interferes with the peptidyl trasnferase-catalyzed step in peptide synthesis
Synercid = Quinupristin (30%) + Dalfopristin (70%)
Clindamycin
Similar to that of the macrolide antibiotics like erythromycin
It inhibits protein synthesis by binding to the bacterial 50S ribosome (It binds to the same site as erythromycin)
Antagonism and cross-resistance between clindamycin and erythromycin have been reported
Tetracycline
Bind to the 30S ribosomal subunit and inhibit bacterial protein synthesis by blocking the attachment of the aminoacyl-tRNA to the A site of the ribosome, resulting in termination of peptide chain growth. More precisely, they are inhibitors of the codon-anticodon interaction.
Chloramphenicol
Binds reversibly to the 50S ribosomal subunit at a site that is near the site for erythromycin and clindamycin (competitive binding interactions occur among these drugs)
It inhibits the peptidyl transferase activity of the ribosome and thus blocks peptide bond formation between the P site and the A site
Linezolid (an oxazolidinone)
interacts with the 23S rRNA of the 50S ribosome
prevents the formation of the initiation complex
Trimethamine
Inhibits dihydrofolate reductase
Quinolones
Interfere with bacterial DNA synthesis by inhibiting topoisomerase II — this blocks DNA religation
What do B-lactams do?
Acylate the transpeptidase Ser residue in the enzyme active site to form a stable product
inhibits peptidoglycan cross linking –> bacterial cell wall
cell wall subject to osmotic stress
