EXAM Flashcards
Most conazoles?
Which one doesnt?
- Lengthen QTc
- But Isavuconazole shortens
Amphotericin B
Spectrum?
Cidal or static?
Toxicity?
- Broad
- Both
- Very toxic
- Nephrotoxic
- Thrombophlebitis (vein clot causes inflammation)
- Fever, shaking, chills, hypotension
Echinocandins
General special properties?
administration?
Metabolism and Excretion?
- The target is so unique that you dont see toxicity with these drugs
- Peptide makes it poorly bioavailable
- Target mutations are common –>relapse is common
- There are no drug interactions
INJECTION
- Slow metabolism
Conazole
MOA
- Block synthesis at a later step than Allylamines
- Blocking P450 resposible for oxidating Lanosterol
- This causes leakage
Pyrazinamide (PZN)
Static or cidal?
DMPK
MOA?
3 things
Toxicity?
Resistance?
Amphotericin spectrum?
Broad pretty much everything.
Second line agents cycloserine and p-aminosalicylic acid (PAS)
Cycloserine MOA, resistance, spectrum
Pamino- Inhibits?, Resistance?
Rifampin
Color?
Sensitive to?
MOA?
Static or Cidal?
Spectrum?
Resistance?
Second line Capreomycin
MOA
static or cidal?
Admin?
Resistance?
Toxicity?
First line treatment of TB needs to do what?
- Block the synthesis of Mycolic Acid and arabinogalactans
WHat other interactions do conazoles have?
Oral bioavailability increases when?
- P-glycoprotein transporters - Mostly the biggers ones
- Increases with increase in acid (isaconazole and posaconazole)
Topical and Supository Conazoles?
- Clotrimazole
- Econazole
- Butoconazole
- Very lipophilic not good for systemic
Bedaquiline (TMC-207)
MOA?
Treatment?
Liposomal targeting of Fungal cell wall?
Selectivity
Role of Liposomes
Toxicities of AmBisome?
- Mammalian have no cell wall
- Attracts to the fungal cell wall - targeting agent
- This makes the drug less nephrotoxic because there is less interaction, renal toxicity can still be seen
Echinocandins MOA?
Interferes with the synthesis of the fungal cell wall
blocks 1,3-B-glucan synthase that converts UDP-glucose to B-D glucan
Ruptures the cell wall
Major coverage and uses of echinocandins (fungins)
- Narrow spectrum
- Candidal infections that are resistant to azoles
- Apergillus infections
- Less common
- Esophageal candidiasis
- Prophylactically in patients undergoing hematopoietic stem cell transplant
Ethionamide
- Similar MOA to INH (mycolic acid synthesis inhibition)
- Only effective against mycobacterium
- Resistance is fast
Amphotericin B
Binding to ergosterol?
- Cation
- Greasy portions bind to each other
Echinocandins resistance?
- Mutation of synthase and/or upregulation of other cell wall components.
Mechanism of action of PZN
- Mechanism of action of pyrazinamide (PZA). PZA enters the bacilli by passive diffusion and is then converted by the nicotinamidase PncA into pyrazinoic acid (POA). POA exits the cell by passive diffusion, as well as by an efflux mechanism, which is not yet well characterized. In their revised mechanism, Zhang and co‐workers show that POA binds RpsA and blocks trans‐translation. Note: for simplicity, only the inner membrane of the mycobacterial cell envelope is depicted.
INH is a ____ that gets converted by ____ then it can inhibit ___
Resistance is common with?
- Prodrug that eventually gets coverted by KatG then it can inhibit INHa
- Mutations in both of these sites pose problems
What are the echinocandins
Caspofungin, Anidulafungin, Micafungin
They are all very similar dont need to know specifics within class
Allylamines?
What do they do?
Cidal or static?
What is their problem?
Inhibit the conversion of squalene to squalene epoxide
Step in Sterol biosynthesis
Effectively block downstream conversion of lanosterol and ergosterol–> Malfunction
Static or cidal depends on the species
Causes build up of squalene
- Membrane tension, faulty membrane
- Build up of squalene
Problem very greasy not good systemically and first pass is an issue.
Not orally available mostly topical use
WHat are the Non-Allylamines squalene epoxidase inhibitors?
- Butenafine - Broader spectrum
- Tolnaftate - Non-prescription preparations for decades.
- Topically used greasy
Isoniazide (INH)
DMPK: Administration?
Distributes on an empty?
Toxicity?
MOA?
Resistance?
Conazole Resistance and Main interaction with drugs and P450?
- Target modification and efflux - This whole thing occurs much more slowly than bacteria
- Interaction with Heme of P450 and Azole nitrogen lone pair.
Coverage of conazoles
Yeast (Candida)
Mold (Asperigillus, Fusarium, Zygomycetes)
- Yeast all- Fluconazole, Itraconazole, Voriconazole, Posaconazole)
- Asperigillus- Itra, Vori, Posa
- Fusarium- Vori and Posa
- Zygo- Posa
How resistant is Restistant TB?
TB
MDR TB
Definition and second line
XDR TB
Amphotericin B
Solubility?
What is it?
Preparation?
Polyene macrolide no bacteria effect
Amphoteric: Acidic carboxyl nd basic primary amino functional groups
Poor water solubility
Prep using emulsifying agents and liposomes
Clinical properties of Rifampin
Usage
Prophylactic usage?
Toxicities?
Interactions?
Name the Allylamines?
Naftifine
Terbinafine (topical and pill)- One example of one that can be used systemically
What are the broad spectrum conazoles?
Vori, Isavu, Posa
What is the general trend with conazoles in terms of spectrum?
Spectrum increases as you go from:
- Fluconazole (No molds)
- Itraconazole
- Voriconazole
- Isavuconazole
- Posaconazole (Broad and best)
Second line and alternative therapies for TB
- Unique second line
- Ethionamide, Cycloserine, PAS, Capremycin, Bedquiline
- Antibiotic classes already discussed
- FQs (levo, oflo, Moxi)
- AGs (kanamycin, amikacin, streptomycin)
- COmbo therapy needs (INH, Pyrazinamide, ethambutol)
Difference between Human and Fungal cells
Sterol they have ergosterol instead of cholesterol
Rifabutin and Rifaximin?
___ Macrolides?
Treatment of?
Rifaximin absorption admin, treats, alternative for?
Standard TB Tx
TB exists in 3 portions:
Six month treatment (___)
7 points
Rationale for Therapeutic Combos
Multiple Targets?
Resistance
Toxicities
- At cell wall mycolic acid and arabanogalactan layer, transcription and translation
- High levels of resistance 3 to 4 durgs to overcome this
- Puts stress on the liver
TB drugs in development
Ethambutol
Only used for?
Static or Cidal?
MOA?
Resistance?
DMPK?
Major Toxicity?
Properties of Rifampin?
DMPK
Metabolism
Excretion?
Conazoles
What do they do?
Ergosterol biosynth inhibitors
Azole group think inhbition of CYP450s
Schematic Diagram of Mycobacterial Cell wall
Or at least the parts that are targeted for TB
8 parts
Antifungal coverage chart
Conazole P450 interactions
3 points to know?
Mechanism of Human P450 interactions?
- All have 3A4
- Voriconazole has the most
- Isavu and Posa have the fewest
Fungin Coverage?
- Good with yeast but variable efficacy with everything else
