my qestions on mid 2 pharma

• discribe the way the fungi devolpe resistance to polyene antibiotic

  they change their cell membrane content by decreasing ergosterol or replace it with other sterols
• what are the SE of amphotericin

  • fever+chills , neurologic effect (if it is taken intrathecal), thrombophlebitis, nephrotoxicity(low GFR, acidosis, low K+'hypotention'), suppretion of the bone marrow normochromic, normocytic anemia
• what is the most toxic antifungal ?

  amphotericin
• which antifungal is limited to life threating systmatic infection

  amphotoricin B
• why giving small doses of amphotoricin B before the original dose

  asses the dgree of a patient's negative responses (anaphlaxis or convulsion)
• to achieve fungicidal effect in the CSF we use combination of

  amphotoricin B and flucytosine
• what is the drug of choice for the treatment of life-threating systemic mycoses

  amphotoricin B
• what is the resouse of amphotoricin B

  streptomyces nodosus
• antifungal MOA

  cell membrane (polyene antibiotic: amphotoricin and nystatin), ergosterol synthesis(azol) or lanosterol (-fine), nucleic synthesis (antimetabolite : 5-flucytosine), mitotic spindal (griseofulvin), cell wall (-fungin)
• in what case does the amphotoricin cause neurologic effect

  when it is taken intrathral
• how can we over come the fever caused by amphotoricin 


  give antipyretic and coticosteroid
• the kinetics of amphotoricin (3)

  insuloble in water(not cross CSF, peritoneal, vitreous, amniotic)(infution slowly with large amount of saline or given in lipoosome formelation), 90% bound to plasma protein, metabolized SLOWLY in liver and excretd in urine
• which antifungal cause the formation of transmembrane pores

  polyene antibiotics
• how can polyene antibiotics form transmembrane

  binding with the ergosterol by lipophilic part and the hydrophilic parts create pore
• which polyene antibiotics not used parenterally

  nystatin
• what is the uses of nystatin

  • orally for oropharyngeal candidiasis
  • intraviginally for vulvoviginal candidiasis
  • topically for cutaneous candidiasis
• which antifungal is teratogenic

  azoles
• how do azoles work

  bind to (cytochrome P450 lanosterol 14a demethylase enzyme)

  which means inhibit the convertion of lanosterol to ergosterol
• azoles activity

  fungi-statis
• what is the cross-reactivity of azoles

  also inhibit the host CYP450 which cause drug interactions and impairment of steroidogenesis
• first azoles orally active is

  ketoconazole
• ketoconazole spectrum

  broad

  orally covers all fungi EXCEPT aspergillus sp.

  topically covers tinea inf., cutaneous candidiasis, seborrheic dermatitis, dandruff
• what is the resistance of ketoconazole

  mutation in c-14a-demethylase binding site + efflux pump
• ketoconazole kinetics (3)

  Absorption in acid environment (antacid, H2Blocker, PPI REDUCE absorption)(cola INCREASE absorption)

  Distribution, no CSF, highly bound to plasma protein

  Elimination in BILE and Metabolise EXTENSIVLY in LIVER
• ketoconazole strongly inhibit

  gonadal + adrenal steroid
• why we shloud not use ketoconazole with amphotoricin B togather

  Because ketoconazole decrease ergosterol so reduce amphotoricin B action (no ergosterol to bind to)
• ketoconazole SE

  GI disturbances

  Endocrine; male: gynecomastia, oligospermia, low libido. female: menstrul irregulation, amenorrhea

  Hypersensitivity

  Hepatotoxicity; elevation in liver enzymes
• which azole lack of endocrine SE

  fluconazole
• fluconazole spectrum

  orally for cutaneaus candidiasis and vaginal candidiasis

  IV for systemic; candidiasis and coccidiodal meningitis
• fluconazole kinetics (3)

  absorption not necessary acid

  minimal binding to plasma protein

  poorly metabolized
• why does fluconazole clinically important

  no endocrine SE + cross CSF
• flucytosine exert what type of activity

  fungicidal
• 5-flucytosine is an analog to

  pyrimidine
• what is the MOA for flucytosine

  antimetabolite; 1- enters the fungi cell via permease enzyme

  2- converted into active form 5-fluorodeoxyuridine 5'-monophasphate(5-FdUMP)

  3- 5-FdUMP binds to thumidylate synthase + inhibite it so disrupting the nucleic acid
• flucytosine spectrum

  previously known as anticancer; NOW used for

  cryptococcus + candida --> causing systemic mycoses + fungal meningitis
• to increase the fungi cell permeability and pentration we use synergism of

  5-FC and Amphotoricin B
• what type of resistance is devolped for 5-FC

  decrease permease and deaminase OR increase synthesis of cytosine
• 5-FC kinetics

  orally absorbed , distributed CSF
• 5-FC SE

  GI disturbance + bone marrow supression(neutropenia and thrombocytopenia) + alopecia + hepatic dysfunction