C4

Question 1

Antifungal drugs?

9

Answer 1

• Clot.RimaZol (ريما)
• Fluconazol
• Itraconazol
• Voriconazol
• Caspofungin (فنجان)
• Flucytosin
• Terbinafine
• Nystatin
• Amphotericin B

Question 2

what about Amphotericin B?

Answer 2

Amphotericin B is a polyene Abx related to nystatin

Question 3

Amphotericin B PharmacoKinetix?

Answer 3

• administered I.V. in 3 forms poorly (absorbed from G.I.T)
  1. nonlipid colloidal suspension
  2. lipid complex
  3. liposomal formulation (less nephrotoxic)
• IV for systemic infection
• topical for ocular/bladder infections
• distribution: all tissues (except CNS)
• Elimination: slow hepatic metabolism
  ( a bit in urine)
• 1/2 life: ± weeks

-

Question 4

Amphotericin MOA?

Answer 4

• fungicidal
• affect the permeability and transport properties of fungal membranes
• bind to Ergosterol (cell membranes) –> leaky pores
• Resistance: uncommon, occurs if membrane ergosterol level or structure decrease

Question 5

Amphotericin B Clinical uses?

Answer 5

• used for initial induction regimens before Azole
• widest Antifungal spectrum
• drug of choice, or codrug of choice, for most systemic mycosis infection caused by (Aspergillus, Candida , Cryptococcus, histoplasma)
• given by slow I.V.

Question 6

Amphotericin Toxicity?

Answer 6

Nephrotoxicity is dose limiting
Neurotoxicity

infusion rxn ( chills, fever, muscle spasm, hypotension)

Question 7

Amphotericin B I.V. Infusion related toxicity?

Answer 7

• fever
• chills
• muscle spasms
• vomiting
• hypotension (shock-like fall in blood pressure)
• effects can be attenuated by: slow infusion rate and premedication with antihistamines, antipyretics, glucocorticoids*

Question 8

Amphotericin B dose limiting toxicity?

Answer 8

• decreases the GFR + RTA renal tubular acidosis (with magnesium and potassium wasting)
• Anemia: decrease of erythropoietin formation
• Liposomal formulations have reduced nephrotoxic effects

Question 9

Amphotericin B Neurotoxicity toxicity?

Answer 9

Intrathecal administration –> seizures and neurologic damage

Question 10

what about Flucytosine?

Answer 10

pyrimidine antimetabolite related to the anticancer 5-FU

Question 11

Flucytosin PharmacoKinetix?

Answer 11

• Bioavailability: effective orally
• distribution: most body (also CNS)
• Elemination: intact in the urine
  (dose must be reduced in patients with renal impairment)

Question 12

Flucytosine MOA?

Answer 12

Inhibits DNA , RNA polymerases

• membrane permease –> accumulate the drug in fungal cells –> converted by cytosine deaminase to –> 5-FU –> inhibits thymidylate synthase
• Resistance can occur rapidly if flucytosine is used alone
• When 5-FC is given with amphotericin B/ itraconazole –> emergence of resistance is decreased and synergistic antifungal effects may occur

Question 13

Flucytosine clinical uses?

Answer 13

• antifungal spectrum of 5-FC is narrow
• limited to the treatment in combination with amphotericin B / itraconazole
• used against:
  1. synergistic with Amphotericin B in Candidemia , cryptococcus neoformans
  2. molds (for chromoblastomycosis)

Question 14

Flucytosine Toxicity?

Answer 14

• Prolonged high plasma LvLs:
  1. reversible bone marrow depression
  2. alopecia
  3. liver dysfunction.

Question 15

Azole Antifungal agents?

FIV(5)

Answer 15

• Fluconazol
• Itraconazol
• Voriconazol
• Clotrimazole

Question 16

Azoles MOA

Answer 16

• inhibit fungal P450 dep- enzymes blocking ergosterol synthesis –> interfere with membrane permeability
• resistance with long-term use azoles (long-term prophylaxis in immunocompromised and neutropenics)

Question 17

Azoles PharmacoKinetix?

Answer 17

• Bioavailability: orally absorbed
• distribution: most body tissues
  (fluconazole has excellent CNS penetration (fungal meningitis)
• metabolism and elimination:
• -> Liver for Itra, Vori, clotrimazole
• -> kidney for Fluco (unchanged in urine)

Question 18

Fluconazole clinical uses?

Answer 18

• Blastomycosis
• alternative drug in candidemia and infections caused by aspergillus, blastomyces, cryptococcus, histoplasma
• treatment and secondary prophylaxis against cryptococcal meningitis (bcz excellent CNS penetration)
• Esophageal and Oropharyngeal candidiasis and most infections by Coccidioides
• A single oral dose usually eradicates vaginal candidiasis
• alternative drug (with amphotericin B) in active Cryptococcus neoformans

Question 19

Itraconazole clinical uses?

Answer 19

• systemic infections:
  Blastomycosis and Sporothrix
• alternative agent against Aspergillus, Coccidioides, Cryptococcus
  Esophageal candidiasis
• subcutaneous chromoblastomycosis
• used in dermatophytoses (especially onychomycosis)

Question 20

Voriconazole clinical uses?

Answer 20

• wider spectrum than itraconazole
• against invasive aspergillosis
• alternative drug in candidemia
• in AIDS patients: candidal esophagitis and stomatitis

Question 21

Azoles Toxicity?

Answer 21

• vomiting
• diarrhea
• rash
• hepatotoxicity (preexisting liver dysfunction)|
• Voriconazole causes immediate but transient visual disturbances including blurring of vision of unknown cause in more than 30% of patients
  + CLASS D risk in pregnancy

Question 22

Echinocandins example?

Answer 22

Caspofungin

Question 23

what about Caspofungin ?

Answer 23

echinocandin

Question 24

Caspofungin pharmacoKinetix?

Answer 24

• Bioavailability: I.V.
• distribution: widely to the tissues
• elimination: hepatic metabolism
• 1/2 life: 9–12h

Question 25

Caspofungin MOA?

Answer 25

- fungicidal | - inhibits Beta-glucan synthase --> inhibits synthesis of beta-Glucan (fungal cell walls)

Question 26

Caspofungin Clinical uses?

Answer 26

- used for disseminated and mucocutaneous Candida infections - salvage therapy in aspergilosis - mucormycosis * used after fail to respond to amphotericin B*

Question 27

caspofungin Toxicity?

Answer 27

- well tolerated - Infusion-related: 1. Hepatotoxicity 2. G.I.T distress 3. fever 4. rash 5. flushing (histamine release) 6. headahce *Combined use of echinocandins with cyclosporine may elevate liver transaminases*

Question 28

Terbinafine MOA?

Answer 28

- fungicidal | - inhibit epoxidation of squalene --> accumulation of toxic levels of squalene--> interfere with ergosterol synthesis

Question 29

Terbinafine Clinical uses?

Answer 29

- oral (DOA: weeks ). / topical - accumulates in keratin - used in muco-cutaneous fungal infections. - effective in onchomycosis

Question 30

Terbinafine Toxicity?

Answer 30

- G.I.T. upsets - rash - headache - taste disturbances

Question 31

Topical Antifungal?

Answer 31

Nystatin

Question 32

what about Nystatin?

Answer 32

- polyene antibiotic | - used topically for superficial infections caused by Candida and dermatophytes

Question 33

Nystatin MOA?

Answer 33

disrupts fungal membranes by binding to ergosterol

Question 34

Nystatin MOA?

Answer 34

disrupts fungal membranes by binding to ergosterol

Question 35

Nystatin clinical uses?

Answer 35

- topically: suppresses local Candida infections | - orally: eradicates GI fungi (if impaired defense)

Question 36

Nystatin clinical uses?

Answer 36

- topically: suppresses local Candida infections | - orally: eradicates GI fungi (if impaired defense)