Anti Fungals

Front 1

Amphotericin B

Back 1

Naturally occurring polyene produced by steptomyces nodosus

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Amphotericin B: Fungal spectrum

Back 2

Histoplasmosis, Candidia albicans, Cryptococcus neoformans, Aspergillus

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Administration of AmpB

Back 3

Topical or Slow IV

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AmpB: Formulations and why

Back 4

As it’s insoluble, it is formulated into sodium deoxycholate (conventional, more renal toxicity) and liposomes (costly, less renal toxicity)

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AmpB: PK (half life) and (CSF)

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Long half life and Low CSF penetration.

Liposome/inflamed meninges - better CSF penetration

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AmpB: excretion

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Low levels are excreted in the urine and bile over a few days. If sodium deoxycholate formulation causes renal dysfunction: decrease dose by 50%

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AmpB: ADR

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Fevers and Chills

Nephrotoxicity (drink more water)

Hypotension (also, hypokalemia. Give K supplements/careful with digioxin)

Thrombophlebitis

Otoxicity

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AmpB: C/I

Back 8

Not really a C/I. But to monitor LFT for patients with hepatic function as it is shown to reduce metabolic capacity

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Can AmpB be used in pregnancy?

Back 9

Yes. It’s safe for pregnancy and tolerable by neonates. Pregnancy Cat B.

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5-FC: MOA

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Enters via cytosine specific permeases > converted by cytosine deamidase to 5FU (cytotoxic to humans)

1. 5FU > 5fUTP (flurouridinetriphosphate) incorporates into fungal RNA and replaces uridylic acid - X protein synthesis

2. 5FU> 5dUMP(flurodexoxymonophosphate)= potent inhibitor of thymidylate synthase - X DNA synthesis

Front 11

Is 5FC narrow or broad spectrum?

Back 11

Narrow. As only some fungi has cytosine deaminases

Front 12

What combination is effective for candidiasis and crytococcus meningitis?

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AmpB+ 5FC

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Can 5FC be used as a monotherapy?

Back 13

No. Due to increasing resistance against 5FC. Monotherapy is not used. It is always combined with other antifungals.

Use with AmpB allows more penetration of 5FC - more synergistic effect + minimise resistance

Front 14

5FC: Administration?

Back 14

Oral

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5FC: CSF penetration

Back 15

Penetrate well in CSF

Front 16

Renal impairment in 5FC

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Need to be dose adjusted as 80% of 5FC is excreted unchanged in urine. But it also means that is can be mean for UTI

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Resistance against 5FC

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Decrease in levels of any enzymes involved in conversion of 5FC to its metabolites and increased synthesis of cytosine during therapy

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ADR of 5FC

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GI

Bone marrow suppression (monitor leukocytes and platelets weekly)

Hepatotoxcity (monitor ALT and AST)

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MOA of enchinocandins

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Inhibit the activity of glucan synthase complex (prevent formation of B1,3 glucan) resulting in loss of structural integrity of cell wall

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Administration of enchinocandins

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IV

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Enchinocandins PK

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Cannot penetrate CSF

Broad spectrum

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Spectra of Enchinocandins

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Aspergillus, most candida species (including those resistant to azoles)

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Enchinocandins pregnancy cat?

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Cat C

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Enchinocandins antifungal activity

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1st line: invasive candidiasis

2nd line: invasive aspergillosis (after failed/ cannot tolerate azoles and ampB)

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Metabolism of Enchinocandins

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Hydrolysis and N acetylation

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Elimination of Enchinocandins

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Urine and feces

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Benefits of caspofungin

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Don’t need to be dose adjusted in renal impairment (unlike 5FC and AmpB)

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Enchinocandins dose adj in?

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Hepatic dysfunction

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ADR of Enchinocandins

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GIT

Fever and chills

Redness and flushing

Thrombocytopenia

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DDI of Enchinocandins

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Close to ZERO for anidulafubgib and micafungin. Only caspofungin has some interaction with CYP.

Front 31

MOA of azoles

Back 31

Inhibit c14 a-demethylase, prevents the demethylation of lanosterol to ergosterol

Front 32

Fluconazole route of administration

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Oral/IV

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Fluconazole main organism target

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1. Histoplasmosis

2. Blasmomycosis

3. Cryptococcal meningitis

4. VVC (single oral dose)

5. Most form of fungal meningitis

6. Candidemia, mucocutanous candidiasis

Front 34

Distribution of Fluconazole

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Lone half life. Distributed to breast milk. High CSF penetration

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Excretion of Fluconazole

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Excreted unchanged in urine. Need to be dose adjusted in those with renal impairment.

Front 36

ADR of fluconazole

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Hepatotoxicity

QT Prolongation

N/V/H/ rashes

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First line for cryptococcal meningitis

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AmpB+ 5FC

Front 38

First line for invasive candidiasis

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Enchinocandins

Front 39

Itraconazole: Route of administration

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Oral capsule (taken after full meals)

Oral solution (taken in empty stomach)

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Itraconazole: Route of administration

Back 40

Oral capsule (taken after full meals)

Oral solution (taken in empty stomach)

Front 41

Itraconazole is recommended to take with which beverage? (Acc to Inthrani)

Back 41

Coke. As it’s acidic. And abs increases in acidic fluids.

Front 42

What drugs can decrease the bioavailability of Itraconazole?

Back 42

PPI and Antacids

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Indication of Itraconazole

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Broad anti fungal spectrum as compared to Fluconazole.

1. Treatment of blasmomycosis and aspergillosis for patients intolerant to AmpB

2. Onycomycosis

3. Oral solution = oropharnygeal and esophageal candidiasis

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Indication of Itraconazole

Back 44

Broad anti fungal spectrum as compared to Fluconazole.

1. Treatment of blasmomycosis and aspergillosis for patients intolerant to AmpB

2. Onycomycosis

3. Oral solution = oropharnygeal and esophageal candidiasis

Front 45

itraconazole distribution

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Well distributed including bones and adipose tissues

Front 46

Indication of Itraconazole

Back 46

Broad anti fungal spectrum as compared to Fluconazole.

1. Treatment of blasmomycosis and aspergillosis for patients intolerant to AmpB

2. Onycomycosis

3. Oral solution = oropharnygeal and esophageal candidiasis

Front 47

itraconazole distribution

Back 47

Well distributed including bones and adipose tissues

Front 48

Absorption of Itraconazole can be decreased by?

Back 48

PPI/Antacids (as Low pH allows better absorption)

Front 49

Indication of Itraconazole

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Broad anti fungal spectrum as compared to Fluconazole.

1. Treatment of blasmomycosis and aspergillosis for patients intolerant to AmpB

2. Onycomycosis

3. Oral solution = oropharnygeal and esophageal candidiasis

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itraconazole distribution

Back 50

Well distributed including bones and adipose tissues

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Absorption of Itraconazole can be decreased by?

Back 51

PPI/Antacids (as Low pH allows better absorption)

Front 52

Itraconazole’s CNS entry

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Poor

Front 53

Indication of Itraconazole

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Broad anti fungal spectrum as compared to Fluconazole.

1. Treatment of blasmomycosis and aspergillosis for patients intolerant to AmpB

2. Onycomycosis

3. Oral solution = oropharnygeal and esophageal candidiasis

Front 54

itraconazole distribution

Back 54

Well distributed including bones and adipose tissues

Front 55

Absorption of Itraconazole can be decreased by?

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PPI/Antacids (as Low pH allows better absorption)

Front 56

Itraconazole’s CNS entry

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Poor

Front 57

Which two drugs are both eliminated by the urine and feces

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Echinocandins and itraconazole

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Itraconzole is metabolized by?

Back 58

The liver

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Itraconzole is metabolized by?

Back 59

The liver

Front 60

Itraconazole is associated with what toxicity?

Back 60

Cardiac toxicity. Thus avoid in patients with cardiac failure.

Front 61

Voriconazole ROA

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Oral/IV

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Voriconazole ROA

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Oral/IV

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Indications of Voriconazole

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Broad spectrum

1st line: invasive aspergillosis (2:AmpB 3. Echinocandins)

Also: candidia infections

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Voriconazole ROA

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Oral/IV

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Indications of Voriconazole

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Broad spectrum

1st line: invasive aspergillosis (2:AmpB 3. Echinocandins)

Also: candidia infections

Front 66

Viriconazole CSF penetration?

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Good

Front 67

Metabolism of Itraconazole

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By CYP450 enzymes

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Metabolism of voriconazole

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By CYP450 enzymes

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Excretion of Voriconazole

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80% of inactive metabolite in the urine

Front 70

Voriconazole is associated with? (Hint: Inthrani’s story)

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Neurotoxicity (hallucination, dellrium)

Front 71

Mechanism of resistance towards azoles

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Mutations in c14 a demethylase gene > decrease azole binding

Efflux pumps the pump azole out of the cell

Front 72

Mechanism of resistance towards azoles

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Mutations in c14 a demethylase gene > decrease azole binding

Efflux pumps the pump azole out of the cell

Front 73

CYP enzymes that azoles interact with

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Inhibitors of

CYP3A4

CYP2C9

CYP2C19

Eg. Of substrates: warfarin cyclosporin, oral hypoglycelmics

Front 74

Azoles in pregnancy?

Back 74

No. They are all teratogenic.

Front 75

Fluconazole, itraconazole, Voriconazole pregnancy Cat?

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C,C,D respectively

Front 76

Topical azoles are called?

Back 76

Imidazoles

Front 77

Topical azoles are called?

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Imidazoles

Front 78

Imidazoles as topical agents has activity against?

Back 78

Epidermophyton

Microsporum

Trichophyton

Candidia

Malassezia

Front 79

Topical azoles are called?

Back 79

Imidazoles

Front 80

Imidazoles as topical agents has activity against?

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Epidermophyton

Microsporum

Trichophyton

Candidia

Malassezia

Front 81

Topical use of antifungals are associated with?

Back 81

Contact dermatitis and edema.

Vulvar irritation for VVC use.

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Clotrimazole’s therapeutic use

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oral and pharyngeal candidiasis>VVC>cutaneous candidiasis> dermatophyte infection

Front 83

Clotrimazole’s therapeutic use

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oral and pharyngeal candidiasis>VVC>cutaneous candidiasis> dermatophyte infection

Front 84

Clortimazole dosage form

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Cream, lotion. Powder, pessaries, troche

Front 85

Miconazole’s dosage form

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Cream,lotion, powder, oral gel

Front 86

Miconazole’s PK

Back 86

Readily penetrates stratum cor rum of skin and stay >4days

Front 87

Miconazole’s PK

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Readily penetrates stratum cor rum of skin and stay >4days

Front 88

Miconazole’s therapeutic use

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Pedis, Curis, versicolor, VVC

Front 89

Nystatin is a

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Polyene

Front 90

Nystatin is similar to

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Amphotericin B

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Administration of Nystatin

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Orally, swish and swallow or swish and spit

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Administration of Nystatin

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Orally, swish and swallow or swish and spit

Front 93

Nystatin is for?

Back 93

- Oropharngeal candidiasis (thrush) - oral

- Intravaginally for VVC

- Cutaneous candidias -topical

- Broad spectrum for oral and GIT fungal infection

Front 94

Administration of Nystatin

Back 94

Orally, swish and swallow or swish and spit

Front 95

Nystatin is for?

Back 95

- Oropharngeal candidiasis (thrush) - oral

- Intravaginally for VVC

- Cutaneous candidias -topical

- Broad spectrum for oral and GIT fungal infection

Front 96

Why is nystatin not use parenterally?

Back 96

Due to systemic toxicity (acute infusion related adverse effects and nephrotoxicity)

Front 97

Terbinafine’s MOA

Back 97

Inhibit squalene epoxidase, prevent its conversion to lanosterol and biosynthesis of ergosterol.

Accumulation of toxic amounts of squalene results in increase membrane permeability and death of fungal cell

Front 98

Terbinafine is active against?

Back 98

Trichophyton (fungi that cause tinea)

Front 99

Terbinafine is active against?

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Trichophyton (fungi that cause tinea)

Front 100

Oral terbinafine is for?

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Onchomycosis and tinea capitis (griseofluvin,terbinafine,itraconazole)

Front 101

Terbinafine is active against?

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Trichophyton (fungi that cause tinea)

Front 102

Oral terbinafine is for?

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Onchomycosis and tinea capitis (griseofluvin,terbinafine,itraconazole)

Front 103

Topical terbinafine is for?

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P, C, C

Pedis, Corporis and Curis

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Terbinafine’s PK

Back 104

40% bioavailable

Highly protein bound

Deposited on skin, nails and adipose tissues

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Oral terbinafine’s metabolism and excretion

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Metabolites by CYP450 enzymes and excreted in the urine mainly

Front 106

Terbinafine should be avoided in patients with

Back 106

Renal impairment and hepatic dysfuction

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ADR of terbinafine

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GIT, HA, rashes, hepatic failure

Exacerbation of autoimmune disease (SLE)

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Terbinafine pregnancy catergory?

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Cat B.

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Terbinafine pregnancy catergory?

Back 109

Oral- Cat B.

Topical (vaginal) - Cat A.

Front 110

Terbinafine in lactating mums -yes or no?

Back 110

No. It is not recommended in breastfeeding due to its active secretion in milk, dk how safe it is.

Front 111

DDI of terbinafine

Back 111

Increase serum conc with CYP450 inhibitors (azoles)

(Metabolised by CYP450)

Inhibit CYP2D6

Which metabolise BB, SSRI, MAOI