Antifungal Drugs

Question 1

What are the targets of antifungal drugs?

Answer 1

Cell wall synthesis-Echinocacandins
Cell membrane-Polyenes, azoles and allylamines
Nucleic acid synthesis-Flucytosine
Mitosis- Griseofulvin

Question 2

What are the characteristics of Echinocacandins?

Answer 2

Drugs specific to fungal cell wall inhibition
Called penicillins of antifungals
Drugs end in «fungin»
Capsofungin- most commonly used
Anidulafungin
Micafungin

Question 3

What is the MOA of echinocacandins?

Answer 3

Inhibits the beta 1,3 glucan synthase located on the cell membrane and thus block the cell wall glucan synthesis

Question 4

What is the clinical use and pharmacokinetics of echinocacandins?

Answer 4

Works in candida (yeast)-fungicidal
Aspergillus (mold)-fungistatic
For esophageal and invasive candidiasis if not response to azol-Not used as a first drug
Well tolerated drug
IV administration, poor oral availability

Question 5

What are the characteristics of Capsofungin?

Answer 5

Very effective in treating candida and aspergillus
For refractory aspergillosis
For patient who are intolerant of other antifungal drugs
AE: infusion related chills, headache
CI: avoid using with cyclosporine (immunosuppressant drug)
PK: dose adjustment needed in hepatic impaired patients
Resistance reported in patients with candida albicans infections

Question 6

What are the characteristics of Anidulafungin and Micafungin?

Answer 6

Anidulafungin has the longest half life of 48 hours
Micafungin is used as a prophylaxis for candida infections in neutropenic patients (HIV and cancer patients)
AE: cause histamine release with cyclosporins and sirolimus

Question 7

What are the characteristics of polyenes?

Answer 7

Fungicides
Inhibit fungal cell membrane
Antifungal agent made from bacteria streptomyces nodosus
Examples: Amphotericin B, Nystatin

Question 8

What is the MOA of Amphotericin B?

Answer 8

Most species fungi are susceptible to it
Lipophilic molecule passes through the fungal cell wall and binds to ergosterol
Aggregates in the ergosterol leads to micropore formation
Rapid leakage of monovalent ions
Cell lysis and death
Stimulates also oxidation dependent macrophages

Question 9

What are the clinical uses and PK of Amphotericin B?

Answer 9

For life threatening systemic fungal infections
Despite side effects, drug of choice for most serious systemic fungal infections
PK: oral slow IV infusion
has a minimum oral absorption
Poor CNS penetration but increase when inflammed
40% of drug excreted in urine over a 7 day period
May be detected for at least 2 months after discontinuation

Question 10

What are the AE and CI of amphotericin B?

Answer 10

Renal toxicity, nephrotoxicity
Vasoconstriction of glomerulus and distal tubule leading to azotemia (high N2 in blood) and anemia (erythropoietin secreted in glomerulus)
Infusion induced chills, aches ( in hospital aspirin given along for prevention)
Usage contraindicated with other nephrotoxic agents like cisplatin, cyclosporin, tacrolimus, aminoglycoside and NSAID

Question 11

What are some less toxic formulations in place of amphotericin B?

Answer 11

Liposomal AmB
AmB lipid complex
AmB colloidal

Question 12

What are the characteristics of Nystatin?

Answer 12

Chemical structure almost identical to amphotericin B
Drug of choice for oroesophageal thrush
Minimally toxic when given topically
No absorption through mucus membrane or intact skin
Topical for diaper rash and vaginal candidiasis
ora use by swish and swallow for oral thrush
Never given IV due to toxicity for systemic
MAin AE is GI disturbance

Question 13

What are the characteristics of azoles?

Answer 13

Inhibit cell membrane
Contain 2 groups: Imidazoles and Triazoles
Drugs end in «azole»
Examples: fluconazole, itraconazole, ketoconazole, voriconazole
For topical use only: miconazole and clotrimazole

Question 14

What is the MOA for azoles?

Answer 14

Inhibit ergosterol synthesis causing cell lysis
Lanosterol is the precursor to ergosterol
demethylation of lanosterol produce ergosterol
Demethylation required 14 alpha demethylase attache dto cytochrome P450
Azole binds to enzyme and blocks lansoterol binding resulting in ergosterol depletion

Question 15

What are the characteristics of ketoconazole?

Answer 15

First oral drug introduce into clinical use
Primarily used topically
Not used for systemic infections
Occasionally used in prostate cancer with anti androgen activity
Main AE are CYP inhibition and hepatotoxicity
Most toxic drug in the azole group but safer than Amphotericin B
No longer used in the USA for nail and skin infections

Question 16

What are the characteristics of Itraconazole?

Answer 16

Used for dimorphic fungi
Extensively used for dermatophytoses and onychomycosis
Not recommended for systemic infections
Carrier molecule cyclodextrin use to enhance solubility dueto its reduce bioavailability
Interact with Cytochrome P450 but lesser than ketoconazole
Main AE are hypertension, hypokalemia, edema, cardiac suppression, liver injury
Reduce bioavailability when taken with Rifampin

Question 17

What are the characteristics of Fluconazole?

Answer 17

Used for fungal meningitis
High degree of water solubility,high oral availability
Very good CSF penetration
Only azole strictly eliminated by urine
First line for stable patients with candidemia
Used for most stable patients with candida albicans
Most commonly used for mcocutaneous candidiasis
Secondary prophylaxis of cryptococcal meningitis
No activity against aspergillus

Question 18

What are the characteristics of voriconazole?

Answer 18

Excellent activity against candida species including fluconazole resistant species like candida krusei
For invasive aspergillus infection
Active against both yeast and mold
Bioavailability exceeds 90%
Inhibit CYP3A4- required dose reduction when used with cyclosporine or tacrolimus
AE are neurotoxicity, visual changes, photosensitivity

Question 19

What are some other azoles?

Answer 19

Posaconazole- only azole with activity against mucorales, used as a step down therapy after initial improvement with amphotericin B
Miconazole and clotrimazole - primarily for treatment of superficial mycoses
Azole AE: hepatotoxicity is common to all azoles
Drug interactions with Warfarin, Rifampin, and most anti seizure medications

Question 20

What are the allylamines drugs?

Answer 20

Inhibit cell membrane
Naftifine
Terbinafine

Question 21

What are the characteristics of Naftifine?

Answer 21

Topical cream for dermatophyte (athlete’s foot, ringworm of the groin and the body)
Has triple action: anti bacterial, anti fungal and anti inflammatory
excreted in urine and feces

Question 22

What are the characteristics of Terbinafine?

Answer 22

Oral drug for onychomycosis
Well tolerated drug with less toxicity, superior to itraconazole
First line therapy due to minimal nephrotoxicity
Inhibit ergosterol synthesis by inhibiting squalene epoxidase
Squalene epoxidase catalyze squalene to squalene epoxide which gives lanosterol
High intracellular squalene toxic to fungi
AE is mild GI upset

Question 23

What is the MOA for Flucytosine?

Answer 23

Inhibits fungal DNA (fungistatic)
Narrow spectrum of action
Pro drug that selectively inhibits DNA and RNA synthesis in fungi
Inside fungal cells flucytosine is converted to 5-fluorouracil (5-FU)
5-FU inhibits thymydylate synthase enzyme resulting in thymine less fungal cells

Question 24

What are the indications and AE of Flucytosine?

Answer 24

Used for cryptococcus and chromoblastomycosis infections
Almost entirely excreted in urine
Develop resistance easily, used as a combination drug with amphotericin B
Causes myelosuppression due to anticancer activity of 5-FU which inhibits DNA synthesis in human cells
Systemic toxicity in host due to DNA and RNA effects

Question 25

What is the MOA for Griseofulvin?

Answer 25

Inhibits mitosis
Have 2 mechanisms
In humans: The drug is deposited in the newly formed keratinocytes and binds to keratin protein thus protect the skin from new infections
In fungi: the drug irreversibly binds to the microtubule of fungi and prevent spindle formation and mitosis

Question 26

What are the indications of Griseofulvin?

Answer 26

Only used in the systemic dermaphytosis
Administered as microcrystalline oral form
Administered 2-6 weeks for skin and hair infections