Summary of mechanisms and indications of anti fungal drugs

1. Module 00

2. Antifungal drugs
By Nehal M. Ramadan (MSc & PhD)
Lecturer of clinical pharmacology
Faculty of Medicine, Mansoura University, Egypt

3. Contact Information
Official Email : nehalpharma@mans.edu.eg
Mobile (Optional) 01113397935
Academic Hours : ( Monday : 10:00 am-1:30 pm)
( …day : 00:00-00:00 am)

4. Learning Outcomes
1. Categorize different antifungal drugs into classes based on their mech.
Of action.
2. Describe mech. Of action, pharmacokinetics, drug interactions, and side
effects of different antifungal drugs
3. Describe briefly main clinical uses of different antifungal drugs
1. Use side effect and drug interaction data to solve a clinical correlate
ext

5. Case Scenario
A 24-year-old man presents to the emergency department reporting chest pain and a
nonproductive cough that began approximately 1 week ago. His symptoms are progressing, and
he now has a low-grade fever, productive cough, hemoptysis, weakness, and anorexia. A chest x-
ray reveals an infiltrate in the upper left lobe of the lungs, and culture and staining of deep
sputum reveal fungal elements of Blastomyces dermatitidis. The patient was started on an
intravenous antifungal. Two weeks later, the patient's serum creatinine was significantly
elevated to 3.0 mg/dL. Which of the following antifungal agents was most likely prescribed for
this patient?
• A. Caspofungin.
• B. Colloidal amphotericin B.
• C. Flucytosine.
• D. Itraconazole.
• E. Voriconazole.

6. Mechanism of action
1
2
3
4
5
6

7. Antifungal drug resistance
Drug Mech. of resistance
Azoles ● ↑ azole efflux
● ↑ production of lanosterol-14α-
demethylase.
● A point mutation in the gene encoding
for lanosterol-14α-demethylase, ERG11
Polyenes ↓ membrane ergosterol/Fungi that lack
ergosterol
Echinocandins Mutations in various subunits of the β-(1,3)-D-
glucan synthase enzyme.
Flucytosine ● Fungus lacks permease
● ↓ cytosine deaminase, or ↓ UMP
pyrophosphorylase enzyme.

8. Clinical uses
Drug Systemic/subcutaneous infections Dermatophytes infections Mucocutaneous
Amphotericin
B
most pathogenic fungi, e.g. Candida, Cryptococcus,
Histoplasma, and Aspergillus species
Nystatin Candida and Fusarium
infections
Clotrimazole Epidermophyton, Microsporum, and
Trichophyton species
Candida infections
Econazole Same as clotrimazole Candida species and
Malassezia furfur (tinea
versicolor)
Fluconazole Candida species and Cryptococcus neoformans Candida infections
Itraconazole Blastomyces, Histoplasma, Sporothrix infections Same as clotrimazole
Ketoconazole Seborrheic dermatitis
Posaconazole Invasive aspergillosis (salvage therapy),
mucormycosis, and Candida infections
Voriconazole Invasive aspergillosis and Candida infections
Superficial

9. Drug Systemic/subcutaneous infections Dermatophytes infections Mucocutaneous
Naftifine and
terbinafine
Same as clotrimazole
Echinocandins Candida infections and aspergillosis (salvage therapy)
Flucytosine With amphotericin B for cryptococcal meningitis
Griseofulvin Tinea capitis and other dermatophyte
Ciclopirox Same as clotrimazole Tinea versicolor
Superficial
Drugs used in the treatment of systemic‫ظ‬subcutaneous mycoses
● A polyene → amphotericin B,
● Azoles → flu, itra, posa, and voriconazole
● Echinocandins
● Flucytosine.
Amphotericin B → used for severe mycoses
Azoles → used for less severe infections.
Newer antifungal agents (e.g., posa, voriconazole, and caspofungin) → salvage therapy to treat invasive Candida and
Aspergillus infections.
Flucytosine → administered + amphotericin B → synergism → treatment of systemic Cryptococcus or Candida infections.
Clinical uses

10. Pharmacokinetics
Drug Route Oral bioavailability Elimination
Amphotericin B IV, oral, intrathecal,
intraventricular, topical
No Hepatic metabolism →
renal
Nystatin Topical No
Clotrimazole Topical No
Econazole Topical No
Fluconazole Oral, IV Good Renal
Itraconazole Oral ?? Hepatic metabolism
Ketoconazole Oral, topical ?? Hepatic metabolism
Posaconazole Oral, IV ?? Hepatic metabolism
Voriconazole Oral, IV Good Hepatic metabolism
Terbinafine Topical, oral Hepatic metabolism
Echinocandins IV No Hepatic metabolism
Flucytosine Oral Good Renal
Griseofulvin Oral, topical Poor Hepatic metabolism
CSF
Gastric
acidity

11. Drug interactions
1. Increased nephrotoxicity → amphotericin B + other nephrotoxic agents such as
cyclosporine, aminoglycosides, or NSAIDs
2. Azoles inhibit human CYP3A4 → cause drug interactions.
Affected drugs include;
● Statins
● some benzodiazepines
● Quinidine
● Warfarin.
● Phenytoin
● Digoxin
Fluconazole has less affinity for human CYP450 enzymes → causes fewer drug
interactions
1. Terbinafine inhibits CYP2D6 → ↑ plasma levels of tricyclic antidepressants, selective
serotonin reuptake inhibitors.
2. Griseofulvin induces CYP3A4 → reduce plasma concentrations of warfarin, oral
contraceptives, and barbiturates..

12. Adverse
effects
Drug Adverse effects
Amphotericin B Nephrotoxicity, hepatotoxicity, arrhythmias, anemia, leukopenia, thrombocytopenia, infusion-related
reactions → pretreat with steroids, antipyretics and anti H1
Clotrimazole Rash, hepatotoxicity, GIT
disturbances
Econazole
Fluconazole Increased risk of birth defects
Itraconazole -ve inotrpic → avoid in ptn with HF
Ketoconazole Inhibits steroid synthesis
Posaconazole
Voriconazole Visual disturbances (altered perception of light, chromatopsia,
photophobia), hepatotoxicity, teratogenic
Terbinafine Rare → rash, hepatotoxicity
Echinocandins Headache, fever, phlebitis, mild hepatotoxicity
Flucytosine Anemia, mild hepatotoxicity
Griseofulvin Rare → headache, dizziness, rash, hepatitis, leukopenia, teratogenic

13. Summary & Wrap up
Antifungal drugs can be classified into:
a. Allylamines → terbinafine and naftifine
b. Azoles →
• imidazoles → miconazole and ketoconazole,
• Triazoles → voriconazole and fluconazole.
c. Polyenes → amphotericin B and nystatin.
d. Echinocandins → caspofungin, micafungin, and anidulafungin
e. Others → Flucytosine, Griseofulvin, and Ciclopirox
Amphotericin B → used for severe mycoses
Azoles → used for less severe infections.
Newer antifungal agents (e.g., posa, voriconazole, and caspofungin) →
salvage therapy to treat invasive Candida and Aspergillus infections.
Flucytosine → administered + amphotericin B → synergism → treatment of systemic
Cryptococcus or Candida infections.

14. Questions
2
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4
Question 1
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Question 2
Answer
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Question 3
Answer
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Question 4
Answer
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15. Discussion & Feedback
10 minutes

16. References
1. Rodrigues, M. (2018). The Multifunctional Fungal Ergosterol. MBio, 9.
https://doi.org/10.1128/mBio.01755-18
2. Brenner, G. Antifungal Drugs. In Stevens, C., & Brenner, G. (2018). Brenner
and Stevens’ Pharmacology (5th Edition). Chapter 42, 475-482. Elsevier
Health Sciences (US).
https://clinicalkeymeded.elsevier.com/books/9780323391665
3. Wecker, L. ([Insert Year of Publication]). Brody's Human Pharmacology (6th
Edition). Elsevier Health Sciences (US).
https://clinicalkeymeded.elsevier.com/books/9780323476522
4. Whalen , Feild, Carinda,, Radhakrishnan, Rajan,, K. (2019). Lippincott
illustrated reviews: pharmacology.
5. Revie NM, Iyer KR, Robbins N, Cowen LE. Antifungal drug resistance:
evolution, mechanisms and impact. Current Opinion in Microbiology. 2018
Oct;45:70-76. DOI: 10.1016/j.mib.2018.02.005. PMID: 29547801; PMCID:
PMC6135714.

17. References
1. Rodrigues, M. (2018). The Multifunctional Fungal Ergosterol. MBio, 9. https://doi.org/10.1128/mBio.01755-18
2. Brenner, G. Antifungal Drugs. In Stevens, C., & Brenner, G. (2018). Brenner and Stevens’ Pharmacology (5th
Edition). Chapter 42, 475-482. Elsevier Health Sciences (US).
https://clinicalkeymeded.elsevier.com/books/9780323391665
3. Wecker, L. ([Insert Year of Publication]). Brody's Human Pharmacology (6th Edition). Elsevier Health Sciences
(US). https://clinicalkeymeded.elsevier.com/books/9780323476522
4. Whalen , Feild, Carinda,, Radhakrishnan, Rajan,, K. (2019). Lippincott illustrated reviews: pharmacology.
5. Revie NM, Iyer KR, Robbins N, Cowen LE. Antifungal drug resistance: evolution, mechanisms and impact.
Current Opinion in Microbiology. 2018 Oct;45:70-76. DOI: 10.1016/j.mib.2018.02.005. PMID: 29547801;
PMCID: PMC6135714.