Antifungal Agents.pptxAntifungal Agents.pptxAntifungal Agents.pptxAntifungal Agents.pptxAntifungal Agents.pptxAntifungal Agents.pptx

1. Antifungal Agents

2. Important notes on antifungal agents
• MOA: differs from class to other.
• Systemic antifungal drugs:
 Flucytosine
 Amphotericin B
 Caspofungin
• Local antifungal drugs (used topically):
 Fluconazole (IV infusion)
 Fosfluconazole (IV bolus)
 Voriconazole
 Ketoconazole (but removed from markets due to its anti-androgenic effect) ……
Used as a second-line treatment for certain forms of advanced prostate cancer.
 Miconazole
 Clotrimazole
 Ketoconazole
 Naftifine
 Griseofulvin (but used orally for fungal infection in the skin)
 Terbinafine (topically & orally for fungal infection in the skin)
 Nystatin (topical & oral for local fungal infection in the GIT “not absorbed”)

5. Case 1
A. Naftifine B. Flucytosine
C. Fluconazole D. Miconazole
MJ is a 67-year-old male heart transplantation patient receiving immunosuppressive therapy
(cyclosporine and corticosteroids) who was readmitted to the hospital 2 months after his
surgery, complaining of fever, malaise, joint pain and painful oral lesions (white plaques).
Cardiac output and renal function tests were normal, indicating that there were no signs of
tissue rejection. A chest radiograph revealed diffuse lung infiltrates. Blood and throat cultures
yielded Candida albicans. Therapy was initiated for MJ with oral flucytosine. The cardiologist
adds another IV infusion antifungal agent.

6. Question 1:
1. Select, from these antifungal drugs, the most appropriate one for IV (infusion)
administration to this patient. Justify your choice on the basis of structure/solubility
properties.
The correct answer is:
Fluconazole (C) is available in both injectable and oral dosage forms. It has water solubility
of (4 mg/ml), due to the presence of a tertiary hydroxyl group and two triazole rings.
Question 2
2. Regarding the mechanism of action, explain the advantage of combining the drug
you have chosen with flucytosine therapy.
The correct answer is:
The chosen drug fluconazole inhibits lanosterol 14α- demethylase essential for the
biosynthesis of ergosterol in the cell membrane affecting its permeability so allow
more flucytosine to enter into the cell and compensate any resistance to flucytosine
which may be developed………synergism.

7. Question 3:
 Taken up by fungi and metabolized to 5-fluorouracil (5-FU) by fungal cytidine
deaminase.
 Then converted to 5- fluorodeoxyuridine which is a thymidylate synthase inhibitor
so, interferes with protein, DNA and RNA biosynthesis.
 Human cells do not contain cytosine deaminase and therefore do not convert
flucytosine to 5-FU.
 However, some intestinal flora convert the drug to 5-FU so, human toxicity results
from this metabolism.
3. Drug No. B (Flucytosine) is not completely safe to human body, explain.
 Flucytosine itself is not cytotoxic, but rather is a pro-drug which is:

9. Question 4:
4. Suggest another triazole antifungal prodrug could be administered by direct (bolus)
IV injection? (Justify your suggestion)
The correct answer is: Fosfluconazole as fosfluconazole is a prodrug of fluconazole with
increased polarity and water solubility (due to the phosphate group) to be used by IV bolus
injection.

10. Question 5:
5. Modify drug No. C (Fluconazole) to afford a more potent antifungal agent? (Justify
your suggestion)
Voriconazole is more potent than fluconazole; this may be due to the increased
lipophilicity by:
I. Replacing triazole ring with 5-fluoropyrimidine ring (a bioisostere of triazole, as its
N3-atom binds to target Fe atom as well).
Insertion of a methyl group.
II.

11. Question 6:
6. Mention the role of the encircled groups in drugs (C & D).
The five-membered hetero-aromatic ring containing either two nitrogen atoms (Imidazole)
or three nitrogen atoms (Triazole) are essential, as N3 of imidazole & N4 of triazole must be
free to binds to 14 α-demethylase iron atom.

12. Case 2
B.Ketoconazole
A.Clotrimazole
D.Griseofulvin
C.Naftifine
W.U. is 5 years old, she complained from skin infection. Her mother took her to the
dermatologist. She told him that the infection started a week ago, the doctor
diagnosed her with tinea pedis and described a topical antifungal agent.

13. Drug Mode of action
A. Clotrimazole
Inhibition of the enzyme 14 α-sterol demethylase (P-450DM),
which is essential for the biosynthesis of ergosterol, the main sterol
found in the fungal cell membranes. (Topical)
B. Ketoconazole
Inhibition of the enzyme 14 α-sterol demethylase (P-450DM),
which is essential for the biosynthesis of ergosterol, the main sterol
found in the fungal cell membranes. It is systemic antifungal agent
taken by oral route.
C. Naftifine
The inhibition of squalene epoxidase which results in:
 Decreasing the total ergosterol content of the fungal cell
membrane which alters the physical-chemical properties of
the membrane ►►► malfunctions of membrane.
 Accumulation of squalene within the fungal cell which is
itself toxic when present in abnormally high amounts.
D. Griseofulvin
Inhibits fungal cell mitosis by disrupting mitotic spindle formation
and thereby inhibits cell division. Griseofulvin may also interfere
directly with DNA replication.
Question 1:
1. Identify and comment on mode of action for different drugs.

14. Question 2:
2. Suggest which of the provided drugs could be used as drug of choice (topically) and
which of them could be used orally for treatment of topical infection?
Drug of choice are drugs (A, B and C) clotrimazole, ketoconazole & naftifine (topically).
Used only orally for treatment of topical infection is drug D (Griseofulvin).
Question 3:
3. Mention the main side effects of ketoconazole associated with its systemic
administration.
• Ketoconazole inhibits the human demethylase required for the conversion of
cholesterol to steroid hormones (testosterone & cortisol) so, it has anti-androgenic and
anti-glucocorticoid effects…. So, it could be used topically for ttt of fungal infection.
• Ketoconazole used as a second-line treatment for certain forms of advanced prostate
cancer.

15. Case 3
F.A. is 45 years old male, he was sent to the hospital complaining of headache,
stiff neck, vomiting, sensitivity to light and numbness. Blood and cerebrospinal fluid
are cultured and examined showing that he suffered from cryptococcal meningitis. So,
the physician diagnosed his case as fungal meningitis and prescribed him amphotericin
B and another antifungal agent for his infection.
A. Amphotericin B B. Flucytosine
C. Terbinafine D. Voriconazole

16. Question 1:
1. Select the most suitable antifungal agent to be combined with amphotericin B.
Justify your answer.
The drug of choice is: Flucytosin (drug B).
The justification is:
As the combination of drugs targeting fungal cell membrane (Amphotericin B) with
flucytosine has a synergistic effect → as they help in the permeation of flucytosine
intracellularly where it acts on the nucleus. On the other hand, combination of azoles and
amphotericin B is not warranted as decrease in the ergosterol in the fungal membrane
caused by azoles may reduce the fungicidal action of amphotericin B. In addition,
terbinafine is used topically or orally for local infection only.
Question 2:
2. Select an antifungal agent/s that is not warranted to be combined with amphotericin
B. Justify your answer.
Voriconazole (Azole) is the correct answer.
As Voriconazole is a member of azoles antifungal agents that inhibit the biosynthesis of
the fungal cell membrane that is the main target for amphotericin B reducing the
fungicidal action of amphotericin B.

17. Question 3:
3. Mention the role of the encircled groups in drugs (A, C & D).
Drug No. Role of the encircled group
A (Amphotericin B)
The no. of conjugated double bonds (=) correlates:
1. Directly with antifungal activity. (High activity)
2. Inversely with the degree of toxicity to human. (Low toxicity)
C (Terbinafine)
Allyl amine is the functional group of terbinafine that
responsible for its mode of action (inhibiting squalene epoxidase,
which is essential for the biosynthesis of ergosterol).
D (Voriconazole)
Increased the potency of voriconazole more than fluconazole;
this may be due to the increased lipophilicity by replacing
triazole ring with 5-fluoropyrimidine ring (a bioisostere of
triazole, as its N3-atom binds to target Fe atom as well).

18. Question 4:
4. Mention the mode of action of compound C (Terbinafine).
It acts by inhibiting squalene epoxidase, which is essential for the biosynthesis of ergosterol,
the main sterol found in the fungal cell membranes→ increase permeability of essential
intracellular ions and accumulation of squalene which is toxic for fungal cells, leading to
cell death.

19. Case 4
A. Nystatin B. Caspofungin
C. Naftifine D. Griseofulvin
A.N. is 25 years old male, he was sent to the hospital complaining of stomach pain,
nausea, vomiting and diarrhea. He admitted that he drunk milk directly from his cow.
He was diagnosed with small intestine fungal overgrowth (SIFO) that spread into his
blood circulation resulted in candidemia. So, the physician prescribed him an oral
antifungal agent for his localized intestinal fungal infection in combination with
another IV antifungal agent for his candidemia.

20. 1. Select the most suitable oral antifungal agent to be used for his local intestinal
infection. Justify your answer.
The drug of choice is: Nystatin (drug A).
The justification is: As it is used to treat local fungal infections lining of the stomach and
intestines. In addition, oral nystatin is not absorbed into bloodstream. Caspofungin (B)
used parenterally only for systemic infection.
On the other hand, naftifine (C) used topically only and griseofulvin (D) used orally for
topical infection in the skin.
Question 2:
2. Select the most suitable IV antifungal agent in this case. Justify your answer.
The drug of choice is: Caspofungin (B).
The justification is: As it is the only drug from the above that could be used to treat systemic
fungal infection.
Question 1:

21. 3. Mention the role of the encircled groups in drug (A).
The no. of conjugated double bonds (=) correlates:
1. Directly with antifungal activity. (Lower activity compared to amphotericin B)
2. Inversely with the degree of toxicity to human. (Higher toxicity compared to amphotericin B)
Question 4:
4. Mention the mode of action of compound B (Caspofungin).
It belongs to a class called echinocandins. The action of echinocandins is based on the inhibition
of β-(1,3)-glucan synthase that builds the fungal cell wall.
Question 3: