2.

12 ANTI-FUNGAL AGENTS PHARMACOLOGY

Dr. Rey Christian Cabreros | October 15, 2018

TRANS GROUP: Tuddao, Unso, Urabe, Urgel LE 2 TRANS 12
TRANS HEADS: Wangkay

OUTLINE

I. Fungal Infection
II. Inhibitors of Ergosterol Synthesis Pathway
A. Allylamines
1. Terbinafine
B. Benzylamines
1. Butenafine
C. Azoles
1. Imidazole
2. Clotrimazole and Miconazole
3. Itraconazole
4. Fluconazole
5. Voriconazole Figure 1. Antifungal targets/selective toxicity. Antifungals can alter
6. Posaconazole and Isavuconazole membrane permeability, target cell wall synthesis, nucleic acid
7. Ravuconazole synthesis, and microtubule functions.
III. Inhibitors of Fungal Membrane Stability
A. Polyenes • Terbinafine: Inhibits first step in ergosterol synthesis
1. Amphotericin B • Azoles: Inhibits second step in ergosterol synthesis
2. Nystatin • Polyenes: Have high affinity for ergosterol in fungal plasma
IV. Inhibitors of Fungal Cell Wall Synthesis
membrane, bind to it causing decreased permeability and pore
A. Echinocandins
1. Caspofungin, Micafungin and Anidulafungin formation 
V. Inhibitor of Fungal Nucleic Acid Synthesis • Echinocandins: Targets β-(1,3)-D-glucans and β-(1,6)-D-
A. Flucytosine glucans sugar polymers forming fungal cell wall, common
VI. Inhibitors of Fungal Mitosis name of this cell wall component is chitin (clue: “chi” in chitin
A. Griseofulvin and echinocandins)
• Flucytosine: Targets nucleic acid synthesis (clue: antibiotic
LEARNING OBJECTIVES
acting on nucleic acid synthesis: fluoroquinolones; antifungal:
flucytosine)
1. Describe the mechanisms of action of the major drugs used for fungal • Griseofulvin: Disrupts microtubule functions.
infections.
2. Describe the clinical uses of Amphotericin B, Nystatin, Flucytosine,
Griseofulvin Fluconazole, Itraconazole, Ketoconazole, Terbinafine and
others
3. Identify the toxic effects of the major anti-fungal drugs.
4. Identify the main oral, topical and IV anti-fungal agents

LEGEND

Remember Lecturer Book Prev. Trans Notes

    

I. FUNGAL INFECTION
• There is an increased incidence of fungal infections in the past
decade. 
• Factors that lead to increasing incidence and severity of
human fungal infections: (make immune system go down)
o Increase use of broad-spectrum antibiotics
o HIV epidemic
o Cancer chemotherapy protocols
o Immunosuppressive therapy
• Patients with higher risk:
Figure 2. Selective toxicity of some representative antifungals.
o Surgical and intensive care unit (ICU) patients
o Patients with prostheses Important criteria for antifungals:
o Patients with compromised immune defenses 1. Broad spectrum of action against a variety of fungal pathogens
o Patients undergone organ transplantation 2. Low drug toxicity
3. Multiple routes of administration
A. Antifungal Agents 4. Excellent penetration into cerebrospinal fluid (CSF), urine, and
bone
• Antifungals can target specific or unique facets of a fungus,
known as selective toxicity. B. Fungal Plasma Membrane
• Limited dosage forms: IV (systemic effect), oral (systemic but • Unique biochemical differences have been exploited in the
first-pass effect), topical (local).  development of antifungal drugs.
o The most important biochemical difference lies in the principal
sterol used to maintain plasma membrane structure and
function.

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o Mammalian cells use cholesterol, fungal cells use ergosterol
o Enzymes to remember:
▪ 1st step: Squalene epoxidase (turn squalene to lanosterol)
− Inhibited by allylamines (terbinafine) and
benzylamines
− Squalene when oxidized becomes free radical and is
toxic to fungus, so squalene accumulation is
fungicidal.
▪ 2nd step: 14-alpha-sterol demethylase (turn lanosterol to
ergosterol)
− Inhibited by azoles
Figure 3. Ergosterol synthesis.
II. INHIBITORS OF ERGOSTEROL SYNTHESIS PATHWAY
A. Allylamines
1. Terbinafine (Lamisil)
• Mechanism: Inhibits Squalene Epoxidase (Figure 3 and 4)
• Oral and topical form
• Elimination half-life is approximately 300 hours
• Accumulates extensively in the skin, nails, and fat
• Clinical Use:
o Orally for Dermatophytosis (Tinea infection) of
corporis, cruris, pedis, capitis
o Up to 90% cure rate for Onychomycosis (infection of the
nail) which is an Epidermophyton genus infection
▪ Drug of choice is Terbinafine (Lamisil) oral form, more
effective than griseofulvin or itraconazole
o Cream or spray: Tinea Pedis, Cruris, & Corporis.
• Adverse Effects:
o GIT disturbance, rash, headaches
o Rarely: Hepatotoxicity, SJS, neutropenia
B. Benzylamine
Benzylamines are structurally similar to allylamines.
1. Butenafine
• Mechanism: Inhibits Squalene Epoxidase (Figure 3 and 4)
• Topical
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• Similar mechanism of action & spectrum of antifungal
activity to that of the allylamines (Dermatophytosis and
Onychomycosis)
Note:
Topical allylamines and benzylamines are more
effective than topical azole agents against common
dermatophytes, especially those causing Tinea pedis.
However, topical terbinafine and butenafine are less
effective than topical azoles against Candida skin infections.
Figure 4. Targets of antifungal drugs. Except for flucytosine (and
possibly griseofulvin, not shown), all currently available antifungals
target the fungal cell membrane or cell wall.
C. Azoles
• More effective in candida compared to terbinafine 
• Has two categories:
1. Imidazoles (Ketoconazole, clotrimazole, miconazole)
2. Triazoles (Itraconazole, voriconazole, fluconazole)
• Categories are based on number of nitrogen atoms in
the azole ring. 
• Mechanism:
o Targets 14α-sterol Demethylase, a fungal cytochrome
p450 enzyme that converts Lanosterol to Ergosterol
(Figure 3 and 4)
Note: Azole are not completely selective for fungal P450 enzyme
and can also inhibit human hepatic P450 enzyme. 
o Prolongs drugs metabolized by this enzyme
• Imidazoles are less selective for fungal P450 than Triazoles
• Drug-to-drug interactions are an important consideration
when prescribing an azole as an antifungal agent
• Azoles are generally nontoxic, and the most common ADR is
minor GI upset. 
Imidazoles
1. Ketoconazole (Oral and Topical)
• Prototype drug for Imidazoles
• Absorption is maximized in an acidic environment (since it is
a weak acid)
• Better absorbed in an empty stomach 
• Poor absorption – in patients taking antacids, H2 blockers,
proton pump inhibitor (due to decreased acidity)
• Poor penetration in CSF and urine (not used in fungal
meningitis) 
• Clinical Use: (Broad spectrum)
o Orally:
▪ Candida sp.
▪ C. immitis
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▪ C. neoformans
▪ H. capsulatum
▪ B. dermatitidis
o Topically:
▪ Dermatophytes
▪ Seborrheic dermatitis
o Used as an off labeled drug to treat increased endocrine
secretions (ex. Cushing’s syndrome, adrenal cancers,
prostatic cancer) due to explanation below.
• Adverse Effects:
o By inhibiting human cytochrome P450
▪ It inhibits adrenal and gonadal steroid hormone
biosynthesis leading to: gynecomastia, impotence,
infertility, menstrual irregularities (endocrine
problems)
▪ Alters the metabolism of other drugs leading to
enhanced toxicity of those agents
Note:  Mantra! Acid loves acid, base loves base. Weak acids
are best absorbed in a very acidic environment. Vice versa with
bases. 
Triazoles
3. Itraconazole (Oral and IV)
• More used in the clinical setting because it is more selective
to fungal P450 enzyme 
• What ketoconazole can do, Itraconazole can do better 
• Broad spectrum; Superior to ketoconazole in safety and
efficacy
• Absorption maximized in an acidic gastric environment
• Poor penetration into CSF and urine
• Less hormonal suppression
• Clinical Use:
o Azole of choice for: Histoplasmosis, Blastomycosis,
Sporotrichosis
o Has activity for Aspergillosis (but still second to
Voriconazole)
o Dermatophytosis and Onychomycosis
• Adverse effects:
o Hepatotoxicity
o Nausea, vomiting, abdominal pain, diarrhea,
hypokalemia, pedal edema, and hair loss
4. Fluconazole (Oral and IV)
• Most widely used antifungal drug (systemic/ disseminated
antifungal infection)
• Absorption not influenced by gastric pH
• Diffuses freely into CSF, sputum, urine and saliva
• Least effect on hepatic cytochrome P450 system among
other azoles
• Limited drug-to-drug interactions
• Wide Therapeutic Window (100-800mg/dL)
• What Itraconazole can do, Fluconazole can do better 
• Clinical Use:
o Blastomycosis, histoplasmosis, sporotrichosis
o Drug of choice for: mucocutaneous candidiasis and
candidemia
o Drug of choice for: coccidioidal meningitis
o Treatment and prophylaxis for: AIDS-associated
cryptococcal meningitis (following an initial 2 week
course of IV amphotericin B)
• NO ACTIVITY against Aspergillosis and candida krusei
(trade off)
• Fungi are becoming resistant by changing their 14α-sterol
demethylase enzyme, and creates efflux pumps

5. Voriconazole
• Inhibits hepatic P450 enzymes to a SIGNIFICANT
EXTENT
• Dose reduction of cyclosporine and tacrolimus
(immunosuppressant agents)
• Phenytoin, rifampin, rifabutin (enzyme inhibitors) will
reduce voriconazole serum levels
• Clinical Use:
Figure 5. Mode of Action of Ketoconazole. Inhibition of P450, 17,20 – o Drug of choice for: invasive Aspergillosis and candida
lyase causing the inhibition of the synthesis of mineralocorticoids,
species including Candida krusei
glucocorticoids and sex steroids.
o Dimorphic fungi (Histoplasma, Blastomyces, Sporothrix)
• Side Effects:
o Hepatotoxicity
2. Clotrimazole and Miconazole (Topical)
o Visual Disturbances (blurring of vision, changes in color
• Only used for non-systemic conditions 
and vision and photophobia)
• If you hear imidazoles (clotrimazole and miconazole) that
o Photosensitivity dermatitis (long term oral use)
are topical first word that should come to your head is
candidiasis (oral, esophagus, vagina) 
Note: IV formulation should not be used in patients with renal failure
• Often used for Vulvovaginal Candidiasis may cause CNS toxicity (accumulation of cyclodextrin)
• Oral clotrimazole troches are available for oral thrush
• In cream form, both agents are useful for dermatophytic Other Azoles briefly mentioned:
infections (tinea corporis, tinea pedis and tinea cruris) *still
terbinafine is more used in dermatophytic infections  6. Posaconazole & Isavuconazole 
• Used to treat
o Aspergillus
o Mucormycosis

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• Posaconazole has the broadest spectrum of the azole family
and used to treat most species of Candida and Aspergillus.
Also has activity against Mucormycosis. 
• Isavuconazole is the newest of the triazoles. Similar
spectrum to Posaconazole and is used to treat invasive
Aspergillus and Mucormycosis. 
7. Ravuconazole 
• A fluconazole derivative in clinical trial with extended
spectrum to Aspergillosis and resistant candida sp. (C.
krusei and C. glabrata)
IV. INHIBITORS OF FUNGAL CELL WALL SYNTHESIS
A. Echinocandins
• Mechanism: Inhibits fungal cell wall synthesis
o Chitin is the major component of fungal cell wall, it is
composed of β-(1,3)-D-glucan, β-(1,6)-D-glucan &
glycoproteins
o These polymers of glucose units are joined by β- (1,3) & β -
(1,6), glycosidic linkages, respectively, are the most
abundant components of the cell wall
o Echinocandins target β- (1-3)- D- glucan synthase (Figure
4)

III. INHIBITORS OF FUNGAL MEMBRANE STABILITY 1. Caspofungin, Micafungin and Anidulafungin (IV only)
o A new class of antifungal agents that target fungal cell wall
• Mechanism: synthesis by non-competitively inhibiting the synthesis
o Binds to ergosterol in the cell membrane to form pores that of β- (1-3)- D- glucans
allow leakage of cellular contents leading to cell death
(Figure 4). • Clinical Use:
o Salvage therapy for invasive Aspergillosis-
A. Polyenes Caspofungin
1. Amphotericin B (IV infusion) o Mucocutaneous candidiasis & candidemia-
• Its affinity for ergosterol is 500 times greater than its affinity Caspofungin, Micafungin
for cholesterol o Esophageal candidiasis & candidemia-
• It generates toxic free radicals upon oxidation of the drug Anidulafungin
• Nearly insoluble in water, prepares as colloidal
suspension IV injection • Side Effects:
• Lipid formulations: Amphotec, Abelcet, AmBisome (lipid- o Generally, well tolerated like Fluconazole
containing preparations)
• High Vd but penetration into the CSF is very low (given • Note: Use of echinocandins in combination with
intrathecal) amphotericin B, flucytosine, itraconazole, or voriconazole in
• Half-life: Approximately 15 days  patients with refractory fungal infections
• Mainly metabolized, some are excreted in the kidney (slow
clearance) V. INHIBITORS OF FUNGAL NUCLEIC ACID SYNTHESIS
• Clinical Use:
A. Flucytosine
o Broadest spectrum of antifungal action; initial
induction regimen to rapidly reduce fungal burden. • Potent inhibitor of thymidylate synthase-inhibition of DNA
o Drug of choice for nearly all life-threatening fungal synthesis
infections: • Water-soluble pyrimidine analog related to 5-FU
▪ Candida albicans • Unavailable in all low and middle income countries
▪ Cryptococcus neoformans, • Not used as a single agent to prevent secondary resistance
▪ Histoplasma capsulatum, • Pharmacokinetics
▪ Blastomyces dermatidis o Well-absorbed (>90% absorption)
▪ Coccidiodes immitis o Serum concentration peaking 1-2 hours after oral dose
▪ Aspergillus o Poorly protein bound but penetrates well into all body
▪ Mucor compartments including CSF
▪ Sporothrix o Eliminated via Glomerular filtration
o Work synergistically with flucytosine in candidiasis o Half-life: 3-4 hours
and cryptococcus o Levels rise rapidly with renal impairment
• Side Effects:
o Immediate systemic reactions: first several hours after • Mechanism of Action (Refer to Figure 6):
drug is given IV, fever, chills, vomiting, headache, o Flucytosine enters the fungal cell via a transmembrane
muscle spasm, hypotension cytosine permease.
o Delayed systemic reactions: Renal toxicity (mediated o Cytosine deaminase converts flucytosine to 5-
vasoconstriction of afferent arterioles), hematologic fluorouracil (5-FU), then converted to 5-FdUMP
toxicity (anemia due to lack of erythropoietin) o 5-FdUMP inhibits thymidylate synthase thereby blocking
the conversion of dUMP to deoxythymidylate (dTMP).
2. Nystatin (oral & topical) o In the absence of dTMP, DNA synthesis is inhibited.
• Increases the permeability of the cell membrane of sensitive
fungi by binding to sterols
• Not absorbed systematically from the skin, vagina or
gastrointestinal tract
• Very toxic to administer parenterally; used topically for
localized infection
• “Swish & swallow” 
• Clinical Use:
o Drug of choice against most Candida organisms
o Most often used for treating local candida infections
▪ Oropharyngeal thrush and vaginal candidiasis

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• Mechanism of Action:
o Deposited in newly forming skin where it binds to keratin,
disrupting microtubules → protecting skin from new infection
(2-6 weeks-for skin and hair infections)
• Pharmacokinetics
o Improved absorption with fatty food
o Administered in a microcrystalline form at a dosage of 1g/d
o Induces hepatic cytochrome P450 enzymes
• Side Effects
o Allergic syndrome (serum sickness, hepatitis)
o Dermatitis
o Disulfiram-like reaction (headaches, lethargy, vertigo &
blurred vision)
o Leukopenia
o Neutropenia (first month of therapy)
o Albuminuria(occasional)
o Avoided in Pregnancy

V. TEST YOUR KNOWLEDGE

1. Which of the following antifungal agents is classified as a

pyrimidine analog?
A. Micafungin
B. Terbinafine
C. Flucytosine
D. Amphotericin B

2. Which antifungal agent acts by inhibiting conversion of squalene

to lanosterol by squalene epoxidase?
A. Terbinafine
B. Flucytosine
C. Griseofulvin
D. Micafungin
Figure 6. Mode of action of Flucytosine. 5-FdUMP = 5-
3. Echinocandins target what enzyme to inhibit fungal cell wall
fluorodeoxyuridine 5′-monophosphate; dTMP = deoxythymidine 5′-
monophosphate. synthesis?
A. β- (1-3)- D- glucan synthase
B. β- (2-3)- L- glucan synthase
• Clinical Use C. β- (1-3)- L- glucan synthase
o Rarely used as a single agent because of fungal D. β- (2- 3)- D- glucan synthase
resistance; it’s usually given with other agents
(Amphotericin B and Itraconazole) for synergy & 4. Which of the following immediate systemic reactions are NOT
to avoid resistance. included as a side effect of Amphotericin B use?
▪ Cryptococcus, candidiasis, aspergillosis A. Fever
(given with amphotericin B) B. Vomiting
▪ Chromoblastomycosis (given with C. Headaches
itraconazole) D. Seizures
• Adverse Effects
o Blood: bone marrow suppression (anemia, 5. Which of the following antifungal agents is MOST likely to cause
leukopenia & thrombocytopenia) renal insufficiency?
o GIT: nausea, vomiting, diarrhea, and hepatic A. Fluconazole
dysfunction. B. Amphotericin B
o The use of drug concentration measurements may C. Itraconazole
be helpful in reducing the incidence of toxic D. Posaconazole
reactions, especially when flucytosine is combined
with nephrotoxic agents such as amphotericin B. 6. A 55-year-old female presents to the hospital with shortness of
o Avoided in Pregnancy breath, fever, and malaise. She has a history of breast cancer,
which was diagnosed 3 months ago, and has been treated with
VI. INHIBITOR OF FUNGAL MITOSIS chemotherapy. Her chest x-ray shows possible pneumonia, and
respiratory cultures are positive for Aspergillus fumigatus. Which
A. Griseofulvin of the following is the MOST appropriate choice for treatment?
• Very insoluble fungistatic drug derived from species of penicillin A. Voriconazole
• Clinical Uses: B. Fluconazole
o Systemic treatment of Dermatophytosis, Trichophyton, C. Flucytosine
Epidermophyton D. Ketoconazole
o Skin and hair infections: 2-6 weeks treatment (to allow
replacement of infected keratin) 7. What is the most common side effect of systemic azoles?
o Nail infection responds very slowly and poorly; may require A. Headache
months of therapy (to allow regrowth of the new protected B. Gastric irritation
nail C. Blurring of vision
o Itraconazole and Terbinafine more effective for D. Joint pains
Onychomycosis

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8. As a resident physician in charge of Lumeng, you were ordered REFERENCES

by the consultant to prescribe any imidazole for her tinea
corporis. Which of the following agents will you give? 1. Lecture Presentation
A. Voriconazole 2. Katzung 14th ed. Chapter 48
B. Miconazole 3. Notes
C. Posaconazole 4. Recording
D. Fluconazole
APPENDIX
9. Maria, in her second trimester of pregnancy, has vulvovaginal
Table 1. Adverse Effects of Antifungals
candidiasis of 2 weeks duration. All of the following antifungal
agents are relatively safe for Maria, EXCEPT: ANTIFUNGAL ADVERSE EFFECT
A. Clotrimazole
B. Miconazole
C. Nystatin Amphotericin B Renal Toxicity, Anemia
D. Voriconazole
Anemia, Leukopenia &
Flucytosine
10. Which antifungal drug is least likely to be effective in the Thrombocytopenia
treatment of esophageal candidiasis if used by the oral route?
A. Griseofulvin Disulfiram-Like Effect, Headaches,
B. Nystatin Lethargy, Vertigo & Blurred Vision
C. Itraconazole
D. Clotrimazole Griseofulvin Hepatotoxic (Occasional), Leukopenia,
Neutropenia (1st Month of Therapy)

Answers: Inducer of Hepatic P450 Enzymes

1. A
Flucytosine= water soluble pyrimidine analog Gynecomastia, Impotence, Infertility,
Micafungin= water soluble, cyclic peptide linked to LCFA Menstrual Irregularities
terbinafine= synthetic allylamine Ketoconazole
Amphotericin B= polyene macrolide
2. B Inhibits Hepatic P450 Enzymes
flucytosine= interferes with fungal DNA synthesis by inhibiting thymidylate
synthetase. Miconazole
Griseofulvin = Binds to keratin precursor cell (in our lecture it disrupts microtubule
function) Itching, Burning, And Sensitization
Micafungin= Targets β-(1-3)-D-glucan synthase Clotrimazole
3. A
4. D. Immediate systemic reactions: fever, chills, vomiting, headache, muscle
spasm, hypotension Itraconazole Hepatotoxic
5. B. Amphotericin B is the best choice since nephrotoxicity is commonly
associated with this medication. Although the dose of fluconazole must be adjusted Hepatotoxic, Visual Disturbance,
for renal insufficiency, it is not associated with causing nephrotoxicity. Itraconazole Dermatitis
and Posaconazole are metabolized by the liver and are not associated with Voriconazole
nephrotoxicity.
6. A. Voriconazole is the drug of choice for aspergillosis. Studies have found it to Inhibits Hepatic P450 Enzymes
be superior to other regimens including amphotericin B. Fluconazole, flucytosine,
and ketoconazole do not have reliable in vitro activity and are therefore not
recommended.
7.B
8.B- Miconazole is the only imidazole the rest is triazole
9.D
10. A- Griseofulvin is the only one which is effective against candidiasis when taken
orally.

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