Antifungal drugs

Definition of Antifungal Drugs

Antifungals are the drugs that treat fungal infections by acting on the synthesis of the fungal
cell membrane, cell wall components, membrane permeability, synthesis of nucleic acids and
on the mitotic spindle function of the fungi during cell division.

Overview of Fungal Infections

Fungi are non-motile eukaryotic single-celled or multinucleate organisms formerly classified as

plants that lack chlorophyll and cannot perform photosynthesis, hence parasitic in nature.
Thousands of species have been identified, out of which some are the cause for local
or systemic fungal infection (mycoses) in patients with AIDS, or humans whose immune systems
are compromised by drug therapy or other means. This may cause serious, sometimes life-
threatening infections.

Introduction into the host’s body is mainly through wounds or inhalation into the lungs and
nasal passages. Diseases caused by fungi are mainly due to the Microsporum, Trichophyton or
Epidermophyton genera.

Various Types of Fungal Infections

Athlete’s Foot

Tinea pedis (Athlete’s foot): The infection is caused by Trichophyton

mentagrophytes and Trichophyton rubrum. It is often located between the toes, with the space
between the fourth and fifth digits most commonly afflicted; however, it can spread if not
treated in time.

Ringworm Infection

Tinea corporis (ringworm): The infection is caused by Microsporum canis, Trichophyton

mentagrophytes via direct skin contact with an infected individual, or by using the personal
care products of the affected individual.

1
Brazilian Blastomycosis

It is caused by Paracoccidioides brasiliensis and is a systemic infection involving mucous

membranes, lymph nodes, bone and lungs and prevalent in South America. Amphotericin B,
Itraconazole or ketoconazole are effective in treating the infection.

Candidiasis

Candidiasis is caused by yeast Candida Albicans. It is commonly present as a saprophyte in the

GI tract and genitourinary system of human beings. However, it can infect locally or
systemically and cause serious systemic infections with multi-system organ failure.

Mucormycosis

The infection is caused by the genera Mucor, Rhizopus, Absidia, and Cunninghamella with the
affected areas being sinuses, eyes, blood, and brain.

Classification of Anti Fungal Drugs

These agents are categorized as:

Topical vs systemic (acting in the bloodstream)

Naturally occurring:

Antifungal Antibiotics (mostly produced by Actinomycetes, classified as ‘higher

bacteria’). Examples: Amphotericin B (AMB), a polyene antimycotic, Nystatin

Antifungals of fungal origin. Example: Griseofulvin, a Heterocyclic Benzofuran discovered in

1939 from a type of Penicillium mold

Synthetic Agents:

Azoles

Imidazoles: Clotrimazole, Econazole, Miconazole, Oxiconazole, Ketoconazole

Triazoles: Fluconazole, Itraconazole, Voriconazole

Anti-metabolites: Flucytosine (5-FC)

2
Allylamine: Terbinafine (Lamisil)

Newest antifungals:

Echinocandins

Membrane β-Glucan synthesis Microtubule Nucleic acid

permeability blockers function inhibitors synthesis blockers
agents

Azoles Echinocandins Griseofulvin Flucytosine

Terbinafine

Polyenes

Antifungal Drugs

“Overview Pharmacology Antifungals” Image created by Lecturio

Below you can find different kinds of antifungal drugs.

Amphotericin B (AMB)

3
It is derived from cultures ofStreptomyces Nodosus and is a very large (‘macrolide’) molecule
belonging to the polyene group of antifungal agents.

Mechanism of Action

The molecule has a high affinity for ergosterol present in the fungal cell membrane and
combines with it in such a way to make a ‘micropore.’ The basic mechanism of the drug is to
disrupt the cell membrane. It is fungicidal at high and fungistatic at low concentrations.

Important: Amphotericin is not active against human and bacterial sterols as the predominant
sterol found in bacteria and humans are cholesterol.

Indication

Amphotericin B is active against a wide range of yeasts and fungi: Candida
Albicans, Histoplasma capsulatum, Cryptococcus neoformans, Blastomyces dermatitidis,
Coccidioidesimmitis, Torulopsis, Rhodotorula, Aspergillus, andSporothrix, etc. It does not have
any anti-bacterial property. It is the most effective drug for resistant cases of kala-azar
and mucocutaneous leishmaniasis.

Pharmacokinetics

Amphotericin B is not absorbed orally; that is why it is administered intravenously and

rarely intrathecally (for fungal meningitis). Amphotericin B has a half-life of 15 days. The
excretion through urine requires a long time, although excretion occurs slowly both in the urine
and bile. Penetration into the CNS is poor; about 60% of AMB is metabolized by the liver.

Side Effects

Nephrotoxicity is the most important side effect. Acute reactions may be triggered by
symptoms consisting of chills, fever, aches, and pain, nausea, vomiting, and dyspnea lasting for
one hour, probably due to the release of cytokines. To reduce the side effects and improve the
tolerability of infusion, formulations of lipid complex, colloidal dispersion, and small unilamellar
vesicles have been introduced.

4
Important: Irreversible renal toxicitycan result in prolonged administration (more than 4g
cumulative dose).

AmBisome (liposome-based), Amphotec (a complex of amphotericin B and cholesteryl sulfate),

Abelcet (consists of amphotericin B complexed with two phospholipids) are the lipidic
formulations available to reduce the renal toxicity of the conventional amphotericin B;
however, these are very costly.

Nystatin

It is also called fungicidin with a similar structure to that of Amphotericin B. It is derived

from Streptomyces noursei and has high systemic toxicity, hence, it is commonly used as a
topical agent.

Mechanism of Action

“Fungal cell membrane and cell wall. Nystatin” Image created by Lecturio

The molecule also has a high affinity for ergosterol present in fungal cell membranes and it
disrupts the cell membrane.

Indication

It is used against monilial vaginitis, corneal, conjunctival and cutaneous candidiasis in the form

of an ointment but is ineffective in dermatophytosis. Nystatin can be added to tetracycline to

5
prevent monilial overgrowth caused by the destruction of the bacterial microflora of the
intestine during tetracycline therapy.

Pharmacokinetics

It is given in the form of vaginal tablets and pastilles for local application only. Nystatin will
treat gut candidiasis and is used in a ‘swish and swallow’ routine for oral candidiasis.

Side Effects

The common side effects associated are itching, irritation and burning. Rarely, nystatin can
cause diarrhea and nausea.

Griseofulvin

Griseofulvin is a narrow-spectrum antifungal agent isolated from cultures of Penicillium

griseofulvum, and is active against dermatophytes, including Epidermophyton, Trichophyton,
Microsporum, but not against fungi causing deep mycosis.

Mechanism of Action

The mechanism of action of griseofulvin is not clear. It is thought to interfere with

mitosis during the fungal hyphaeformation. It also causes abnormal metaphase in the division
of cells by acting in a way that the daughter nuclei fail to move apart, or move only a short
distance during division. It does not inhibit polymerization of tubulin, but binds to polymerized
microtubules and disorients them.

Pharmacokinetics

The absorption of the drug is improved by taking it with a fatty meal and by microfining the
drug particles. Griseofulvin gets deposited in keratinforming cells of skin, hair, and nails;
concentrating in tinea infected cells because it is fungistatic and not cidal. The newly formed
keratin is not affected by the fungus.

6
Effects with griseofulvin use are infrequent, but the drug causes gastrointestinal upsets,
headache, and photosensitivity. Allergic reactions(rashes and fever) may occur. The drug
is contraindicated in pregnant women.

Azoles and Triazole Agents

These are synthetically derived antifungal agents, both used orally and topically. They are used
for treating a large number of infections caused by dermatophytes, Candida, other fungi
involved in deep mycosis, Nocardia, some gram-positive and anaerobic bacteria,
e.g., Staphylococcus aureus, Enterococcus faecalis, Bacteroides fragilis and Leishmania.

Mechanism of Action

“Fungal cell membrane and cell wall. Azole antifungals.”Image created by Lecturio

The azoles constitute imidazoles and triazoles subgroups and act by inhibiting CYP P450 14 α-
demethylase enzyme in fungi which causes the conversion of lanosterol to ergosterol. Other
P450s in sterol biosynthesis may also be affected.

The nitrogen of the azole ring forms a bond with the heme iron of the fungal P450 preventing
substrate and oxygen binding, leading to changes in shape and physical properties of the fungi
membrane, leading to permeability and fluidity changes. They also inhibit the transformation of
yeast cells into hyphae, the invasive and the pathogenic form of the parasite.

7
Ketoconazole (KTZ)

It is available in the form of a cream or in shampoos at a strength of 1 or 2 % for treating  tinea

pedis, tinea corporis, tinea cruris, and cutaneous candidiasis. It can also be administered orally.

Pharmacokinetics

The oral absorption of KTZ is improved by gastric acidity because it is more soluble at lower
pH. Hepatic metabolism is extensive for the drug; metabolites are excreted through urine and
feces. The half-life is short and varies from 1.5—6 hours.

Side Effects

The drug causes inhibition of adrenocortical steroid and testosterone synthesis with high doses,

leading to gynecomastia, loss of hair and libido in male patients. In females, menstrual
irregularities may occur. Hepatotoxicityis also a side effect but is rarely fatal.

Clotrimazole

The topical application of the drug is useful in treating tinea pedis, ringworms, otomycosis, and
oral/cutaneous vaginal candidiasis. It is the preferred drug for treating vaginitis because of a
long residual effect after a once-daily application. The drug is also combined sometimes with
glucocorticoids, which are anti-inflammatory in nature.

Side Effects

The drug is well tolerated; however, causes a local irritation with a stingingand burning
sensation occurring in some. No systemic toxicity is seen after topical use.

Fluconazole

It is marketed in the form of a tablet or suspension to treat yeast infections of the

vagina, mouth, throat, esophagus, abdomen, and lungs.

Important: it is a drug of choice for esophageal and invasive

candidiasis and coccidioidomycoses.

8
Pharmacokinetics

Fluconazole is 94 % absorbed; oral bioavailability is unaffected by food or gastric pH. It

is primarily excreted unchanged in the urine with a t1/2 of 25—30 hours.

Side Effects

Prominent side effects are nausea, vomiting, abdominal pain, rash, and headache. Elevation
of hepatic transaminase has been noted in AIDSpatients. As compared to other azoles, it has
the least effect on liver microsomal enzymes.

Voriconazole

The drug is present in the form of oral suspension, tablets or parenteral injection. It is used to
treat serious fungal infections and may be used in patients who have not responded to other
antifungal agents.

Rashes, visual disturbances, QT prolongation and an acute reaction on the IV injection are the
significant adverse effects.

Flucytosine (5-FC)

It is an antifungal drug, which acts by blocking the pyrimidine and DNA synthesis in fungi. It is

converted to its active metabolite (5-FU) by fungal cells.

The pathway of conversion is below:

Flucytosine → (5-FC) →5-Fluorouracil (5-FU) → 5-fluorodeoxyuridine monophosphate

No toxicity in humans due to 5-FC as human cells can’t convert 5-FC to 5-FU.

It is not used as a single agent for fungal infections but is used with other antifungal agents such
as amphotericin B (cryptococcal meningitis) and itraconazole (chromoblastomycosis).

Side-effects are reversible bone marrow depression, liver dysfunction, and alopecia.

9
Terbinafine

It is fungicidal and is given in shorter course therapy and the relapse rates are low. It is
particularly useful against Dermatophytes, especially nail infections, along with the treatment
of candida infection.  It is available for oral, as well as topical use.

Mechanism of Action

It acts as a non-competitive inhibitor of ‘squalene epoxidase’, an enzyme in ergosterol

biosynthesis by fungi. Accumulation of toxic squalene within fungal cells leads to the fungicidal
action.

Pharmacokinetics

Approximately 75 % of oral terbinafine is absorbed. The drug is lipophilic and is widely

distributed in the body, strongly plasma protein bound and concentrated in sebum, stratum
corneum and nail plates. Elimination t1/2 of 11—16 hours is prolonged to 10 days after the
repeated dosing schedule.

Side Effects

The common side effects are gastric upset, rash and taste disturbance. Some cases of hepatic
dysfunction, hematological disorder, and severe cutaneous reaction also occur.

Echinocandins

These are recently discovered antifungal drugs. Examples of drugs in this class are caspofungin
and dulafungin.

Mechanism of action

They act by blocking the synthesis of β (1—3)-glucan in fungus.

They are active against Candida spp., Aspergillus spp., pneumocystis carinii;however, they are

not active against Cryptococcus neoformans.

10
Pharmacokinetics

They are poorly absorbed from the GI tract, thus they are only available as intravenous
formation.

Side effects

They are well tolerated and have only minor gastrointestinal side-effects such as nausea and
vomiting. Other side-effects are headache and flushing.

11