ANTIFUNGAL DRUGS

By
Rushikesh G. Diware
RSCP Buldhana
 Content
• Introduction

• Types of Fungal Diseases

• Classification

• Chemistry of antifungal drugs

• Mechanism of action

• Uses

• ADR
Introduction

• Less Progress as compared to antibacterial drugs

• Infection occur superficial including skin, mucosal membrane,

• Systemic infection is rare deu to immunity

• Systemic infection occur in low immunity patients, AIDS, patient with

immunosuppressant, having anticancer therapy

• These agent low down immunity

 History
• Fungi is on of the causing agent for various infections

• Two microbiologists, Schönlein and Gruby, studied the fungus Trichophyton

schoenleinii in 1839.

• Langenbeck reported the yeast like microorganism responsible for thrush (C. albicans).

• Gruby isolated the fungus responsible for favus on potato slices, rubbed it on the head of
a child, and produced the disease.

• fungal infections fall into two well-defined groups:

• the superficial and the deepseated mycoses.

Fungus Introduction: Yeast, Molds, rusts, Mushrooms

• The superficial mycoses are most common

• caused, for the most part, by a relatively homogeneous group of fungi, the

dermatophytes.

• These include the various forms of tinea, or ringworm,

• infections of the hair or hair follicles, the superficial

• infections of the intertriginous or flat areas of hairless skin, and infections of the nails

• These lesions are mild, superficial, and restricted.

Cont…

• The causative microbes are specialized saprophytes

• They have unusual ability to digest keratin.

• They have their ultimate reservoir in the soil. Unlike

• the deep-seated mycoses, however, they are frequently

• transmitted from one host to another (e.g., athlete’s foot).

• species of yeast, Candida, also produces a dermatophyte like disease.

Obligate Parasites
Superficial infections
Systemic Mycoses

• The deep-seated, systemic mycoses have a sporadic distribution,

• being common in some parts of the world

• unknown in other geographical areas.

• These diseases have a heterogeneous etiology caused by the systemic organisms

• include histoplasmosis, sporotrichosis, blastomycosis, coccidioidomycosis,

cryptococcosis, and paracoccidioidomycosis.

• The causative agents are soil-inhabiting saprophytes with the ability to adapt to
the internal environment of their host
Cont…
• Share a common route of infection.

• Fungal spores are inhaled into the lung, and a mild, cold like condition may result.

• Most cases, disease is inapparent.

• The immune system deals with these infections by walling them off or by
producing the giant cells that are common in type iv hypersensitivities.

• Causative organisms of the systemic infections are not typically transmitted from
one host to another

• Infection by the organism in an endemic area may be very common.

Cont….
• Few infections develop into the severe, deep, spreading, and often-fatal
disease seen in some persons.

• If the infection is symptomatic, the clinical signs may be those of a mild,

self-limiting disease;

• If infection may become progressive, with severe symptoms, tissue and

organ damage, and, frequently, death.

• Recovery from a deep-seated infection of this type is accompanied by an

uncertain anamnestic immune response.
 Opportunistic Fungal Infections

• In recent years, because of overzealous use of antibacterial antibiotics, the use of

immunosuppressive agents, cytotoxins, irradiation, and steroids, a new category
of systemic mycoses has become prominent. These are the opportunistic fungal
infections.

• There has been a precipitous rise in the incidence of these diseases.

• The patient, as a result of drug therapy, underlying disease, or medical

manipulation, is deprived of the normal defenses conferred by microbial flora.

• This allows organisms of normally low inherent virulence to exploit the host.
 Cont….
• Such infections include systemic candidiasis, aspergillosis, and mucormycosis.

• Bacterial infections such as Gram-negative septicemia, nocardiosis, and

Pseudomonas infection,

• fungal infections such as with Pneumocystis carinii,

• viral opportunists such as cytomegalovirus also attack such patients

• C. albicans is a particularly common opportunist.

• This yeast is a member of the normal microbial flora of human hosts, especially in
the vagina.
 Cutaneous Infections (Dermatophytoses
• most common types of human fungal disease

• occur at keratinized epidermis and keratinized epidermal appendages

• severity of an infection depends largely on the location of the lesion and

the species of the fungus involved

• Candida spp., produce clinically similar diseases

• homogeneous group of fungi, termed the dermatophytes

• They use highly insoluble scleroprotein keratin

Common infectious fungi
• Dermatophyte species belongs to family Gymnoascaceae,

• Other species of family species of the family are Onygenaceae, and certain tineae

• genera Trichophyton

• T. rubrum for nails, beard, smooth skin infection

• T. tonsurans for scalp, beard, nails infection

• T. violaceum [scalp, skin nails],

• T. mentagrophytes [commonest cause of athlete’s foot],

• T. verrucosum [scalp, beard],

• T. rubrum [psoriasis-like lesions of smooth skin, infections of nails]),

• Microsporum (M. gypseum [scalp],

• M. fulvum [scalp, hairless skin], and M. canis [scalp, hairless skin]), Epidermophyton (eczema) contain the most common dermatophytes.
Topical Agents for Dermatophytoses

• 1. FATTY ACIDS: Propionic Acid, Zinc Propionate, Sodium Caprylate,

Zinc Caprylate, Undecylenic Acid, Triacetin, Salicylic Acid, Benzoic
Acid, and Resorcinol

• PHENOLS AND THEIR DERIVATIVES: Haloprogin, Clioquinol, Ciclopirox

Olamine,

• Nucleoside Antifungals: lucytosine

• Antifungal Antibiotics
• POLYENES: Amphotericin B, Nystatin, Natamycin,
• Other Antifungal Antibiotics: Griseofulvin

•Allylamines and Related Compounds:Naftifine Hydrochloride, Terbinafine

Hydrochloride, olnaftate

•Azole Antifungal Agents:

•A. Imidazoles: Clotrimazole, Econazole Nitrate, Butoconazole Nitrate, Sulconazole Nitrate,
Oxiconazole Nitrate, Tioconazole, Miconazole Nitrate, Ketoconazole,

•B. Triazoles: Flucanazole, Fosflucanazole, Vericonazole, Itraconazole, Terconazole,

Posaconazole

•Mropholines: Amorolfine

•NEWER ANTIFUNGAL : voriconazole

Topical Agents for Dermatophytoses

• Dermatophytoses are called tinea, or ringworm.

• Treatment has been directed to surface areas of the skin.

• The skin is a formidable barrier to drug penetration

• topical agents work best if an adjuvant is added

• Keratolytic agents such as salicylic acid or other α-hydroxy

compounds perform this function reasonably well.
Fatty Acids
• Adults have an acidic, fatty substance in and on the skin called sebum.

• Sebum functions as a natural antifungal agent,

• part of the innate immune system.

• used for years with the idea that if a substance similar to sebum could be applied to the infected
area, the effect of the sebum would be augmented and fungi could be eradicated.

• fatty acids or their salts does in fact have an antifungal effect

• The higher–molecular-weight fatty acids have the advantage of having lower volatility.

• Salts of fatty acids are also fungicidal and provide nonvolatile forms for topical

• application.
Drugs
• Propionic Acid

• Zinc Propionate

• Zinc Caprylate

• Undecylenic Acid

• Triacetin

• Salicylic Acid

• Resorcinol
PHENOLS AND THEIR DERIVATIVES
• possess topical antifungal properties.

• Hexylresorcinols and parachlorometaxylenol have been used for the

treatment of tinea infections.

• Clioquinol and haloprogin, are still official in the USP.

• A third agent, ciclopirox olamine, is not a phenol but has properties

like those of phenols.

• All of these agents appear to interfere with cell membrane integrity

and function in susceptible fungi.
• Haloprogin: superficial tinea infections

• Clioquinol: atopic dermatitis, eczema, psoriasis, and impetigo.

• A 3% ointment or cream has been used vaginally as a treatmentfor Trichomonas vaginalis
vaginitis. The best use for Vioform is in the topical treatment of fungal infections such as
athlete’s foot and jock itch.

• Ciclopirox Olamine: broad-spectrum antifungal agent topical use.

• It is active against dermatophytes as well as pathogenic yeasts (C. albicans) cutaneous

candidiasis, tinea corporis, tinea cruris, tinea pedis, and tinea versicolor.

• It is a second-line agent for the treatment of onychomycosis (ringworm of the nails).

Nucleoside Antifungals

• Flucytosine

• 5-Fluorocytosine, 5-FC

• Orally active antifungal agent

• very narrow spectrum of activity

• indicated only for the treatment of serious systemic infections caused by

susceptible strains of Candida and Cryptococcus spp.

• incorporated into RNA, causing faulty RNA synthesis.

Antifungal Antibiotics

• Complex in structure

• There are two classes: the polyenes, which contain a large number of agents
with only a few being useful,

• and griseofulvin (one member of the class).

• Polyenes contains contain a system of conjugated double bonds in macrocyclic

lactone rings

• larger and contain the conjugated -ene system of double bonds

• no activity against bacteria, rickettsia, or viruses, but they are highly potent,
broad-spectrum antifungal agents.
POLYENES

• isolated from soil bacteria of the genus Streptomyces

• contain a system of conjugated double bonds

• Fall into two groupings on the basis of the size of the macrolide ring.

• The 26-membered–ring polyenes, such as natamycin (pimaricin),

• 38-membered macrocycles, such as amphotericin B and nystatin

• Contains series of hydroxyl groups on the acid-derived portion of the ring

• Glycosidically linked deoxyaminohexose called mycosamine

• inhibit Candida spp., Coccidioides immitis, Cryptococcus neoformans,
H. capsulatum, Blastomyces dermatitidis, Mucor mucedo, Aspergillus
fumigatus, Cephalosporium spp., and Fusarium spp.

• Amphotericin B, the only polyene useful for the treatment of serious

systemic infections,

• Other polyenes have limited systemic activity due to toxicities of the

drugs, their low water solubilities, and their poor chemical stabilities
Mechanism of action
• Polyenes three-dimensional shape

• a barrel-like nonpolar structure capped by a polar group (the sugar),

• they penetrate the fungal cell membrane, acting as “false membrane components,”

• bind closely with ergosterol

• causing membrane disruption, cessation of membrane enzyme activity, and loss of cellular
constituents, especially potassium ions.

• The drug is fungistatic at low concentrations

• and fungicidal at high concentrations.

• This suggests that at low concentrations, the polyenes bind to a membranebound

• enzyme component, such as an ATPase.

 Amphotericin B

• Isolated in 1956 by Gold et al.

• purified from the fermentation beer of a soil culture of the actinomycete Streptomyces nodosus,
isolated in Venezuela.

• mixture of two compounds, designated amphotericins A and B.

• In test cultures, compound B proved to be more active,

• interact with membrane sterols (ergosterol in fungi) to produce an aggregate

• forms a transmembrane channel.

• Intermolecular hydrogen bonding interactions among hydroxyl, carboxyl, and amino groups

• stabilize the channel in its open form,

• destroying symport activity and allowing the cytoplasmic contents to leak out
Amphotericin B
• Amphoteric substance, with a primary amino group attached to the mycosamine ring
and a carboxyl group on the macrocycle.

• Parenteral amphotericin B is indicated for the treatment of severe, potentially life-

threatening fungal infections, disseminated forms of coccidioidomycosis and
histoplasmosis, sporotrichosis, north american blastomycosis, cryptococcosis,
mucormycosis, and aspergillosis.

• The effect is similar with cholesterol

• 80% of patients treated with amphotericin B develop nephrotoxicity. Fever, headache,

anorexia, gastrointestinal distress, malaise, and muscle and joint pain are common.

• Pain at the site of injection and thrombophlebitis

• The drug must never be administered intramuscularly

• The hemolytic activity of may be a consequence

• ability to leach cholesterol from erythrocyte cell membranes

• For fungal infections of the central nervous system (CNS)

• (e.g., cryptococcosis), amphotericin B is mixed with cerebrospinal fluid (CSF)

that is obtained from a spinal tap

• injection is supplied as a sterile lyophilized cake or powder with 41 mg of

sodium deoxycholate stabilized as a buffered colloidal dispersion in micelles

• amphotericin B admixed with a lipid carrier

Nystatin (Mycostatin)
• Isolated in 1951 from a strain of the actinomycete Streptomyces noursei by Hazen and Brown

• yellow to light tan powder very slightly soluble in water and sparingly soluble in organic solvents

• unstable to moisture, heat, and light.

• The aglycone portion of nystatin is called nystatinolide.

• It consists of a 38-membered macrolide lactone ring containing single tetraene and diene moieties separated
by two methylene groups

• The aglycone also contains eight hydroxyl groups, one carboxyl group, and the lactone ester

• The entire compound is constructed by linking the aglycone to mycosamine.

• The complete structure of nystatin has been determined by chemical degradation and x-ray crystallography.
• not absorbed systemically when administered by the oral route.

• It is nearly insoluble under all conditions.

• It is also too toxic to be administered parenterally.

• used only as a topical agent.

• Nystatin is a valuable agent for the treatment of local and gastrointestinal monilial infections caused

by C. albicans and other Candida species.

• For the treatment of cutaneous and mucocutaneous candidiasis, it is supplied as a cream, an

ointment, and a powder.

• Vaginal tablets are available for the control of vaginal candidiasis.

• Oral tablets and troches are used in the treatment of gastrointestinal and oral candidiasis.

• Combinations of nystatin with tetracycline can be used to prevent monilial overgrowth caused by
Natamycin (pimaricin; Natacyn)
• is a polyene antibiotic
• Obtained from cultures of Streptomyces natalensis.
• Consists of a 26-membered lactone ring containing
• tetraene chromophore,
• α, β-unsaturated lactone carbonyl group
• three hydroxyl groups, a carboxyl group, a trans epoxide, and a
glycosidically joined mycosamine.
• natamycin is amphoteric.
• cause both potassium ion leakage and cell lysis
• activity against several yeasts and filamentous fungi, including Candida,
Aspergillus, Cephalosporium, Penicillium, and Fusarium spp.
Other Antifungal Antibiotics:
Griseofulvin
• first reported in 1939 by Oxford et al

• obtained from the fungus Penicillium griseofulvum.

• Isolated originally as a “curling factor” in plants.

• Application of extracts containing the antibiotic to fungus-infected leaf parts

caused the leaf to curl up.

• used for many years for its antifungal action in plants and animals

• 1959, griseofulvin was introduced into human medicine for the treatment of
tinea infections by the systemic route.
• Griseofulvin is an example of a rare structure in nature,

• spiro compound.

• 7-chloro-2,4,6-trimethoxy- 6,β-methylspiro[benzofuran-2(3H)-1-
[2]cyclohexene]- 3,4-dione.

• The compound is a white, bitter, heat-stable powder or crystalline

solid

• sparingly soluble in water but soluble in alcohol and other nonpolar

solvents. It is very stable when dry.
• used for a long time for the systemically delivered treatment of refractory ringworm
infections

• of the body, hair, nails, and feet caused by species of dermatophytic fungi including
Trichophyton, Microsporum, and Epidermophyton

• After systemic absorption,

• is carried by the systemic circulation and capillary beds to the skin, nails, and hair follicles,

• where it concentrates in keratin precursor cells, which are gradually exfoliated and
replaced by healthy tissue

• ADR: allergic reactions such as rash and urticaria, gastrointestinal upset, headache,
dizziness, and insomnia
 Allylamines and Related Compounds
• Discovered as a result of random screening of a chemical inventory

• Enhanced potency and potential oral activity

• Interfere with an early step in ergosterol biosynthesis,

• Epoxidation of squalene catalyzed by squalene epoxidase.

• Squalene epoxidase forms an epoxide at the c2–c3 position of qualene

• Opening of the epoxide under acid catalysis yields a carbocation that initiates the “squalene
zipper” reaction that forms the steroid nucleus.

• Inhibition of squalene epoxidase shuts down the biosynthesis of ergosterol

• Causes an accumulation of squalene, which destabilizes the fungal cell membrane.

• The allylamines exert a fungicidal action against dermatophytes and other filamentous fungi,

• their action against pathogenic yeasts, such as Candida spp., is largely fungistatic

• mammalian squalene epoxidase is weakly inhibited

• Cholesterol biosynthesis does not appear to be altered in mammals

• naftifine and terbinafine, have been approved as topical agents for the treatment of tinea pedis,

tinea cruris, and tinea corporis

• caused by Trichophyton rubrum, Trichophyton mentagrophytes, or Epidermophyton floccosum

• Allylamines are weak bases that form hydrochloride salts that are slightly soluble in water.
Naftifine Hydrochloride
• N-Methyl-N-(3-phenyl2-propenyl)-1-naphthalenemethanamine HCL (Naftin)

• white crystalline powder that is soluble in polar solvents such as ethanol and
methylene chloride.

• used a 1% concentration in a cream and in a gel for the topical treatment

• Used for ringworm, athlete’s foot, and jock itch.

• Also shows effective on ringworm of the beard, ringworm of the scalp and tinea
versicolor.
 Terbinafine Hydrochloride

• The highly lipophilic

• free base is insoluble in water.

• available in a 1% cream for topical administration

• Used for treatment of tinea pedis, tinea corporis, and tinea cruris.

• Terbinafine is more potent than naftifine

• demonstrated oral activity against onychomycosis (ringworm of the nails).

• It has not been approved for oral administration.

Tolnaftate

• O,2-Naphthyl m,N-dimethylthiocarbanilate

• thioester of β-naphthol,

• fungicidal against dermatophytes, such as Trichophyton, Microsporum, and Epidermophyton

spp., that cause superficial tinea infections.

• available in a concentration of 1% in creams, powders, aerosols, gels, and solutions

• Used for the treatment of ringworm, jock itch, and athlete’s foot.

• Act as an inhibitor of squalene epoxidase

• Tolnaftate is formulated into preparations

• intended to be used with artificial fingernails to counteract the increased chance of ringworm of
Azole Antifungal Agents

• Class of synthetic antifungal agents

• possess a unique mechanism of action.

• achieve selectivity for the infecting fungus over the host.

• Can be used for dermatophytoses to life-threatening, deep systemic fungal infections.

• The first members of the class were highly substituted imidazoles, such as
clotrimazole and miconazole.

• imidazole ring could be replaced with a bioisosteric 1,2,4-triazole ring without

adversely affecting the antifungal properties of the molecule.
ANTIFUNGAL SPECTRUM

• superficial infections of the skin and mucous membranes,

• dermatophytes such as Trichophyton, Epidermophyton, and

Microsporum spp.

• yeasts such as C. albicans.

• also exhibit activity against yeasts that cause systemic infections,

including C. immitis, C. neoformans, Paracoccidioides brasiliensis,

• Petriellidium boydii, B. dermatitidis, and H. capsulatum.

MECHANISM OF ACTION
• high in vitro concentrations the azoles are fungicidal;

• at low in vitro concentrations they are fungistatic.

• fungicidal effect is clearly associated with damage to the cell membrane, with
the loss of essential cellular components such as potassium ions and amino acids

• fungistatic effect associated with inhibition of membrane-bound enzymes.

• A cytochrome P450-class enzyme, lanosterol 14-demethylase

• P450 possesses a heme moiety as part of its structure

• basic electron pairs of the azole rings can occupy a binding site on P450
• Lanosterol 14-demethylase is also required for mammalian
biosynthesis of cholesterol,
• azoles are known to inhibit cholesterol biosynthesis
• higher concentrations of the azoles are needed to inhibit the
mammalian enzyme.
• 1,2,4-triazoles appear to cause a lower incidence of endocrine effects
and hepatotoxicity than the corresponding imidazoles,
• because of a lower affinity for the mammalian cytochrome P450
enzymes involved.
• Clotrimazole: 1-(o-Chloro-,-diphenylbenzyl)imidazole

• is a broad-spectrum antifungal drugs

used topically for the treatment of tinea infections and candidiasis.

• It is a weak base that can be solubilized by dilute mineral acids.

• Available as solution in polyethylene glycol 400, a lotion, and a cream in a concentration of 1%.

• Indicated for the treatment of tinea pedis, tinea cruris, tinea capitis, tinea versicolor, or
cutaneous candidiasis.

• A 1% vaginal cream and tablets of 100 mg and 500 mg are available for vulvovaginal candidiasis.

• Clotrimazole is extremely stable, with a shelf life of more than 5 years.

• severe gastrointestinal disturbances. Not orally effective not used systematically

• Econazole Nitrate
• 1-[2-[(4-Chlorophenyl)methoxy]-2-(2,4-dichlorophenyl)- ethyl]-1H-imidazole
(Spectazole)
• used as a 1% cream for the topical treatment of local tinea infections and
cutaneous candidiasis.

• Butoconazole Nitrate
• 1-[4-(4-Chlorophenyl)-2-[(2,6-dichlorophenyl)-thio]butyl]- 1H-imidazole
• extremely broad-spectrum antifungal
• effective against C. albicans.
• supplied as a vaginal cream containing 2% of the salt
• Used for treatment of vaginal candidiasis.
• Oxiconazole Nitrate
• (Z)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanone- O-[2,4-
dichlorophenyl)methyl]oxime mononitrate
• used in cream and lotion dosage forms in 1% concentration
• Used for tinea pedis, tinea corporis, and tinea capitis.

• Tioconazole
• 1-[2-[(2-chloro-3-thienyl)methoxy]2-(2,4-dichlorophenyl)- ethyl]-1H-
imidazole
• used for vulvovaginal candidiasis.
• A vaginal ointment containing 6.5% of the free base is available.
Tioconazole is more effective against Torulopsis glabrata than are
other azoles
• Miconazole Nitrate
• 1-[2-(2,4-Dichlorophenyl)-2-[2,4-dichlorophenyl]- methoxy]ethyl]-1H-
imidazole mononitrate
• Free base injection used for candidiasis, coccidioidomycosis,
cryptococcosis, petriellidiosis, and paracoccidioidomycosis
• ADR: thrombophlebitis, pruritus, fever, and gastrointestinal upset
• Ketoconazole:
• 1-Acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2(1H-imidazole-1- ylmethyl)-
1,3-dioxolan-4-yl]methoxy]phenyl]piperazine
• broad-spectrum imidazole oral bioavailability of ketoconazole
depends on a acidic pH for dissolution and absorption
• H2-histamine antagonists and anticholinergics inhibit gastric
secretion interfere with its oral absorption
• ADR: Hepatotoxicity, inhibit cholesterol biosynthesis, lower
testosterone and corticosterone levels
• nausea and vomiting; others are—loss of appetite, headache,
• paresthesia, rashes and hair loss.