Antifungals Flashcards
What are antifungals?
Antifungal drugs are chemical agents that selectively
eliminate fungal pathogens from the host with minimal
toxicity and are used for the treatment of fungal
infections (mycoses) in animals.
What are fungi?
Fungi are eukaryotic unicellular or
multicellular organisms that contain chitin in their
cell wall and include microorganisms (yeasts,
dermatophytes and molds) as well as macroorganisms
(mushrooms)
Types of fungi based on feeding
Saprophytic fungi: feed on dead tissues
Parasitic fungi: feed on living tissues
What is fungal infection of the nails called?
Onychomycosis
What are the types of onychomycosis?
- White superficial onychomycosis
- Proximal subungual onychomycosis
- Distal subungual onychomycosis
What are dermatophytoses?
Fungal
infections of skin and hair
AKA Tinea
What is Tinea pedis?
athletes’ foot
What is tinea cruris?
Fungal infection of the groin
What is tinea capitis?
Fungal infection of the scalp
What is a tineal infection of the nails called?
Tinea unguium
What is tinea mannum?
Fungal infection of the hand
What is mucosamycosis?
Candida infection of body mucosa
What organism causes mucosamycoses?
Candida
albicans
Examples of mucosamycoses
- Oral candidiasis: mouth
- Vaginal candidiasis: vaginal mucosa
- Candida intertrigo: skin folds- groin, armpits, buttocks
- Candida interdigitalis: between fingers, foot digits
- Candida onychomycosis: nail
What are the causative organisms of Onychomycosis and Dermatophytosis?
Epidermophyton floccosum, Trichophyton rubrum or
Microsporum canis
What iis the point of origin of systemic fungal pathogens?
The lungs
Types of systemic fungal infections
- Aspergillosis
- Coccidioidomycosis
- Cryptococcosis
- Histoplasmosis
- Paracoccidioidomycosis
- Pneumocystosis
- Sporotrichosis
- Cryptosporidiosis
Cause of Aspergillosis
Aspergillus fumigatus.
Affects skin and lungs
Cause of Coccidioidomycosis
Coccidioides
immitis.
Affects lung,
skin, and joints
Cause of Cryptococcosis
Cryptococcus
neoformans.
Affects lung, brain and
skin and may become disseminated
Cause of Histoplasmosis
Histoplasma
capsulatum.
Affects primarily the
lung but may be disseminated.
Cause of Paracoccidioidomycosis
Paracoccidioides brasiliensis.
Affects lungs, mouth and skin
or disseminate
Cause of Pneumocystosis
Pneumocystis
carinii/jirovecii.
Affects lung and skin and may
become disseminate
Cause of Sporotrichosis
Sporothrix schenckii.
Affects
mainly the skin.
Causes of Cryptosporidiosis
Cryptosporidium hominis, Cryptosporidium parvum, and Cryptosporidium
meleagridis
Mixed infection is
possible
Cryptosporidiosis is an intestinal infection caused by ingesting food or water contaminated with infected faeces.
True or false
True
What are the risk factors for mycoses?
- Excessive use of antibiotics
- Steroid treatments
- HIV/AIDS infection
- Cancer chemotherapy
- Very old and very young people
- Diabetes
Classes of antifungal agents
(1) The Polyene Antifungals
(2) Azole antifungals
(3) Allylamine
(4) Echinocandins
(5) Antimetabolite
(6) Antimitotics
What are polyene antifungals?
They are macrocyclic molecules with multiple double bonds and a heavily hydroxylated region opposite the conjugated system and a mycosamine group (an aminoglycoside) often attached to the molecule.
What is the source of polyene antifungals?
Streptomyces specie
Examples of polyene antifungals
(1) amphotericin B
(2) nystatin
(3)
candicidin
(4) rimocidin
(5) fillipin
(6) natamycin
(pimaricin)
(7) hamycin
Mechanism of action of polyene antifungals
The polyene antifungals cause death of fungi by binding to ergosterol, the principal sterol in
their cell membrane, thereby causing formation of pores on the membrane and leakage of intracellular components such as
monovalent ions (k+, Na+, H+ , Cl-), enzymes and other small organic molecules.
Why are human cells less susceptible to the effects of polyene antifungals?
Because their
sterol component is cholesterol and not ergosterol.
Some polyene antifungals such as amphotericin B and filipin still
bind to cholesterol at therapeutic doses and this may account
for their side effects.
Uses of Amphotericin B
Due to severe ADR, its use is limited to severe systemic fungal infection such as
Aspergillosis, blastomycoses, cryptococcosis,
coccidioidomycosis, paracoccidioidomycoses, histoplamosis etc.
It is used IV
What species are resistant to amphotericin B
Pseudaschellaria boydii, Fusarium
spp, Trichosporon spp, Candida lusitaniae and Candida
guillermondii
Adverse effects of Amphotericin B
Phlebitis at site of infusion,
chills,
liver
damage,
hearing loss,
visual impairment,
bone
marrow toxicity,
cardiac arrest,
rash,
renal toxicity
How does Amphotericin B cause renal toxicity?
Suppression of
glomerular filtration
How is renal toxicity caused by Amphotericin B countered?
Administration of sodium chloride
Uses of Nystatin
Only for oral, vaginal and GIT
candidiasis.
Uses of Natamycin
Superficial fungal infections (both
yeasts and mold) of the eye.
What are Azole antifungals?
Antifungals possessing the azole ring in their chemical structure
Classes of Azole antifungals
Imidazoles,
Triazoles
Thiazoles
Examples of Imidazoles
Clotrimazole
Ketoconazole
Butoconazole
Isoconazole
Econazole
Bifonazole
Examples of triazoles
Fluconazole
Terconazole
Hexaconazole
Albaconazole
Itraconazole
Ravuconazole
Examples of thiazoles
Abafungin
Mechanism of action of azole antifungals
Besides abafungin, the azole
block the synthesis of ergosterol by inhibiting the enzyme lanosterol -14 alpha – demethylase, which is
necessary for the conversion of lanosterol to ergosterol.
This leads to distruption of fungal membrane’s structure and functions and inhibition of fungal growth.
Mechanism of action of abafungin
Inhibits fungal sterol
24c-methyl transferase
Abafungin has antibacterial properties.
True or false
True
Uses of Imidazoles
They are mainly
administered topically in pessaries, ovules, solutions, creams or shampoo for the treatment of candidiasis and dermatophytosis
Uses of ketoconazole
- It is applied topically for the treatment of candidiasis and dermatophytosis
- It is administered
systemically by mouth for the treatment of
blastomycosis and other mycoses
Ketoconazole is effective agains aspergillosis.
True or false
False
Uses of clotrimazole
- It is applied topically for the treatment of candidiasis and dermatophytosis
- It is also used in ear drops for the
treatment of ear infections.
Uses of triazoles
- The triazoles have replaced amphotericin B in
the treatment of systemic mycoses. - It is also
used routinely to treat candidemia,
cryptococcosis and coccidioidomycosis.
Uses of fluconazole
Fluconazole is effective in a single dose of
150mg for vaginal candidiasis
Uses of itraconazole
Itraconazole is effective in the treatment of blastomycosis, coccidioidomycosis, aspergillosis,
cryptococcosis, histoplasmosis and sporotrichosis.
Adverse effects of triazoles
Nausea and vomiting
Liver toxicity
What are the contraindications of ketoconazole?
Alcohol and antimetabolite antifungals
What are allylamines?
An allylamine is an organic compound, a colorless liquid and the simplest stable unsaturated amine
Examples of allylamines
Butenafine Amorolfine Naftifine Terbinafine
B-A-N-T
Mechanism of action of allylamines
They block ergosterol synthesis through inhibition of the enzyme squalene epoxidase, which converts squalene to squalene epoxide, which is converted to lanosterol.
Adverse effects of terbinafine
liver toxicity, myalgia, skin rash, GIT disturbance, visual disturbance, taste disturbance, insomnia, depression, headache, dizziness and blood dyscrasia.
Uses of terbinafine
- Terbinafine is mainly effective against the dermatophytes and is used topically in creams for superficial fungal skin infection such as tinea barbae, tinea corporis, tinea pedis.
- It is also used in oral tablet form for treatment of cutaneous fungal skin infection such as onchomychosis (tinea unguium) of toenail and fingernail
What are echinocandin antifungals
The echinocandins are large lipopeptide
molecules. They are the newest antifungals.
Examples of echinocandins
Caspofungin, Anidulafungin, and Micafungin
C-A-M
Mechanism of action of echinocandins
They block the synthesis of Beta (1,3) glucan in fungal cell wall by inhibiting the enzyme beta glucan synthase.
This causes cell wall damage and fungal death.
Uses of echinocandins
- They are administered parenterally in an immunocompromised patient for the treatment of systemic fungal infections, especially invasive candidiasis, candidemia and aspergillosis.
Echinocandins are administered orally.
True or false
False.
They are not administered orally due to low bioavailability
Echinocandins are not active against fusarium spp and cryptococcus neoformans
True
Adverse effects of echinocandin
local phlebitis, fever, haemolysis and abnormal liver function tests
Echinocandins have severe adverse effects.
True or False
False.
The side effects are mild.
Examples of antimetabolite antifungals
Flucytosine
Mechanism of action of flucytosine
Flucytosine is a pyrimidine
analogue that inhibits RNA and DNA synthesis.
In fungal cytoplasm, Flucytosine (5-fluorocytosine) is converted into 5-fluorouracil, which is further converted to 5-fluorouridine
triphosphate and 5-fluorodeoxyuridine
monophosphate.
The latter (5-FM) inhibits RNA synthesis while the former (5-FT) blocks DNA synthesis through inhibition of the enzyme thymidylate synthetase.
Uses of flucytosine
In combination with amphotericin B, it is the treatment of choice for cryptococcal meningitis
Adverse effects of flucytosine
hepatic dysfunction,
jaundice, crystalluria, renal failure, headache,
hallucination, hearing loss, parkinsonism, rash,
anaphylaxis and blood dyscrasia
Examples of antimitotic antifungals
Griseofulvin
Mechanism of action of griseofulvin
Griseofulvin inhibits
mitosis in fungi by binding to fungal
microtubules and altering the process of mitosis
Uses of griseofulvin
It is used both in human and animals to treat fungal skin infections (dermatophytosis)
Griseofulvin contraindications
Griseofulvin is a cytochrome P450 enzyme inducer and is known to reduce the effectiveness of oral contraceptive.
Adverse effects of griseofulvin
headache, dizziness, nausea,
vomiting, diarrhea, insomnia, skin rash,
antabuse reaction with alcohol
Fungicides vs. antifungals
While antifungals are used in animals, fungicides are used on plants
