This document discusses anti-fungal drugs. It begins by defining fungi and describing their characteristics. It then discusses the structure of fungi including their cell wall, cell membrane, and intracellular components. It notes that anti-fungal drugs target the fungal cell wall, cell membrane, DNA/RNA synthesis, and mitosis. The document categorizes anti-fungal drugs and describes several major classes - polyenes, azoles, echinocandins, griseofulvin, and flucytosine. It provides details on several important anti-fungal drugs, including their mechanisms of action, pharmacokinetics, clinical uses, and side effects.

1. By: Meenakshi Gupta
M.Pharm.
Pharmacology
Anti-fungal drugs

2. What is Fungus?
Definition: A fungus is any member of the group of eukaryotic
organisms that includes unicellular microorganisms such as yeasts and
molds, as well as multicellular fungi that produce familiar fruiting forms
known as mushrooms.
Characteristics
 Most fungi grow as tubular filaments called hyphae. An interwoven
mass of hyphae is called a mycelium.
 The walls of hyphae are often strengthened with chitin, a polymer of
N-acetyl glucosamine.
 Fungi disperse themselves by releasing spores, usually windblown.
 Fungi are heterotrophic.

3. Structure of fungi
A. Cell Wall:
The cell wall is made up of:
1) chitin (polymers of acetylated amino sugar N-acetyl-glucosamine)
2) glucan (polymers of glucose)
3) proteins (polymers of amino acids).
Glucan and chitin are components of the primary wall.
Proteins are components of the
secondary wall.
Other components include chitosan,
melanins and lipids. Enzymes include
cellulase which acts on cellulose of plants.

5. B. Cell Membrane:
contains ergosterol and zymosterol in contrast to
humans which contains cholesterol. Cell membrane
also contains glycoproteins, lipids & sterols.
C. Inside the cell:
Golgi apparatus, ribosomes bound to ER &
cytoskeleton with microtubules, microfilaments
& intermediate filaments. It also contains
nucleus enclosed by nuclear membrane.

6. Four targets in fungal
pathogens:
Fungal Cell Wall
Fungal Cell Membrane
DNA/RNA Synthesis
Inhibition of fungal mitosis

7. Anti- fungal drugs
 These are drugs used for superficial and deep
(systemic) fungal infections.
 Mostly associated with the use of broad- spectrum
antibiotics, corticosteroids, anti-cancer/ immuno-
suppresants drugs, dentures, indwelling catheters
& implants, and emergence of AIDS.
 As a result of breakdown of host defense
mechanisms by the above agents, saprophytic
fungi easily invade living tissue.

8. What Are Superficial Fungal
Infections?
Superficial fungal infections attack tissues on the surface of the body, which
include the skin, nails, or hair. Some common examples are ringworm,
athlete's foot, jock itch, and yeast infections. Candida yeast infections are
usually found on the skin, in the mouth, in the vagina, on the head of the
penis, or around the nails. Superficial fungal infections are somewhat
contagious and pass from person to person through direct contact or, less
commonly, through clothes or contact with surfaces of other objects in the
environment.
Examples: Tinea manuum(Hand)
Tinia capitis(Scalp)
Tinea corporis(Body)
Tinea pedis(Foot)

9. Some fungi are normally present in the body, kept under control by the
body's immune system. If the immune system is abnormally weak,
however, the fungi can grow out of control and cause illness. These are
termed opportunistic infections. Among the most common opportunistic
fungal infections that affect people are:
 candidiasis
 aspergillosis
 phycomycosis
 cryptococcosis
Symptoms may include cough, fever, chills, night sweats, anorexia (loss
of appetite), weight loss, general fatigue, and depression.
What Are Systemic Fungal Infections?

10. CLASSIFICATION:
A. According to the mechanism of action:
1. Drugs affecting synthesis of ergosterol (cell membrane):
Ketoconazole
Fluconazole
Itraconzole
Voriconazole
2. Drugs affecting function of cell membrane:
Polyenes : Natamycin
Nystatin
Amphotericin B

11. 3.Block nucleic acid synthesis:
Flucystosine
4. Disrupt microtubular fuction:
Griseofulvin
5. Reduction of cell wall viability:
pradimiccin
nikkomycin
6. Fungal protein synthesis inhibitors:
jordanians

12. B. According to route of administration:
1.Topical: Nystatin
Amphotericin B
Clotrimazole
Econazole
2. Oral: Miconazole
Ketoconazole
Fluconazole
Itraconzole
Flucystosine
Terbinafine

13. 3. Intraveneous: Amphotericin B
Miconazole
Flucystosine
Fluconazole
C. According to the chemical structure:
1.Polyenes : Natamycin
Nystatin
Amphotericin B
2. Azoles :
(a) Imidazoles : Miconazole
Ketoconazole
Clotrimazole
Econazole
(b) Triazoles : Fluconazole
Itraconzole
Isavuconazole
Ravuconazole
Voriconazole

14. 3. Heterocyclic Benzofurans: griseofulvin
4. Echinocandins: caspofungins
micafungin
5. Miscellaneous drugs: Undecylenic acid
Benzoic acid
Salicylic acid
Propionic acid
Caprylic acid
Potassium iodide
Vaccines

15. D. Therapeutic classification:
1. Superficial:
Dermatopltyes: Griseofulvin
Terbanafin
Ketoconazole
Nystatin
Candidacies: Fluconazole
Miconazole
2. Systemic:
ketoconazole: Histoplasm & blastomycosis
Amphotericin B: Cryptococcus, zygomycosis
Flucytosine: Candiasis, Cryptococcus

16. A. POLYENE ANTIBIOTICS:
Name derived from their highly double-bonded structure.
Amphotericin B:
Obtained from streptomyces nodosus.
Broad-spectrum polyene macrolide.
Fungicidal drug at high concentration & static at lower levels.
MOA: Polyene antifungals such as amphotericin B act by binding to
ergosterol in the fungal cell membrane. They combine with it, get
inserted into the membrane and several polyene molecules together
orient themselves in such a way as to form a ‘micropore’. The micropore
is stabilised by membrane sterols which fill up spaces between the AMB
molecules on the lipophilic side- constituting the outer surface of the
pore. Thus, cell permeability is markedly increased.

19. Pharmacokinetics:
• AMB is not absorbed enterally; hence can
be given orally for intestinal candidiasis
without systemic toxicity.
• Drug concentration achieved in infected
skin is very low, & hence ineffective
against superficial fungal infections.
• Penetration in brain & CSF is poor (but
extremely effective in fungal meningitis
when combined with 5-FC)

20. Liposomal Amphotericin B
• New lipid formulations
• AMB is incorporated into lipid
formulations to reduce toxicity &
enhance efficacy.
• This allows higher dose to be
used without increasing the
toxicity.
• Much more expensive than
ordinary AMB.

21. Side effects
Infusion related
Fever & chills,
Dyspnoea,
Nausea & vomiting,
Hypotension,
Convulsions
Long term toxicity
Nephrotoxicity
K & Mg wasting
Anaemia
(↓erythropoietin)
To reduce the severity of the infusion-related reactions, pretreatment with an
antipyretic (acetaminophen), antihistamines, and anti-emetics may be given.

22. Uses:
 Applied topically for oral, vaginal & cutaneous candidiasis and
otomycosis.
 Often used in febrile neutropenic patients
 Most effective in resistant cases of kala azar and mucocutaneous
leishmaniasis.

23. 2. ECHINOCANDINS:
 New class of potent semi synthetic antifungal antibiotics.
 Contains complex cyclic lipopeptide structure.
 Low toxicity compared to AMB.
Caspofungins:
 Active against candida and aspergillus.
 Not absorbed orally; has to be infused i.v.
 Distributed into tissues, but does not enter CSF.
 Extensive metabolism & excreted in urine & faeces.
 Used in deep and invasive candidiasis, Oesophageal candidiasis
& therapy of nonresponsive invasive aspergillosis.

24. Mechanism of Action
Inhibit the synthesis of B
glucan in the fungal cell wall
Disruption of the fungal
cell wall and cell death.

26. Adverse Effects
 Rashes
 Vomiting
 Dyspnoea
 Hypokalemia
 Joint pain

27. 3.HETEROCYCLIC BENZOFURAN:
 Griseofulvin is fungistatic for most dermatophytes,
shows selective toxicity.
 It interferes with mitosis- multi nucleated and stunted
fungal hyphae are produced under its action. It causes
abnormal metaphase configuration. It binds with
polymerised microtubules and interferes with their
functions.
 Pharmacokinetics: low water solubility hence absorption
is improved by taking it with fat. Gets deposited in
keratin forming cells of skin, hairs & nails. It is largely,
metabolised & excreted in urine.
 Adverse effect: head ache, g.i.t. disturbances, CNS
symptoms & peripheral neuritis, rashes, photo allergy,
gynaceomastia.
 Uses: dermatophytosis, athletes foot.

28. 4.ANTI-METABOLITE:
Flucytosine (5-FC):
 Pyrimidine antimetabolite
 Inactive until it reaches inside the fungal cell
 Narrow spectrum fungistatic, active against cryptococcus
neoformans, torula, chromoblastomyces & a few strains of
candida.
 Adverse effect: dose dependent bone marrow depression,
gastrointestinal disturbances, liver dysfunction.

29. Flucytosine is taken up by fungal cells via
the enzyme cytosine permease.
It is converted intracellularly first to 5-FU
and then to 5-fluorodeoxyuridine
monophosphate (FdUMP) and fluorouridine
triphosphate (FUTP), which inhibit DNA and
RNA synthesis, respectively.

31. Clinical use at present is confined to
combination therapy, either with:
 Amphotericin B for cryptococcal
meningitis , or
 Itraconazole for
chromoblastomycosis

32. 5.IMIDAZOLE & TRIAZOLES
 Most extensively used anti-fungal drugs
 Broad spectrum anti fungal activity
MOA: These drugs act by reducing the synthesis of
ergosterol by inhibiting cytochrome p450 3A enzyme i.e. 14
alpha demethylase, thus accumulating 14 alpha methyl
sterol thereby interrupting the synthesis of ergosterol.
Inhibition of this critical enzyme in the ergosterol synthesis
pathway leads to the depletion of ergosterol in the cell
membrane and accumulation of toxic intermediate sterols,
causing increased membrane permeability and inhibition of
fungal growth

34.  KETOCONAZOLE:
older, more toxic, replaced by itraconazole, but less costly
• The first oral azole introduced into clinical use.
• It is less selective for fungal P450 than are the newer azoles.
• Absorption variable (better in acidic medium)
• Penetration in brain & CSF is poor
• In high doses inhibits adrenocortical steroids and testosterone synthesis, resulting in
gynecomastia in some males.
 FLUCONAZOLE:
Broad-spectrum Fungicidal drug;
• It is also somewhat effective against some Gram-positive & anaerobic bacteria
• Of the orally administered fluconazole 94% is absorbed;
• Penetration in brain & CSF is good, hence used for cryptococcal meningitis

35.  POSACONAZOLE:
 The newest triazole
 It is the broadest spectrum member of the azole family.
 It is the only azole with significant activity against the agents of zygomycosis and
mucormycosis.
ADVERSE EFFECT:
 Relatively nontoxic.
 Minor GI upset
 Abnormalities in liver enzymes (inhibit cytochrome P450 enzymes)
 Very rarely, clinical hepatitis
CLINICAL USE:
Candida Cryptococcus
Blastomyces Histoplasma
Coccidiodes Dermatophytes

36. 6.ALLYLAMINE:
Terbinafine:
 Synthetic allylamine.
 Orally Active.
MOA: It interferes with
ergosterol
biosynthesis by:
Inhibiting the fungal
enzyme squalene
epoxidase
Accumulation of the
sterol squalene

38.  Like the azole drugs, it interferes with ergosterol
biosynthesis, but rather than interacting with the P450
system, terbinafine inhibits the fungal enzyme squalene
epoxidase.
 This leads to the accumulation of the sterol squalene,
which is toxic to the organism.
Adverse effects: GI upset
Rash
Pruritis
Headache.
Uses: localised tinea pedis
onychomycosis
cutaneous & mucosal candidiasis

40. TOPICAL ANTIFUNGALS
 Used for dermatophtoysis.
 Includes: Tolnafate
Cicloprox olamine
Undecylenic acid
Benzoic acid
Quiniodochlor
Sodium thiosulphate

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