This PPT covers the Drug therapy for Fungal diseases. It includes classification of antifungal drugs and Pharmacotherapy of all antifungal drugs

1. PREPARED BY: JEGAN. S. NADAR
ANTIFUNGAL DRUGS

2. ANTI-FUNGAL DRUGS
● Infectious diseases caused by fungi are called mycoses, and they are often
chronic in nature.
● Mycotic infections may be superficial and involve only the skin (cutaneous
mycoses extending into the epidermis), while others may penetrate the skin,
causing subcutaneous or systemic infections
● Unlike bacteria, fungi are eukaryotic, with rigid cell walls composed largely of
chitin rather than peptidoglycan (a characteristic component of most bacterial cell
walls). Jegan

3. ANTI-FUNGAL DRUGS
● Inaddition, the fungal cell membrane contains ergosterol rather than the
cholesterol found in mammalian membranes.
● These structural characteristics are useful in targeting chemotherapeutic agents
against fungal infections.
● Fungal infections are generally resistant to antibiotics, and conversely, bacteria
are resistant to antifungal agents.
Jegan

4. CLASSIFICATION
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7. POLYENE ANTIBIOTICS
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8. Amphotericin B (AMB)
● It is obtained from Streptomyces nodosus.
● The polyenes have high affinity for ergosterol present in 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’.
Jegan

9. ANTI-FUNGAL DRUGS● The hydrophilic side forms the interior of the pore through which ions,
amino acids and other water-soluble substances move out.
● The micropore is stabilized by membrane sterols which fill up the spaces
between the AMB molecules on the lipophilic side—constituting the outer
surface of the pore.
● Thus, cell permeability is markedly increased.
● The pores disrupt membrane function, allowing electrolytes (particularly
potassium) and small molecules to leak from the cell, resulting in cell death.
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10. Amphotericin B (AMB)
● Amphotericin B is either fungicidal or fungistatic, depending on the
organism and the concentration of the drug.
● It is fungicidal at high and static at low concentrations

11. Amphotericin B (AMB)
● Amphotericin B is administered by slow, IV infusion
● Amphotericin B is insoluble in water and must be
coformulated with either sodium deoxycholate
(conventional) or a variety of artificial lipids to form
liposomes.
● It gets widely distributed in the body, but penetration
in CSF is poor.
● Amphotericin B does cross the placenta.

12. Adverse effects
● Amphotericin B has a low therapeutic index. The total adult daily dose of the
conventional formulation should not exceed 1.5 mg/kg/d, whereas lipid
formulations have been given safely in doses up to 10 mg/kg/d
● Fever and chills
● Renal impairment
● Hypotension
● Thrombophlebitis
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13. ECHINOCANDINS

14. Caspofungin
● It is the first and the prototype member of the class, active mainly against
Candida and Aspergillus.
● The mechanism of action is different from other antifungals, viz. it inhibits the
synthesis of β-1,3-glucan, which is a unique component of the fungal cell wall.
● Cross linking between chitin (a fibrillar polysaccharide) and β-1,3-glucan gives
toughness to the fungal cell wall.
● Weakening of the cell wall by caspofungin leads to osmotic susceptibility of fungal
cell, which then succumbs
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15. HETEROCYCLIC BENZOFURAN

16. Griseofulvin
● It was one of the early antibiotics extracted from Penicillium griseofulvum
● Its only use is in the systemic treatment of dermatophytosis
● The absorption of griseofulvin from g.i.t. is somewhat irregular because of its
very low water solubility.
● Ultrafine crystalline preparations are absorbed adequately from the
gastrointestinal tract,
● Absorption is enhanced by high-fat meals
● Drug interaction with Warfarin and Phenobbarbitol
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18. ANTIMETABOLITE ANTIFUNGALS

19. FLUCYTOSINE
● It is a pyrimidine antimetabolite which is inactive as such.
● After uptake into fungal cells, it is converted into 5-fluorouracil and then to
5-fluorodeoxyuridylic acid which is an inhibitor of thymidylate synthesis.
● Thymidylic acid is a component of DNA
● This disrupt nucleic acid and protein synthesis
● Amphotericin B increases cell permeability, allowing more 5-FC to
penetrate the cell and leading to synergistic effects.
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20. ● 5-FC is a narrow spectrum fungistatic
● It is active against
◎Cryptococcus neoformans,
◎Torula,
◎Chromoblastomyces
◎few strains of Candida.
● Other fungi and bacteria are insensitive
● 5-FC is well absorbed by the oral route. It distributes
throughout the body water and penetrates well into
the CSF.

21. file:///media/sjiprstaff/K
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22. FLUCYTOSINE
● Toxicity of 5-FC is lower than that of AMB
● Consists of dose-dependent bone marrow depression and gastrointestinal
disturbances, particularly enteritis and diarrhoea.
● Liver dysfunction is mild and reversible.
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23. IMIDAZOLES AND TRIAZOLES

24. IMIDAZOLES AND TRIAZOLES
● Azole antifungals are made up of two different classes of drug imidazoles
and triazoles.
● Although these drugs have similar mechanisms of action and spectra of
activity, their pharmacokinetics and therapeutic uses vary significantly.
● In general, imidazoles are given topically for cutaneous infections
● Whereas triazoles are given systemically for the treatment or prophylaxis
of cutaneous and systemic fungal infections.
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25. IMIDAZOLES AND TRIAZOLES
● Azoles are predominantly fungistatic.
● They inhibit C-14 α-demethylase (a cytochrome P450 [CYP450]
enzyme),
● This blocks the demethylation of lanosterol to ergosterol, the principal
sterol of fungal membranes
● The inhibition of ergosterol biosynthesis disrupts membrane structure and
function, which, in turn, inhibits fungal cell growth.
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26. Clotrimazole
● It is effective in the topical treatment of tinea infections like ringworm
● It is also effective against oropharyngeal candidiasis
● It is particularly favoured for vaginitis because of a long lasting residual
effect after once daily application. A 7 day course is generally used
● Clotrimazole is well tolerated by most patients. Local irritation with stinging
and burning sensation occurs in some.
● No systemic toxicity is seen after topical use.
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27. Ketoconazole
● Ketoconazole was the first oral azole introduced into clinical use.
● It is distinguished from triazoles by its greater propensity to inhibit
mammalian cytochrome P450 enzymes; that is, it is less selective for fungal
P450 than are the newer azoles.
● As a result, systemic ketoconazole has fallen out of clinical use.
● Ketoconazole is replaced by newer Triazoles
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28. Fluconazole
● Fluconazole was the first member of the triazole class of antifungal agents.
● It is the least active of all triazoles, with most of its spectrum limited to
yeasts and some dimorphic fungi.
● Fungicidal concentrations are achieved in nails, vagina and saliva;
penetration into brain and CSF is good.
● Dose reduction is needed in renal impairment.

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30. Fluconazole
● It is a water-soluble triazole having a wider range of activity than KTZ
● Indications include
● Cryptococcal meningitis,
● Systemic candidiasis in both normal and immunocompromised patients,
● Mucosal candidiasis in both normal and immunocompromised patients,
● Coccidioidal meningitis
● Some tinea infections.
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31. ALLYAMINE

32. Terbinafine
● This orally and topically active drug against dermatophytes and Candida
belongs to a new allylamine class of antifungals
● It is fungicidal in nature
● It acts as a non-competitive inhibitor of ‘squalene epoxidase’,
● The mammalian enzyme is inhibited only by 1000-fold higher concentration
of terbinafine
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34. Terbinafine
● These agents act by inhibiting squalene
epoxidase, thereby blocking the
biosynthesis of ergosterol, an essential
component of the fungal cell membrane
● Accumulation of toxic amounts of
squalene results in increased membrane
permeability and death of the fungal cell.
Jegan

35. Thank You