pharmacology of antifungal agents

1. RVS Chaitanya koppala
Assistant professor,
lovely professional university
ANTIFUNGAL
AGENTS

2. ANTIFUNGAL AGENTS
• common in Diabetes Mellitus, Cancer, AIDS,
Pregnancy and in patients on
immunosuppressive therapy such as
prolonged course of corticosteriods, broad
spectrum antibiotics, anticancer drugs, etc.
• Treatment of fungal infections is somewhat
difficult than bacterial infection because of
various factors.

3. Antifungal Drugs
• Fungal infectious occur due to :
• 1- Abuse of broad spectrum antibiotics
• 2- Decrease in the patient immunity

4. FUNGAL INFECTIONS/CAUSATIVE
ORGANISMS
SUPERFICIAL MYCOSIS
• Dermatophytes
• Epidermophyton
• Trichophyton
• Microsporum
• Candida
• Malassezia Furfur
DEEP MYCOSIS
• Asperigillus
• Blastomyces
• Cryptococcus
• Coccidioides
• Candida
• Histoplasma
• Mucormycosis
• Sporotrichosis

5. Types of fungal infections
• 1. Superficial : Affect skin – mucous
membrane.e.g.
• Tinea versicolor
• Dermatophytes : Fungi that affect keratin
layer of skin, hair, nail.e.g.tinea pedis ,ring
worm infection
• Candidiasis : Yeast-like, oral thrush, vulvo-
vaginitis , nail infections.

6. 2- Deep infections
• Affect internal organs as :
lung
heart
brain
endocarditis
meningitis.

7. 1. ANTIBIOTICS
A)Polyenes: amphotericin B, Nystatin, Hamycin,
Natamycin
B)Heterocyclic Benzofuran: Griseofulvin
2. Antimetabolite: Flucytosine (5-FC)
3. Azoles:
A)Imidazoles (topical): Clotrimazole, Econazole,
Miconazole, Oxiconazole.
Systemic: ketoconazole.
B)Trizoles (systemic): Fluconazole, Itraconazole,
Voriconazole.
Classification of Antifungal Drugs

8. 4. Allylamine: Terbinafine
5. Other topical agents: Tolnaftate
Undecylenic acid
Benzoic acid
Quiniodochlor
Ciclopirox olamine
Butenafine
Sodium thiosulfate.

10. Classification According to Route of
Administration
• Systemic :
• Griseofulvin , Amphotericin- B , Ketoconazole , Fluconazole ,
Terbinafine.
• Topical
• In candidiasis :
• Imidazoles : Ketoconazole , Miconazole.
• Triazoles : Terconazole.
• Polyene macrolides : Nystatin , Amphotericin-B
• Gentian violet : Has antifungal & antibacterial.

12. Amphotericin B
• Amphotericin A & B are antifungal antibiotics.
• Amphotericin A is not used clinically.
• It is a natural polyene macrolide
• (polyene = many double bonds )
• (macrolide = containing a large lactone ring )

13. Pharmacokinetics
• Poorly absorbed orally, is effective for fungal
infection of gastrointestinal tract.
• For systemic infections given as slow I.V.I.
• Highly bound to plasma protein .
• Poorly crossing BBB.
• Metabolized in liver
• Excreted slowly in urine over a period of several
days.
• Half-life 15 days.

14. Mechanism of action
• It is a selective fungicidal drug.
• Disrupt fungal cell membrane by binding to
ergosterol , so alters the permeability of the cell
membrane leading to leakage of intracellular ions &
macromolecules ( cell death ).

18. Resistance to Amphotericin B
• If ergosterol binding is impaired either by :
• Decreasing the membrane concentration of
ergosterol.
• Or by modyfing the sterol target molecule.

19. Adverse Effects
• 1- Immediate reactions ( Infusion –related toxicity ).
• Fever, muscle spasm, vomiting ,headache, hypotension.
• Can be avoided by :
• A. Slowing the infusion
• B. Decreasing the daily dose
• C. Premedication with antipyretics, antihistamincs or
corticosteroids.

20. Slower toxicity
• Most serious is renal toxicity (nearly in all
patients ).
• Hypokalemia
• Hypomagnesaemia
• Impaired liver functions
• Thrombocytopenia
• Anemia

21. Clinical uses
• Has a broad spectrum of activity
• Fungicidal action.
• The drug of choice for life-threatening mycotic infections.
• For induction regimen for serious fungal infection.
• Also, for chronic therapy & preventive therapy of relapse.
• In cancer patients with neutropenia who remain febrile on
broad –spectrum antibiotics.

22. Routes of Administration
• 1- Slow I.V.I. For systemic fungal disease.
• 2- Intrathecal for fungal C.N.S. infections.
• Topical drops & direct subconjunctival injection for
Mycotic corneal ulcers & keratitis.
• 3- Local injection into the joint in fungal arthritis.
• 4- Bladder irrigation in Candiduria.

23. Liposomal preparations of
amphotericin B
• Amphotericin B is packaged in a lipid- associated
delivery system to reduce binding to human cell
membrane , so reducing :
• A. Nephrotoxicity
• B. Infusion toxicity
• Also, more effective
• More expensive

24. Azoles
• A group of synthetic fungistatic agents with a broad
spectrum of activity .
• They have
antibacterial
antiprotozoal
anthelminthic
antifungal activity .

26. Mechanism of Action
• 1-Inhibit the fungal cytochrome P450 enzyme, (α-
demethylase) which is responsible for converting
lanosterol to ergosterol ( the main sterol in fungal
cell membrane ).
• 2- Inhibition of mitochondrial cytochrome oxidase
leading to accumulation of peroxides that cause
autodigestion of the fungus.
• 3- Imidazoles may alter RNA& DNA metabolism.

27. Azoles
• They are antibacterial , antiprotozoal, anthelminthic
& antifungal.
• They are fungistatic agents.
• They are classified into :
Imidazole group
Triazole group

28. Imidazoles
• Ketoconazole
• Miconazole
• Clotrimazole
• They lack selectivity ,they inhibit human gonadal
and steroid synthesis leading to decrease
testosterone & cortisol production.
• Also, inhibit human P-450 hepatic enzyme.

29. Ketoconazole
• Well absorbed orally .
• Bioavailability is decreased with antacids, H2
blockers , proton pump inhibitors & food .
• Cola drinks improve absorption in patients with
achlorhydria.
• Half-life increases with the dose , it is (7-8 hrs).
• Inactivated in liver & excreted in bile (feces ) &
urine.
• Does not cross BBB.

30. Clinical uses Adverse effects
• Used topically or
systematic (oral route
only ) to treat :
• 1- Oral & vaginal
candidiasis.
• 2- Dermatophytosis.
• 3- Systemic mycoses &
mucocutaneous
candidiasis.
• Nausea, vomiting
,anorexia
• Hepatotoxic
• Inhibits human P 450
enzymes
• Inhibits adrenal &
gonadal steroids leading
to :
• Menstrual irregularities
• Loss of libido
• Impotence
• Gynaecomastia in males

31. Triazoles
• Fluconazole
• Itraconazole
• Voriconazole
• They are :
• Selective
• Resistant to degradation
• Causing less endocrine disturbance

32. Fluconazole
• Water soluble, Completely absorbed from GIT
• Excellent bioavailability after oral administration
• Bioavailability is not affected by food or gastric PH
• Conc. in plasma is same by oral or IV route
• Penetrates well BBB so, it is the drug of choice of
cryptococcal meningitis
• Safely given in patients receiving bone marrow
transplants (reducing fungal infections)
• Excreted mainly through kidney
• Half-life 25-30 hours
• Resistance is not a problem

33. Clinical uses
• Candidiasis
• ( is effective in all forms
of mucocutaneous
candidiasis)
• Cryptococcus meningitis
• Histoplasmosis,
blastomycosis, , ring
worm.
• Not effective in
aspergillosis
Side effects
• Nausea, vomiting,
headache, skin rash ,
diarrhea, abdominal pain ,
reversible alopecia.
• Hepatic failure may lead to
death
• Highly teratogenic ( as
other azoles)
• Inhibit P450 cytochrome
• No endocrine side effects

34. Flucytosine (5-FC)
• Converted within the fungal cell to 5-
fluorouracil( Not in human cell ), that inhibits
thymidylate synthetase enzyme that inhibits DNA
synthesis.
• ( Amphotericin B increases cell permeability ,
allowing more 5-FC to penetrate the cell, they are
synergistic).

35. Griseofulvin
• Fungistatic, has a narrow spectrum
• Given orally (Absorption increases with fatty meal )
• Half-life 24 hours
• Taken selectively by newly formed skin &
concentrated in the keratin.
• Induces cytochrome P450 enzymes
• Should be given for 2-6weeks for skin & hair
infections to allow replacement of infected keratin
by the resistant structure

36. Griseofulvin(cont.)
• Inhibits fungal mitosis by interfering with microtubule
function
• Used to treat dermatophyte infections ( ring worm of skin,
hair, nails ).
• Highly effective in athlete,
s foot.
• Ineffective topically.
• Not effective in subcutaneous or deep mycosis.
• Adverse effects ;
• Peripheral neuritis, mental confusion, fatigue, vertigo,GIT
upset,enzyme inducer, blurred vision.
• Increases alcohol intoxication.

37. Antifungal Drugs Used For Topical Fungal
Infections
• 1. Topical azole derivatives
• 2. Nystatin& Amphotericin
• 3. Terbinafine
• 4. Tolnaftate
• 5. Naftifine
• 6. Griseofulvin

39. THANK YOU