Pharmacology of anti fungal agents

1. RVS Chaitanya koppala
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.
• 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.
• 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.
• 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. 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.

28. 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.

29. 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

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

31. 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

32. 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. THANK YOU