Antifungal drugs

1. Anti fungal drugs
Sanju Kaladharan

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

4. 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.

5. 2- Deep infections
• Affect internal organs as : lung ,heart , brain
leading to pneumonia , endocarditis ,
meningitis.

6. Classification of Antifungal Drugs
1. Antibiotics
A. Polyenes: Amphotericin B (AMB), Nystatin, Hamycin
B. Echinocandins:Caspofungin, Micafungin, Anidulafungin
C. Heterocyclic benzofuran: Griseofulvin
2. Antimetabolite Flucytosine (5-FC)
3. Azoles
A. Imidazoles
Topical: Clotrimazole, Econazole, Miconazole, Oxiconazole
Systemic: Ketoconazole
4. Allylamine Terbinafine
5. Other topical agents
Tolnaftate, Undecylenic acid, Benzoic acid,
Quiniodochlor, Ciclopirox olamine, Butenafine,
Sod. thiosulfate.

7. 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.
•

8. In Dermatophytes :
• Squalene epoxidase inhibitors : Terbinafine &
• Naftifine.
• Tolnaftate.
• White field ointment : 12% Benzoic acid & 6%
Salicylic acid .
• Castellani paint.

9. 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 )

10. 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.

11. 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 ).

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

14. 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.
• D. A test dose.

15. 2- Slower toxicity
• Most serious is renal toxicity (nearly in all
patients ).
• Hypokalemia
• Hypomagnesaemia
• Impaired liver functions
• Thrombocytopenia
• Anemia

16. 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.

17. 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.

18. 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

19. Nystatin
• It is a polyene macrolide ,similar in structure &
mechanism to amphotericin B.
• Too toxic for systemic use.
• Used only topically.
• It is available as creams, ointment , suppositories &
other preparations.
• Not significantly absorbed from skin, mucous
membrane, GIT .

20. Clinical uses
• Prevent or treat superficial candidiasis of mouth,
esophagus, intestinal tract.
• Vaginal candidiasis
• Can be used in combination with antibacterial
agents & corticosteroids.

22. Echinocandins

23. echinocandins
• Targets fungal cell wall
• Lipopeptide molecules that non competitively
inhibit (1,3)beta d –glucan synthase enzyme
• The enzymes form glucan, a major component
of fungal cell wall
• Known as Penicillin of antifungals

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

25. 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.

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

30. 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.

31. 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).

32. Ketoconazole (cont.)
• Inactivated in liver & excreted in bile (feces ) &
urine.
• Does not cross BBB.

33. Clinical uses
• Used topically or systematic (oral route only ) to
treat :
• 1- Oral & vaginal candidiasis.
• 2- Dermatophytosis.
• 3- Systemic mycoses & mucocutaneous candidiasis.

34. Adverse Effects
• Nausea, vomiting ,anorexia
• Hepatotoxic
• Inhibits human P 450 enzymes
• Inhibits adrenal & gonadal steroids leading to :
• Menstrual irregularities
• Loss of libido
• Impotence
• Gynaecomastia in males

35. Contraindications & Drug interactions
• Contraindicated in :
• Prgnancy, lactation ,hepatic dysfunction
• Interact with enzyme inhibitors , enzyme inducers.
• H2 blockers & antacids decrease its absorption

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

37. Itraconazole
• Lacks endocrine side effects
• Has a broad spectrum activity
• Given orally & IV
• Food increases its absorption
• Metabolized in liver to active metabolite
• Highly lipid soluble ,well distributed to bone,
sputum ,adipose tissues.
• Can not cross BBB

38. Itraconazole (cont.)
• Half-life 30-40 hours
• Used orally in dermatophytosis & vulvo-vaginal
candidiasis.
• IV only in serious infections.
• Effective in AIDS-associated histoplasmosis
• Side effects :
• Nausea, vomiting, hypokalemia, hypertension,
edema, inhibits the metabolism of many drugs as
oral anticoagulants.

39. 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
• Has the least effect on hepatic microsomal enzymes

40. Fluconazole (cont.)
• Drug interactions are less common
• 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

41. Clinical uses
• Candidiasis
• ( is effective in all forms of mucocutaneous
candidiasis)
• Cryptococcus meningitis
• Histoplasmosis, blastomycosis, , ring worm.
• Not effective in aspergillosis

42. 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

43. Voriconazole
• A broad spectrum antifungal agent
• Given orally or IV
• High oral bioavailability
• Penetrates tissues well including CSF
• Inhibit P450
• Used for the treatment of invasive aspergillosis &
serious infections.
• Reversible visual disturbances

44. Flucytosine
• Synthetic pyrimidine antimetabolite (cytotoxic drug
) often given in combination with amphotericin B &
itraconazole.
• Systemic fungistatic

45. Mechanism of action
• 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).

46. Pharmacokinetics
• Rapidly & well absorbed orally
• Widely distributed including CSF.
• Mainly excreted unchanged through kidney
• Half-life 3-6 hours

47. Clinical uses
• Severe deep fungal infections as in meningitis
• Generally given with amphotericin B
• For cryptococcal meningitis in AIDS patients

48. Adverse Effects
• Nausea, vomiting , diarrhea, severe enterocolitis
• Reversible neutropenia, thrombocytopenia, bone
marrow depression
• Alopecia
• Elevation in hepatic enzymes
• (some adverse effects related to 5-Fu formed by
intestinal organisms from5-FC)

49. Caspofungin
• Inhibits the synthesis of fungal cell wall by
inhibiting the synthesis of β(1,3)-D-glucan, leading
to lysis & cell death.
• Given by IV route only
• Highly bound to plasma proteins
• Half-life 9-11 hours
• Slowly metabolized by hydrolysis & N-acetylation.
• Elimination is nearly equal between the urinary &
fecal routes.

50. Clinical uses
• Effective in aspergillus & candida infections.
• Second line for those who have failed or cannot
tolerate amphotericin B or itraconazole.
• Adverse effects :
• Nausea, vomiting
• Flushing( release of histamine from mast cells)
• Very expensive

51. 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

54. 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.

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

56. Topical Antifungal Agents
• Used in superficial fungal infections , such as :
• Dermatophytosis ( ring worm), candidiasis, fungal
keratitis.
• They are not effective in mycoses of the nails & hair
or subcutaneous mycoses.
• The preferred formulation for cutaneous
application is cream or solution.

57. Azoles for topical use
• In the form of vaginal creams, suppositories,
tablets for vaginal candidiasis given once
daily .

58. CLOTRIMAZOLE
• Absorption is less than 0.5% from intact skin, 3-10%
from vagina (its activity remains for 3 days ).
• Used in dermatophytes , cutaneous candidiasis &
vulvovaginal candidiasis.
• Causes : Erythema, edema, , urticaria & mild vaginal
burning sensation.

59. ITRACONAZOLE
• Effective for treatment of onychomycoses.
• Should not be given in patients with ventricular
dysfunction.
• Evaluation of hepatic function is recommended.

60. TOLNAFTATE
• Effective in most cutaneous mycosis.
• Ineffective against Candida.
• Used in tinea pedis ( cure rate 80% ).
• Used as cream, gel, powder, topical solution.
• Applied twice daily.

61. NAFTIFINE
• Broad spectrum fungicidal .
• Available as cream or gel.
• Effective for treatment of tinea cruris.

62. Antimetabolites

63. allylamines

64. TERBINAFINE
• Drug of choice for treating dermatophytes
(onychomycoses).
• Better tolerated ,needs shorter duration of therapy.
• Inhibits fungal squalene epoxidase, decreases
• The synthesis of ergosterol .(Accumulation of
squalene ,which is toxic to the organism causing
death of fungal cell).

65. • Fungicidal ,its activity is limited to candida albicans
& dermatophytes.
• Effective for treatment of onychomycoses
• 6 weeks for finger nail infection & 12 weeks for toe
nail infections .
• Well absorbed orally , bioavailability decreases due
to first pass metabolism in liver.

66. • Highly protein binding
• Accumulates in skin , nails, fat.
• Severely hepatotoxic, liver failure even death.
• Accumulate in breast milk , should not be given to
nursing mother.
• GIT upset (diarrhea, dyspepsia, nausea )
• Taste & visual disturbance.