Antifungal drugs work by targeting differences between fungal and human cell membranes and metabolism. Azoles like fluconazole inhibit ergosterol synthesis while polyenes like amphotericin B bind to ergosterol in the fungal cell membrane. Topical antifungals like nystatin and tolnaftate treat superficial infections while systemic drugs like fluconazole and itraconazole treat deep infections. Common adverse effects include nausea, liver toxicity, and drug interactions. The choice of antifungal depends on the infecting organism, infection severity, and route of administration needed.

1. Antifungal Drugs
 Infectious diseases caused by fungi are called
mycoses, and they are often chronic in nature.
 Fungal infectious occur due to :
 1- Abuse of broad spectrum antibiotics
 2- Decrease in the patient immunity

2.  They have rigid cell walls composed
largely of a polymer of N-
acetylglucosamine rather than
peptidoglycan (a characteristic component
of most bacterial cell walls).
 The fungal cell membrane contains
ergosterol rather than the cholesterol found
in mammalian membranes.
 These chemical characteristics are useful in
targeting chemotherapeutic agents against
fungal infections

3. 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.

4. 2- Deep infections
 Affect internal organs as : lung ,heart ,
brain leading to pneumonia ,
endocarditis , meningitis.

5. Classification of Antifungal Drugs
1- Antifungal Antibiotics :
 Griseofulvin
 Polyene macrolide : Amphotericin- B &
Nystatin
2- Synthetic :
 Azoles :
A) Imidazoles : Ketoconazole , Miconazole
B) Triazoles : Fluconazole , Itraconazole

6. Synthetic Antifungal ( contin…)
 Flucytosine
 Squalene epoxidase inhibitors :
e.g.Terbinafine & Naftifine.

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 : 11% 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 16 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 modifying 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.
3- 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

20. 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 .

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

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

23. 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.

24. Azoles
They are classified into :
 Imidazole group
 Triazole group

25. 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.

26. 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).

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

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

29. 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

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

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

33. 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

34. 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.

35. Fluconazole
 Water soluble
 Completely absorbed from GIT
 Excellent bioavailability after oral
administration
 Bioavailability is not affected by food or
gastric PH
 Concentrated in plasma is same by oral or IV
route
 Has the least effect on hepatic microsomal
enzymes

36. 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

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

38. 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

39. 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

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

41. 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).

42. Phrmacokinetics
 Rapidly & well absorbed orally
 Widely distributed including CSF.
 Mainly excreted unchanged through kidney
 Half-life 3-6 hours

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

44. Adverse Effects
 Nausea, vomiting , diarrhea, severe
enterocolitis
 Reversible neutropenia, thrombocytopenia,
bone marrow depression
 Alopecia
 Elevation in hepatic enzymes

45. 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.

46. 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

47. Griseofulvin
 Fungistatic, has a narrow spectrum
 Given orally (Absorption increases with fatty
meal )
 Half-life 26 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

48. 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.

49. 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.

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

51. 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).

52.  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.

53.  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.