antifungal drugs

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

2. 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.

3. 2- Deep infections
 Affect internal organs as : lung ,heart ,
brain leading to pneumonia ,
endocarditis , meningitis.

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

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

6. 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.


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

8. 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 )

9. 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.

10. 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 ).

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

12. 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.

13. 2- Slower toxicity
 Most serious is renal toxicity (nearly in all
patients ).
 Hypokalemia
 Hypomagnesaemia
 Impaired liver functions
 Thrombocytopenia
 Anemia

14. 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.

15. 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.

16. 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

17. 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 .

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

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

20. 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.

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

22. 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.

23. 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).

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

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

26. 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

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

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

29. 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

30. 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.

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
 Has the least effect on hepatic microsomal
enzymes

32. 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

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

34. 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

35. 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

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

37. 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).

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

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

40. 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)

41. 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.

42. 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

43. 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

44. 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.

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

46. 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.

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

48. 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.

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

50. 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.

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

52. 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).

53.  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.

54.  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.