1. Antifungal Drugs

2. Fungi
Fungi are more complex than bacteria and require a different approach to anti infective therapy—
Fungal diseases are called mycoses.

3. Fungi 1. Much, more complex than bacteria
2. Some species normally grow on skin and mucosal surfaces.

4. Fungi Classifying fungal infections. Superficial mycoses dermatophytic
Affect scalp, skin, nails, mucous membranes (oral cavity, vagina)
Treated with topical agents
Low incidence of side effects
Systemic mycoses
Affect internal organs (lungs, brain, digestive organs) less common than superficial mycoses
Sometimes fatal to clients with suppressed immune systems
Treated with oral or parenteral agents
More side effects

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

6. The most significant difference between human and fungal cell membranes is in the sterols present.
Ergosterol, instead of cholesterol, is the primary component of the cell membrane in fungi. The primary function of ergosterols is to modulate membrane fluidity and provide a "sparking" function used to initiate growth and increase the size of the yeast cell.

7. Fungal cell.

8. Human fungal infections have increased dramatically in incidence and severity in recent years, due to:
advances in surgery,
cancer treatment,
increases in the use of broad-spectrum antimicrobials and the
HIV epidemic These changes have resulted in increased numbers of patients at risk for fungal infections.

9. It is an oral common in about half of the general population.
the most important fungus of in dentistry is a yeast belonging to the genus Candida.
It is an oral common in about half of the general population.
Fungi may cause benign infection of the skin ,nail or hair ,relatively trivial infection of mucous membranes,
or systemic infection causing progressive often fatal disease.

10. Classification of Antifungal Drugs
1- Antifungal Antibiotics :
Griseofulvin
Polyene macrolide : Amphotericin- B & Nystatin
2- Synthetic :
Azoles :
A) Imidazoles : Ketoconazole , Miconazole
B) Triazoles : Fluconazole , Itraconazole
Flucytosine
Squalene epoxidase inhibitors : e.g.
Terbinafine & Naftifine.

11. 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. Antifungal agents
Anti fungal agent can be classified according to mechanism of action into:
Agent form pores in the cell membrane
polyenes ( amphotericin B and Nystatin)
2. Agents disrupt ergosterol synthesis.
a. Azole. Include Imidazole and triazole
b. Allylamines. As terbinafine
3. gents disrupts the mitotic spindle
as Grisofulvin and caspofungin
4. Agents inhibiting DNA synthesis As Fluorocytosine

13. Antifungal mechanism of action
Antifungal agent

14. 1- Agent form pores in the cell membrane
Polyenes:
Amphotericin B
Amphotericin B has a broad spectrum of antifungal activity and is effective against Candida species.
amphotericin B is obtained from Streptomyces Nodosus and is the gold standard for the treatment of many invasive or life-threatening mycoses.

15. Amphotericin A & B are antifungal antibiotics.
Amphotericin A is not used clinically.
amphotericin B is either fungistatic or fungicidal depending on
concentration of the drug present
the pH of the surrounding medium
the nature of the infecting organism

16. Mechanism of action
The primary mechanism of antifungal action of Amphotericin B results from its binding to ergosterol, a component of the cell membrane of sensitive fungi.
This binding forms channels in the membrane, altering its permeability and causing leakage of Na+, K+, and H+ ions.

18. Resistance to amphotericin B is associated with a replacement of ergosterol with other sterols in the fungal plasma membrane.

19. Dosage and administration
Amphotericin is not absorbed when given orally and intravenous formulation must be used to treat systemic disease.
So it is administered by slow intravenous infusion (over a period of 2 to 6 hours each day)
Amphotericin B applied topically as a 3% cream, ointment, or lotion is useful in the treatment of superficial Candida infections.

20. Adverse Effects A- Immediate reactions ( Infusion –related toxicity).
Local phlebitis at the injection site can occur.
Fever, muscle spasm, vomiting ,headache, hypotension.
Can be avoided by :
Slowing the infusion
Decreasing the daily dose
Premedication with antipyretics, antihistamincs or corticosteroids.

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

22. Nystatin
Nystatin has a spectrum of activity slightly narrower than that of amphotericin B.
As with amphotericin B, Nystatin is either fungi static or fungicidal.
Nystatin is used primarily to treat candidal infections of the mucosa, skin, intestinal tract, and vagina.
topical nystatin remains a drug of choice for the treatment of candidal infections of the oral cavity (oral moniliasis, thrush, denture stomatitis.

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

24. Dosage and administration
Nystatin is not appreciably absorbed from the skin, mucous membranes, or gastrointestinal tract.
After oral administration, the bulk of the administered dose appears unchanged in the feces.
Because of unacceptable systemic toxicity, Nystatin is never given parenterally

25. Side effect
Nystatin is only mild and transient gastrointestinal disturbances such as nausea, vomiting, and diarrhea have occurred after oral ingestion.
The major complaint associated with Nystatin is a bitter, foul taste.

26. 2. Agents disrupt Ergosterol synthesis
a. Azole.
Include Imidazole and triazole: A group of synthetic fungistatic agents with a broad spectrum of activity .
b. Allylamines. As terbinafine

27. a. Azole antifungal drugs
Azole agents are synthetic compounds.
Include Imidazole (e.g ketoconazole, Miconazole, Clotrimazole)
and Triazole (e.g Itraconazole, fluconazole)
Azole agents has broad spectrum of activity against common fungal pathogens (e.g., Candida species, Cryptococcus .

28. Mechanism of action
Azole antifungals inhibit the fungal cytochrome dependent enzyme (α-demethylase) , thereby interrupting the synthesis of ergosterol.

29. Mechanism of action
Inhibition of this enzyme pathway leads to the depletion of ergosterol in the cell membrane and accumulation of toxic intermediate sterols ( peroxides that cause autodigestion of the fungus.), causing increased membrane permeability and inhibition of fungal growth

30. Clotrimazole Indication
Clotrimazole is an imidazole antifungal drug used for various mucosal and cutaneous infections.
Clotrimazole also appears to be highly effective and is the drug of choice for the treatment of oral candidiasis in patients with AIDS.

31. Dosage and administration
For the treatment of oral candidiasis, Clotrimazole is available as a 10-mg troche.
Clotrimazole troche: Slow dissolution in the mouth results in the binding of Clotrimazole to the oral mucosa, from which it is gradually released to maintain at least fungistatic concentrations for several hours.

32. The swallowed drug is metabolized in the liver and eliminated in the feces along with unabsorbed drug.

33. Clinical uses
Clotrimazole used in the treatment of Oropharyngeal candidiasis
Side effect
The adverse effects are usually Irritation associated with topical Clotrimazole.
occasionally minor gastrointestinal upset may follow oral ingestion of the drug .

34. Ketaconazole M. of action
Block the demethylation of lanosterol to ergosterol which the principle sterol of fungal membrane thereby inhibit fungal cell growth.

36. Side effect Allergic reaction GIT disturbance Hepatic dysfunction
Endocrine effect result from blocking androgen and adrenal steroid synthesis so may cause gynaecomastia and decrease libido ,impotence in men and menstrual irregularities in women.

37. Drug Interaction
Inhibit P450 Cytochrome can potentiate the toxicity of cyclosporin,phenytoin warfarin.
Rifampin, H2 Inhibitors decrease the action of ketaconazole

39. Triazole : Fluconazole
Indications
It is effective in the treatment of mucosal candidiasis, including oropharyngeal and esophageal candidiasis.
Weekly use of fluconazole was suggested to have prophylactic value against mucosal candidiasis in HIV patients.
Side effect
Nausea, vomiting, gastric pain, headache, and rashes are most common adverse effects

40. b. Allylamines Terbinafine
It is a synthetic allylamine. It is fungicidal. Like the azole drugs it interferes with ergosterol biosynthesis.
Is available in an oral formulation and is used at a dosage of 250 mg/d. It is used in the treatment of dermatophytoses.
Side effect
Adverse effects are rare, consisting primarily of gastrointestinal upset and headache.

41. 3. Agents disrupts the mitotic spindle
Mechanism of action
These agent interacts with polymerized microtubules, causing the disruption of the mitotic spindle and eventually fungal mitosis.

42. Griseofulvin
It was first isolated from Penicillium griseofulvum
Indication
griseofulvin readily reaches the skin, hair, and nails, where it binds avidly to newly synthesized keratin and inhibits fungal invasion through surface keratin. So it indicated in dermatophyte infections for which topical therapy is ineffective, principally that involving hair or nails

43. Side effect
Side effects are uncommon, but griseofulvin may induce nausea, vomiting, diarrhea, fatigue, headache, and mental confusion.
The drug may also cause hematologic and dermatologic reactions

44. 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.

45. Caspofungin receive approval in January 2001 invasive aspergillosis
not responding or intolerant to other antifungal therapies

46. Pharmacokinetics: Caspofungin
Excretion
primarily by hepatic metabolism
Elimination half-life
9 to 12 hours
Plasma protein binding
96% following a single dose of 70 mg

47. Clinical uses Caspofungin in oropharyngeal and esophageal candidiasis
50 and 70 mg/d IV infusion for 14 days
Significantly fewer drug-related adverse events
Fever
Phlebitis
Headache
Rash

48. 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

49. 4.Agents inhibiting DNA synthesis
Fluorocytosine
Mechanism of action
flucytosine is a small molecule is transported into susceptible fungal cells by a specific enzyme cytosine permease and converted in the cytoplasm by cytosine deaminase to 5-fluorouracil (5-FU).

50. 5-fluorouracil (5-FU) is phosphorylated and incorporated into RNA where it causes miscoding and halts protein synthesis.
Additionally, phosphorylated 5-FU is converted to its deoxynucleoside, which inhibits DNA synthesis by blocking the functions of a key enzyme in DNA replication.

51. Mechanism of action flucytosine

52. Indication
indicated for the treatment of systemic candidiasis and cryptococcosis.
Side effect
The major toxicity of flucytosine is depression of the bone marrow, resulting in anemia, leukopenia, and thrombocytopenia.
Also flucytosine may cause nausea, vomiting, diarrhea, and (rarely) severe enterocolitis

53. Antifungal Activity

54. Thank you