Series of Pharmacology lectures to undergraduate medical students, based on illustrations and hints that aid studying from standard textbook.

1. CHEMOTHERAPY
HIGHLIGHTS
MOHAMED BAHR; MD, PHD
Antifungal Drugs

2. Mohamed Bahr; MD, PhD
ANTIFUNGAL
DRUGS

3. Mohamed Bahr; MD, PhD
MECHANISMS

4. Mohamed Bahr; MD, PhD
CLASSIFICATION
Fungal infections could be classified into:
Superficial fungal infections:
Dermatophytes: Tinea capitis (scalp), corporis (body), unguium (nails;
onychomycosis), cruris (crotch), and pedis (foot)
Candida:
• Cutaneous, vaginal, oropharyngeal and gastrointestinal candidiasis.
• Mucocutaneous candidiasis in severely immunodeficient patients and can
spread to deep tissues (disseminated).
Deep fungal infections:
Fungal pneumonia, gastroenteritis, endocarditis or meningitis.

5. Mohamed Bahr; MD, PhD
Systemic
Drugs for
Systemic
Infections
Amphotercin-B
Flucytosine
Azoles: ketoconazole -
itraconazole - fluconazole -
voriconazole
Echinocandins: caspofungin

6. Mohamed Bahr; MD, PhD
Drugs for
Mucocutaneous
Infections
Systemic
Drugs
Azoles (candida -
dermatophytes)
Griseofulvin (dermatophytes)
Terbinafine (dermatophytes)
Topical
Drugs
Azoles (candida -
dermatophytes)
Nystatin (candida)
Terbinafine – naftifine
(dermatophytes)
Gentian violet (candida) -
whitefield ointment
(dermatophytes)

7. Mohamed Bahr; MD, PhD
Superficial fungal infections are treated first with topical
agents.
Systemic therapy is used in:
• Resistance to topical therapy.
• Wide or inaccessible area.
• Severe infections of hair, skin, and nails.
• Decreased immunity of the patient.

8. Mohamed Bahr; MD, PhD
AMPHOTERICIN B

9. Mohamed Bahr; MD, PhD
INDICATIONS: MOST IMPORTANT
ANTIFUNGAL IN DEEP INFECTIONS
Severe life-threatening (IV, not absorbed PO).
Meningitis (intrathecal- does not reach CSF after IVI).

10. Mohamed Bahr; MD, PhD
SIDE EFFECTS AND
TOXICITY
IVI →
Kidney and Anemia
Heart

11. Mohamed Bahr; MD, PhD

12. Mohamed Bahr; MD, PhD Illustration ONLY

13. Mohamed Bahr; MD, PhD
FLUCYTOSINE (5-FU)
Cytotoxic. It is transformed to
fluorouracil (FU)→ inhibits
nucleic acid synthesis.

14. Mohamed Bahr; MD, PhD
INDICATIONS: GIVEN PO
WITH AMPHOTERICIN
Cryptococcal meningitis.
Disseminated candidiasis.

15. Mohamed Bahr; MD, PhD
ADVERSE EFFECTS
(CYTOTOXIC DRUG)
1. Bone marrow depression.
2. Hair loss.
3. Hepatotoxic.
4. Enterocolitis.

16. Mohamed Bahr; MD, PhD
ADVANTAGES OF COMBINATION
OF FLUCYTOSINE WITH
AMPHOTERICIN B
↓ Resistance to
flucytosine.
↓ Amphotericin
nephrotoxicity (lower
doses of amphotericin
are used).

17. Mohamed Bahr; MD, PhD
AZOLES

18. Mohamed Bahr; MD, PhD
Fungistatic. Inhibition of ergosterol
synthesis of cell membrane by inhibiting
cytochrome P450-dependent 14-α-
demethylase responsible for conversion of
lanosterol to ergosterol.

19. Mohamed Bahr; MD, PhD
1. KETOCONAZOLE
1st oral broad spectrum antifungal for:
1. Deep fungal infections (mild - nonmeningeal): 2nd line to
amphotericin B.
2. Candidal infection.
3. Dermatophytes resistant to griseofulvin and terbinafine
(oral and topical).

20. Mohamed Bahr; MD, PhD
INTERACTIONS WITH
COMBINATIONS
PK: Avoid Combination with:
Antacids or H2 blockers → ↓ gastric acidity → ↓
ketoconazole absorption.
PD: Amphotericin B: ketoconazole → ↓ amphotericin
effect by ↓ ergosterol.

21. Mohamed Bahr; MD, PhD
ADVERSE EFFECTS
1. GIT: nausea - vomiting
2. Hypersensitivity: rash
3. Hepatotoxic (serious)
4. Teratogenic

22. Mohamed Bahr; MD, PhD Illustration ONLY

23. Mohamed Bahr; MD, PhD
Enzyme inhibitor: human cytochrome P450 (serious)
• ↓ Steroid synthesis which depends on cytochrome P450:
• ↓ Corticosteroids → adrenal suppression (used in Cushing's
disease).
• ↓ Testosterone → gynecomastia, impotence (used in cancer
prostate).
• ↓ Female sex hormones → menstrual irregularities, infertility.
• ↓ Metabolism of drugs → drug interactions:
• ↑ Level of astemizole and terfenadine → arrhythmias.
• ↑ Level of oral anticoagulants, antiepileptics …

24. Mohamed Bahr; MD, PhD
2. ITRACONAZOLE AND
FLUCONAZOLE (PO - IV)

25. Mohamed Bahr; MD, PhD
Ketoconazole Itraconazole Fluconazole
Efficacy Less More More
Hepatotoxicity
Adrenal
Suppression
Drug Interactions
More Less Less
Dosing Single
Plasma protein
binding
Extensive Extensive Minimal
CSF distribution Excellent (fungal
meningitis)
Renal Excretion Yes
Antacids Stable

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CASPOFUNGIN
Beta Glucan Synthase Inhibitor

27. Mohamed Bahr; MD, PhD
USES (IV)
Candidiasis and invasive aspergillosis
refractory to amphotericin B.

28. Mohamed Bahr; MD, PhD
GRISEOFULVIN

29. Mohamed Bahr; MD, PhD
• Concentrated in newly formed keratin preventing its
infection by:
• Interfering with microtubular function→ interfere
with mitosis.
• Inhibiting nucleic acid synthesis.
• When infected keratin is shed it is replaced by
uninfected one.

30. Mohamed Bahr; MD, PhD
INDICATIONS
Dermatophyte infections (PO, ↑ absorption by
high-fat diet).

31. Mohamed Bahr; MD, PhD
ADVERSE EFFECTS (LARGELY
REPLACED BY ITRACONAZOLE
AND TERBINAFINE)
GIT: nausea - vomiting.
Neurotoxicity: headache - mental confusion.
Hepatotoxic.
Enzyme inducer → ↓ warfarin level.

32. Mohamed Bahr; MD, PhD

33. Mohamed Bahr; MD, PhD
TERBINAFINE
Inhibition of squalene epoxidase enzyme which is
essential for ergosterol synthesis of cell
membrane → accumulation of toxic squalene.

34. Mohamed Bahr; MD, PhD

35. Mohamed Bahr; MD, PhD
ADVANTAGES OVER
AZOLES
Squalene epoxidase enzyme is not present in
human.
No inhibition of cytochrome P450 (no serious
adverse effect of azoles).

36. Mohamed Bahr; MD, PhD
INDICATIONS
Systemic (oral) and topical for dermatophytes.
More effective than griseofulvin.

37. Mohamed Bahr; MD, PhD
SIDE EFFECTS (SAFE): GIT
AND TASTE DISTURBANCES.

38. Mohamed Bahr; MD, PhD
NYSTATIN
Binds to ergosterol of fungal cell membrane → formation of
artificial pores → damage of membrane → leakage of
important cell constituents → cell death.

39. Mohamed Bahr; MD, PhD
INDICATIONS (TOO TOXIC
FOR SYSTEMIC USE)
Used locally in:
Oropharyngeal and GI candida: PO (not absorbed).
Cutaneous candida: topical (nonirritant - rarely causes allergy).
Vaginal candida: given both topically and orally because quite
often vaginal candida is associated with gastrointestinal candida
which acts as a source of reinfection of vagina.

40. Mohamed Bahr; MD, PhD
REFERENCES
Lippincott’s Illustrated Reviews, 5th ed.
Color Atlas of Pharmacology, 2nd ed.
Goodman and Gilman's The Pharmacological Basis of
Therapeutics, 12th ed.