Pharmacology

• PHRS – 303 LECTURE - Antifungal Drugs I-II


  Lecture on antifungal drugs
• PHBS - 301


  Course code
• At the end of the lecture, the students should be able to:

  1. Describe the mechanisms of actions of drugs used for fungal infections.

  2. Describe the clinical uses and pharmacokinetic profile of various antifungal drugs.

  3. Identify antifungal drugs for treatment of systemic mycoses and cutaneous mycoses.

  4. Recognize the adverse and toxic effects of the major antifungal drugs.
• Fungus as Organism


  • Eukaryotic organism that have cell wall composed basically of chitin, glucans, glycoproteins, and pigments
  • Fungal cell membrane is enriched with diverse lipids, typically contains ergosterol that maintain cell membrane integrity, similar to cholesterol in animal cells

  
• Fungal infection (mycosis)


  • Superficial mycoses: dermatophytosis affecting the skin (tinea called ringworm) or nails (onychomycosis)
  • Subcutaneous mycoses: muscle and connective tissue immediately below the skin
  • Systemic mycoses: blood or internal organs
• Most Common Fungal Pathogens


  • Candida albicans
  • Cryptococcus neoformans
  • Aspergillus species
  • Histoplasma capsulatum
  • Coccidioides immitis
  • Blastomyces dermatitidis
• Systemic mycoses are most difficult to treat and often life-threatening.
• Fungal infections are usually opportunistic infections occur in patients with immune suppression due to:

  • Indiscriminate use of broad-spectrum antibiotics,
  • Immunosuppressants (corticosteroid) overuse following organ transplant,
  • Human immunodeficiency virus (HIV),
  • Cancer chemotherapy
• Targets of Antifungal Drugs


  • Fungal cell membrane ergosterol
  • Fungal cell membrane ergosterol synthesis
  • Fungal nucleic acid synthesis
  • Fungal mitotic spindle and mitosis
  • Fungal cell wall synthesis
• Antifungal Drugs


  • Polyene antibiotics (Amphotericin B, Nystatin)
  • Azoles: Imidazoles and Triazoles
  • Antimetabolite agents (5–Flucytosine)
  • Griseofulvin
  • Echinocandins (Caspofungin, micafungin, and anidulafungin)
• Amphotericin B


  • Naturally occurring polyene macrolide antibiotic produced by Streptomyces nodosus
  • Remains the drug of choice for the treatment of several life-threatening systemic mycoses
• Amphotericin B


  • Antifungal spectrum: either fungicidal or fungistatic, depending on the fungal type and the drug concentration
  • Effective against a wide range of fungi, including Candida albicans, Histoplasma capsulatum, Cryptococcus neoformans, Coccidioides immitis, Blastomyces dermatitidis, & many Aspergillus strains
• Mechanism of action of Amphotericin B


  1. Lipophilic side (polyenes) binds with ergosterol and phospholipid in the fungal cell membrane

  2. Hydrophilic side (polyhydroxyl) forms transmembrane pores (channels) that disrupt membrane function result in leakage of cell contents and electrolyte (K+), result in cell death
• Amphotericin B - Pharmacokinetics


  • Insoluble in water (poorly absorbed orally); cannot cross into cerebral spinal fluid (CSF), vitreous humor, peritoneal fluid or amniotic fluid
  • Administered slow IV infusion (co-formulated with sodium deoxycholate to enhance solubility or artificial lipids to form liposomes)
  • Extensively bound to plasma proteins (90%)
  • Metabolized slowly in the liver & excreted in urine
• Amphotericin B - Adverse Effects


  • Acute reaction (fever, chills)
  • Neurologic effects (headache, nausea, and vomiting)
  • Thrombophlebitis
  • Nephrotoxicity
  • Hypotension
  • Bone marrow suppression
• Amphotericin B - Precautions


  • Resistance is associated with decreased ergosterol content or replacement by other sterols in the fungal membrane
  • The total adult daily dose the conventional formulation should not exceed 1.5 mg/kg
  • The liposomal preparations have been given safely in doses up to 10 mg/kg/d
  • Small test doses are usually administered to assess the degree of a patient's negative responses, such as anaphylaxis or convulsions
• Nystatin


  • Polyene antifungal antibiotic, structure, mechanism of action, and resistance profile resemble amphotericin B
  • Not used parenterally due to systemic toxicity (nephrotoxicity)
  • Only used locally for the treatment of cutaneous and oral Candida infections
• Nystatin - Administration


  • Orally ("swish and swallow" or "swish and spit") for treatment of oropharyngeal candidiasis (thrush)
  • Intravaginally for vulvovaginal candidiasis
  • Topically for cutaneous candidiasis
• Azole Antifungals


  • Imidazoles: Clotrimazole, Seconazole, Oxiconazole, Miconazole, Econazole, Butoconazole, Sulconazole, Terconazole
  • Triazoles: Voriconazole, Itraconazole, Posaconazole, Fluconazole
• Azole Antifungals


  • Predominantly Fungistatic (inhibit fungal cell growth)
  • Mechanism of action: inhibiting ergosterol synthesis by binding to cytochrome P450 lanosterol 14α-demethylase enzyme
• Ketoconazole


  • First orally effective broad-spectrum antifungal systemically available azole
  • Rarely used today for systemic fungal infection due to the risk for severe liver injury, adrenal insufficiency, and adverse drug interactions
  • Mechanism of action: block fungal ergosterol synthesis
  • Resistance: mutations in the C-14 α-demethylase that reduce azole binding or development of efflux pump
• Ketoconazole - Pharmacokinetics


  • Well absorbed orally, requires acidic environment favors dissolution and absorption
  • Drugs that reduce gastric acidity, such as antacids, H2-blockers, and proton pump inhibitors, can impair absorption
• Azoles


  Teratogenic, should be avoided in pregnancy, unless...
• Ketoconazole


  • First orally effective broad-spectrum antifungal systemically available azole
  • Rarely used today for systemic fungal infection due to the risk for severe liver injury, adrenal insufficiency, and adverse drug interactions
  • Mechanism of action: block fungal ergosterol synthesis
  • Resistance: mutations in the C-14 α-demethylase that reduce azole binding or development of efflux pump
  • Orally active against many fungi, except aspergillus species
  • Topically used to treat tinea infections, cutaneous candidiasis, seborrheic dermatitis and dandruff
• Ketoconazole - Pharmacokinetics


  • Well absorbed orally, requires acidic environment
  • Drugs that reduce gastric acidity impair absorption
  • Readily distributed, does not enter CSF, highly bound to plasma proteins
  • Extensively metabolized by liver, primarily excreted in the bile
  • Potent inhibitor of CYP450 enzymes, can potentiate toxicities of other drugs
  • Strong inhibitor of gonadal and adrenal steroid hormone synthesis
• Ketoconazole and amphotericin B


  Should not be used together, as the decrease in ergosterol in the fungal membrane reduces the fungicidal action of amphotericin B
• Ketoconazole - Adverse effects


  • Most commonly GI disturbances, including nausea, vomiting & anorexia
  • Endocrine: gynecomastia, oligospermia, decreased libido, & impotence in males; menstrual irregularities & amenorrhea in females
  • Hypersensitivity reaction (allergies) - skin rashes and itching
  • Elevation of liver enzymes (hepatotoxicity) rarely occurs but requires immediate cessation of ketoconazole treatment
• Ketoconazole is teratogenic, as other azoles, and should not be used in pregnancy
• Fluconazole


  • Clinically important because of its lack of the endocrine side effects and its penetrability into the CSF
  • Administered orally against most forms of cutaneous candidiasis and as a single oral dose for treatment of vaginal candidiasis
  • Administered intravenously for systemic fungal infections: candidiasis & coccidiodal meningitis
  • Absorption not dependent on gastric acidity, minimal binding to plasma proteins and poorly metabolized
• Fluconazole - Adverse effects


  • Nausea, vomiting, and rashes; also inhibit CYP450 metabolizing drugs
• Summary of Triazole Antifungals


  • Ketoconazole
  • Fluconazole
• Flucytosine


  • Synthetic pyrimidine analog (antimetabolite antifungal)
  • Mechanism of action: enters the fungal cell via a cytosine-specific permease enzyme, converted by fungal deaminase enzyme to 5-fluorouracil (5-FU), and then to 5-fluorodeoxyuridine 5′-monophosphate (5-FdUMP) which inhibits thymidylate synthase or produce 5-FdUTP that incorporates into fungal RNA, thus, disrupting nucleic acid and protein synthesis
  • Earlier used as anticancer agent, now used against Cryptococcus, and Candida, which are involved in systemic mycoses and fungal meningitis
  • Often used in combination with amphotericin B, since amphotericin B increases cell permeability and penetration
  • Resistance: decreased levels of the permease or deaminase enzymes or increased synthesis of cytosine
  • Absorbed orally, distributed and penetrated into CSF
  • Adverse effects: GI disturbances, bone marrow suppression (neutropenia, thrombocytopenia), alopecia & hepatic dysfunction
• Griseofulvin


  • Heterocyclic nitrofurans Derived from Penicillium griseofulvum, but no antibacterial activity
  • Only fungistatic, active against most dermatophytes, used for the treatment of superficial fungal infections of the nails, skin and hair
  • Requires treatment of 6 to 12 months
  • Mechanism of action: disruption of mitotic spindle and inhibition of fungal mitosis ‒ results in multinucleated hyphae
• Griseofulvin - Pharmacokinetics


  • Oral administration, irregular (erratic) absorption, absorption is enhanced by high-fatty food
  • Good systemic distribution, but accumulates in newly synthesized, keratinized tissues (nails, skin and hair)
  • Metabolized in the liver, and excreted in the urine, with t½ =24 hrs
  • Induces hepatic CYP450 metabolism of a number of drugs, including anticoagulants
• Griseofulvin - Adverse effects


  • GI upsets, hepatotoxicity, Leukopenia & photosensitivity
• Terbinafine


  • Belongs to a newer allylamine class of antifungals
  • Mechanism of action: inhibits fungal squalene epoxidase, an enzyme involved in the synthesis of ergosterol thereby decreasing, accumulation of toxic amounts of squalene result in cell death
  • The drug of choice for treating dermatophytoses (skin and nails fungal infections), and especially for onychomycoses
  • Orally, for treating onychomycosis (toenails & fingernails, therapy requires 3 months)
  • Topically, for treating tinea pedis, (athlete foot), tinea corporis (body ringworm), and tinea cruris (the groin); treatment is usually 1 week
  • Appears to be significantly more effective than alternative 'azoles' for treating onychomycosis
  • The fungicidal effect is due to the more rapid activity of terbinafine (250 mg daily for 12 weeks) compared to fluconazole (150 mg once weekly for up to 24 weeks)
• Caspofungin


  • A lipopeptide drug belongs to new class of antifungals termed the echinocandins
  • Mechanism of action: blocks synthesis of glucan in fungal cell wall by inhibiting β(1,3)-D-glucan synthase enzyme, disturbing the integrity of the fungal cell wall leading to cell lysis
  • Indication: IV once daily, as a second-line agent for treatment of invasive aspergillosis & candidiasis in patients who have failed or cannot tolerate amphotericin B or azole
  • Adverse effects include fever, rash, nausea, phlebitis and flushing (due to the release of histamine from mast cells)