C.4

Question 1

Antifungal

Answer 1

1. Cell membrane inhibitors: Clotrimazol, Fluconazol, Itraconazol, Voriconazol, Terbinafine
2. Cell wall synthesis inhibitors: Caspofungin
3. Pore formation: Nystatin, Amphotericin B
4. Protein synthesis inhibitor: Flucytosin

Question 2

Azole derivatives

Answer 2

MOA: Inhibition of C14-α-demethylase
(inhibits conversion of lanosterol→ergosterol)→ the membrane structure changes→ impairment of the membrane fuctions;
Pharmacokinetics: good absorption p.o;
Spectrum: Candida sp, Aspergillus, Cryptococcus, Blastomycosis, Coccidioidiomycosis, Paracoccidioides Brasiliensis, Sporothrix schenckii, Mucor, Fusarium, dermatophytons;
Local use: Clotrimazole;
Systemic use: Itraconazole, Voriconazole, Fluconazole

Question 3

Clotrimazole

Answer 3

Extra: imidazole structure, used mostly locally

Question 4

Fluconazole

Answer 4

Pharmacokinetics: enter CNS, excreted mainly by urine, accumulated in nails and skin;
SEs: GI symptoms, headache, rarely- neuropathy, hepatitis, agranulocytosis, steven-Johnsons synd., TEN;
IND: used in dermato- and onycomycosis, Cryptococcus meningitis, 1st choice in mucocutan candidiosis (GI, GU tracts), often used in ICU to treat sepsis (e.g. candida sepsis)

Question 5

Itraconazole

Answer 5

Pharmacokinetics: poorly enters CNS, eliminated mainly via the GItract;
SEs: neuropathy, hypokalemia, allergy;
Extra: CYP3A4 inhibitor;
IND: effective against Aspergillus as well, used in dermato- and onycomycosis

Question 6

Voriconazole

Answer 6

Pharmacokinetics: enters CNS, excreted mainly by urine;
SEs: QT↑, TdP, photosensitivity, skin malignancies, hepatotoxicity, toxic epidermal necrosis (TEN), visual disturbances;
IND: effective against Aspergillus, often used in ICU for sepsis (e.g. Candida sepsis)

Question 7

Terbinafine

Answer 7

MOA: inhibits the fungal enzyme squalene epoxidase
(→squalenes accumulate →toxic effect and lack of ergosterol),
fungicidal,
broad spectrum;
Pharmacokinetics: good p.o absorption, accumulates in skin, hair and nails;
SEs: GI, skin reactions (rarely SJS), liver enzyme elevation;
Contra-IND: pregnancy;
IND: local and systemic treatment of onyco- and dermatomycosis (dermatophytons), some candida infections

Question 8

Nystatin

Answer 8

MOA: form pores in the fungal membrane →lysis of the fungus;
Pharmacokinetics: NOT absorbed p.o, local effect in the GI tract, poor absorption from skin and mucosal surfaces;
SEs: nausea, vomiting, diarrhea, exanthema;
IND: candidiasis of oral cavity and esophagus, infections of GI tract, superficial infections of the skin and mucosa

Question 9

Amphotericin B

Answer 9

MOA: form pores in the fungal membrane→ lysis of the fungus;
Pharmacokinetics: only parenteral use, good distribution except CNS, liposomal form- better effect, less SEs, slow elimination via the kidney;
IND: useful drug in nearly all life-threatening mycotic infections (mycosis of the organs, sepsis), coccidio- or candida meningitis (-intracranially), topically applied for ocular or bladder infections, effective in leishmaniasis;
SEs: nephrotoxic (significantly reduced with liposomal Amph B), neurotoxic (paresthesias), anemia, chills, fever

Question 10

Caspofungin

Answer 10

MOA: inhibits the synthesis of β-(1,3)-D-glucan (→disruption of fungal cell wall);
IND: Candida and Aspergillus infections, sepsis, multiresistant infections;
SEs: well tolerated, fever, GI, flush, liver enzyme elevation, hypokalemia, bronchospasm, anemia;
ROA: ONLY i.v

Question 11

Flucytosine

Answer 11

MOA: Prodrug, Inhibit protein synthesis (5-FU is formed in the fungal cell→ incorporated into RNA→ inhibits protein synthesis);
Pharmacokinetics: good absorption p.o, good distribution, enters CNS, short T1/2, eliminated by urine (dose adjustment at impaired renal function);
SEs: BM and hepatotoxicity, GI, toxic enterocolitis (rare, at high serum levels), myelosuppression, hair loss;
IND: synergistic effect with AmpB (they are given together), effective mainly against Cryptococcus neoformans and Candida sp

Question 12

Types of fungi

Answer 12

Yeasts, Molds, Dimorphis, Dermatophytons

Question 13

Cell membrane synthesis inhibitors

Answer 13

• Ergosterol synthesis inhibitors
• Polysaccharide synthesis inhibitors

Question 14

Membrane function inhibitors

Answer 14

• Polyene macrolides

Question 15

Sites of interventions of antifungal drugs

Answer 15

1. Cell membrane synthesis inhibitors
2. Membrane function inhibitors
3. Nucleic acid synthesis inhibitors (antimetabolites)
4. Mitosis inhibitors