Antifungal drugs

Question 1

list factors that contribute to the increased prevalence of fungal infection

Answer 1

Increasing prevalence of fungal infections
* widespread use of broad-spectrum antibiotics - eliminate nonpathogenic bacterial competitors
* use of immunosuppressant
* AIDS
* cancer chemotherapy
* diabetes

Question 2

describe the classification of mycoses and the relevant site of infection

Answer 2

superficial –> outermost epidermal layer of skin (i.e., stratum corneum) or outer surface of hair shafts

cutaneous –> epidermal layer of skin, hair shafts, and nails

subcutaneous –> dermal and underlying layers of skin

systemic –> * serious infections of internal organs - gain access via the respiratory tract, the GI tract, or blood vessels

• primary vs. opportunistic pathogens

Question 3

describe the pharmacokinetics - Echinocandins

Answer 3

• poor oral absorption - i.v. administration
• concentration-dependent activity - Cmax:MIC

Question 4

mechanism of action - Echinocandins

Answer 4

• fungicidal for Candida species - treat invasive candidiasis
• fungistatic for Aspergillus species
• bind to β-1,3-glucan synthase → inhibit β-1,3-glucan synthesis (inhibiting cell wall synthesis)

Question 5

adverse effects - Echinocandins

Answer 5

• nausea, vomiting and diarrhoea
• infusion-related reactions

Question 6

provide an example - Echinocandins

Answer 6

caspofungin

Question 7

describe the pharmacokinetics - polyenes

Answer 7

• poor oral absorption
  
  • treat infection of the upper GI tract
  • systemic infection - slow i.v. infusion
• minimal hepatic metabolism
  
  • mainly faecal elimination

Question 8

mechanism of action - polyenes

Answer 8

interaction with ergosterol is key to antifungal activity
- ergosterol in fungi - regulation of cellular process; membrane stability and fluidity

• form pores - leakage of intracellular contents, e.g., K+ ions
• interactions at the surface of cell membranes

Question 9

adverse effects - polyenes

Answer 9

• infusion-related - inflammatory response
• nephrotoxicity - interactions with cell membranes
• liposomal formulations - ↓ toxicity

Question 10

provide an example - polyenes

Answer 10

Amphotericin B

Question 10

mechanism of action - allylamines

Answer 10

targets squalene monooxygenase
- this inhibits intermediates in the formation of ergosterol

Question 11

adverse effects - allylamines

Answer 11

• GI disturbance
• rash
• muscle pain

Question 12

provide an example - allylamines

Answer 12

terbinafine

Question 13

mechanism of action - Azoles

Answer 13

Fungostatic
targets 14 alpha-demethylase
- an intermediate in the ergosterol pathway inhibiting biosynthesis

Question 14

adverse effects - Azoles

Answer 14

• GI disturbance
• hepatotoxicity
• cardiotoxicity - QT interval prolongation
• a CYP3A4 inhibitor - drug-drug interaction

Question 15

provide an example - Azoles

Answer 15

itraconazole