Antifungals Flashcards
A) What is cutaneous tinea (ringworm) caused by?
B) What is candidiasis caused by?
A)
- Dermatophytic molds
B)
- Opportunistic yeasts notably candida albicans
What are antifungals used to treat?
Infections (mycoses) caused by fungi
- Majority of mycoses present as relatively superficial non-life threatening conditions caused by molds and yeasts
How are fungal cells different from mammals even though they are both eukaryotes?
fungal cells possess cell walls AND a different steroidal structural component in cell membranes i.e. ERGOSTEROL
What are the TWO main drug MOA for antifungals?
- COMMONLY INVOLVES STRUCTURAL DISRUPTION OF FUNGAL CELL MEMBRANES
- MANY ANTIFUNGALS ACT AS ENZYME INHIBITORS THAT PREVENT FUNGAL BIOSYNTHESIS OF ERGOSTEROL
What are the FIVE drug classes of antifungals? Which one is the most largest and most popular drug group?
- FATTY ACIDS
- PHENOLS and DERIVATIVES
- POLYENES
- ALLYLAMINES
- AZOLES (largest and most popular drug group)
For fatty acids;
A) What are they used to treat?
B) What are they comprised of?
C) What does increase the chain length do?
D) What is the MOA?
A)
- Topical treatment of tinea (atheletes foot)
B)
- Comprise of lipophilic carboxylic acids which are most commonly formulated as non-volatile zinc (Zn2+) salts
C)
- Increasing the chain length of the fatty acid reduces drug volatility and also increases antifungal potency
D)
- Augmentation of sebum (adding more sebum) –> a mixture of fatty compounds with antifungal properties found in/on skin
For Phenols and Derivatives;
A) What are they used to treat?
B) What are they comprised of?
C) What is the MOA?
A)
- Topical treatments against dermatophytes
B)
- Comprise of halogenated (most notably chloro) phenolic and phenol hydroxy group substituted compounds
C)
- Interference with the structural integrity of fungal cell membranes causing cellular leakage
For Polyenes;
A) What are they comprised of?
B) What are two distinct molecular units
C) What is the MOA?
C) Large polyenes (more C=C bonds) are more potent but?
D) Why are they applied topically
A)
Represent complex amphoteric compounds that possess a large cyclic component that consists of a highly conjugated system of alkene C=C bonds
B)
- Macrocyclic lactone = large 26 or 38-membered cyclic ester unit with two discrete chemical areas consisting of an upper polar region (polyhydroxyl along with a CO2H, pKa =4-5) and a lower lipophilic polyene chain region (with 5-7 C=C bonds)
- Mycosamine = polar hydrophilic·sugar-based glycone ring unit containing a basic 1o amino group (pKa - 8-9)
C)
- MOA involves acute fungal cell membrane disruption with each polyene molecule operating as a false membrane component that binds to ergosterol and cause cell leakages
D)
- But also show greater toxicity
E)
- All possess poor stability and aqueous solubility leading to negligible oral absorption
For Allylamines;
A) What are they used to treat?
B) What are they comprised of?
C) Why are they used topically?
D) MOA? What does this lead to?
A)
- Topical treatment of dermatophytic skin and nail infections (tinea)
B)
- Comprise of lipophilic allyl amine derivatives with a tertiary amine (basic, pKa = 8-9) linked to two large hydrocarbon units
C)
- high lipophilicity possess very low water solubility
D)
- Act as SQUALENE EPOXIDASE INHIBITORS –> a key enzyme in the early stage of Ergosterol biosynthesis
- Inhibition leads to defects in the fungal cell membranes
For Azoles;
A) What dosage forms does it come in
B) What is it comprised of?
C) What is the key structural feature?
D) What are the two chemical sub-groups that the azole ring may have?
E) What contributes to drug lipophilicity
F) MOA?
G) What does Azole N-3 or N-4 atom strongly bind to? What does this result in?
H) Why may hepatotoxicity, side effects, and drug-drug interactions occur in azole antifungals?
A)
- Include topical and oral agents with clinical use dependent on mycosis type and level of infection
B)
- Comprise of VERY LIPOPHILIC WEAK-MILD BASES (pKa = 4-7) which typically display very low aqueous solubility
C)
- Key structural feature is a monosubstituted 5-membered aromatic AZOLE ring (Basic group) with 2-3 nitrogen atoms
D)
- IMIDAZOLES (1,3 Diazoles) – with two N atoms at ring positions 1 and 3. 1st generation.
- TRIAZOLES (1,2,4 Triazoles) - possess three N atoms at ring positions 1, 2 and 4. Latest 2nd Generation.
E)
- Aromatic groups
F)
- LANOSTEROL 14α-DEMETHYLASE INHIBITORS –> key enzyme in Ergosterol biosynthesis
- 14α-Demethylase is a CYP450 type enzyme that catalyzes Me group removal from Lanosterol
- Enzyme inhibition leads to fungal cell membrane defects
G)
- Strongly binds to the Fe2+ containing haem cofactor via complexation thus preventing normal enzyme oxidative bioactivity
H)
- Azole antifungals (especially imidazoles) functions as very potent inhibitors of CYP450 metabolizing enzymes (esp CYP3A4)
What are the differences between imidazole (first generation) and triazole (second generation) azole antifungals?
- Triazole (second generation antifungals) are more potent/specific than 1st generation drugs and also show broader antifungal range with less CYP activity
- Triazole can be used orally/systematically due to lower toxicity/CYP inhibition
