Antifungal Pharmacology Flashcards
What is the overall function of the fungal cell membrane/wall
To control cellular permeability and protects cell from stress
What does ergosterol do?
Maintains cell membrane integrity
What does squalene expoxidase do?
Catalyzes first oxygenation step in sterol biosynthesis
*rate limiting step
*if this is targeted then there will be no fungal cell membrane
What is Chitin?
Base polysaccharide creating durability for the cell wall
*it is a bridge between the cell membrane and cell wall
What is B-glucan synthase?
A complex that synthesizes beta glucans
What is a B-glucan?
The most important structural polysaccharide
*B-1,3-D are the most important
What are Azoles?
- Most commonly used anti fungal agents
- The agents are available in large number of formulations
- A variety of routes are used
- Known for the strong inhibition of many cytochrome P-450 enzymes
*the Azoles have the potential to result in many serious life-threatening drug interactions
What will CYP inhibitors do? (AZOLES)
The CYP inhibitors will allow a certain drug to stay in the body for a prolonged time which increases the drugs potency
*causing serious life threatening interactions
What will CYP inducers do?
They will increase metabolism of drugs
*EX: Being on a CYP inducer and warfarin will decrease the warfarin potency making the drug less effective
What is the MOA of Azoles?
- Will inhibit the synthesis of ergosterol (which helps maintain cell membrane integrity)
- The result will be cell death
- Azoles inhibit P-450 enzymes midway in the ergosterol pathway
What does Fluconazole (Diflucan) cover?
It is the most used Azoles
1. Candidia species
*except C. Glabrata and C. Krusei
What does Fluconazole NOT cover?
- C. Glabrata
- C. Krusei
- Aspergillus species
- Fusarium species
- Zygomycetes
What are the common uses of Fluconazole?
- Candidiasis
- Cryptococcal meningitis
*has excellent CNS penetration - Prophylaxis against candida (trying to prevent candida infection before it happens)
What is the most common dose of Fluconazole?
Vaginal 150mg X 1 dose
What are the SE or ADRs of Fluconazole?
Generally well-tolerated
1. GI” distress
2. Rash
3. Hepatic toxicity
What are the drug interaction of Fluconazole?
- Inhibits CYP3A4 and CYP2C9
*be careful with lovastatin, simvastatin and warfarin - QT prolongation
- Lower likelihood of serious drug interactions vs other Azoles
What dosing adjustments should be made with Fluconazole?
- Decrease dose by 50%
- It is the only Azoles that is cleared renally
*adjust for renal clearance
What is the common use for Miconazole?
- Vulvovaginal candidiasis
- In many OTC creams, powders, and gel
What is a common drug form of clotrimazole?
- Creams, ointments, for topical applications
- Available in a 10mg troche (cough drop) used 5 times a day for 7-14 days oropharyngeal candidas
What WAS ketoconazole made into?
- An oral formulation
*no longer used due to the potentially fatal liver and adrenal complications
What are the common forms of Ketoconazole?
Creams, gels, shampoo
What are the ADRs of ketoconazole?
- Hepatoxicity
- QTc prolongation (which happens for all Azoles)
What does Itraconazole cover?
- Adds sensitivity to what Fluconazole did not
*aspergillosis
*C. Glabrata
*C. Krusei
What is the correct way to take the solution formulation of Itraconazole?
*Preferred for systemic infections
1. Has better bioavailability (more stays in our system)
2. Take on an empty stomach
What is the correct way to take he capsule formulation of Itraconazole?
- Taken with a full meal (to increase absorption)
What is the common use of Itraconazole?
- Treat fungal infections in both immunocompromised and immunocompetent hosts
When will Itraconazole will used when a patient is refractory to amphotericin B?
When a patient has Aspergillosis
*Itraconazole is commonly used
If a patient is using Itraconazole and has onychomycosis of the toenails and fingernails how long is the tretment?
12 weeks
What are the ADR/ SE of Itraconazole?
- Nausea
- CHF exacerbation (do not use in heart failure patients)
What are the drug interactions of Itraconazole?
- Strong inhibitor of CYP3A4
*should not be used with many other drugs
What does Voriconazole have better activity against?
Improved activity against: Aspergillosis (first line agent for this infection)
More reliable activity: C. Glabrata and C. Krusei
What do Echinocandins have the most activity against?
- Candida species
*including C. Krusei and C. Glabrata - Aspergillus
What is the problem with using Echinocandins?
- Only available for IV administration
- Very expensive
When would Echinocandins generally be used?
- Esophageal candidiasis
- Systemic Candida infections
- Empiric treatment of presumed fungal infections
*Used as a last resort
What is the MOA of Echinocandins?
- Inhibit the synthesis of B (1-3) D-glucagan
*It is an essential component of the fungal cell membrane
What is the ADR risk of Echinocandins?
- Low risk of SE
What are the common Echinocandins?
- Caspofungin (cancidas)
- Micafungin (mycamine)
*Histamine-like effects - Anidulafungin (Eraxis)
What is the most commonly used Echinocandins?
Caspofungin
*have dosing adjustments
What are the common CYP inducers?
- Phenytoin
- Rifampin
- Carbamazepine
*These will reduce the drug substrate
*The drug will be less effective
What are the characteristics of the Amphotericin B products?
- Have the BROADEST activity of all anti fungal agents
What is the MOA of Amphotericin B?
- The polyene structure
*it binds to ergosterol IN the fungal cell membrane and leads to loss of membrane integrity and cell death
What is conventional amphotericin B?
Deoxycholate
*not used as much bc of the development of several effective and less toxic agents
*least expensive
What are some of the ADRs of deoxycholate?
- Infusion reactions
*Fever
*chills
*headaches - Nephrotoxicity
What are the characteristics of Lipid-base Amphotericin B?
- Can be prescribe 2 times the does as conventional Amphotericin B
*Conventional cannot exceed 1.5mg/kg/day (will lead to cardiopulmonary arrest) - Expensive
What are the different types of lipid-base amphotericin B
- Abelcef
- AmBisome
- Amphotec
What are the ADRs of lipid-base Amphotericin B
- Much less likely to result in nephrotoxicity/electrolyte disorders vs conventional
- Infusion reactions are less likely
- Liver toxicities appear more likely with lipid-based products bs conventional
What is the MOA of Nystatin?
Similar to Amphotericin
*Will bind to ergosterol IN fungal cell membrane and leads to loss of membrane integrity and cell death
What are some formulations of Nystain?
- Topical products (creams, ointments, powders, vaginal suppositories)
- Suspension that is used for thrush
What is the typical dosage for Nystatin?
- 5ml 4 times a day for 7-14 days
- Swish and spit / swish and swallow (if thrush has spread to throat)
What is the mechanism of flucytosine (Ancoban)
- Interferes with fungal DNA synthesis (works inside the cell)
What is Flucytosine (Ancoban) most commonly used for?
- Cryptococcal meningitis
*will always be used in COMBO with another drug
*Amphotericin B
What should happen to the dosage of Flucytosine (Ancoban) if a patient has renal failure?
Decrease the dosage
What are the ADRs of Flucytosine (Ancoban)?
- Can result in life-threatening bone marrow toxicity
*monitor CBC with diff
What is Terbinafine available as?
- Cream for topical applications (skin, hair, nails)
- Tablet for nail infections
*250mg QD for at least 6 weeks
