Lecture 22: Antifungals Flashcards
What is the clasification of fungal infections?
- Superficial [cosmetic, not life-threatening]
- Subcutaneous [implanted in skin; lesion]
- Systemic/Invasive [deep tissues]
What are some of the superficial and cutaneous fungal infections?
- Dermatophytosis: Classic skin infections [Ringworm, Athletes Foot, Jock itch] Involves 3 genera (Epidermophyton, Trichophyton, Microsporum)
- Onychomycosis: Nail infections
Capitis = ringworm of scalp
Pedis = athletes foot
What is important to know about the Invasive fungal infections [systemic]?
- Usually begin in lung
- May go into blastomyces [bone, skin, joints] or Histoplasma [GI, Adrenal, Bone, Skin]
- Normally asymptomatic
- WONT spread fast
What antifungal drugs are known as the “Polyenes”
- Amphotericin B
What are some of the important features to note about Amphotericin B?
- “Amphoteric” = Acidic and Basic groups
- Mycosamine group = Binding to ergosterol
- Hydroxyl groups help with binding NOT fnugicidal activity
- Fungicidal
What is the mechanism of action for Amphotericin B?
- Binds to ergosterol –> causing leaky channels [Ca/Na/K] –> cell death
What is the pharmacokinetics of Amphotericin B?
- Poorly absorbed PO - NEED IV
- PO is ONLY for GI infections [same as vanc for C. Diff]
- IV for Systemic Infections
Spinal Injection for FUNGAL MENINGITIS??
What are some of the adverse effects for Amphotericin B?
- Infusion Related [Fever, Chills, Vomiting, Headache, Hypotension…]
- Renal Damage
- Liver Issues
PRETREAT with Diphenhydramine or Acetaminophen
What are some of the therapeutic applications for Amphotericin B?
- Systemic Infections: Amphortericin B [broad Spec; DOC for life-threanteing fungal infections]
- Superfficial Fungal Infections: Nystatin [polyene similar to Amp B]
What are some of the Amphotericin Formulation?
- Conventional = Amp B or Fungizone [Collodial Suspension]
- Lipid Formulations [Amphotec; Ambisome; Abelcet]
Amphotec = ABCD
Ambisome = L-AMB
Abelec = ABLC
What is important to know about the Lipid Formulation of Amphotericin?
- Reduce Nephrotoxicity
- Act as reservoirs
- Ambsiome decreased infusion toxicities
- Amphotec = less nephrotoxcity BUT more fever
Breifly dicuss the Ergosterol Synthesis Pathway?
- MOST Fungi have Ergosterol in membranes
- Squalene –> Squalene Epoxide [by Squalene Epoxidase] –> Lanosterol –> –> –> Ergosterol [by P450 14a-demethylase]
- Similar to cholesterol in humans
What antifungal drugs are known as the “Allylamines”?
- Terbinafine
What is the mechanism of action for Terbinafine?
- Inhibits Squalene epoxidase
- CAN cause an increase of TOXIC levels of Squalene
What is important to know about Terbinafine and what it is good against?
- Fungicidal
- Mainly for Dermatophytes [even Onychomycoses]
- PO or Topically [for like Ringworm, Nail Infections]
What are some of the other formulations of Terbinafine?
- Naftifine [Lotrimin] & Butenafine [Lotrimin Ultra]
- Tolnaftate [Tinactin]
- Butenafine is GOOD against Candida, Cryptococcus, Aspergillus compared to Terbinafine
Also Anti-inflammatory
What is the mechanism of action for the “Azole” antifungal drugs?
- Inhibition of 14 a-demthylase [inhibits that second step of ergosterol synthesis]; causing a build-up of toxic sterols
- 5-membered armoatic ring with N
- Fungistatic
BIND IN THE FE3+ SPOT OF P450
What is the selectivity of the “Azoles”?
- Humans uses the same enzymes to make cholesterol
- Fungal Enzymes are MORE sensitive [Ketocon IC50 for Candida = 10^-9]
Human = 10^-6
What is the metabolism of the “Azoles”?
- Metabolized by Liver P450 [1st pass]
- Reduced Metabolism used for Systemic infections [Ketocon, Flucon, Itracon, Voricon, Posacon, Isavunvon]
These will have increased Spec WITH decreased side effects
What is important to understand about the early “Azoles”?
- Clotrimazole and Miconaozole were the 1st
- Used for later generation azoles
- Alterations Changes: Spec, CYPs, Elimination
What is important to know about Ketoconazole?
- First azole with good oral bioavailability
- Dioxolane ring and reduced 3A
What is important to know about Itraconazole?
- Based on Ketocon
- Triazole [3 N on a Aromatic instead on 2]
- Improved specificity for P450
What is important to know about Fluconazole?
- Modified Ketocon
- 2 Triazoles [3 N on aromatic]
- F in place of Cl
- Hydroxyl Group
- NO Dioxolane Ring
What is important to know about Voriconazole?
- Based on Flucon
- Has 1 Triazole, Hydroxyl, F groups
- Fluoropyridine Ring instead of other Triazole
- Methyl group added [helps with binding and increased spec]
What is important to know about Posaconazole?
- Derived form Itracon
- Furan Ring [alters and increases spec]
- F replaces Cl
- PO or IV
What is important to know about Isavuconazole?
- Structurally similar to Voricon
- Water Soluble PRODRUG [reduces nephrotoxcity]
- LONG half life
PRODRUG is Isavuconazonuim
What is important to know about the Drug Interactions with the “Azoles”?
CYP450
- Metabolized and Inhibit liver P450 Enzymes
- Inducers can decrease triazole leves
- Ketocon potent inhibitor of 3A4
RIFAMPIN very potent inducer
What are some of the drug interactions for Ketoconazole?
- Inhibited metabolism of terfenadine and cisapride [Removed]
- Increases AUC and Half Life of Triazolam
- Increases Bioavailability of Cyclosporin
- 3A4 inducers Reduce ketocon levels
What are some of the individual Metabolism of the “Azoles”?
Itra, Flu, Vori, Posac
- Itracon: by 3A4 in Liver
- Flucon: unchanges by kidneys
- Voricon: by 2C19>3A4»2C9 in Liver
- Posacon: by Glucuronidation [inactive]
What is the clinical uses of Fluconazole?
- Penetrates CSF
- Spec: C. Albicans & other Candida [Most commonly used for Mucocutaneous Candida]
- Cryoticoccus Neoformans [Azole of Choice]
resistance toward –> Krusei & Glabrata
What is the clinical uses for Itraconazole?
- Spec similar to Flucon + Aspergillus
- Azole of Choice for Histroplasma, Blastoymces, Sporothrix
- Used for Dermaphytoses & Onchomycoese
- Bad Taste
What is the clinical uses for Voriconazole?
- High oral biavailabilty
- CSF level 1/2 of plasma
- Good toward Candida [some flucon resistant ones]
- MORE effective to Aspergillus than Amp B
**CONTRAINDICATED in pregnany [Cat D]
**
What are the clinical uses for Posaconazole and Isavuconazole?
- Posacon: same as voricon
- Isavucon: Spec same as voricon; good for aspergillosis and mucormycosis
What are some of the better topical azoles used for superficial fungal infections?
- Clotrim & Micon are most common
- Ketocon is a shampoo
- Efinaconazole 1st topical for Onychomycosis
What antifungal drugs are known as the Echinocandins?
- Caspofungin
- Micafungin
- Anidulafungin
Lipopeptides
ALL ARE IV
What is the mechanism of action for the Echinocandins?
- Inhibits synthesis of b(1-3)glucan [part of fungal cell wall]; weakin the cell wall causing leakage
- Mammals DO NOT have this
- Fungicidal
What is the clincial uses for the Enchinocandins?
- Caspo: Disseminated & mucocutaneous candida [those that fail Amp B]
- Mica: Mucocutaneous Candida [prophylaxis in Bone marrow transplants]
- Anidula: Esphogeal Candidiasis & Invasive Candidiasis
MICA and ANIDULA have less adverse events
What is the metabolism of echinocandins?
- NOT metabolised by liver CYPs
- Degraded in blood and tissues [Ring opens and peptide hydrolysis]
What is the mechanism of action for Flucytosine?
- PRODRUG; inhibits thymidyalte synthesis nad interferes with protein synthesis
- Converted in 5-FU –> 5-FdUMP –> Thymidylate cant break it down –> inhibiting DNA synthesis
What is the Pharmacokinetics for Flucytosine?
- ONLY PO
- Removed from kidneys
- Renal Issues = Toxicities
What are some of the clinical uses for Flucytosine?
- Cryptococcus Neoformans [combo with Amp B]
- Some Candida Sp.
- Apsergillus
Narrow window; TOO HIGH = toxic & TOO LOW = resistant
What antifugal drugs have Hepatic toxicities?
- ALL Azoles
- Amp B
- 5-FC
- Enhincoandins
What antifugal drugs have Renal toxicities?
- Amp B
- IV Voriconazole [Cyclodextrins?]
What antifugal drugs have CNS toxicities?
- Voriconazole
What antifugal drugs have Photopsia toxicities?
- Voriconazole
What antifugal drugs have Cutaneous toxicities?
- Rash [ALL ANTIFUNGAL]
- Photosensitivity? [Voriconazole]
What antifugal drugs have GI toxicities?
- Itraconazole
- Posaconazole
- 5-FC
What antifugal drugs have Cardiac toxicities?
Cardiomyopathy? QTc Prolongatin?
- Myopathy [Itraconazole]
- QTc Prologation [ALL Azoles (drug interactions)]
What antifugal drugs have Infusion Reactions toxicities?
- Amp B
- Echinocandins
What antifugal drugs have Bone Marrow Suppression toxicities?
- 5-FC
- Amp B
What is important to know about antifungals used during pregnancy?
- TOPICAL IS OK
- Amp B is treatment of choice for systemic
- AZOLES avoid during prenancy
- Single dose of Flucon for yeast infections
