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PHRM 865: Theraputics V > Lecture 22: Antifungals > Flashcards

Lecture 22: Antifungals Flashcards

1
Q

What is the clasification of fungal infections?

A
  • Superficial [cosmetic, not life-threatening]
  • Subcutaneous [implanted in skin; lesion]
  • Systemic/Invasive [deep tissues]
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2
Q

What are some of the superficial and cutaneous fungal infections?

A
  • 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

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3
Q

What is important to know about the Invasive fungal infections [systemic]?

A
  • Usually begin in lung
  • May go into blastomyces [bone, skin, joints] or Histoplasma [GI, Adrenal, Bone, Skin]
  • Normally asymptomatic
  • WONT spread fast
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4
Q

What antifungal drugs are known as the “Polyenes”

A
  • Amphotericin B
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5
Q

What are some of the important features to note about Amphotericin B?

A
  • “Amphoteric” = Acidic and Basic groups
  • Mycosamine group = Binding to ergosterol
  • Hydroxyl groups help with binding NOT fnugicidal activity
  • Fungicidal
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6
Q

What is the mechanism of action for Amphotericin B?

A
  • Binds to ergosterol –> causing leaky channels [Ca/Na/K] –> cell death
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7
Q

What is the pharmacokinetics of Amphotericin B?

A
  • 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??

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8
Q

What are some of the adverse effects for Amphotericin B?

A
  • Infusion Related [Fever, Chills, Vomiting, Headache, Hypotension…]
  • Renal Damage
  • Liver Issues

PRETREAT with Diphenhydramine or Acetaminophen

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9
Q

What are some of the therapeutic applications for Amphotericin B?

A
  • Systemic Infections: Amphortericin B [broad Spec; DOC for life-threanteing fungal infections]
  • Superfficial Fungal Infections: Nystatin [polyene similar to Amp B]
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10
Q

What are some of the Amphotericin Formulation?

A
  • Conventional = Amp B or Fungizone [Collodial Suspension]
  • Lipid Formulations [Amphotec; Ambisome; Abelcet]

Amphotec = ABCD
Ambisome = L-AMB
Abelec = ABLC

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11
Q

What is important to know about the Lipid Formulation of Amphotericin?

A
  • Reduce Nephrotoxicity
  • Act as reservoirs
  • Ambsiome decreased infusion toxicities
  • Amphotec = less nephrotoxcity BUT more fever
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12
Q

Breifly dicuss the Ergosterol Synthesis Pathway?

A
  • MOST Fungi have Ergosterol in membranes
  • Squalene –> Squalene Epoxide [by Squalene Epoxidase] –> Lanosterol –> –> –> Ergosterol [by P450 14a-demethylase]
  • Similar to cholesterol in humans
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13
Q

What antifungal drugs are known as the “Allylamines”?

A
  • Terbinafine
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14
Q

What is the mechanism of action for Terbinafine?

A
  • Inhibits Squalene epoxidase
  • CAN cause an increase of TOXIC levels of Squalene
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15
Q

What is important to know about Terbinafine and what it is good against?

A
  • Fungicidal
  • Mainly for Dermatophytes [even Onychomycoses]
  • PO or Topically [for like Ringworm, Nail Infections]
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16
Q

What are some of the other formulations of Terbinafine?

A
  • Naftifine [Lotrimin] & Butenafine [Lotrimin Ultra]
  • Tolnaftate [Tinactin]
  • Butenafine is GOOD against Candida, Cryptococcus, Aspergillus compared to Terbinafine

Also Anti-inflammatory

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17
Q

What is the mechanism of action for the “Azole” antifungal drugs?

A
  • 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

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18
Q

What is the selectivity of the “Azoles”?

A
  • Humans uses the same enzymes to make cholesterol
  • Fungal Enzymes are MORE sensitive [Ketocon IC50 for Candida = 10^-9]

Human = 10^-6

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19
Q

What is the metabolism of the “Azoles”?

A
  • 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

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20
Q

What is important to understand about the early “Azoles”?

A
  • Clotrimazole and Miconaozole were the 1st
  • Used for later generation azoles
  • Alterations Changes: Spec, CYPs, Elimination
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21
Q

What is important to know about Ketoconazole?

A
  • First azole with good oral bioavailability
  • Dioxolane ring and reduced 3A
22
Q

What is important to know about Itraconazole?

A
  • Based on Ketocon
  • Triazole [3 N on a Aromatic instead on 2]
  • Improved specificity for P450
23
Q

What is important to know about Fluconazole?

A
  • Modified Ketocon
  • 2 Triazoles [3 N on aromatic]
  • F in place of Cl
  • Hydroxyl Group
  • NO Dioxolane Ring
24
Q

What is important to know about Voriconazole?

A
  • Based on Flucon
  • Has 1 Triazole, Hydroxyl, F groups
  • Fluoropyridine Ring instead of other Triazole
  • Methyl group added [helps with binding and increased spec]
25
Q

What is important to know about Posaconazole?

A
  • Derived form Itracon
  • Furan Ring [alters and increases spec]
  • F replaces Cl
  • PO or IV
26
Q

What is important to know about Isavuconazole?

A
  • Structurally similar to Voricon
  • Water Soluble PRODRUG [reduces nephrotoxcity]
  • LONG half life

PRODRUG is Isavuconazonuim

27
Q

What is important to know about the Drug Interactions with the “Azoles”?

CYP450

A
  • Metabolized and Inhibit liver P450 Enzymes
  • Inducers can decrease triazole leves
  • Ketocon potent inhibitor of 3A4

RIFAMPIN very potent inducer

28
Q

What are some of the drug interactions for Ketoconazole?

A
  • Inhibited metabolism of terfenadine and cisapride [Removed]
  • Increases AUC and Half Life of Triazolam
  • Increases Bioavailability of Cyclosporin
  • 3A4 inducers Reduce ketocon levels
29
Q

What are some of the individual Metabolism of the “Azoles”?

Itra, Flu, Vori, Posac

A
  • Itracon: by 3A4 in Liver
  • Flucon: unchanges by kidneys
  • Voricon: by 2C19>3A4»2C9 in Liver
  • Posacon: by Glucuronidation [inactive]
30
Q

What is the clinical uses of Fluconazole?

A
  • Penetrates CSF
  • Spec: C. Albicans & other Candida [Most commonly used for Mucocutaneous Candida]
  • Cryoticoccus Neoformans [Azole of Choice]

resistance toward –> Krusei & Glabrata

31
Q

What is the clinical uses for Itraconazole?

A
  • Spec similar to Flucon + Aspergillus
  • Azole of Choice for Histroplasma, Blastoymces, Sporothrix
  • Used for Dermaphytoses & Onchomycoese
  • Bad Taste
32
Q

What is the clinical uses for Voriconazole?

A
  • 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]

33
Q

**

What are the clinical uses for Posaconazole and Isavuconazole?

A
  • Posacon: same as voricon
  • Isavucon: Spec same as voricon; good for aspergillosis and mucormycosis
34
Q

What are some of the better topical azoles used for superficial fungal infections?

A
  • Clotrim & Micon are most common
  • Ketocon is a shampoo
  • Efinaconazole 1st topical for Onychomycosis
35
Q

What antifungal drugs are known as the Echinocandins?

A
  • Caspofungin
  • Micafungin
  • Anidulafungin

Lipopeptides
ALL ARE IV

36
Q

What is the mechanism of action for the Echinocandins?

A
  • Inhibits synthesis of b(1-3)glucan [part of fungal cell wall]; weakin the cell wall causing leakage
  • Mammals DO NOT have this
  • Fungicidal
37
Q

What is the clincial uses for the Enchinocandins?

A
  • 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

38
Q

What is the metabolism of echinocandins?

A
  • NOT metabolised by liver CYPs
  • Degraded in blood and tissues [Ring opens and peptide hydrolysis]
39
Q

What is the mechanism of action for Flucytosine?

A
  • PRODRUG; inhibits thymidyalte synthesis nad interferes with protein synthesis
  • Converted in 5-FU –> 5-FdUMP –> Thymidylate cant break it down –> inhibiting DNA synthesis
40
Q

What is the Pharmacokinetics for Flucytosine?

A
  • ONLY PO
  • Removed from kidneys
  • Renal Issues = Toxicities
41
Q

What are some of the clinical uses for Flucytosine?

A
  • Cryptococcus Neoformans [combo with Amp B]
  • Some Candida Sp.
  • Apsergillus

Narrow window; TOO HIGH = toxic & TOO LOW = resistant

42
Q

What antifugal drugs have Hepatic toxicities?

A
  • ALL Azoles
  • Amp B
  • 5-FC
  • Enhincoandins
43
Q

What antifugal drugs have Renal toxicities?

A
  • Amp B
  • IV Voriconazole [Cyclodextrins?]
44
Q

What antifugal drugs have CNS toxicities?

A
  • Voriconazole
45
Q

What antifugal drugs have Photopsia toxicities?

A
  • Voriconazole
46
Q

What antifugal drugs have Cutaneous toxicities?

A
  • Rash [ALL ANTIFUNGAL]
  • Photosensitivity? [Voriconazole]
47
Q

What antifugal drugs have GI toxicities?

A
  • Itraconazole
  • Posaconazole
  • 5-FC
48
Q

What antifugal drugs have Cardiac toxicities?

Cardiomyopathy? QTc Prolongatin?

A
  • Myopathy [Itraconazole]
  • QTc Prologation [ALL Azoles (drug interactions)]
49
Q

What antifugal drugs have Infusion Reactions toxicities?

A
  • Amp B
  • Echinocandins
50
Q

What antifugal drugs have Bone Marrow Suppression toxicities?

A
  • 5-FC
  • Amp B
51
Q

What is important to know about antifungals used during pregnancy?

A
  • TOPICAL IS OK
  • Amp B is treatment of choice for systemic
  • AZOLES avoid during prenancy
  • Single dose of Flucon for yeast infections

PHRM 865: Theraputics V (42 decks)

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