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Clinical Pharmacology II > Antifungals > Flashcards

Antifungals Flashcards

1
Q

What are fungi?

A 
eukaryotic
heterophilic
achrorophyllus
Gram positive
Saprobe
Widely prevalent in the environment
250,000 species
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2
Q

How many fungi are pathogenic?

A

300

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3
Q

What causes fungi to become pathogenic?

A

The patients immune system

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4
Q

What are risk factors for getting fungi?

A 
HIV/AIDS
Diabetes
TB
Cystic Fibrosis
Cancer
Catherization
Organ Transplantation
Burn/Trauma
Prolonged antibiotic use
Corticosteroid use
Antineoplastic therapy
Plastics/Prosthetic devices
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5
Q

What are the routes of transmission for fungi?

A

Respiratory through inhalation of spores
Traumatic implantation
direct contact

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6
Q

What are the two most common fungi in the US?

A

Aspergillosis

Candidiasis

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7
Q

Which diseases have a high occurrence globally?

A

Aspergillosis
Candidiasis
Cryptococcosis
Pneumocystosis

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8
Q

Which diseases have a high occurrence in the US?

A

Blastomycosis
Coccidioidomycosis
Histoplasmosis

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9
Q

What are the three pathogenic fungi?

A

Yeast
Dimorphic
Molds

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10
Q

What species of fungi are Yeasts?

A

Candida spp.
Pneumocystis jirovecii
Cryptococcus neoformans

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11
Q

What species of fungi are dimorphic?

A

Blastomyces
Coccidiodomyces
Histoplasma
Sporotrichosis

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12
Q

What species of fungi are Molds?

A

Aspergillus
Mucor
Dermatophytes

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13
Q

What is Candida?

A

Normal commensal flora of the skin, GI, and GU tracts

Candida albacans is the most frequent species isolated in pathogenic infections

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14
Q

What is Cryptococcus?

A

Most common species is Cryptococcal neoformans

Acquired by inhalation and causes pneumonia

Meningitis is common in HIV/AIDS patients and solid organ transplant patients

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15
Q

What is Aspergillus?

A

Purely pathogenic mold

Fumigatus
Flavus
Niger

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16
Q

What are the five major types of fungal infections?

A 
Superficial 
Mucocutaneous
Subcutaneous
Systemic
Opportunistic
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17
Q

What are superficial and cutaneous mycoses?

A

Common and limited to superficial and keratinized layers of the skin, hair, and nails

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18
Q

What is piedra?

A

affects the hair follicles causing black and white nodules

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19
Q

What is tinea nigra?

A

brown of black lesions of the skin

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20
Q

What is tinea capitis?

A

Foliculitis of the scalp and eyebrows

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21
Q

What is favus?

A

destruction of the hair follicle

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22
Q

What is pityriasis?

A

Dermatitis which causes redness of the skin and itchiness

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23
Q

What are cutaneous and mucocutaneous mycoses?

A

Associated with skin, eyes, sinuses, oropharynx, and external ears

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24
Q

What is ringworm?

A

skin lesions that have red margins, scales and itchiness

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25
Q

What is onychomycosis?

A

chronic fungal infection of the nail bed

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26
Q

What is hyperkeratosis?

A

extended scaly areas on the hands and feet

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27
Q

What is mucocutaneous candidiasis?

A

Colonization of the mucous membranes caused by candida albicans

Associated with immunosuppression or loss of immunocompetence

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28
Q

What is thrush?

A

fungal growth of the oral cavity

Can be oropharyngeal or oroesophageal

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29
Q

What is vulvovaginitis?

A

fungal growth of the vaginal canal

Associated with hormonal imbalance

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30
Q

What are subcutaneous mycoses?

A

localized primary infections of the subcutaneous tissue

Involves the lymphatics and leads to cysts and granulomas

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31
Q

What is sporotrichosis?

A

traumatic implantation of fungal pathogen

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32
Q

What is paranasal mycosis?

A

infection of the paranasal sinuses causing granulomas

33
Q

What is zygomatic Rhinitis?

A

fungal invasion of tissue through arteries causing thrombosis and can involve the CNS

34
Q

What is systemic mycoces?

A

Associated with immunocompromised status/immunosuppression

Acquired by inhalation or contaminated medical equipment

Involves skin and deep viscera that affect organs

35
Q

What are the three major antifungal agents?

A 
Polyenes
Azoles
Echinocandins
Allylamines - Topical Agents
Misc.
36
Q

What are allylamines?

A

Topical Agents

MOA: inhibit the enzyme squalene epoxidase, another enzyme required for ergosterol synthesis; destroys plasma membrane

37
Q

What is terbinafine?

A

DOC for topical agents

Oral

Treats Onycomycosis

38
Q

What is amorolfine?

A

Nail lacquer

39
Q

What is Naftifine?

A

Treats tinea/cutanoues infections

40
Q

What is Butenafine and Clotrimazole?

A

treats Vulvovaginits

41
Q

What should you use for tinea treatment?

A

ointment or spray

DO NOT USE POWDER

42
Q

What are polyenes?

A

MOA: bind with sterols in the fungal cell membrane, principally ergosterol; causes cell contents to leak out and the cell dies

animal cells are much less susceptible to this

43
Q

What is Nystatin?

A

First antibiotic against fungi

Use: Candida species only

Adminstration:
Oral - is poorly absorbed from the GI tract and almost entirely excreted in feces unchanged; too toxic to be used systemically
Topical - no absorbed from intact skin or mucous membranes

44
Q

What is Amophotericin B?

A

Soluble in both basic and acidic environments but insoluble in water = amphoteric

BROAD SPECTRUM/EMPIRIC THERAPY

MOA: binds to ergosterol within fungal cell membrane causing depolarization of membrane; pores form allowing leakage of intracellular contents and concentration dependent killing of cell occurs

45
Q

What are the formulations of Amphotericin B?

A

Amphotericin B deoxycholate?
Amphotericin B Colloidal dispersion
Amphotericin B lipid complex
Liposomal amphotericin B

46
Q

What fungi are Amphotericin B not effective against?

A

Candida lusitanae
Fusarium
Tricosporon
Scedosporium

47
Q

What is amphotericin B deoxycholate (conventional)?

A

Distributes quickly out of blood and into liver and other organs and slowly renters circulation = effects linger hours to days after taking

Poor Penetration: CNS, saliva, bronchial secretions, pancreas, muscle and bone

ADRs:
Glomerular nephrotoxicity - decrease GFR
Tubular Nephrotoxicity - K, Mg, and bicarb wasting
Decreased erythropoietin production
Chills, Fevers, Tachypnea, hypotension
48
Q

What is the support management for conventional amphotericin B?

A

Fluids
Add K, Mg, and bicarb
Avoid concurrent nephrotoxic agents
Premed with acetaminophen, diphenhydramine, or hydrocortisone
Add heparin to the infusion to manage thrombophlebitis

49
Q

What is amphotericin B colloidal dispersion?

A

Cholesterol sulfate in equimolar amounts to amphotericin B

Similar kinetics to conventional

Reduced rate of nephrotoxicity compared to conventional

Dosing: 3 to 4 mg/kg once daily

50
Q

What is amphotericin B lipid complex?

A

Distributed into tissues more rapidly than conventional; highest levels in spleen, liver, and lungs; lowest levels in lymph nodes, kidneys, heart, and brain

Lower Cmax and smaller AUC than conventional

Reduced frequency and severity of infusion related reactions

Reduced rate of nephrotoxicity

Dosing: 5 mg/kg once daily

51
Q

What is liposomal amphotericin B (Ambisome)?

A

Higher AUC and larger AUC

Higher concentrations achieved in lung, liver, and spleen
Lower concentrations in kidneys, brain, lymph nodes, and heart

May achieve higher brain concentrations compared to other amphotericin B formulations

Reduced frequency and severity of infusion related reactions

Reduced rate of nephrotoxicity

Dosing: 3 to 6 mg/kg once daily

52
Q

What is the MOA of Azoles?

A

Inhibit 14 alpha-demethylase which converts lanosterol to ergosterol and is required in fungal cell membrane synthesis; also blocks steroid synthesis in humans

53
Q

What Imidazoles are not antifungals but rather work on worms and parasites?

A

Mebendazole

Thiabendazole

54
Q

What are imidazoles used for?

A 
topical agents against:
tinea corporis
tinea cruris
tinea pedis
oropharyngeal candidiasis
vulvovaginal candidiasis
contact dermatitis
vulvular irritation
55
Q

What is Ketoconazole?

A

DOES NOT COVER ASPERGILLUS

Use: Candida, Blastomycosis, Histoplasmosis
Coccidioidomycosis, and Paracocciodioidomycosis

Needs acidic gastric pH for absorption if taken orally = acid suppressants like tums or PPI’s would inhibit it

Distribution: epidermis, synovial fluid, saliva, lungs; not into CSF or eye

DECREASE DOSE FOR SEVERE LIVER FAILURE

ADRs: Gi distress, rash, INCREASED LFTs, Hepatitis (within first 4 months of use), dose dependent inhibition of synthesis of testosterone causing impotence or gynecomastia, MENSTRUAL IRREGULARITIES, ALOPECIA, dose related decrease in cortisol synthesis, Hypermineralcorticoid state, teratogenic in animals

56
Q

What does Flucoazole NOT cover?

A 
Candida krusei
Aspergillus
Fusarium
Scedosporium
Zygomycetes
57
Q

What does Isavuconazole cover?

A

ASPERGILLUS ONLY

58
Q

What does Itraconazole NOT cover?

A 
Zygomycetes
Scedosporium
Fusarium
Candida krusei
Candida glabrata
59
Q

What does Voriconazole NOT cover?

A

Zygomycetes

Scedosporium

60
Q

What does Posaconazole NOT cover?

A

Scedosporium

61
Q

What is Fluconazole?

A

Absorption: PO and IV 90% bioavailable

Distribution: Wide; good CNS penetration

Metabolism: Inhibits CYP 2C9, 2C19, 3A4

Elimination: 80% excreted unchanged in urine

ADRs: Well tolerated, GI intolerance, Elevated LFTs, and Rash

MUST RENALLY DOSE ADJUST SO THAT IT DOESN’T BUILD UP IN BODY

62
Q

What is Isacuconazole?

A

Absorption: PO and IV; excellent bioavailable

Distribution: half life is 130 hours

Metabolism: Hydrolyzation; substrate of CYP 3A4 and 3A5

Elimination: Fecal

ADRs: GI, dose and concentration dependent QTc SHORTENING, fatigue, chest pain, hypokalemia, hypomagnesemia, nephrotoxicity, hypotension

MUST GIVE LOADING DOSE FOR IV/PO

63
Q

What is itraconzaole?

A

Absorption: PO and IV; capsules with food; suspension on empty stomach

Distribution: low urinary levels; poor CNS penetration

Metabolism: inhibits CYP 2C9 and potent 3A4

Elimination: excreted in feces

ADRs: C/I in patients with CHF due to negative inotropic effects, QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest in the setting of DDIs, hepatotoxicity, rash, hypokalemia, GI intolerance

Use: severe refractory cases of onycomycosis

NEED TO GIVE ORAL DOSE HIGHER

64
Q

What is voriconazole?

A

Absorption: PO, IV, and ophthalmic; 90% oral bioavailable

Distribution: wide; good CNS penetration

Metabolism: inhibits CYP 2C19, 2C9, and 3A4

Elimination: minimal renal excretion

Need cirrhotic liver dosing and renal impairment dosing

Don’t use if patient is on too many CYP enzyme metabolizers

ADRs: VISUAL/AUDITORY DISTURBANCES, peripheral edema, rash, N/V/D, hepatotoxicity, HA, fever

Severe ADRs: SJS, liver failure, anaphylaxis, renal failure, QTc prolongation

65
Q

What is Posaconazole?

A

Absorption: PO and IV; take with high fat meal; Oral tablet is given once daily with food; oral suspension is given in divided doses with food

Distribution: Widely distributed into tissues

Metabolism: Not by P450, but inhibitor of 3A4

Elimination: Minimal renal excretion of parent compound; 66% excreted in feces

ADRs: hepatotoxicity, QTc prolongation, GI intolerance

66
Q

What is the Fluconazole dosing for renal impairment?

A

CrCl > 50 ml/min = give full dose
CrCl < 50 ml/min = 50% dose
Dialysis = replace full dose after each session

67
Q

What is the cirrhotic dosing for Voriconazole?

A

IV = 6 mg/kg for 2 doses, then 2 mg/kg every 12 hours

Oral =
> 40 kg = 100 mg every 12 hours
< 40 kg = 50 mg every 12 hours

68
Q

What is the renal impairment dosing for Voriconazole?

A

CrCl < 50 ml/min = use oral formulation to avoid accumulation of cyclodextrin solubilizer

69
Q

What are Echinocandins?

A

FUNGINS

MOA: inhibits the synthesis of glucan in the cell wall, probably via the enzyme 1, 3-beta glucan synthase

70
Q

What do echinocandins NOT cover?

A

Cryptococcus
Fusarium
Scedosporidium
Zygomycetes

71
Q

What is Caspofungin?

A

Absorption: IV only

Distribution: Extensive into tissues; minimally CNS penetration

Metabolism: Spontaneous degredation, hydrolysis, and N-acetylation

Elimination: Urinary

Half life: 9-23 hours

Dose adjust for Child-Pugh 7-9 and CYP inducers; requires loading dose

DDIs: penytoin, rifampin, carbamazepine = decrease effect
Cyclosporine = increases AUC causing hepatotoxicity; AVOID
Tacrolimus reduction

ADRs: tends to have higher frequency of liver related lab abnormalities; higher frequency of infusion related pain and phlebitis

72
Q

What is Micafungin?

A

Absorption: IV only

Distirbution: Extensive into tissues; minimally CNS penetration

Metabolism: spontaneous degradation, hydrolysis, and N-acetylation

Elmination: Urinary

Half life: 11-21 hours

DDIs: Nifedipine = monitor BP
Sirolimus = monitor levels

73
Q

What is Anidulafungin?

A

Absorption: IV only

Distribution: Extensive into tissues; minimally CNS penetration

Metabolism: chemical degradated; not hepatically metabolized

Elimination: urinary

Half life: 26.5 hours

Requires loading dose

74
Q

What are the ADRs of Echinocandins?

A 
Generally well tolerated
Infusion related reactions of fever and phlebitis
GI intolerance
Hypokalemia
Hypomagnesemia
ELEVATED LFTs
75
Q

What is Flucytosine?

A

An antimetabolite

MOA: leads to miscoding of fungal RNA and interferes with DNA synthesis

CANNOT BE USED ALONE AND MUST BE USED WITH ANOTHER ANTIFUNGAL

Half life: 2-5 hours in normal people; 85 hours in patients with anuria

Distribution: tissues, CSF, and bodily fluids

Toxicities: bone marrow suppression, hepatotoxicity, enterocolitis; occur most commonly in patients with renal impairment

C/I in pregnancy

Monitor concentrations closely

76
Q

What is Griseofulvin?

A

oral

MOA: binds to polymerized microtubules and inhibits fungal mitosis

Use: Onychomycosis

77
Q

What does Flucytosine NOT cover?

A

Candida krusei

78
Q

What antifungal agent should be used in synergy with Flucytosine?

A

Amphotericin B

Clinical Pharmacology II (25 decks)

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