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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
What is onychomycosis?
chronic fungal infection of the nail bed
26
What is hyperkeratosis?
extended scaly areas on the hands and feet
27
What is mucocutaneous candidiasis?
Colonization of the mucous membranes caused by candida albicans Associated with immunosuppression or loss of immunocompetence
28
What is thrush?
fungal growth of the oral cavity Can be oropharyngeal or oroesophageal
29
What is vulvovaginitis?
fungal growth of the vaginal canal Associated with hormonal imbalance
30
What are subcutaneous mycoses?
localized primary infections of the subcutaneous tissue Involves the lymphatics and leads to cysts and granulomas
31
What is sporotrichosis?
traumatic implantation of fungal pathogen
32
What is paranasal mycosis?
infection of the paranasal sinuses causing granulomas
33
What is zygomatic Rhinitis?
fungal invasion of tissue through arteries causing thrombosis and can involve the CNS
34
What is systemic mycoces?
Associated with immunocompromised status/immunosuppression Acquired by inhalation or contaminated medical equipment Involves skin and deep viscera that affect organs
35
What are the three major antifungal agents?
``` Polyenes Azoles Echinocandins Allylamines - Topical Agents Misc. ```
36
What are allylamines?
Topical Agents MOA: inhibit the enzyme squalene epoxidase, another enzyme required for ergosterol synthesis; destroys plasma membrane
37
What is terbinafine?
DOC for topical agents Oral Treats Onycomycosis
38
What is amorolfine?
Nail lacquer
39
What is Naftifine?
Treats tinea/cutanoues infections
40
What is Butenafine and Clotrimazole?
treats Vulvovaginits
41
What should you use for tinea treatment?
ointment or spray DO NOT USE POWDER
42
What are polyenes?
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
What is Nystatin?
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
What is Amophotericin B?
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
What are the formulations of Amphotericin B?
Amphotericin B deoxycholate? Amphotericin B Colloidal dispersion Amphotericin B lipid complex Liposomal amphotericin B
46
What fungi are Amphotericin B not effective against?
Candida lusitanae Fusarium Tricosporon Scedosporium
47
What is amphotericin B deoxycholate (conventional)?
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
What is the support management for conventional amphotericin B?
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
What is amphotericin B colloidal dispersion?
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
What is amphotericin B lipid complex?
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
What is liposomal amphotericin B (Ambisome)?
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
What is the MOA of Azoles?
Inhibit 14 alpha-demethylase which converts lanosterol to ergosterol and is required in fungal cell membrane synthesis; also blocks steroid synthesis in humans
53
What Imidazoles are not antifungals but rather work on worms and parasites?
Mebendazole | Thiabendazole
54
What are imidazoles used for?
``` topical agents against: tinea corporis tinea cruris tinea pedis oropharyngeal candidiasis vulvovaginal candidiasis contact dermatitis vulvular irritation ```
55
What is Ketoconazole?
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
What does Flucoazole NOT cover?
``` Candida krusei Aspergillus Fusarium Scedosporium Zygomycetes ```
57
What does Isavuconazole cover?
ASPERGILLUS ONLY
58
What does Itraconazole NOT cover?
``` Zygomycetes Scedosporium Fusarium Candida krusei Candida glabrata ```
59
What does Voriconazole NOT cover?
Zygomycetes | Scedosporium
60
What does Posaconazole NOT cover?
Scedosporium
61
What is Fluconazole?
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
What is Isacuconazole?
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
What is itraconzaole?
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
What is voriconazole?
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
What is Posaconazole?
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
What is the Fluconazole dosing for renal impairment?
CrCl > 50 ml/min = give full dose CrCl < 50 ml/min = 50% dose Dialysis = replace full dose after each session
67
What is the cirrhotic dosing for Voriconazole?
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
What is the renal impairment dosing for Voriconazole?
CrCl < 50 ml/min = use oral formulation to avoid accumulation of cyclodextrin solubilizer
69
What are Echinocandins?
FUNGINS MOA: inhibits the synthesis of glucan in the cell wall, probably via the enzyme 1, 3-beta glucan synthase
70
What do echinocandins NOT cover?
Cryptococcus Fusarium Scedosporidium Zygomycetes
71
What is Caspofungin?
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
What is Micafungin?
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
What is Anidulafungin?
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
What are the ADRs of Echinocandins?
``` Generally well tolerated Infusion related reactions of fever and phlebitis GI intolerance Hypokalemia Hypomagnesemia ELEVATED LFTs ```
75
What is Flucytosine?
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
What is Griseofulvin?
oral MOA: binds to polymerized microtubules and inhibits fungal mitosis Use: Onychomycosis
77
What does Flucytosine NOT cover?
Candida krusei
78
What antifungal agent should be used in synergy with Flucytosine?
Amphotericin B

Clinical Pharmacology II (25 decks)

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