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pr3151 > antifungal and antiprotozoal > Flashcards

antifungal and antiprotozoal Flashcards

1
Q

what are mycoses/ mycotic infection

A

infection caused by fungi, chronic in nature, can be superficial and involve only skin (oral and vaginal thrush) while others may penetrate the skin causing SC or systemic infections

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2
Q

what are the differences in structure of a fungal cell

A

fungi are eukaryotic cell with rigid cell wall largely composed on chitin rather than peptidoglycan and its cell membrane contains ergosterol rather than cholesterol found in mammalian membrane

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3
Q

what are the classes of antifungal drugs

A

polyenes, antimetabolites, echinocandins, squalene epoxidase inhibitors, azoles

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4
Q

what are the drugs used for SC and systemic fungal infections and what classes are they

A

amphotericin B (polyenes), flucytosine (antimetabolite), caspofungin (echinocandins), triazole (azoles)

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5
Q

what are the drugs used for cutaneous fungal infections and what classes are they

A

nyastatin (polyenes), terbinafine (squalene epoxidase inhibitor), imidazole (azole)

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6
Q

what is the moa of polyenes

A

polyenes bind to ergosterol in plasma membranes of sensitive fungal cells and causes pore formation which results disruption of pore membrane function and causes the electrolytes esp K+ and small molecules to leak out of the cell thus resulting in cell death

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7
Q

what is the moa of antimetabolites

A

5-flucytosine enters fungal cell through cytosine specific permeases and is converted to its metabolically active form 5-FU by cytosine deaminase

a) 5-FU is converted into 5-fluorouridine triphosphate (FUTP) which is incorporated into fungal RNA in place of uridylic acid which results in inhibition of protein synthesis

b) 5-FU is metabolised into 5-fluorodeoxyuridine monophosphate (5-FdUMP) which is a potent inhibitor of thymidylate synthase, a key enzyme of DNA syntheisis

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8
Q

what is the moa of azoles

A

inhibits c14-alpha demethylase cyp450 enzyme, leading to the blocking of demethylation of lanosterol into ergosterol which is the principal sterol of fungal membranes

inhibition of ergosterol synthesis can disrupt membrane structure and function as it is important for cell wall integrity thus result in inhibition of fungal growth

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9
Q

what is the moa of echinocandins

A

strength of fungal cel wall maintained by fibrilar polysacharides like beta-1-3-glucan and chitin which covalently bond to each other and to other peptides

glucan synthase complex in plasma membrane catalyses synthesis of beta-1-3-glucan

echinocandins act by inhibiting glucan synthase complex and thus inhibits synthesis of beta-1-3-glucan which would affect cell wall synthesis and loss of structural integrity of cell wall

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10
Q

what is the moa of squalene epoxidase inhibitors

A

inhibit activity of squalene epoxidase which blocks squalene conversion into lanosterol and thus inhibit biosynthesis of ergosterol which is an essential component of fungal cell membrane

leads to toxic accumulation of squalene which causes increased membrane permeability and death of fungal cell

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11
Q

what are the characteristics of amphotericin B

A

naturally occurring polyene, lipophilic, produced by streptomyces, nodusus

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12
Q

what kind of activity does amphotericin B have and what are the indications for it

A

bactericidal and bacteriostatic effect depending on type of organism and conc of drug

effective for candida albicans, histoplasmosis, cryptococcus neoformans, aspergillus

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13
Q

what type of formulations can amphotericin B have

A

conventional and lipophilic form

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14
Q

what is the conventional form of amphotericin B

A

coformulated with sodium deoxycholate

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15
Q

is amphotericin B soluble or insoluble in water

A

insoluble

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16
Q

PK characteristics of amphotericin B

A

topical or slow IV, GI absorption negligible

extensively bound to plasma proteins, long half life, poor csf penetration but increased with inflammation and liposomal formulation have better csf penetration

low levels of drug and metabolites appear in urine over a long period of time, some eliminated via bile

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17
Q

what are the adverse effects of amphotericin B

A

fever and chills, nephrotoxicity, electrolyte imbalances, htn, bone marrow suppression, anemia, thrombophlebitis

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18
Q

what pregnancy category is amphotericin B

A

category B

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19
Q

is 5-flucytosine soluble or insoluble in water

A

soluble

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20
Q

what is the concern with 5-flucytosine

A

resistance

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21
Q

what is the type of activity for 5-flucytosine and what are its indications

A

fungistatic

narrow spectrum as some fungi lack cytosine deaminase
used for systemic yeast infections or with amphotericin B for cryptococcus (meningitis and pulmonary infection) and candidiasis

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22
Q

what are the mechanisms of resistance for 5-flucytosine

A
  1. mutations in the enzymes resulting in decreased level of the enzymes
  2. increased synthesis of cytosine during therapy
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23
Q

PK characteristics of 5-flucytosine

A

PO

good csf penetration

80% excreted unchanged in urine, renal dose adjustments requied

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24
Q

what are the adverse effects of 5-flucytosine

A

GI, severe bone marrow suppression due to 5-FU metabolite, hepatotoxicity

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25
Q

what labs should be monitored when using 5-flucytosine in view of its adverse effects

A

severe bone marrow suppression monitor leukocytes and PLT weekly

hepatotocity monitor ALT and AST weekly

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26
Q

what are examples of echinocandins

A

caspofungin, micafungin, anidulafungin

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27
Q

what is the spectrum of activity of echinocandins

A

second line for invasive aspergillus (behind amphotericin B and azoles), first line for invasive candidiasis incl azole resistant

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28
Q

PK properties of echinocandins

A

poor oral F

extensive protein binding 97%, low csf penetration

metabolised slowly by hydrolysis and N-acetylation, not metabolised by cyp

eliminated in urine and feces, not renally cleared so do not need renal dose adjustments

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29
Q

what are the adverse effects of echinocandins

A

minimal, DDIs for caspofungin and micafungin

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30
Q

what pregnancy category is echinocandins

A

category C

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31
Q

what are examples of triazoles

A

fluconazole, posaconazole, itraconazole, voriconazole

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32
Q

what are the mechanisms of resistance to triazoles

A
  1. mutation of the c14alpha-demethylase gene
  2. efflux pumps
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33
Q

what type of activity does triazoles have

A

fungistatic

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34
Q

what are the indications for fluconazole

A

candida, meningitis, histoplasmosis

35
Q

what are the indications for posaconazole

A

candida, aspergillus, fusarium, zygomycetes

36
Q

what are the indications for itraconazole

A

wider spectrum than fluconazole
histoplasmosis, blastomycosis, aspergillosis if intolerant to amphotericin B
onychomycosis if immunocompromised
esophageal and oropharyngeal candidiasis

37
Q

what are the indications for voriconazole

A

broad spectrum, first line for invasive aspergillosis
candida

38
Q

PK characteristics of fluconazole

A

PO (almost completely absorbed from GI tract), IV

long half life, well distributed into body fluids and breast milk, csf conc can reach 50-90%

renally cleared, excreted unchanged in urine, renal dose adjustments required

39
Q

what are the adverse side effects of fluconazole

A

GI (N,V, headache, skin rash)
hepatotoxicity
QT prolongation
hair loss

40
Q

what is the pregnancy category of fluconazole

A

category C

41
Q

PK characteristics of posaconazole

A

PO (capsules, syrup), IV
F increased with high fat meal, F of syrup lower and further decreased with PPI

long half life, poor csf penetration

mainly eliminated by feces no need for renal dose adjustment if PO

42
Q

what is contained in IV posaconazole and what is its effect

A

IV posaconazole contains cyclodextrin which is nephrotoxic

43
Q

what are the adverse effects of posaconazole

A

GI (N,V, rash, headache)
hepatotoxicity
QT prolongation

44
Q

what pregnancy category is posaconazole

A

category C

45
Q

PK characteristics of itraconazole

A

PO (capsules, solution)
absorption decreased in presence of antacid and PPI, lower pH better absorption

well distributed into most tissues incl bone and adipose, poor csf penetration

metabolised in liver

drug and its inactive metabolites excreted in feces and urine, no renal adjustments if PO

46
Q

what are the adverse effects of itraconazole

A

GI (N,V, headache, skin rash)
hepatotoxicity
QT prolongation
cardiotoxicity

47
Q

what is periostitis

A

inflamm of bone tissue

48
Q

what drug can cause periostitis

A

voriconazole

49
Q

PK characteristics of voriconazole

A

PO (tablets, syrups)
best taken on empty stomach, high oral F

penetrate well into tissues, good csf penetration

metabolised by cyp (do not take with PPI)

inactive metabolites excreted via urine no renal dose adjustments

50
Q

what are the adverse effects of voriconazole

A

GI (N, V, headache, skin rash)
hepatotoxicity
QT prolongation
nephrotoxicity
periostitis

51
Q

what pregnancy category is voriconazole

A

category D

52
Q

what are the drug interactions for triazoles

A

all triazoles inhibit 3a4 and interfere with 2c9 and 2c19 cyp450 isoenzymes

53
Q

can triazoles be used in pregnancy

A

no, it is teratogenic

54
Q

what are examples of imidazoles

A

clotrimazole, miconazole

55
Q

what is the route of administration of imidazoles

A

topical

56
Q

what are the indications for imidazoles

A

tinea cruris, tinea pedis, tinea corporis, oropharyngeal candidiasis, vulvovaginal candidiasis

57
Q

what does capitis refer to

A

scalp

58
Q

what does faciei refer to

A

face

59
Q

what does corporis refer to

A

arms, legs, trunk

60
Q

what does barbae refer to

A

facial hair

61
Q

what does manuum refer to

A

hands, palm

62
Q

what does cruris refer to

A

groin

63
Q

what does pedis refer to

A

feet

64
Q

what does unguium refer to

A

fingernails, toenails

65
Q

what is the spectrum of activity of imidazoles

A

epidermophyton, microsporum, trichophyton, candida, malassezia

66
Q

what are the indications specifically for clotrimazole

A

dermatophyte infections
vulvovaginal/ pharyngeal/ cutaenous candidiasis

67
Q

what are the indications specifically for miconazole

A

tinea cruris, pedis, versicolor
vulvovaginal candidiasis

68
Q

PK characteristics of clotrimazole

A

powder, cream, lotion, pessary, troce (lozenge)

<0.5% absorbed after application, 3-10% if vagina

absorbed and metabolised in liver, excreted in bile

69
Q

what are the adverse effects of clotrimazole

A

contact dermatitis
vulvar irritation
edema
GI disturbances if PO
elevated liver enzymes if PO

70
Q

PK characteristics of miconazole

A

cream, lotion, powder, pessary, oral gel

readily penetrates stratum corneum of skin and persists for more than 4 days after application

less than 1% absorbed into blood, no more than 1.3% from vagina

71
Q

what are the adverse effects of miconazole

A

contact dermatitis, vulvar irritation, edema, GI disturbances if PO

72
Q

what route is nyastatin

A

topical, PO

73
Q

why is nyastatin not given parenterally

A

systemic toxicity

74
Q

what is the indications for nyastatin

A

oropharyngeal, vulvovaginal, cutaenous candidiasis

75
Q

PK characteristics of nyastatin

A

oral (suspensions, tablets), pessary, cream

not absorbed from GI tract, skin or vagina

76
Q

what are the adverse effects of nyastatin

A

rare after PO, skin irritation if topical

77
Q

what does trichophyton, microsporum and epidermophyton cause

A

tinea

78
Q

what are the indications for terbinafine and what route

A

onychomycoses (PO)
tinea capitis (PO)
tinea cruris (topical)
tinea corporis (topical)
tinea pedis (topical)

79
Q

PK characteristics of terbinafine

A

oral, IV
40% F due to first pass metabolism

highly protein bound and accumulates in keratin

extensively metabolised by several cyp450

excreted mainly in urine

80
Q

what special populations is terbinafine c/i for

A

moderate to severe renal impairment or hepatic dysfunction
nursing mothers as secreted into breast milk

81
Q

what are the adverse effects of terbinafine

A

GI disturbances, headache, rash, elevation of liver enzymes (AST, ALT)

82
Q

what pregnancy category is terbinafine

A

PO - category B
vaginal - category A

83
Q

what are the drug interactions of terbinafine

A

terbinafine is an inhibitor of cyp450

pr3151 (12 decks)

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