Anti-Fungal Drugs

Question 1

systemic mycoses can be treated with

Answer 1

amphotericin B(iv)

flucytosine

Azoles(oral)

Question 2

Cutaneous Candidiasis can be treated by

Answer 2

Nystatin

Azoles

Question 3

dermatophytic infections can be treated by

Answer 3

Azoles(topical/oral)

Griseofulvin

Question 4

what are the polyene antifungals

Answer 4

amphotericin B and nystatin

Question 5

what is the mechanism of aciton of amphotericin B

Answer 5

it interacts hydrophobically with erosterol in the fungal cell membrane, forming a pore

then potassium and other small molecules are lost through the pore, causing death

Question 6

amphotericin B exhibits what pharmacokinetics

Answer 6

very poor oral absorption

Question 7

Amphotericin B is sequestered

Answer 7

in tissue membranes very low serum levels

Question 8

how do you administer amphotericin B

Answer 8

as a freshly prepared suspension liposomal preparations

Question 9

the half life of amphotericin B is

Answer 9

long 15 days

Question 10

two types of polyene antifungals which are amphotericin B and nystatin. These drugs have an

Answer 10

amino sugar at one end which is polar but the rest of the molecule is an amphipath. One portion of the amphipathic molecule is unsaturated and therefore likes lipid whereas the other side of the same molecule has a lot of hydroxy groups on it and therefore likes water.

Question 11

what are the adverse effects

Answer 11

Question 12

There are some newer liposomal preparations that bypass the problem of having to make a fresh preparation with each use and some of the toxic effects associated with amphotericin B

Answer 12

So instead of doing this by cellular preparation, there are several liposomal formulations where they make an artificial phospholipid membrane in which amphotericin B is embedded (i.e. micelle). However the problem with the liposomal preparations of amphotericin B is that they’re very expensive. So we still mostly give amphotericin B in a deoxycholate type of suspension and that can be delivered to the patient. You only switch over to the liposomal preparation if the patient is showing signs of renal impairment while on the conventional preparation

Question 13

narrow spectrum of activity; most strains of cryptococcus neoformans

Answer 13

flucytosine

Question 14

flucytosine is usually used in combination with

Answer 14

amphotericin B

Question 15

what is the mechanism of Flucytosine

Answer 15

1. Flucytosine is fungicidal.
   
   1. The fungal cell has a pump. Because of the leaky membrane induced by amphotericin B, flucytosine can gain access into the fungal cell using the pump more readily. We don’t have the pump so flucytosine cannot get into human cells as well but it does get in to some extent.
   2. Then an enzyme in the fungal cell deaminates flucytosine to remove the amine group so that we wind up with 5-flurouracil. 5-flurouracil is a major component in the treatment of some neoplasms.
   3. Then in the fungal cell 5-flurouracil is converted into 5-fluro deoxy UMP (5-FdUMP).
   4. 5-FdUMP is an inhibitor of thymidylate synthase. Therefore 5-FdUMP will prevent the fungal cell from making thymidine.

Because there’s less thymidine in the fungal cell, it will not be able to undergo cell division and you wind up with a significant deleterious effect on the fungi

Question 16

what are the pharmacokinetics of Flucytosine

Answer 16

it is absorbed well orally

it is dependent upon renal function for elimination

penetrates well into the CNS=70% of serum levels

Question 17

25% exhibit nausea, vomiting, severe diarrhea and enterocolitis

25% exhibit exlevation of hepatic enzymes

15% exhibit bone marrow depression: anemia, leukopenia, thrombocytopenia

Answer 17

flucytosine

Question 18

what are the azole

Answer 18

imidazoles and triazoles

Question 19

What are the imidazoles

Answer 19

Ketoconazole

miconazole

econazole

clotrimazole

Question 20

what are the triazoles

Answer 20

Fluconazole

itraconazole

terconazole

Question 21

what is the mechanism of action for azoles

Answer 21

all azoles have the same mechanism of inhibiting the cytP450 dependent 14-a-demethylation of sterols. This leads to decreased ergosterol synthesis and the accumulation of 14-methyl sterols in the fungal membrane

Question 22

what is the selective toxicity seen in azoles

Answer 22

The heme iron of cytochrome p450 binds the triazole or imidazole ring structure. The azole ring structure has a greater affinity for the heme iron in the fungal cytochrome p450 than the human cytochrome p450

Question 23

out of ketoconazole, fluconazole and itraconazole, which has the highest bioavailability, highes CSF/serum percentage, and most active in the urine

Answer 23

fluconazole

ketoconazole and itraconazole are distributed highest in protein binding, and have the lowest in CSF/serum concentration

Question 24

what are the adverse reactions of ketoconazoles

Answer 24

Gastrointestinal distress

Rash, pruritis,

elevated hepatic enzymes

decreased sex steroid

decreased cortisol synthesis

severe hepatotoxicity

Question 25

what are the adverse reactions of fluconazoles

Answer 25

gastrointestinal distress

rash

elevated hepatic enzymes

no effect on host steroid synthesis

Question 26

All azoles have a

Answer 26

teratogenic potential

Question 27

compare the discontinuation use of ketoconazole and fluconazole

Answer 27

only 1 to 2% patients must discontinue fluconazole becuase of adverse effects

Question 28

what drug interactions have been associated with azoles

Answer 28

they inhibit hepatic microsomal drug metabolizing enzymes to varying extents

Arrhytmias with terfenadine and astemizole

increased levels of cyclosporine

increased bleeding time with warfarin

hypoglycemia with oral hypoglycemics

increased serum levels of phenytoin

increased serumlevels of digoxin

Question 29

rifampin decreases blood levels of

Answer 29

azoles

Question 30

phenytoin decreases blood levels of

Answer 30

intraconazole

Question 31

if a patient is suffering from candidiasis, coccidioidomycosis cryptococcus chronic suppresion give them

Answer 31

fluconazoles

Question 32

if the patient is experiencing Blastomycosis, histoplasmosis, sporotrichosis, aspergillosis give them

Answer 32

itraconazole

Question 33

if the patient has pseudallescheriasis

Answer 33

ketoconazole

Question 34

when a patient has candidiasis treat them with

Answer 34

nystatin suspensions or creams becuase it is not absorbed orally

topical azoles are also good

Question 35

Fungicidal synthetic alllylamine si

Answer 35

terbinafine

Question 36

terbinafine inhibits

Answer 36

squalene eposidase leading to the acuumulation of toxic levels of squalene in the organism

Question 37

terbinafine is effective in

Answer 37

the treatment of dermatophytic infections

it is better than griseofulvin or itraconazole

Question 38

what are the adverse reactions with terbinafine

Answer 38

headache and GI symptoms (diarrhea, abdominal pain, nausea

rarely, hepatotoxicity and severe skin allergy

Question 39

Griseofulvin is only effective against

Answer 39

dermatophytes

Question 40

what is the mehanism of action of griseofulvin

Answer 40

binds to tubilin in mitotic spindles and causes the inhibition of cell division. It arrests cells in metaphase

Question 41

infections treated with griseofulvin are cleared from

Answer 41

the inner layers of the dermis first so that duration of therapy is dependent on the rate at which the structure naturally replaces itself

Question 42

adverse effects of griseofulvin are

Answer 42

headache, cns, gi disturbances, serum sickness, angioedema, cross sensitivity with penicillins

Question 43

griseofulvin is contraindicated in

Answer 43

acute intermittent porphyria

Question 44

Griseofulvin is cross sensitive with

Answer 44

penicillins