Antifungal And Antiviral Drugs

Front 1

What are the 3 major classes of antifungal drugs?

Back 1

3 major antifungal classes:

1) Polyene (nystatin, amphotericin B)

2) Azole (ketocon-, itracon-, flucon-, voriconazole)

3) Allylamine (terbinafine)

Front 2

Name the 2 polyene anti-fungal agents.

What is their mechanism of action?

Back 2

Polyene anti-fungals:

1) nystatin
2) amphotericin B

These agents bind ergosterol and form channels in the membrane that allow small molecules to leak out, leaving the fungi unable to maintain their internal environment.

Front 3

What is the difference in the clinical use of nystatin and amphotericin B?

Back 3

Nystatin is used for treatment of localized fungal infections, like thrush.

Amphotericin B is the gold standard for treating serious systemic fungal infections.

Front 4

What are the adverse reactions associated with amphotericin B?

Back 4

--hypersensitivity
--fevers, chills, headache
--decreased renal function occurs in over 80% of patients

Front 5

Name the 4 azole anti-fungal agents.

What is their mechanism of action?

Back 5

1) ketoconazole (1st generation)
2) itraconazole (2nd gen)
3) fluconazole (2nd gen)
4) voriconazole (3rd gen)

These drugs inhibit fungal lanosterol 14-demethylase, which is required for conversion of lanosterol to ergosterol. Inhibition of this enzyme leads to aberrant precursors to ergosterol synthesis. Ergosterol is depleted and the cytoplasmic membrane is not formed.

Front 6

Describe the azole drugs' spectrum of antifungal activity.

Back 6

Azole drugs have a broad anti-fungal spectrum. They are active against..

--Blastomyces
--Candida
--Cryptococcus
--Coccidioides
--Hisplasma
--Sporothrix

Front 7

Identify the azole drug described by these pharmacokinetic and pharmacodynamic descriptions..

1) widely distributed into body tissues and fluids with high concentrations found in the urine and skin after oral administration

2) requires low gastric pH for absorption

3) distributes extensively into lipophlic tissues but aqeous tissues contain negligible amounts

4) distributes well into the CSF and eliminated primarily by the kidneys

5) accumulates in stratum corneus and can be detected in the nail for up to 9 months

6) has the greatest ability of the azoles to inhibit mammalian P450s

7) least likely of the azoles to cause drug interactions due to P450 inhibition

8) the only P450 this drug inhibits is CYP3A4

9) may cause gynecomastia, menstrual irregularities due to inhibition of steroidal and gonadal P450s

Back 7

1) widely distributed into body tissues and fluids with high concentrations found in the urine and skin after oral administration = FLUCONAZOLE

2) requires low gastric pH for absorption = KETOCONAZOLE

3) distributes extensively into lipophlic tissues but aqeous tissues contain negligible amounts = ITRACONAZOLE

4) distributes well into the CSF and eliminated primarily by the kidneys = FLUCONAZOLE

5) accumulates in stratum corneus and can be detected in the nail for up to 9 months = ITRACONAZOLE

6) has the greatest ability of the azoles to inhibit mammalian P450s = KETOCONAZOLE

7) least likely of the azoles to cause drug interactions due to P450 inhibition = FLUCONAZOLE

8) the only P450 this drug inhibits is CYP3A4 = ITRACONAZOLE

9) may cause gynecomastia, menstrual irregularities due to inhibition of steroidal and gonadal P450s = KETOCONAZOLE

Front 8

This anti-fungal treats invasive fungal infections, including aspergillosis in children who are intolerant of conventional antifungal therapy.

a) ketoconazole
b) itraconazole
c) flucoconazole
d) voriconazole

Back 8

This anti-fungal treats invasive fungal infections, including aspergillosis in children who are intolerant of conventional antifungal therapy.

d) voriconazole

Front 9

When combined with itraconazole, this antifungal produces synergistic activity against Aspergillus infections.

Back 9

When combined with itraconazole, the antifungal TERBINAFINE produces synergistic activity against Aspergillus infections.

Front 10

What is the mechanism of action of terbinafine?

What are its clinical uses?

Back 10

Terbinafine prevents squalene epoxidation, which is an early step in the synthesis of ergosterol.

Terbinafine is active against:
--dermatophytes
--molds
--dimorphic fungi
--Cryptococcus
--some Candida
--some Aspergillus

Front 11

This antifungal is approved for treatment of invasive aspergillosis that is azole-resistant and doesn't respond to any other antifungals.

a) amphotericin B
b) terbinafine
c) caspofungin

Back 11

This antifungal is approved for treatment of invasive aspergillosis that is azole-resistant and doesn't respond to any other antifungals.

c) caspofungin

Front 12

Describe the pharmacokinetics of amphotericin B.

--absorption
--half life
--excretion

Back 12

Amphotericin B

1) not well absorbed so given IV
2) slowly excreted in the urine
3) half-life of 15 days

Front 13

Describe the mechanism of action of flucytosine.

Back 13

Flucytosine is converted in the fungal cytoplasm by cytosine deaminase to 5-fluorouracil. 5-FU causes RNA miscoding and inhibits DNA synthesis.

Front 14

What are the adverse reactions associated with flucytosine?

Back 14

Flucytosine may cause.

1) lethal bone marrow depression due to flucytosine conversion to 5-FU

2) GI upset

3) rash

4) hepatic dysfunction

Front 15

Synergistic effects are produced when either terbinafine or flucytosine are combined with this antifungal...

a) ketoconazole
b) nystatin
c) amphotericin B
d) caspofungin

Back 15

Synergistic effects are produced when either terbinafine or flucytosine are combined with this antifungal...

c) amphotericin B

Front 16

Which of the following anti-fungals does NOT inhibit ergosterol biosynthesis as part of its mechanism of action:

a) itraconazole
b) flucytosine
c) amphotericin B
d) terbinafine

Back 16

Which of the following anti-fungals does NOT inhibit ergosterol biosynthesis as part of its mechanism of action:

b) flucytosine

Flucytosine is converted by the fungal enzyme cytosine deaminase to 5-FU, which causes RNA miscoding and inhibits DNA synthesis.

Front 17

Which 2 anti-viral agents are used as prophylaxis against influenza A?

Which 2 anti-viral agents as used as prophylaxis against both influenza A and B?

Back 17

Influenza A prophylaxis: amantadine, rimantadine

Influenza A and B prophylaxis: oseltamivir, zanamivir

Front 18

Describe the mechanism of action of amantadine and rimantadine.

What is the clinical use of these agents?

Back 18

Amantadine and rimantadine block the action of the M2 ion channel found in influenza A viruses. This channel is required for nucelocapsid release after viral fusion with the endosomal membrane. Inhibition of this channel, then, blocks viral uncoating and disassembly of the virion during endocytosis.

These agents are used for prophylaxis during influenza A epidemics.

Front 19

Describe the mechanism of action of oseltamivir and zanamivir.

What is the clinical use of these agents?

How are these agents administered?

Back 19

Neuraminidase is an influenza virus enzyme that usually removes sialic acid from the surface of viral particles. This prevents the viral particles from clumping, allowing them to be infectious.

Oseltamivir and zanamivir inhibit the neuraminidase enzyme, leading to viral clumping and making the viral particles noninfectious.

These agents are used as prophylaxis against both influenza A and B.

Zanamivir is administered via inhalation and oseltamivir is taken orally.

Front 20

Describe the mechanism of action of ribavirin.

What is the clinical use of this agent?

Back 20

Ribavirin is a guanosine analg that is phosphorylated by intracellular enzymes to form a triphosphate. This triphosphate inhibits viral RNA polymerase and competitively inhibits the guanosine triphosphoate-dependent 5'-capping of the influenza viral mRNA.

Ribavirin has activity against influenza, RSV and adenoviruses.
Also, ribavirin + INF-alpha is used to treat hepatitis C.

Front 21

Describe the mechanism of action of the synthetic nucleoside anti-virals such as acyclovir.

Back 21

Acyclovir is a purine nucleoside analog and must be metabolically activated to a triphosphate.

The initial phosphorylation is carried out by viral thymidine kinase. The 2nd and 3rd phosphorylations are carried out by mammalian enzymes.

Once a triphosphate, it can inhibit viral DNA polymerase or it can be incorporated into viral DNA to cause premature chain termination. This termination occurs due to the lack of 3'-OH group on the triphosphate.

Front 22

Viruses that do not have thymidine kinase..

a) are killed more effectively by acyclovir
b) are unaffected by acyclovir
c) are equally as affected by acyclovir as those viruses with thymidine kinase

Back 22

Viruses that do not have thymidine kinase..

b) are unaffected by acyclovir

Acyclovir requires activation by the viral enzyme thymidine kinase. Without the enzyme, the drug cannot be activated and the virus will be unaffected.

Front 23

How does famciclovir differ from acyclovir in terms of (a) spectrum and (b) mechanism of action.

Back 23

Acyclovir treats serious HSV and VZV infections. It also has some activity against CMV. Acyclovir requires the viral enzyme thymidine kinase and works by either bindng DNA polymerase and slowing replication or by incorporating itself into viral DNA and causing chain termination.

Famciclovir has activity against HSV, VZV and EBV. It does not need to be activated by viral enzymes, as it is converted to an active moiety (penciclovir). And it does not cause chain termination.

Front 24

Identify the antiviral drug described by the following:

1) treats resistant CMV retinitis and acyclovir-resistant HSV

2) when combined with INF-alpha, treats hepatitis C

3) found in high concentrations within CMV cells and acts to slow DNA chain extension

4) neuramindiase inhibitor that is administered by inhalation

5) has activity against EBV and HSV and does not require viral enzyme activation

6) usually given IV for treatment of serious HSV and VZV infections

7) applied locally to treat HSV keratoconjunctivitis

8) used as prophylaxis against influenza A

9) treats CMV retinitis and esophagitis and can prevent CMV disease in transplant patients

10) acylovir ester that is given orally

Back 24

1) treats resistant CMV retinitis and acyclovir-resistant HSV = FOSCARNET

2) when combined with INF-alpha, treats hepatitis C = RIBAVIRIN

3) found in high concentrations within CMV cells and acts to slow DNA chain extension = GANCICLOVIR

4) neuramindiase inhibitor that is administered by inhalation = ZANAMIVIR

5) has activity against EBV and HSV and does not require viral enzyme activation = FAMCICLOVIR

6) usually given IV for treatment of serious HSV and VZV infections = ACYCLOVIR

7) applied locally to treat HSV keratoconjunctivitis = TRIFLURIDINE

8) used as prophylaxis against influenza A = AMANTADINE, RAMANTADINE

9) treats CMV retinitis and esophagitis and can prevent CMV disease in transplant patients = GANCICLOVIR

10) acylovir ester that is given orally = VALACYCLOVIR

Front 25

How does ganciclovir differ from acyclovir in terms of treating CMV infections?

Back 25

In HSV or VZV-infected cells, ganciclovir is activated the same way as acyclovir - via a viral thymidine kinase.

In CMV cells, however, ganciclovir mono-phosphorylation is carried out by a protein kinase encoded by the UL97 gene. While acyclovir triphosphate is a more potent inhibitor of CMV, acyclovir is a poor substrate for the UL97 gene product.

Ganciclovir triphosphate concentration in CMV infected cells is 10x higher than that of acyclovir triphosphate.

Ganciclovir also differs from acyclovir in that it is not a chain terminator. It incorporates into viral DNA and slows DNA chain extension.

Front 26

Identify the antiviral drug associated with the following adverse effects:

1) may cause granulocytopenia and thrombocytopenia

2) crystalline nephropathy after IV administration

3) bronchospasm may occur after this prophylactic agent is administered by inhalation

4) prophylactic agent may cause confusion, hallucinations, and seizures

5) prophylactic agent that may cause delirium in children after oral administration

Back 26

1) may cause granulocytopenia and thrombocytopenia = GANCICLOVIR

2) crystalline nephropathy after IV administration = ACYCLOVIR

3) bronchospasm may occur after this prophylactic agent is administered by inhalation = ZANAMIVIR

4) prophylactic agent may cause confusion, hallucinations, and seizures = AMANTADINE

5) prophylactic agent that may cause delirium in children after oral administration = OSELTAMIVIR

Front 27

This non-nucleoside antiviral binds to viral DNA or RNA polyermase and inhibits the enzyme.

a) foscarnet
b) acyclovir
c) abacivir

Back 27

This non-nucleoside antiviral binds to viral DNA or RNA polyermase and inhibits the enzyme.

a) foscarnet

Front 28

What are the 6 classes of drugs used to treat HIV?

Which of these 6 are most important?

Back 28

1) nRTI's**
2) nnRTI's**
3) protease inhibitors**
4) fusion inhibitors
5) entry inhibitors
6) integrase inhibitors

The 3 groups with ** are the most important

Front 29

HAART is the current paradigm for the treatment of HIV.

HAART is based on 3 key observations... What are they?

Back 29

Highly Active AntiRetroviral Therapy

HAART is based on several observations:
1) HIV rapdily becomes resistant when a single drug is employed
2) survivorship is inversely related to the circulating level of HIV RNA in the blood
3) survivorship is positively correlated with CD4 count

Front 30

The mechanism of action of the nRTI's in the treatment of HIV is identical to that of..

a) ribavirin's mechanism of action against hepatitis C
b) nnRTI's mechanism of action against HIV
c) acyclovir mechanism of action against HSV

There is one key difference though.. What is it?

Back 30

The mechanism of action of the nRTI's in the treatment of HIV is identical to that of..

c) acyclovir's mechanism of action against HSV

The key difference between the 2 mechanims is that the nRTI's target HIV's reverse transcriptase enzyme rather than a viral DNA polymerase.

Front 31

What are the adverse effects associated with the nRTI's?

Back 31

nRTI adverse effects:

--lactic acidosis
--hepatic steatosis
--peripheral neuropathy
--myopathy
--lipoatrophy

*these adverse effects might be due to the fact that these drugs inhibit mitochondrial DNA polymerase-gamma and cause mitochondrial dysfunction

Front 32

Describe the mechanism of action of the nnRTI's.

How do nnRTI's differ from nRTI's?

Back 32

The parent compounds of nnRTI's are active and no intracellular metabolism is necessary.

nnRTI's allosterically bind in a noncompetitive fashion to a hydrophobic pocket near the active site of the reverse transcirptase and "lock" the enzyme into an inactive state.

nnRTI's differ from nRTI's in that they don't require intracellular metabolism and that they are active against HIV-1 except for subtype O and are inactive against HIV-2 strains.

Front 33

List the nRTI agents used to treat HIV.

Back 33

nRTI agents:

1) emtricitabine
2) tenofovir
3) abacavir
4) lamivudine
5) didanosine
6) zidovudine

Front 34

List the nnRTI agents used to treat HIV.

Back 34

nnRTI agents..

1) efavirenz
2) nevirapine

Front 35

What are the adverse effects associated with the nnRTI's?

Back 35

nnRTI adverse effects...

--may cause a severe rash
--they are metabolized by P450 enzymes so drug interactions can occur with protease inhibitors and many other drugs

Front 36

List the protease inhibitors used to treat HIV.

What is their mechanism of action?

Back 36

Protease inhibitors:

1) atazanavir
2) fosamprenavir
3) darunavir
4) lopinavir
5) saquinavir

Mature HIV virions are produced when the virus buds off the cell surface and gag and gag-pol precursors are cleaved by a viral protease. This process is essential for maturation of the virus. The PI's bind the active site of the protease enzyme and inhibit both HIV-1 and HIV-2.

Front 37

What are the adverse effects of the protease inhibitors?

Back 37

Protease inhibitor adverse effects..

--Gi intolerance
--increased bleeding in hemophiliacs
--hyperglycemia
--fat wasting and redistribution (buffalo hump)
--lipodystrophy
--hyperlipidemia

Front 38

What is the mechanism of action of the HIV fusion inhibitor, enfuvirtide?

Back 38

Enfuvirtide is a fusion inhibitor and prevents the HIV envelope from fusing the cell membrane of CD4 cells, thereby blocking viral entry and replication.

Enfuvirtide binds to gp41 on the virus and prevents conformational change required to permit fusion of HIV with the cell membrane

Front 39

What is the mechanism of action of the HIV entry inhibitor, maraviroc?

Back 39

Maraviroc binds to the CCR5 receptor on CD4+ cells. This receptor usually acts as a coreceptor for HIV and maraviroc's blocking of CCR5 prevents HIV's entry into the cell.

Front 40

This HIV drug inhibits integrase and prevents the insertion of HIV DNA into the human genome.

a) maraviroc
b) raltegravir
c) enfuvirtide
d) atazanavir

Back 40

This HIV drug inhibits integrase and prevents the insertion of HIV DNA into the human genome.

b) raltegravir

Front 41

TRUE or FALSE

HIV isolates resistant to nRTIs and protease inhibitors are also resistant to nnRTI's.

Back 41

FALSE

This is the true statement:
HIV isolates resistant to nRTIs and protease inhibitors REMAIN SENSITIVE to nnRTI, but cross-resistance is common within the nnRTI class.

Front 42

Each of the following describes the mechanism of action of a class of drugs used to treat HIV. Identify the class based on the descriptions (nRTI, protease inhibitor, etc).

1) active parent drug that binds in a noncompetitive fashion near the active site of the reverse transcriptase, rendering it inactive

2) binds to CCR5 on CD4+ cells

3) binds to gp41 on HIV and prevents an essential conformational change

4) intracellularly phosphorylated to triphosphate forms and compete with normal triphosphates for HIV reverse transcriptase

5) binds to active site of an HIV enzyme that functions in the cleavage gag and gag-pol precursors

6) prevents HIV from inserting into the human genome

7) may become incorporated into growing proviral DNA chains, leading to chain termination

Back 42

1) active parent drug that binds in a noncompetitive fashion near the active site of the reverse transcriptase, rendering it inactive = nnRTI

2) binds to CCR5 on CD4+ cells = ENTRY INHIBITOR (maraviroc)

3) binds to gp41 on HIV and prevents an essential conformational change = FUSION INHIBITOR (enfuvirtide)

4) intracellularly phosphorylated to triphosphate forms and compete with normal triphosphates for HIV reverse transcriptase = nRTI

5) binds to active site of an HIV enzyme that functions in the cleavage gag and gag-pol precursors = PROTEASE INHIBITOR

6) prevents HIV from inserting into the human genome = INTEGRASE INHIBITOR (raltegravir)

7) may become incorporated into growing proviral DNA chains, leading to chain termination = nRTI

Front 43

HIV that uses CXCR4 as the coreceptor will be resistant to this drug:

a) raltegravir
b) atazanavir
c) maraviroc
d) abacavir

Back 43

HIV that uses CXCR4 as the coreceptor will be resistant to this drug:

c) maraviroc

Front 44

What is the purpose of adding ritonavir to an HIV treatment regimen?

Back 44

Ritonavir is a protease inhibitor that is a very potent inhibitor of P450.

In regimens that consist of 2 nRTI's + a PI, ritonavir is given at subtherapeutic doses to block the metabolism of the protease inhibitor.

Front 45

What is the currently preferred HIV treatment regimen that consists of
2 nRTI + 1 nnRTI ?

Back 45

2 nRTI's + 1 nnRTI

Tenofovir + emtricitabine (both nRTI's) + efavirenz (nnRTI)

Front 46

What other agent should be added to the following HIV treatment regimen?

Regimen: Tenofovir + emtricitabine + atazanavir

a) ribavirin
b) ritonavir
c) ramantadine

Back 46

What other agent should be added to the following HIV treatment regimen?

Regimen: Tenofovir + emtricitabine + atazanavir

Answer: b) ritonavir

Ritonavir blocks the metabolism of the protease inhibitor, atazanavir. The other 2 agents in the regimen are nRTI's.