HSV

Question 1

Acyclovir activation

Answer 1

PRODRUG
Structure: acyclic guanosine lacking 3’OH

Acyclovir–>viral thymidine kinase–>acyclovir-MP–>cellular GMP kinase–>acyclovir-DP–>cellular kinase–>acyclovir-TP (active form)

With viral thymidine kinase located in virus, allows it to selectively accumulate in infected cells after phosphorylation (trapped)

Question 2

Acyclovir MOA

Answer 2

Acyclovir-TP competitively inhibits viral DNA polymerase by competing with endogenous dGTP to inhibit viral replication

Acyclovir-TP is incorporated into the DNA acting as an immediate chain-terminator with lack of 3’OH

Question 3

Acyclovir spectrum

Answer 3

HSV-1, HSV-2, VZV

Question 4

Acyclovir PK

Answer 4

Oral bioavailability is 10-20%
Not affected by food

Renally eliminated by glomerular filtration and tubular secretion
- renally dose adjusted
- removed by HD (10%/hr)

Dose adjust in obesity (adj BW)

Question 5

Acyclovir Side effects

Answer 5

Nephrotoxicity–>IV
- reversible increase in BUN and SCr
- Add fluids when administering

Neurotoxicity–>reversible
Thrombophlebitis–>IV
Headache–>oral only

Question 6

Acyclovir Resistance

Answer 6

Mutation in viral thymidine kinase (most common)

Mutation in viral DNA polymerase

Question 7

Valacyclovir activation

Answer 7

PRODRUG
Structure: L-valyl ester of acyclovir

Valacyclovir–>dipeptide transporter–>intestinal + hepatic esterase–>acyclovir–>acyclovir-TP

Question 8

Valacyclovir MOA

Answer 8

Acyclovir-TP competitively inhibits viral DNA polymerase by competing with endogenous dGTP to inhibit viral replication

Acyclovir-TP is incorporated into DNA acting as an immediate chain-terminator with lack of 3’OH

Question 9

Valacyclovir PK

Answer 9

Oral bioavailability is 50%
Not affected by food

Renally eliminated by glomerular filtration and tubular secretion
- renally dose adjusted
- removed by HD

Question 10

Famciclovir Activation

Answer 10

PRODRUG
1st pass metabolism

Famciclovir–>esterase (removes 1 ester)–>intermediate–>esterase (removes 1 ester–>intermediate–>oxidase (adds carbonyl)–>penciclovir–>viral and cellular kinase–>penciclovir-TP

Question 11

Famciclovir MOA

Answer 11

Penciclovir-TP competitively inhibits viral DNA polymerase by competing with endogenous dGTP to inhibit viral replication

Penciclovir-TP does NOT cause immediate chain termination–>allows for short chain elongation due to 3’OH

Question 12

Famciclovir spectrum

Answer 12

Acute herpes zoster
Primary and recurrent HSV-2

Question 13

Penciclovir spectrum

Answer 13

Recurrent herpes labialis

Question 14

Famciclovir PK

Answer 14

Oral bioavailability as famciclovir is 70%
Linear kinetics: concentration increases proportional to drug given

Renally excreted by glomerular filtration and tubular secretion (90%)
- renally dose adjusted

Question 15

Famciclovir drug interaction

Answer 15

Probenecid–>decreases renal clearance

Question 16

Famciclovir cross-resistance

Answer 16

Viral kinase mutation confer cross-resistance to penciclovir and acyclovir

Question 17

Ganciclovir

Answer 17

PRODRUG

Question 18

Ganciclovir MOA

Answer 18

Ganciclovir-TP competitively inhibits viral DNA polymerase by competing with endogenous dGTP to inhibit viral replication

Ganciclovir-TP does NOT cause immediate chain termination–>allows for short chain elongation due to 3’OH

Question 19

Ganciclovir spectrum

Answer 19

CMV retinitis–>IV,IO,PO
CMV prophylaxis–>PO

Question 20

Ganciclovir PK

Answer 20

Oral bioavailability is 6-9%
- take with food to increase absorption

T1/2=12-24 hours

Renally eliminated by glomerular filtration and tubular secretion (90%)
- renally dose adjusted
- HD removes 50%

Question 21

Ganciclovir side effects

Answer 21

Bone marrow suppression
-reversible
-neutropenia (40%), thrombocytopenia (20%)
- monitor CBC: stop if ANC < 500/mm3 or platelet < 25,000/mm3

Phlebitis

Question 22

Ganciclovir resistance

Answer 22

Mutations in CMV kinase (UL97 gene)
- No cross-resistance with cidofovir or foscarnet

Mutations in CMV DNA polymerase (UL54)
- Cross-resistance with cidofovir or foscarnet

Question 23

Valganciclovir

Answer 23

PRODRUG
Structure: monovalyl ester of ganciclovir

Rapidly converted to ganciclovir by intestinal and hepatic esterases

Question 24

Valganciclovir MOA

Answer 24

Ganciclovir-TP competitively inhibits viral DNA polymerase by competing with endogenous dGTP to inhibit viral replication

Ganciclovir-TP does NOT cause immediate chain termination–>allows for short chain elongation due to 3’OH

Question 25

Valganciclovir spectrum

Answer 25

CMV retinitis (AIDS patients)

Question 26

Valganciclovir PK

Answer 26

Oral bioavailability is 60% - take with food to increase AUC by 30% Renally eliminated by glomerular filtration and tubular secretion - renally dose adjusted - HD removes 50%

Question 27

Foscarnet structure

Answer 27

inorganic pyrophosphate (phosphonoformic acid)

Question 28

Foscarnet MOA

Answer 28

Carboxyl overlaps with binding site of B-phosphate and phosphonates occupy position of y-phosphate-->blocks pyrophosphate binding site of viral DNA polymerase-->inhibits cleavage of pyrophosphate from dNTPs-->traps polymerase in closed formation DOES NOT REQUIRE PHOSPHORYLATION

Question 29

Foscarnet spectrum

Answer 29

Last line for CMV retinitis - dose adjusted based on renal function - synergy with ganciclovir for CMV

Question 30

Foscarnet PK

Answer 30

Poor oral bioavailability-->IV only - up to 30% may be deposited into bone due to phosphate Moderate CNS concentration (13-68%) Renally eliminated unchanged via glomerular filtration - renally dose adjusted - HD removes 50%

Question 31

Foscarnet SE

Answer 31

Nephrotoxicity-->dose limiting Hydrate with 0.75-1 L of NS or D5W prior to first infusion - hydrate 0.75-1 L for 90-120 mg/kg after - hydrate 0.5 L for 40-60 mg/kg after Hypocalcemia Hypokalemia Hypomagnesemia Hypo/hyperphosphatemia Headaches

Question 32

Foscarnet drug interactions

Answer 32

nephrotoxic drugs, pentamidine

Question 33

Foscarnet resistance

Answer 33

Mutation in viral DNA polymerase Mutation in HIV RT Cross-resistance in ganciclovir for CMV isolates

Question 34

Cidofivir activation

Answer 34

acyclic nucleoside phosphonate analog of cytosine phosphonate cannot be cleaved by cellular esterases-->stable Cidofivir-MP (native form)-->cellular kinase-->cidofivir-DP-->cellular kinase-->cidofivir-TP (active

Question 35

Cidofivir MOA

Answer 35

Cidofivir-TP competitively inhibits viral DNA polymerase by competing with endogenous dGTP to inhibit viral replication Cidofivir-TP is incorporated into DNA acting as a chain-terminator - requires two consecutive incorporations Poor substrate for cellular (human) DNA polymerase but higher selective for viral DNA polymerase

Question 36

Cidofivir spectrum

Answer 36

HSV-1, HSV-2, VZV, CMV CMV retinitis (IV)

Question 37

Cidofivir PK

Answer 37

Long intracellular t1/2 life=17-65 h Phosphocholine metabolite can serve as intracellular reservoir of 87 hours

Question 38

Cidofivir side effects

Answer 38

nephrotoxicity-->dose-limiting

Question 39

Penciclovir vs Acyclovir

Answer 39

Penciclovir> acyclovir for affinity to HSV thymidine kinase - levels of penciclovir-TP are higher than acyclovir-TP in infected cells Penciclovir-TP> acyclovir-TP for stability in HSV infected cells - t1/2 is much longer Acyclovir-TP>penciclovir-TP for viral DNA polymerase Net: similar efficacy