Antiviral Drugs-Walker

Front 1

Nucleic Acids (DNA AND RNA)
What is a nucleoside?
a nucleotide?

Back 1

Nucleoside=sugar + base
Nucleotide+nucleoside + phosphate

Front 2

What are the Purines?

Back 2

Adenine and Guanine (in both RNA AND DNA)

*PURE AS GOLD

Front 3

What are the pyrimidines?

Back 3

Cytosine-both DNA and RNA
Thymine-only DNA (Uracil-RNA)

Front 4

Many antiviral drugs are prodrugs. what are these?

Back 4

prodrugs-inactive analogues of nucleosides. The host/viral kinases phosphorylate the drug into active form.

*Integration of nucleotides into viral or host DNA-inhibits further nucleic acid synthesis --BASIS OF ANTIVIRAL MECHANISM

Front 5

**read the first couple pages of slides

Back 5

do it

Front 6

What drugs for Ocular herpes simplex?

Back 6

TRIFLURIDINE, IDOXURIDINE, VIDARABINE, GANCICLOVIR

Front 7

Drugs for ocular and systemic herpes zoster?

Back 7

Acyclovir, Valacyclovier, Famcyclovir

Front 8

Drugs for CMV infections?

Back 8

GANCYCLOVIR, FOSCARNET, ZIDOVUDINE, FOMIVIRSEN, AND CIDOFOVIR

Front 9

Trifluotothymidine
(a prodrug of thymidine) facts

Back 9

Trifluotothymidine
(a prodrug of thymidine):
-phosphorylated by both host and viral kinases
-good corneal penetration due to biphasic solubility

Front 10

Trifluotothymidine
(a prodrug of thymidine) MOA:

Back 10

Trifluotothymidine
(a prodrug of thymidine):
*inhibits DNA synthesis by inhibiting enzyme thymidine synthetase
-incorportation into the host and viral DNA = faulty DNA

**INHIBITION OF VIRAL REPLICATION AND HOST TOXICITY

Front 11

Trifluotothymidine
(a prodrug of thymidine) clinical uses

and what is it superior too?

*and what MAY it be useful in treating what disease?

Back 11

Trifluotothymidine
(a prodrug of thymidine) clinical uses:
-limited to topical on eye because too toxic for systemic

*superior to IDU and Vidarabine (lower failure rate and shorter response time)
*may be useful in TX of Thygeson's

Front 12

Trifluotothymidine
(a prodrug of thymidine)

Back 12

1% solution 1 qtt 9x/day -14 days or less until re-epithelialization and then 1 qtt.4h 7 days while awake

**should NOT be used more than 21 days
-does NOT have a recurrence rate
*used concurrently with topical steroid to TX corneal stromal herpes to inhibit the recurrence of active epithelial disease

Front 13

Trifluotothymidine side effects:
(a prodrug of thymidine)

Back 13

Trifluotothymidine
(a prodrug of thymidine)
side effects: are reversible after stop drug!!
-corneal epithelial defects, erosions, edema
-transient burning/stinging
- keratitis sicca, delayed wound healing
-IOP elevation
-Long term use: NON-reversible conj scarring, punctal occlusion and ptosis

Front 14

Iododeoxyuridine is a prodrug analoge of?

Back 14

Iododeoxyuridine is a prodrug analogue of Thymidine

*phosphorylated by host and virus into active form

Front 15

Iododeoxyuridine MOA?

Back 15

Iododeoxyuridine is a prodrug analogue of Thymidine

*phosphorylated by host and virus into active form
*iNCOPORPORATED into host and viral DNA- creates fraudULENT DNA leading to synthesis of ALTERED host and viral proteins--so have antiviral action and host toxicity
*the toxicity limits the use to topical for ocular

Front 16

what was the the first antiviral drug synthesized?

Back 16

Iododeoxyuridine-- is a prodrug analogue of Thymidine

*phosphorylated by host and virus into active form

Front 17

Iododeoxyuridine clinical uses?

what is the primary indication?

what percent of pts cured in two weeks?
does it reduce recurrent rate?
does it penetrate cornea?

Back 17

Iododeoxyuridine clinical uses?
what is the primary indication-corneal dendritic or geographic HSV infection

**75% of patients cured in 2 weeks

**IT does NOT reduce recurrence rate or prevent latency
**it does NOT penetrate cornea (b/c of low water solubility)
**toxicity can disrupt corneal healing and mimic active dendrite

Front 18

Iododeoxyuridine doses

Back 18

Iododeoxyuridine doses:
0.1% solution 1 qtt. 1h during the day and 1 qtt q.2h at night until improvement occurs--cont 3-5 days after healing complete

Front 19

Iododeoxyuridine side effects

Back 19

Iododeoxyuridine side effects:
similar to those caused by trifluridine

Front 20

Vidarabine
is a prodrug of what?

Back 20

Vidarabine
is a prodrug of what?

Adenosine

Front 21

Vidarabine
moa?

ALSO ACTIVE AGAINST? (WHAT VIRUSES, ETC)

Back 21

Vidarabine
moa?
-phosphorylated by host and viral kinases
-once incorporated inot DNA, it inhibits DNA polymerase (takes less conc to inhibi virus than host)
*can interfere with RNA synthesis


-also active against vaccinia, CMV, AND VZV

Front 22

Vidarabine CLINICAL USES?

Back 22

Vidarabine
-dendritic and geographic keratitis
-can be used systemically for HSV ecephalitis

-dendritic and geographic keratitis (3% ointment for max of 21 days--re-epithelialization occurs in 6-7 days)
-can be used systemically for HSV ecephalitis

Front 23

Vidarabine side effects?

Back 23

Vidarabine side effcts
similar to those caused by IDU and Viroptic
**overall less toxic than IDU

Front 24

Ganciclovir is what analogue?

Back 24

Ganciclovir is what analogue?
a quanine nucleoside analogue (similar to acyclovir structure but better for CMV)

**this drug can be converted to monophophate by several kinases (infection-induced kinases, viral-thymidine kinases, herpes deoxyquanosine kinases)

Front 25

Ganciclovir MOA

Back 25

Ganciclovir is what analogue?

**this drug can be converted to monophophate by several kinases (infection-induced kinases, viral-thymidine kinases, herpes deoxyquanosine kinases)

*host enzymes or viral kinase enzymes convert the monophosphate into the active triphosphate form
*this active triphosphate form inhibits viral DNA polymerase but NOTTTT the host polymerase!

(the active form also incorporates into viral and host DNA--causing antiviral activity and host toxicity)

Front 26

Ganciclovir clinical uses

Back 26

Ganciclovir clinical uses:
-acute herpes simplex keratitis (2+ years old)
(one drop 5x/day until ucler heals and then tid seven more days)

Front 27

Ganciclovir adverse rxns

Back 27

Ganciclovir rxns:
bluured vision, ocular irritation, punctate keratitis, and conj hyperemia

**topical form is quite safe and lacks the significant systemic effects associated with oral and IV forms

Front 28

Acyclovir is a what analogue prodrug?

and is active against what?

Back 28

Acyclovir is a what guanasine analogue prodrug

and is active against what? HSV AND VZV

Front 29

Acyclovir moa

Back 29

Acyclovier moa:

*has selective toxicity against virus and very little to host (good!) because more active monophosphorylation of drug by HERPES-SPECIFIED THYMIDINE KINASE compared to host cell kinases

*mono form metabolized into active form-triphosphate form (by the host cell enzymes) and active form cannot pass through cell membrane
-therefore, the active form is primarily produced in the viral infected cells (50-100x more than in normal cells)
**the active form affects viral DNA polymerase much more than host's, and can cause permanent termination of DNA chain elongation
**so good because affects virus without much host cell toxicity

*does not prevent recurrence or latency

(some herpes viruses that have altered DNA are resistant to acyclovir--but not to some other drugs)

Front 30

Acyclovir clinical uses:

Back 30

Acyclovir clinical uses:
1. Genital HSV (oral, IV, and ointment)
2.corneal epithelial herpes (ointment)
3. Prevent corneal epithelial recurrence (with steroid)
4. H. zoster Ophthalmicus and systemic zoster and corneal herpes simplex infection (oral)
5. VZV Keratouveitis (Topical)
6. Retinal necrosis syndrome (IV)

Front 31

Acyclovir SIDE EFFECTS
oral?
IV?
Topical?

Back 31

Acyclovir SIDE EFFECTS:
WITH ORAL:
-vomiting, diarrhea, headache, vertigo, arhralgia (and less commonly can also get skin rash, insomnia, fatigue, fever, menstrual abnormality, sore throat, acne, and lymphadenopathy)

With IV administration:
phlebitis, rash/hives, transient elevation of BUN, and creatine, renal abnormalities

Topical:
mild pain, burning, stinging, or pruritis

Front 32

Valacyclovir and Famcyclovir are what kind of drugs?

Back 32

Valacyclovir and Famcyclovir are what kind of drugs?

Orally administered prodrugs

Front 33

Valacyclovir (Valtrex) is hydrolized to what?

and Famcyclovir (Famvir) metabolized to what?

Back 33

Valacyclovir (Valtrex) is hydrolized to what? Acyclovir in liver and intestine

and Famcyclovir (Famvir) metabolized to what? Penciclovir

Front 34

Valacyclovir (Valtrex) and Famcyclovir (Famvir) are better than acyclovir why?

and what are they used to TX?

Back 34

Valacyclovir (Valtrex) and Famcyclovir (Famvir) are better than acyclovir why?

*both need a lower dose because of improved pharmakokinetics and dynamics
**both have GREATER BIOAVAILABILITY than acyclovir

**they both have same uses as acyclovir--tx of HSV and VZV infections

Front 35

GANCICLOVIR IS WHAT KIND OF PRODRUG?

Back 35

GANCICLOVIR IS WHAT KIND OF PRODRUG?
Guanine nucleoside analog prodrug
(similar to aciclovir but better CMV activity)

Front 36

GANCICLOVIR METABOLISM AND ACTIVE ANTIVIRAL FORM IS SIMILAR TO WHAT DRUG?

Back 36

ganciclovir similar to:
Zirgan

**also note that Ganciclovir is 10-25x more active against CMV than Aciclovir but more toxic to host cells

Front 37

Ganciclovir (zirgan) moa?

major toxicity with?

Back 37

Ganciclovir moa?
*active form incorporated into viral and host DNA

**major toxicity: done marrow suprresion

(RECALL METABOLISM similar to Zirgan)

Front 38

Ganciclovir uses?

administrated how?

Back 38

1. active against herpes family (except some forms like oral and IV not used for all because of bone marrow suppression/toxicity)
2. CMV retinitis in AIDS pats (1st drug approved for)
3.also approved for CMV retinitis in immunosuppressed (tx reults in regression of the retinitis, but the viral inibition is reversible high level of recurrence)

**IV therapy followed by oral (or intravitreal if not tolerant of other routes)

Front 39

CMV retinitis in AIDS pts-- 1st drug approved for?

Back 39

ganciclovir (zirgan)

Front 40

Foscarnet is a ___analog

Back 40

Foscarnet is a ___analog: pyropphosphate analog
**NOT a prodrug!!

Front 41

Foscarnet (Foscavir) moa?

Back 41

Foscarnet moa?
It inhibits DNA polymerase of all herpes family and reverse transcriptase of HIV at a concentration that does not affect the host DNA polymerase
(**affects the binding site of DNA polymerase)

Front 42

what drug is as effective as ganciclovir but can be used to tx CMV retinitis if ganciclovir cannot?

Back 42

Foscarnet (Foscavir)

**if administered with ganciclovir, both drugs can be administered at lower than their usual conc.

Front 43

what do you use Foscarnet (Foscavir) for?

Back 43

Foscarnet (Foscavir)
to TX AIDS pts that have herpetic infections resistant to Aciclovir

Front 44

Foscarnet (Foscavir) side effects?

which SE most important?

Back 44

Foscarnet (Foscavir)

**most important side effect is RENAL IMPAIRMENT
-other:seizures, fever, GI probs

Front 45

CIDOFOVIR (VISTIDE) is what kind of prodrug?

Back 45

CIDOFOVIR (VISTIDE) is a cytosine nucleoside analog (prodrug)

Front 46

CIDOFOVIR (VISTIDE) moa?

Back 46

CIDOFOVIR (VISTIDE)
-is phophorylated into active form by kinases
**CMV replication inhibited by selective inhibition of viral DNA synth (it inhibits the viral DNA polymerase at conc 8-600x lower than host)

Front 47

CIDOFOVIR (VISTIDE) administered?

Back 47

CIDOFOVIR (VISTIDE)
-give with IV for CMV retinitis in AIDS pts
-in VITRO against HSV1 AND HSV2, VZV, EBV, HHV6, adenovirus, and human papilloma virus

**excreted by the kidney

Front 48

CIDOFOVIR (VISTIDE) adverse effects?

major one?

Back 48

CIDOFOVIR (VISTIDE) SE's

major: Nephrotoxicity

other: neutropenia, dec IOP and ocular hypotony,"", anterior Uveitis, and metabolic acidosis

(neutropenia=low # neutrophhils)

Front 49

Fomivirsen (Vitravene) is what type of drug?
and mainly used to TX what?

Back 49

Fomivirsen (Vitravene) is an antisence agent

to TX CMV retinitis for pts resistant to ganciclovir, foscarnet, and cidovir

Front 50

How to TX CMV retinitis for pts resistant to ganciclovir, foscarnet, and cidovir?

Back 50

Fomivirsen (Vitravene)

Front 51

Fomivirsen (Vitravene) moa

Back 51

Fomivirsen (Vitravene)
-has a nucleotide sequence complementary to a sequence in CMV mRNA transcripts (of the IE2 region)
-binding of this drug in inhibits prodection of viral proteins necessary for infection

Front 52

Fomivirsen (Vitravene) admin?

does it interefere with other antiviral drugs?

Back 52

Fomivirsen (Vitravene): administered by intravitreal injections (on days 1, 15, and thereafter)

**does NOT interfere with action of other antivirals (can add to ganciclovir and foscarnet)

Front 53

GANCICLOVIR (Again) 2 forms

Back 53

1. Zirgan
2. VITRASERT

(GANCICLOVIR)

Front 54

Ganciclovir (VITRASERT) (version) clinical use?

Back 54

Ganciclovir (VITRASERT) (version) clinical use?
-surgical intravitreal insertion fot TX of CMV retinitis in AIDS pts

**drug not a cure but helps control the disease

Front 55

Ganciclovir (VITRASERT) (version) complications?

Back 55

Ganciclovir (VITRASERT) (version) complications?
*can be severe and include (but not limited to)
-intraocular hemorhrage
-cataracts
-elevated IOP and permanent vision loss