Pharmacology Lecture 35

Front 1

Obligate intracellular parasites that consist of either double or single stranded DNA or RNA enclosed in a protein coat (capsid)

Back 1

viruses

Front 2

Some viruses may have a ______ ________ that may contain antigenic glycoproteins like a capsid

Back 2

lipid envelope

Front 3

Most viruses contain these which are essential for viral replication inside the host cell-->they hijack host metabolic machinery

Back 3

viral enzymes

Front 4

Amantadine, Oseltamivir, Rimantadine, and Zanamivir are all what type of agents

Back 4

anti-influenza agents

Front 5

Adefovir, Entecavir, Interferon, Lamivudine, Telbivudine are all what type of agents

Back 5

anti-hepatitis agents

Front 6

Acyclovir, Cidofovir, Famiciclovir, Fomivirsen, Foscarnet, Ganciclovir, Penciclovir, Valacyclovir, Valganiciclovir, Vadarabine are all what type of agents

Back 6

anti-herpes virus agents

Front 7

what type of herpes includes infections of the mouth, face, skin, esophagus and brain?

Back 7

herpes simplex virus 1 (HSV-1)

Front 8

what type of herpes includes infections of the genitals, rectum, hands and meninges?

Back 8

herpes simplex virus 2 (HSV-2)

Front 9

This type of herpes virus infects 40% of adults worldwide and most show no symptoms unless immunocompromised or elderly

Back 9

cytomegalovirus (CMV)

Front 10

This type of herpes virus is the cause of chicken pox and singles

Back 10

varicella-roster virus (VZV)

Front 11

For herpes viruses, what phase of replication do antiviral Rx usually act during?

Back 11

acute phase, NOT latent phase

Front 12

This drug is the L-valyl ester of acyclovir and is rapidly converted to acyclovir following oral administration via 1st pass enzymatic hydrolysis

Back 12

Valacyclovir

Front 13

Acyclovir is the Rx of choice for ___ ___________ and is most commonly used for genital herpes

Back 13

HSV encephalitis

Front 14

This HSV Rx is a GUANOSINE analog that is converted to mono-phosphate form via viral thymidine KINASE

Back 14

acyclovir

Front 15

What two forms is acyclovir mono-phosphate converted into and by what?

Back 15

di and tri phosphates by the HOST cell

Front 16

This form of acyclovir competes with dGTP as a substrate for viral DNA polymerase and is incorporated into viral DNA causing premature DNA chain termination and also binds IRREVERSIBLY to the DNA polymerase which inactivates the enzyme

Back 16

acyclovir tri-phosphate

Front 17

Acyclovir resistance to this type of virus includes:
1. absence or partial production of viral thymidine kinase
2. altered thymidine kinase substrate specificity
3. altered viral DNA polymerase

Back 17

herpes simplex virus

Front 18

What type of herpes simplex virus is resistant to acyclovir because it lacks a specific viral thymidine kinase

Back 18

cytomegalovirus (CMV)

Front 19

MOA for this drug:
converted to a mono-phosphate form via the viral thymidine kinase and is then converted to the di- and tri- phosphate forms by the host cell. the tri-phosphate form competes with dGTP as a substrate for viral DNA polymerase and is incorporated into viral DNA causing premature DNA chain termination
*also binds irreversibly to the DNA polymerase inactivating the enzyme

Back 19

acyclovir MOA

Front 20

These two drugs for HSV are ACYCLIC guanosine nucleoside derivatives

Back 20

famciclovir and penciclovir

Front 21

famciclovir is a PRO-DRUG that is metabolized to __________

Back 21

penciclovir

Front 22

What is the route of administration for penciclovir

Back 22

topically

Front 23

what is the route of administration for famciclovir

Back 23

oral

Front 24

HSV1, HSV2, and VZV are the antiviral spectrum for these two drugs

Back 24

penciclovir and famciclovir

Front 25

MOA for this drug:
this pro-drug is metabolized to penciclovir, which is then mono-phosphorylated by viral thymidine kinase and cellular enzymes convert it to the triphosphate form which inhibits HSV DNA polymerase

Back 25

famciclovir

Front 26

This analog of acyclovir has up to 100x greater activity against CMV
*CMV has resistance to acyclovir

Back 26

ganciclovir

Front 27

MOA for this drug:
Activated through conversion to the triphosphate form by viral and host enzymes and competitively inhibits viral DNA polymerase and is incorporated into DNA, decreasing the rate of chain elongation
*much like MOA for acyclovir

Back 27

ganciclovir

Front 28

Main Rx for cytomegalovirus

Back 28

ganciclovir

Front 29

CMV is deficient in thymidine kinase and instead uses protein kinase phosphotransferase, ____

Back 29

UL97

Front 30

This drug is approved for treatment of CMV retinitis in AIDS patients

Back 30

cidofovir

Front 31

This drug for CMV is a nucleotide analog of CYTOSINE and its phosphorylation is NOT dependent upon viral enzymes

Back 31

cidofovir

Front 32

This Rx for CMV has a significant risk for RENAL toxicity and can be administered by IV, intravitreal and topical formulations

Back 32

cidofovir

Front 33

This Rx for CMV is an ANTISENSE OLIGONUCLEOTIDE directed against CMV mRNA

Back 33

fomivirsen

Front 34

MOA for this drug:
complementary to the mRNA sequence for major immediate-early transcriptional region of CMV and inhibits CMV replication by having the virus bind to the cells

Back 34

fomivirsen

Front 35

This drug is ACTIVE against CMV strains resistant to ganciclovir, cidofovir and foscarnet

Back 35

fomivirsen

Front 36

This Rx for CMV is administered through IV only, and can be used in those who have failed or cannot tolerate other Rx for CMV retinitis
*adverse events: iritis, vitritis, changes in vision

Back 36

fomivirsen

Front 37

Classification of this type of virus infections:
core proteins (A, B or C), species of origin (avian, swine) and geographic site of isolation

Back 37

respiratory influenza strainsq

Front 38

What type of influenza is the only form that causes pandemics?

Back 38

influenza A

Front 39

What are the three main classes of Rx for respiratory virus infections based on their MOA

Back 39

1. Inhibitors of viral un-coating
2. Inhibitors of neuraminidase
3. Inhibitors of RNA capping and function

Front 40

These two INFLUENZA A (only) drugs are tricyclic amines

Back 40

amantadine and rimantadine

Front 41

___________ is α-methyl derivative of amantadine

Back 41

rimantadine

Front 42

Adverse events for these influenza Rx include CNS-related ranging from insomnia → seizures; also embryotoxic and teratogenic in rodents

Back 42

amantadine and rimantadine

Front 43

These two Rx for influenza A are 70-90% effective in preventing infection if Rx is begun at time of, or prior to, exposure to the virus

Back 43

amantadine and rimantadine

Front 44

MOA for these two influenza drugs:
inhibit VIRAL UN-COATING by blacking M2 (a viral membrane matrix protein that functions as a proton ion channel-required for fusion of viral membrane with cell membrane creating the endosome)

Back 44

amantadine and rimantadine

Front 45

The acidic environment of the endosome, formed by the fusion of the viral membrane with the cell membrane, is required for what

Back 45

viral uncoating

Front 46

By inhibiting the uncoating of the viral RNA within infected host cells, Amantadine and Rimantadine (influenza Rxs) prevent

Back 46

viral replication

Front 47

Resistance to amantadine and rimantadine influenza A Rxs develop rapidly in what percentage of patients

Back 47

50%

Front 48

MOA for resistance to amantadine and rimantadine:
______ ________ substitution in M2

Back 48

amino acid substitution

Front 49

These two influenza Rxs work for influenza A and B and are SIALIC ACID analogs

Back 49

oselamivir and zanamivir

Front 50

This influenza Rx is orally delivered pro-drug that is activated via hepatic esterases

Back 50

oseltamivir

Front 51

This influenza Rx is delivered directly to the respiratory tract via inhalation with 10-20% of the dose delivered to the lung

Back 51

zanamivir

Front 52

These two influenza Rxs are NEURAMINIDASE INHIBITORS for their MOA

Back 52

oseltamivir and zanamivir

Front 53

These two influenza drugs competitively and REVERSIBLY interact with the active enzyme site to inhibit its activity causing the viron aggregation at the internal surface of infected cells and decreasing the spread of virus within the respiratory tract

Back 53

oseltamivir and zanamivir

Front 54

This influenza virus enzyme is found on the surface of the virus and cleaves SIALIC ACID residues on glycoproteins required for virus replication...the virus attaches to cell surface via hemagglutinin/sialic acid binding during replication

Back 54

neuraminidase enzyme

Front 55

Cleavage via this enzyme is essential for release of the virus from infected cells in influenza virus

Back 55

neuraminidase enzyme

Front 56

Resistance to these two influenza Rxs is associated with mutations in hemagglutinin and or neuraminidase genes

Back 56

oseltamivir and zanamivir

Front 57

This is an Rx for viral respiratory infections and hepatitis
*BROAD SPECTRUM FOR DNA AND RNA VIRUSES

Back 57

Ribavirin

Front 58

This Rx uses oral admin for hepatitis C virus in combo with interferon and in aerosolized formulation via nebulizer to children and infants with sever RSV bronchiolitis of pneumonia

Back 58

ribavirin

Front 59

What is the active form of ribavirin?

Back 59

5’ ribavirin-triphosphate

Front 60

What type of anti-virus has viral activities of active drugs that include:
1. Inhibits guanosine triphosphate formation
2. Prevents mRNA capping
3. Blocks RNA-dependent RNA polymerase

Back 60

anti-influenza virus

Front 61

What are the types of hepatitis viruses?

Back 61

A, B, C and E

Front 62

Hepatitis _ and _ are the most common causes of chronic hepatitis, cirrhosis and hepatocellular carcinoma

Back 62

hep B and C

Front 63

What type of transmission do HBV and HCV have?

Back 63

blood-borne transmission
*sharing dirty needles, blood transfusion and sexual contact

Front 64

Current therapies for hep B and C are ________ rather than curative

Back 64

suppressive

Front 65

This Rx for hepatitis are host cytokines that exert complex antiviral, immunomodulatory and antiproliferative effects

Back 65

interferons

Front 66

What are the three types of interferons

Back 66

α, β, γ

Front 67

These are synthesized by host cells in response to various inducer stimuli and cause biochemical changes that result in reduced ability of viruses to infect cells

Back 67

interferons

Front 68

Injectable pegylated formulated (subQ and IM-improves t1/2) of IFNα (IFN α-2a and α-2b) are approved for treatment of these two types of hepatitis infections

Back 68

HBV and HCV

Front 69

Adverse events of this Rx for hepatitis include:
flu-like symptoms, dose-limiting bone marrow suppression, hypersensitivity and liver toxicity (rare)

Back 69

interferon

Front 70

MOA for this hepatitis Rx:
Binds to specific receptors and signal via JAK/STAT signaling pathways leading to nuclear translocation of cellular protein complex which binds to genes containing the specific response element→ synthesis > 24 proteins which contribute to viral resistance

Back 70

interferon MOA

Front 71

Inhibit viral penetration
Inhibit viral gene transcription
Inhibit viral protein translation
Inhibit viral protein processing
Inhibit virus maturation
All actions of the MOA of this hepatitis Rx

Back 71

interferon

Front 72

This hep Rx is specifically for HBV, is well tolerated and has no DDI
*discontinuation of Rx results in severe exacerbation of hepatitis in 25% of patients

Back 72

Adefovir dipivoxil

Front 73

MOA for this hepatitis Rx:
It is first DE-ESTERIFIED to its pro-drug form and converted to di-phosphate form which is a COMPETITIVE INHIBITOR OF VIRAL DNA POLYMERASE and RT and serves as CHAIN TERMINATOR TO VIRAL DNA SYNTHESIS

Back 73

adefovir dipivoxil

Front 74

This Rx for hepatitis is a CYTOSINE analog that is activated via phosphorylation by host cell to triphosphate active form

Back 74

lamivudine

Front 75

The MOA of this Rx for hepatitis is competitively inhibiting HBV DNA polymerase
*also inhibits HIV reverse transcriptase

Back 75

lamivudine

Front 76

This hepatitis Rx has enhanced antiviral activity with combo Rx of adefovir or penciclovir against hepatic adenoviruses

Back 76

lamivudine

Front 77

Single-nucleotide changes leading to critical amino acid substitutions in a target protein often are sufficient to cause what?

Back 77

antiviral drug resistance

Front 78

Current agents inhibit active replication so viral replication may resume following what

Back 78

drug removal

Front 79

Most drug-resistant viruses are recovered from __________ patients or those with chronic infections with high viral replicative loads and repeated or prolonged courses of antiviral treatment

Back 79

immunocompromised patients

Front 80

Do current antiviral agents eliminate non-replicating or latent virus

Back 80

NO they do not

Front 81

Clinical efficacy of antiviral Rx depends on achieving inhibitory concentrations where?

Back 81

at the site of infection, within the infected cells