Pharm Final Lecture 2

Front 1

how do viruses replicate?

Back 1

Entry into host cell
Uncoating of viral nucleic acid
Synthesis of early reg. proteins
i.e. nucleic acid polymerases
Synthesis of RNA and DNA
Synthesis of structural proteins
Assembly of viral particles
Release from cell

Front 2

nucleoside analogues

Back 2

prodrugs first synthesized by viral thymidine (selective for infected cells)-->host kinases activate; competitively inhibit viral DNA polymerase preventing synthesis of viral DNA
resistant when tyrosine kinase (TK) activity is lost

Front 3

acyclovir

Back 3

HSV >> VZV > EBV > CMV ; oral F=22%
Nucleoside analogue Phosphorylated by viral thymidine kinase, then converted to active metabolite by host kinase; Competitively inhibits DNA polymerase (no synthesis).
Additionally: incorporated into nascent viral DNA and terminates elongation.
ORAL, IV and topical

HSV: 1st episode suppression, recurrent; Oral therapy: Labialis, genitalis, proctitis; IV: Severe HSV, herpes encephalitis, neonatal herpes (varicella in immunocomprimized and zoster in immunocomprimised)
Topical: genitalis, mild labialis
VZV: (less effective for shingles than vala or fam)
Varicella: chicken pox
NO CMV TX.
prophylaxis for CMV
Resistance when viral thymidine kinase activity is lost (drug is not activated). All nucleoside analogues: Prevents viral replication and shedding; shortens time to heal.
DOES NOT ELIMINATE virus.
Renal excretion.
(Gancyclovir is more effective for CMV)

Front 4

valacyclovir

Back 4

HSV >> VZV > EBV > CMV
oral F=55%; prodrug of acyclovir
Nucleoside analogue

Phosphorylated by viral thymidine kinase, then converted to active metabolite by host kinase; Competitively inhibits DNA polymerase.
ORAL
1st episode suppress recurrent HSV: labialis, genitalis, proctitis
VZV: (shingles)
Prophylaxis CMV
Resistance when viral thymidine kinase activity is lost (drug is not activated). All nucleoside analogues: Prevents viral replication and shedding; shortens time to heal.

(Gancyclovir is more effective for CMV)
Less frequent dosing than acyclovir so better compliance.
does not eliminate virus

Front 5

famiciclovir

Back 5

HSV >> VZV > EBV > CMV
oral F=80%-->penciclovir after absorption
Nucleoside analogue
Phosphorylated by viral thymidine kinase, then converted to active metabolite by host kinase; Competitively inhibits DNA polymerase
ORAL (Most bioavailable at 80%)
HSV: labialis, genitalis, proctitis
VZV: (shingles)
NO CMV at all
Resistance when viral thymidine kinase activity is lost. All nucleoside analogues: Prevents viral replication and shedding; shortens time to heal.

Renal AND fecal excretion.
Converts to penciclovir
Less frequent dosing than acyclovir so better compliance

Front 6

penciclovir

Back 6

Nucleoside analogue (The active metabolite of famciclovir)
Phosphorylated by viral thymidine kinase, then converted to active metabolite by host kinase; Competitively inhibits DNA polymerase
Topical
HSV: recurrent labialis --
All nucleoside analogues: Prevents viral replication and shedding; shortens time to heal.

Front 7

2 drugs more effective against shingles

Back 7

valacyclovir and famiciclovir

Front 8

nucleoside analogue eliminated by? exception?

Back 8

renal excretion
famiciclovir--renal and fecal excretion

Front 9

2 drugs for prophylaxis of CMV

Back 9

valacyclvir and acylovir

Front 10

trifluridine

Back 10

Nucleoside analogue
Phosphorylated by viral thymidine kinase, then converted to active metabolite by host kinase; Competitively inhibits DNA polymerase
Topical ocular
HSV: keratoconjunctivitis
Well tolerated.
-- All nucleoside analogues: Prevents viral replication and shedding; shortens time to heal.

Front 11

what drug treats chicken pox?

Back 11

acylcovir

Front 12

topical drug for recurrent labialis HSV

Back 12

penciclovir

Front 13

ganciclovir

Back 13

Nucleoside analogue Same as valacyclovir.
ORAL and IV
DOC for CMV (oral for prophylaxis; IV or oral for CMV maintenance)
CMV retinitis w/ IV; oral-CMV prophylaxis, retintis
Leukopenia
Thrombocytopenia 100x more active against CMV than acyclovir.
All nucleoside analogues: Prevents viral replication and shedding; shortens time to heal.

****Ganciclovir is phosphorylated by a viral kinase in CMV infected cells; Competitively inhibits viral DNA polymerase; 100X more active against CMV than ACV

Front 14

cidofovir

Back 14

Nucleoside analogue Activated independent of viral enzymes.
alternate b/c of more sideeffects
IV
CMV: (alternate choice after gan)
Maintenance, CMV retinitis ind and malt?
CONTRAINDICATION: renal insufficiency and when taking aminoglycosides or Amphotericin B (due to add'n of renal toxicity)
Nephrotoxicity
Neutropenia
Metabolic acidosis -- All nucleoside analogues: Prevents viral replication and shedding; shortens time to heal.

Front 15

foscarnet

Back 15

Nucleoside analogue (a pyrophosphate derivative) Activated independent of viral enzymes OR host kinases. Blocks pyrophosphate-binding sites on viral DNA polymerase (no attachment of nucleoside precursors to DNA) IV HSV: acyclovir-resistant
herpes genitalis
VZV: acyclovir-resistant
shingles
CMV: 2nd line
maintenance
(If gan-resistant
or if pt. had
severe
neutropenia rxn
to gan) Renal toxicity
Cardiac arrhythmias PREHYDRATION is a must due to renal toxicity.

All nucleoside analogues: Prevents viral replication and shedding; shortens time to heal.

***still distrupts replication

Front 16

DOC for CMV

Back 16

ganciclovir

Front 17

what to use for CMV if resistant to primary drugs

Back 17

foscarnet

Front 18

what to use for HSV/VZV if resistant to acylovir

Back 18

foscarnet

Front 19

NNRI

Back 19

nucleoside reverse transcriptase inhibitor
Synthetic derivatives of nucleosides
Converted to active triphosphate metabolite (nucleotide) by host kinases
Compete for entry into viral DNA (rxn which is catalyzed by reverse transcriptase)
Cause DNA chain termination
given in combination-->single drug therapy inc resistance

Front 20

purine cogener NRTI

Back 20

didanosine

Front 21

name 4 pyrimidine cogeners of NRTIs

Back 21

lamivudine, stavudine, emtiricitabine, zidovudine (AZT)

Front 22

didanosine

Back 22

Nucleoside Reverse Transcriptase Inhibitor (NRTI)
--Purine cogener- Synthetic nucleoside  nucleotide by host kinases; nucleotide competes w/endogenous nucleoside triphospates for entry into viral DNA (rxn catalized by reverse transcriptase); DNA chain termination ORAL (in combo) HIV
Combo of different classes prevents resistance (2 NRTIs are often combined w/ NNRTI or a protease inhibitor)

Pancreatitis
Peripheral neuropathy (All NRTI) crosses BBB
Renal excretion

If adverse effects occur, pull back on dose, don't have to stop tx.

Front 23

most common side effect of NNRTI

Back 23

rash

Front 24

side effect of didanosine

Back 24

pancreatitis and peripheral neuropathy

Front 25

NRTI you can't combine!

Back 25

stavudine and zidovudine (antagonistic)

Front 26

oral drug that treats Hep B

Back 26

lamivudine

Front 27

NRTI that can be IV

Back 27

zidoviudine

Front 28

side effects of zidoviudine

Back 28

bone marrow suppression, anemia, neutropenia

Front 29

lamivudine

Back 29

Nucleoside Reverse Transcriptase Inhibitor (NRTI)
--Pyrimidine cogener-- Synthetic nucleoside -->nucleotide by host kinases; nucleotide competes w/endogenous nucleoside triphospates for entry into viral DNA (rxn catalized by reverse transcriptase); DNA chain termination
ORAL (in combo)
HIV Hep B
Combo of different classes prevents resistance (2 NRTIs are often combined w/ NNRTI or a protease inhibitor)
SE: Lactic acidosis, Hepatic steatosis
(All NRTI) crosses BBB
Renal excretion

Front 30

stavudine

Back 30

Nucleoside Reverse Transcriptase Inhibitor (NRTI)
--Pyrimidine cogener--
Synthetic nucleoside --> nucleotide by host kinases; nucleotide competes w/endogenous nucleoside triphospates for entry into viral DNA (rxn catalized by reverse transcriptase); DNA chain termination
ORAL (in combo)
HIV
Combo of different classes prevents resistance (2 NRTIs are often combined w/ NNRTI or a protease inhibitor)

CAN NOT combo with zidovudine –antagonistic effect
SE-Pancreatitis
(All NRTI) crosses BBB
Renal excretion
Can be used in lieu of zidovudine, if rxn.

Front 31

Emtricitabine

Back 31

Nucleoside Reverse Transcriptase Inhibitor (NRTI)
--Pyrimidine cogener--
Synthetic nucleoside --> nucleotide by host kinases; nucleotide competes w/endogenous nucleoside triphospates for entry into viral DNA (rxn catalized by reverse transcriptase); DNA chain termination
ORAL (in combo)
HIV
Combo of different classes prevents resistance (2 NRTIs are often combined w/ NNRTI or a protease inhibitor)
(All NRTI) crosses BBB
Renal excretion

Front 32

zidovudine

Back 32

AZT; Nucleoside Reverse Transcriptase Inhibitor (NRTI)
--Pyrimidine cogener--
Synthetic nucleoside -->nucleotide by host kinases; nucleotide competes w/endogenous nucleoside triphospates for entry into viral DNA (rxn catalized by reverse transcriptase); DNA chain termination
ORAL (in combo) and IV
HIV
combo of different classes prevents resistance (2 NRTIs are often combined w/ NNRTI or a protease inhibitor)
CAN NOT combo with stavudine –antagonistic effect
SE: Bone marrow suppression,
Anemia, Neutropenia
(All NRTI) crosses BBB
Renal excretion

Front 33

efavirenz

Back 33

Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) Direct inhibition of reverse transcriptase (no activation req’d); disrupts catalytic site. ORAL HIV Combo req'd.
Interact'n with protease inhib.
Rash
CONTRAINDICATION: Pregnancy (teratogenic) Crosses BBB
Renal AND fecal excretion
Most POTENT NNRTI (once a day dosing)

Front 34

nevirapine

Back 34

Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) Direct inhibition of reverse transcriptase (no activation req’d); disrupts catalytic site. ORAL HIV Combo req'd.

Rash; hepatotoxicity
Induces P450 system  drug interactions (including ↓ effect of protease inhibitors) Crosses BBB
Renal AND fecal excretion

Front 35

atazanavir

Back 35

Protease Inhibitor Binds active site of HIV protease; production of immature, noninfectious viral particles. ORAL HIV Combo of different classes prevents resistance (2 NRTIs are often combined w/a protease inhibitor)
Interaction with NNRTI
(in book: hyperbilirubinemia, PR interval prolongation)

SE: breast hypertrophy, central adiposity, hyperlipidemia and insulin resistance---All protease inhibitors can cause disruption of lipid and CHO metabolism

Front 36

Lopinavir

Back 36

Protease Inhibitor Binds active site of HIV protease; production of immature, noninfectious viral particles. ORAL HIV (Combo req'd.)
Interaction with NNRTI (in book: GI intolerance)

SE: breast hypertrophy, central adiposity, hyperlipidemia and insulin resistance---All protease inhibitors can cause disruption of lipid and CHO metabolism

Front 37

Ritonavir

Back 37

Inhibitor of Protease Inhibitor Inhibits metabolism of protease inhibitors; increases ½ life of other protease inhibitors. ORAL HIV (in book: GI intolerance, hepatitis, inhibition of other drugs: antiarrythmics, opioids, tricyclic antidepressants) Ritonavir + Lopinavir are combo of choice


SE: breast hypertrophy, central adiposity, hyperlipidemia and insulin resistance---All protease inhibitors can cause disruption of lipid and CHO metabolism

Front 38

enfuvirtide

Back 38

Fusion Inhibitor Inhibits fusion of HIV with host cell. Specifically binds gp41, blocking viral entry. SubQ injection (2x daily) HIV (in book: injection site rxns, hypersensitivity rxns) Good alternative when resistance or intolerance occurs w/other drug classes.

Front 39

amantadine

Back 39

Synthetic tricycylic amine compound Prevents uncoating (inhibits viral M2 proton selective ion channel-This channel is needed for acidification and subsequent uncoating and nucleic acid transfer from the endosome into the host cell cytoplasm ) of influenza A particles after cell entry.
ORAL (also liquid preps for kids) Influenza A
Not effective against Influenza B
REDUCE dose in renal insufficiency.
Crosses BBB, so more negative
CNS effects. Give w/in 48 hrs: Reduces severity and duration.

Front 40

rimantadine

Back 40

Synthetic tricycylic amine compound Prevents uncoating (inhibits viral M2 proton selective ion channel--This channel is needed for acidification and subsequent uncoating and nucleic acid transfer from the endosome into the host cell cytoplasm
) of influenza A particles after cell entry.
ORAL (also liquid preps for kids)
Influenza A (DOC)
Not effective against Influenza B
REDUCE dose in renal insufficiency.
DOES NOT cross BBB, so less
side effects.Give w/in 48 hrs: Reduces severity and duration.

Front 41

oseltamivir

Back 41

Neuraminidase inhibitor
Inhibit neuraminidase so that virions can not be released from surface of infected cell.
ORAL
Influenza A and B
(prophylaxis and
treatment)
Dose reduction NOT necessary in renal insufficiency
Give w/in 48 hrs: Reduces severity and duration.
Viral neuraminidase inactivates mucus by breaking linkages. The inhibitor allows our mucus to be active against the virus.

Front 42

zanamivir

Back 42

Neuraminidase inhibitor Inhibit neuraminidase so that virions can not be released from surface of infected cell.
NASAL
Influenza A and B
Dose reduction NOT necessary in renal insufficiency
Viral neuraminidase inactivates mucus by breaking linkages. The inhibitor allows our mucus to be active against the virus.

Front 43

ribavirin

Back 43

Guanosine analog
Inhibits synthesis of viral nucleic acid d/t reduced guanosine triphosphate levels; Inhibits host cell nucleic acid synthesis.
Aerosol (RSV)
IV (HCV)
RSV , Hep C (in combo with IFN-α2b drugs)
(In book: Teratogenic)

****Alone for RSV; combo with IFNalpha2b for hepatitis C;
IFN alone for hepatitis B
Recall lamivudine is also effective against Hep B

Front 44

interferon a

Back 44

Interferon
A DNA recombinant; Signals immune pathways; induction of antiviral proteins in the host cells. (Boosts hosts immune response)
SubQ or IM
Hep B, Hep C (in combo w/
ribavirin)
(in book: also papillomaviruses, Kaposi's sarcoma, hairy cell leukemia, genital warts, CML, mal. melanoma, multiple myeloma, renal ca.) --
Recall that lamivudine (an NRTI) also treats Hep B.

Front 45

2 things effective against hep B

Back 45

lamivudine and interferon alpha

Front 46

how to treat hep C

Back 46

ribavirin and IFN-a2b drugs

Front 47

subQ injection for HIV

Back 47

enfurvirtide

Front 48

DOC for influenza A

Back 48

rimantadine

Front 49

amantadine does/not cross BBB?

Back 49

it does

Front 50

rimantadine does/not cross BBB

Back 50

does not so less side effects

Front 51

oral drug treats influenza A and B

Back 51

oseltamivir

Front 52

nasal drug treats influenza A and B

Back 52

zanamivir

Front 53

drugs that treats RSV

Back 53

ribavirin

Front 54

NNRTI

Back 54

NNTRI-Do not require metabolic activation, Directly inhibit reverse transcriptase, Single-drug therapy increases risk of resistance, Rash is most common side effect; cross the BBB, renal and fecal excretion

Front 55

Protease inhibitor

Back 55

Protease Inhibitors-Bind to the active site of HIV protease, Results in the production of immature, noninfectious viral particles;

SE: breast hypertrophy, central adiposity, hyperlipidemia and insulin resistance---All protease inhibitors can cause disruption of lipid and CHO metabolism

Front 56

fusion inhibitor

Back 56

Inhibits fusion of HIV with host cell, gp120 directs virus to host cell, gp41 fascilitates viral entry

Front 57

drug that is a fusion inhibitor

Back 57

enfurvirtide

Front 58

Influenza A and B are effectively treated with oseltamivir and zanamivir. The mechanism of action for these antiviral agents is inhibition of
DNA polymerase,
Reverse transcriptase,
Thymidine kinase,
Neuraminidase,
Viral protease

Back 58

neuramidase---This enzyme on the lipid envelope prevents viral clumping and binding to already infected cells. This interference disrupts infectivity.

DNA polym-acyclovir, famciclovir, valacyclovir, ganciclovir and cidofovir
reverse transcriptase--didanosine, lamivudine, stavudine, zidovudine, efavirenz and nevirapine
TK-Activates several antivirals (i.e., acyclovir, famciclovir, valacyclovir
viral protease--Anti-HIV agents are protease inhibitors

Front 59

drugs that inhibit DNA polymerase

Back 59

acyclovir, famciclovir, valacyclovir, ganciclovir and cidofovir

Front 60

drugs that inhibit reverse transcriptase

Back 60

didanosine, lamivudine, stavudine, zidovudine, efavirenz and nevirapine

Front 61

thymidine kinase activates?

Back 61

Activates several antivirals (i.e., acyclovir, famciclovir, valacyclovir

Front 62

The most common mechanism of HSV resistance to acyclovir is

Structural change in viral TK,
Mutation in DNA pol gene,
Loss of ability to produce TK,
Structural change in reverse transcriptase



Mutation in gene that encodes for phosphotransferase

Back 62

usually very few have structural changes or mut DNA polymerase

most lose the ability to synthesize TK
Viral specific thymidine kinase needed to activate acyclovir, which inhibits DNA polymerase.

Front 63

An AIDS patient is being treated with a combination of the drugs listed below. Which of these is most likely to cause breast hypertrophy, central adiposity, hyperlipidemia and insulin resistance?

Zidovudine
Atazanavir
Ketoconazole
Sulfamethoxazole
Trimethoprim

Back 63

atazanavir---All protease inhibitors can cause disruption of lipid and CHO metabolism

zidovudine--Bone marrow suppression, anemia and neutropenia
ketoconazole-Antifungal; nausea, rash, hepatic injury and hematopoetic toxicity
SMX--Antibacterial; nausea, rashes, headache and hematologic disorders
TMP--Antibacterial; nausea, rashes, hematologic disorders

Front 64

side effect of PI

Back 64

SE: breast hypertrophy, central adiposity, hyperlipidemia and insulin resistance---All protease inhibitors can cause disruption of lipid and CHO metabolism