Module 2 Pharmacology

Front 1

Influenza overview

Back 1

- common viral diesase caused by influenza viruses A and B
- usually self-limiting within 3-4 days of fever, chills, myalgia
- causes 20,000 deaths/yr in USA; elderly and patients with chronic diseases most at risk

Front 2

Influenza therapy

Back 2

**First line therapy is immunization -- prevents influenza and decreases severity

rimantidine and oseltamivir

Front 3

Rimantidine MOA?

Back 3

blocks uncoating of the viral RNA inside the human cells by interfering with the function of the viral M2 protein which functions as an ion channel

**only active against influenza A

Front 4

Rimantidine clinical effects?

Back 4

-- prophylaxis use decreases risk of infection by 50-90%
-- reduces symptoms if tx begun within 48h of onset
-- fewer CNS S/Es so better use in elderly patients and patients w/ renal disease
-- influenza A H3N2 resistance has rendered this drug ineffective for prophylaxis and treatment of the most current flu virus******

Front 5

Oseltamivir MOA?

Back 5

-- blocks release of new viral particles from infected cells via inhibition of viral neuraminidase

Front 6

Oseltamivir therapeutic effects?

Back 6

-- decrease duration of symptoms by one day; do NOT decrease incidence of complications

-- current strain of avian H5N1 virus appears to still be susceptible to the NA inhibitor

Front 7

Herpes Simplex viruses

Back 7

1. HSV-1 = fever blister, keratoconjunctivitis
2. HSV-2 = genital herpes, neonatal herpes
-- incurable STD with periods of exacerbations/remissions
-- incidence has increased 30+% since late 1970s
-- 22 million older than 12 affected
--45 million seropositive for HSV-2
3. Varicella-zoster virus = chicken pox, shingles, encephalitis, pneumonia
4. CMV = retinitis

Front 8

Name the drugs used to treat HSV and VZV?

Back 8

acyclovir
valacyclovir
famciclovir
penciclovir
foscarnet

Front 9

MOA of acyclovir, valacyclovir, penciclovir, famciclovir, and valgangcyclovir?

Back 9

***inhibit viral DNA polymerase, but not effective against non-replicating, latent viruses

--acyclovir is guanosine derivative that must be phosph 3 times to yield active metabolite, acyclovir triphosphate
-- virus-specific thymidine kinase found ONLY in infected cells, produces the monophosphate
-- phosphorylase enzymes of the host cell then produce the di and triphosphates
-- acyclovir triphosphate competes with the dGTP at the viral DNA polymerase and also causes chain termination when incorporated into the viral DNA

Front 10

Resistance to acyclovir, valacyclovir, penciclovir, famciclovir, and valgangcyclovir?

Back 10

Most common form is mutation of the viral thymidine kinase which prevents conversion of acyclovir to the monophosphate.

Resistance to one drug leads to cross resistance.

Front 11

Therapeutic uses of p.o. acyclovir and valacyclovir?

Back 11

1. fever blister - begin therapy ASAP
2. Primary or recurrent genital herpes
3. Suppressive therapy for recurrent genital herpes - has been used for 10+ years in some patients w/o adverse S/Es
4. Treatment of HSV proctitis
5. Herpes zoster

Front 12

S/E of acyclovir and valacyclovir?

Back 12

n/v, diarrhea, and headache

Front 13

MOA of foscarnet?

Back 13

given i.v.

-- is an inorganic pyrophosphate which acts directly to inhibit viral DNA and RNA polymerases and HIV reverse transcriptase
-- No activation by viral or host-cell enzymes is required

Front 14

Therapeutic use of foscarnet?

Back 14

Treat HSV and VZV which are resistant to acyclovir

Treat CMV which is resistant to ganciclovir

Front 15

HSV, VZV med dosing and availability?

Back 15

acyclovir = p.o., i.v., and topical
F(p.o.) = 15-20%

valacyclovir = p.o. (F=48%)
-- is a prodrug converted to acyclovir
-- oral tx w/ valacyclovir results in plasms conc that are 3-5xgreater than those achieved with oral acyclovir
-- decrease dose of acyclovir and valacyclovir in patients with renal failure

famciclovir = p.o. converted to active drug penciclovir

penciclovir = topical

Front 16

Drugs to treat Herpes keratitis?

Back 16

trifluridine

Front 17

Trifluridine MOA?

Back 17

-- is converted to trifluridine triphosphate by host-cell enzymes
-- the active metabolite inhibits viral DNA synthesis

Front 18

Drugs to treat CMV?

Back 18

ganciclovir
valganciclovir
foscarnet
fomivirisen

Front 19

Foscarnet MOA?

Back 19

given i.v.

-- is an inorganic pyrophosphate which acts directly to inhibit viral DNA and RNA polymerases and HIV reverse transcriptase
-- no activation via viral or host-cell enzymes is required

Front 20

Foscarnet therapeutic use?

Back 20

-- used to treat HSV and VZV which are resistant to acyclovir

-- Used to treat CMV which is resistant to ganciclovir

Front 21

Fomivirisen MOA?

Back 21

It is an antisense oligonucleotide which binds to mRNA and prevents viral replication

Front 22

What is HIV?

Back 22

It is an RNA retrovirus which invades (CD4+) T cells

Front 23

Steps in the HIV viral life cycle?

Back 23

1. Attachment and fusion
2. Uncoating
3. Reverse transcription of viral RNA via reverse transcriptase
4. Integration into human DNA in Tcell nucleus
5. Transcription
6. Translation
7. Processing by viral protease which cuts viral proteins into subunits needed for assembly of viral particles
8. Assembly and release via "budding" at T cell surface
9. Eventually infected T cells die

Front 24

Why does HIV cause death?

Back 24

--T cells are killed faster than they can be produces
--The lack of T cells causes immunodeficiency
--this leads to development of tumors and infections
--immune deficiency syndrome (AIDS) reached when CD4+ count <200

Front 25

What determines the rate of progression of the disease?

Back 25

The CD4+ count and viral load (number of copies of RNA)

Front 26

What classes of drugs are used to treat HIV?

Back 26

fusion inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors

Front 27

What is the name of the fusion inhibiting drug?

Back 27

enfuvirtide

Front 28

Enfuvirtide MOA?

Back 28

It is a synthetic peptide which blocks fusion of the viral and T cell mbrns so HIV can't enter CD4+ cell

Front 29

Enfuvirtide cross resistance, mode of administration?

Back 29

Shows no cross resistance with other classes of antiretrovirals!!

Given s.c. with half life of 4h

Front 30

Name the NRTIs.

Back 30

zidovudine
lamivudine
abacavir
tenofovir

Front 31

NRTI MOA?

Back 31

-- These nucleosides are converted to "false" nucleotides by intracellular kinases

-- These "false" nucleotides competitively inhibit HIV reverse transcriptase and cause chain termination of the viral DNA

-- NRTIs can also be incorporated into the viral DNA

Front 32

NRTI cross-resistance?

Back 32

SOME cross-resistance in this class b/c each of the drugs has a slightly different MOA

Front 33

Name the NNRTIs.

Back 33

nivirapine
efavirenz

Front 34

NNRTI MOA?

Back 34

--they do not require phosphorylation to be active inhibitors
--directly inhibit reverse transcriptase to stop HIV replication
--bind to a site different than that of the NRTIs and thus do not compete with the nucleotides for binding to the reverse transcriptase

--Net effects: blockade of both RNA-dep-DNA-pol and DNA-dep-DNA-pol

Front 35

NNRTI resistance?

Back 35

--resistance develops quickly with monotherapy because all of these drugs have the same MOA

--resistance to one means resistance to all NNRTIs

--used with NRTIs b/c they have a different MOA

Front 36

NNRTI interactions?

Back 36

many CYP450 interactions

Front 37

Name the protease inhibitors.

Back 37

saquinavir
ritonavir

Front 38

Protease inhibitor MOA?

Back 38

--block viral protease to prevent the cleavage of viral polyproteins into the functional subunits needed for the assembly of the new virus particles

Front 39

What's special about ritonavir?

Back 39

-- it is used as a "pharmacokinetic enhancer
-- inhibits the CYP450 which metabolizes saquinavir to decrease the daily dose of saquinavir needed to maintain an effective plasma concentration of saquinavir
-- effectively decreases hepatic clearance so daily maintentance dose of saquinavir can be reduced