L16-17 Antivirals

Question 1

What is the MOA of acyclovir and why is it relatively non-toxic?

Answer 1

Taken into cell and phosphorylated by viral thymidine kinase to a monophosphate form–concentrates the drug 30-300x in herpes infected cells
Further phosphorylated by host cell to triphosphate form that competes for dGTP spot in viral DNA stopping replication by inhibiting DNA polymerase

Question 2

What are the two primary drugs used for Herpes and how are they different?

Answer 2

Acyclovir (Zovirax)

Valacyclovir (Valtrex)–prodrug converted to acyclovir providing higher serum levels and greater effectiveness

Question 3

What are the uses of acyclovir (Zovirax)?

Answer 3

Initial episodes of genital herpes–oral and topical, recurrent episodes to reduce spread, herpes keratitis–topically, HSV encephalitis or neonatal herpes–IV, prophylaxis in organ transplant, in immune compromised used prophylactically for herpes simplex, herpes zoster, varicella-zoster, in AIDS for hairy leukoplakia

Question 4

What are the side effects of acyclovir?

Answer 4

Somnolence and lethargy when combined with zidovudine
High IV dose can cause renal tubular obstruction especially with cyclosporine–avoided with hydration and slow infusion
Safe for pregnancy

Question 5

Famciclovir (Famvir)

Answer 5

Works much like acyclovir–guanine analog that inhibits DNA polymerase, phosphorylated by viral thymidine kinase
Converted in vivo to Penciclovir (Denavir) which can be used topically for herpes labialis
Longer intracellular t1/2 than acyclovir
Excreted by kidney
Used for acute treatment of herpes zoster, also used for initial treatment and prevention of genital herpes

Question 6

Trifluridine (Viroptic)

Answer 6

Thymidine analog that inhibits viral DNA synthesis
Active against HSV 1 and 2
Topical use for herpes resistant to acyclovir
Toxicity: visual haze

Question 7

Docosanol (Abreva)

Answer 7

Inhibits fusion of HSV to plasma membrane

Topical use for cold sores

Question 8

MOA of Ganciclovir Sodium (Cytovene) and Valganciclovir (Valcyte)

Answer 8

Synthetic analogue of guanine like acyclovir but far more active against CMV and also less selective so more toxic to host
Phosphorylated by thymidine kinase in cells with herpes and viral protein kinase phosphotransferase in cells with CMV

Question 9

Difference between Ganciclovir Sodium (Cytovene) and Valganciclovir (Valcyte)

Answer 9

Oral availability of Ganciclovir is not great but Valganciclovir is much better

Question 10

When is ganciclovir used?

Answer 10

IV for life or sight threatening CMV
Transplant patients to reduce risk of CMV
Can be implanted in eye for 5-8 months to treat CMV retinitis

Question 11

When is valganciclovir used?

Answer 11

Orally for prophylaxis and therapy of CMV infections

Question 12

Ganciclovir toxicity

Answer 12

Neutropenia and thrombocytopenia possible, mainly IV and combined with zidovudine
Nausea, headache
Teratogenic and carcinogenic in animals but appears safe in humans

Question 13

Cidofovir (Vistide)

Answer 13

Cytosine analog that works similar to acyclovir and ganciclovir in inhibiting DNA synthesis in virus but doesn’t need activation
Used for CMV retinitis in HIV patients and for resistant herpes
Renal tubular necrosis can occur–prevent with hydration and probenacid

Question 14

Foscarnet (Foscavir)

Answer 14

Analogue of inorganic phosphate that prevents DNA polymerase and RNA polymerase and reverse transcriptase
Treats acyclovir resistant HSV and CMV retinitis
Can be combined with ganciclovir
Kidney elimination
Nephrotoxic in renal insufficiency–dose chosen based on creatinine clearance
Hypocalcemia, seizures, hallucinations, genital ulcers,can occur
Teratogenic

Question 15

Fomivirsen (Vitravene)

Answer 15

Inhibits CMV replication and protein synthesis
Administered by intravitreal injection to treat CMV retinitis in HIV patients who failed other therapy
Causes ocular inflammation and visual impairment

Question 16

Oseltamivir (Tamiflu) and Zanamivir (Relenza)

Answer 16

Use: Influenza
MOA: inhibit neuraminidase which prevents release of virus from the cell
Oseltamivir given orally, activated in gut and liver, excreted in kidneys
Zanamivir given intranasally or by oral inhaler because not well absorbed orally
SE: Zanamivir can worsen COPD and cause bronchospasm in asthma
Oseltamivir can cause nausea and vomiting but is reduced if taken with food

Question 17

Amantadine (Symmetrel), Rimantadine (Flumadine)

Answer 17

Block uncoating of virus preventing release of nucleic acids
Well absorbed orally
Kidner excretion
Use: prevent and treat influenza type A2 (Asian) in high risk patients, prophylaxis
SE: nausea, amantadine is dopamine agonist can cause CNS effects including hallucinations, confusion, anxiety, rimantadine does not cross BBB and doesn’t have these effects

Question 18

Ribavirin (Virazole)

Answer 18

Use: RSV–hospitalized infants and kids with severe infection given aerosol, herpes, influenza, oral combined with interferon-alpha 2b or sofosbuvir to treat HepC, IV therapy can be life-saving in Lassa fever
MOA: Purine nucleoside analogue prevents mRNA synth
Toxicity: TERATOGENIC!–pregnant people can’t even administer it, dyspnea even with oral, chest soreness, cardiac arrest, hypotension, headache, anemia, depression, suicide

Question 19

Treatment of Hep B

Answer 19

Acute Hep B is normally self-limiting
Chronic Hep B is treated with reverse transcriptase inhibitors that also inhibit HBV DNA polymerase. Goal in treatment is to cause seroconversion to HBsAg negative but treatment will continue for life. Many also used for HIV.
Tenofovir (Viread): DOC
Entecavir (Baraclude): competitive inhibitor of HBV DNA polymerase
Lamivudine (Epivir): resistance common, but well tolerated even with hepatic decompensation
Telbivudine (Tyzeka): competitive inhibitor of HBV DNA polymerase

Question 20

Interferon alfa-2b (Sylatron)

Answer 20

Acts at several levels to inhibit viral protein synthesis and viral replication allowing the immune system to react
Toxicity significant: flu-like, myalgia, arthralgia, depression, neutropenia, anemia, thrombocytopenia, edema, hypotension
Depot injection 1x/week for 2-4 years
First treatment for HepC in combination with ribavirin
Mostly replaced by other drugs now

Question 21

Simeprevir (Olysio)

Answer 21

HepC treatment
Blocks serine protease that is essential for making viral proteins needed for replication
Often used in combination
SE: anemia, leukopenia, neutropenia, rash, dyspnea, fatigue

Question 22

Sofosbuvir (Sovaldi); Sofosbuvir/ledipasvir (Harvoni)

Answer 22

Hep C treatment
Sofosbuvir is nucleoside analog that inhibits viral NS5B RNA polymerase blocking replication of HCV
Ledipasvir inhibits HCV NS5A and prevents replication
Combo is very effective and costs almost $100,000
SE: fatigue, headache, extreme irritability

Question 23

Elbasvir/Grazoprevir (zepatier)

Answer 23

Hep C treatment
Elbasvir inhibits HCV NS5A
Grazoprevir inhibits HCV NS3/4A
Approved Jan 2016

Question 24

Dasabuvir, Ombitasvir, Paritaprevir, Ritonavir (Viekira)

Answer 24

Hep C treatment inhibiting various protein synthesis enzymes

Question 25

Describe the replication process of HIV

Answer 25

RNA virus with a glycoprotein coat that recognizes and binds CD4-T-cells Fuses with cell membrane and loses coat releasing RNA and reverse transcriptase into the cell Reverse transcriptase copies the RNA into DNA that is then integrated into host DNA by integrase enzyme When genome is copied, viral DNA forms vRNA and viral mRNA that becomes one long protein that is cleaved by a protease into final proteins Drugs target the reverse transcriptase, integrase, protease enzymes Fusion inhibitors used in patients that have become resistant to other drugs

Question 26

General characteristics of Nucleoside Reverse Transcriptase Inhibitors (NRTI's)

Answer 26

Nucleoside analogues that inhibit reverse transcriptase by terminating the chain Rarely cause Lactic acidosis and Hepatotoxicity, more common in obese, previous liver disease, and long-term use Regimines often include two NRTI's and another drug with different mechanism

Question 27

Zidovudine (Retrovir)

Answer 27

First HIV drug widely used NRTI Deoxythymidine analogue Short acting–5 doses/day May cause myelosuppression-anemia or neutropenia Combinations: w/ Lamivudine (Combivir), w/ Lamivudine and Abacavir (Trizivir) Interactions: Increased toxicity with agents that are neurotoxic, nephrotoxic, or affect bone marrow w/ acetaminophen or ganciclovir causes neutropenia w/ acyclovir causes somnolence and lethargy w/ cimetidine and benzos inhibits metabolism in liver probenecid impairs elimination

Question 28

Lamivudine (Epivir, 3TC)

Answer 28

HIV treatment NRTI cytosine analogue, competitive inhibitor of reverse transcriptase Monotherapy leads to change in enzyme causing resistance, but increases sensitivity to zidovudine Combine withzidovudine or other RTI's to treat HIV Also treats chronic HBV Well-tolerated and included in many regimens

Question 29

Tenofovir (Viread)

Answer 29

HIV treatment NRTI Adenosine analogue active against HIV-1 With emtricitabine for treating HIV naive patients Nausea, vomiting, abd pain, flatulence SE's

Question 30

Emtricitabine (Emtriva)

Answer 30

``` HIV treatment NRTI Cytosine analogue Cross-resistance to lamivudine likely Used for HBV SE: diarrhea, nausea, rash (well tolerated) ```

Question 31

Abacavir (Ziagen)

Answer 31

Guanasine analogue NRTI HIV treatment Used with lamivudine for initial treatment if patient negative for HLA-B5701–leads to serious hypersensitivity

Question 32

Didanosine; ddI (videx), Stavudine (ddt; Zerit); Zalcitabine (ddC; Hivid)

Answer 32

Older NRTI's no longer used inhibit mitochondrial DNA synthesis which may lead to peripheral neuropathy May cause pancreatitis (esp didanosine)

Question 33

What are the first and second line drugs for HIV?

Answer 33

1st Tenofovir/Emtricitabine | 2nd Abacavir/Lamivudine

Question 34

MOA of NNRTI's

Answer 34

Bind directly to reverse transcriptase inhibiting formation of DNA Do not require phosphorylation like NRTI's Often combined with NRTI's because use alone causes resistance fast! Metabolized by CYP3A4 so many drug interactions

Question 35

Efavirenz (Sustiva)

Answer 35

HIV drug Drug of first choice in NNRTI group Teratogenic! and decreases effectiveness of oral contraceptives Penetrates CNS and causes dizziness, drowsiness, insomnia, headache

Question 36

Rilpivirine (Edurant)

Answer 36

NNRTI HIV drug Not teratogenic like Efavirenz SE-depression Do not use in patients with hepatitis co-infection

Question 37

What class are the -gravir's?

Answer 37

Integrase inhibitors for HIV

Question 38

Dolutegravir (Tivicay)

Answer 38

HIV drug Integrase inhibitor Combined with NRTI's Increases levels of Metformin so should not be combined

Question 39

Elvitegravir (Vitekta)

Answer 39

HIV drug Integrase inhibitor Combined with NRTI's Must be combined with cobicistat or ritonavir to inhibit CYP3A4 and increase bioavailability Cobicistat inhibits some intestinal transports increaseing absorption of this drug Cobicistat also inhibits creatinine secretion and should not be used in patients with low creatinine clearance

Question 40

Raltegravir (Isentress)

Answer 40

HIV drug Integrase inhibitor Resistance develops with use Rifampin will decrease concentration

Question 41

Characteristics of HIV protease inhibitors

Answer 41

Inhibits protease that breaks up the large protein into the parts needed to fill the capsule etc Mutations and resistance are common Always used in combination with RTI's to treat HIV Most have poor bioavailability and are metabolized by CYP3A4 so drugs that inhibit it will increase PI levels Do not combine with St John's wart or any other drug that would induce CYP3A4 (rifampin, rifabutin, phenytoin, phenobarbital, carbamazapine) SE: Altered fat distribution similar to cushing's, insulin resistance and hyperglycemia, increased cholesterol but should not be combined with statins, bleeding in hemophilia patients

Question 42

What drugs induce CYP3A4?

Answer 42

rifampin, rifabutin, phenytoin, phenobarbital, carbamazapine

Question 43

Darunavir (Prezista)

Answer 43

``` HIV Protease inhibitor First choice in this class SE: headache and bad dreams Combined with Cobicistat (Prezcobix) or Ritonavir to increase bioavailability Taken with food ```

Question 44

Cobicistat (Prezcobix)

Answer 44

Used to inhibit CYP3A4 in order to increase availability of drugs: Elvitegravir–integrase inhibitor Protease inhibitors

Question 45

Atazenavir (Reyataz)

Answer 45

``` HIV Protease inhibitor Second choice in class Less effect on lipoproteins than other PI's Inhibits CYP3A4 May increase bilirubin May cause rash, nausea, hyperglycemia ```

Question 46

Ritonavir (Norvir)

Answer 46

HIV Protease inhibitor | Inhibits CYP3A4 and is used for this purpose to increase availability of other HIV drugs

Question 47

Saquinavir (Invirase)

Answer 47

HIV Protease inhibitor Admin with Ritonavir and food May prolong QT

Question 48

Indinavir (Crixivan)

Answer 48

HIV Protease inhibitor Empty stomach admin, good CSF May cause nephrolithiasis and asymptomatic bilirubinemis

Question 49

Nelfinavir (Viracept)

Answer 49

HIV Protease inhibitor | Both inhibits and induces CYP3A

Question 50

Lopinavir /Ritonavir (Kaletra)

Answer 50

HIV Protease inhibitor

Question 51

Amprenavir (Agenerase)/Fosamprenavir (Lexia)

Answer 51

HIV Protease inhibitor Oral Contains propylene glycol–avoid disulfiram, metronidazole, and alcohol Inhibits CYP3A4 Causes Steven-Johnson syndrome Contraindicated in pregnancy, renal failure, liver disease

Question 52

Tipranavir (Aptivus)

Answer 52

Non-peptide protease inhibitor for HIV Used in HIV that has become resistant to other protease inhibitors With ritonavir and food Inhibits CYP3A so should not be given with drugs metabolized by it: benzos, statins, amiodarone Do not combine with drugs that induce CYP3A4: rifampin, St John's Can cause hepatotoxicity

Question 53

Enfuvirtide (Fuzeon)

Answer 53

Binds GP41 and prevents fusion of HIV to cell membrane Used in patients with advanced disease who have not responded well to other therapies It is a peptide and must be given by subQ injection Increases likelihood of bacterial pneumonia

Question 54

Maraviroc (Selzentry)

Answer 54

Inhibits fusion of HIV by binding CCR5 on CD4 T-cells Only used in HIV that is tropic to this receptor and when other treatments did not work Can cause hepatotoxicity