L16-17 Antivirals Flashcards
What is the MOA of acyclovir and why is it relatively non-toxic?
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
What are the two primary drugs used for Herpes and how are they different?
Acyclovir (Zovirax)
Valacyclovir (Valtrex)–prodrug converted to acyclovir providing higher serum levels and greater effectiveness
What are the uses of acyclovir (Zovirax)?
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
What are the side effects of acyclovir?
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
Famciclovir (Famvir)
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
Trifluridine (Viroptic)
Thymidine analog that inhibits viral DNA synthesis
Active against HSV 1 and 2
Topical use for herpes resistant to acyclovir
Toxicity: visual haze
Docosanol (Abreva)
Inhibits fusion of HSV to plasma membrane
Topical use for cold sores
MOA of Ganciclovir Sodium (Cytovene) and Valganciclovir (Valcyte)
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
Difference between Ganciclovir Sodium (Cytovene) and Valganciclovir (Valcyte)
Oral availability of Ganciclovir is not great but Valganciclovir is much better
When is ganciclovir used?
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
When is valganciclovir used?
Orally for prophylaxis and therapy of CMV infections
Ganciclovir toxicity
Neutropenia and thrombocytopenia possible, mainly IV and combined with zidovudine
Nausea, headache
Teratogenic and carcinogenic in animals but appears safe in humans
Cidofovir (Vistide)
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
Foscarnet (Foscavir)
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
Fomivirsen (Vitravene)
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
Oseltamivir (Tamiflu) and Zanamivir (Relenza)
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
Amantadine (Symmetrel), Rimantadine (Flumadine)
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
Ribavirin (Virazole)
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
Treatment of Hep B
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
Interferon alfa-2b (Sylatron)
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
Simeprevir (Olysio)
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
Sofosbuvir (Sovaldi); Sofosbuvir/ledipasvir (Harvoni)
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
Elbasvir/Grazoprevir (zepatier)
Hep C treatment
Elbasvir inhibits HCV NS5A
Grazoprevir inhibits HCV NS3/4A
Approved Jan 2016
Dasabuvir, Ombitasvir, Paritaprevir, Ritonavir (Viekira)
Hep C treatment inhibiting various protein synthesis enzymes
Describe the replication process of HIV
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
General characteristics of Nucleoside Reverse Transcriptase Inhibitors (NRTI’s)
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
Zidovudine (Retrovir)
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
Lamivudine (Epivir, 3TC)
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
Tenofovir (Viread)
HIV treatment
NRTI
Adenosine analogue active against HIV-1
With emtricitabine for treating HIV naive patients
Nausea, vomiting, abd pain, flatulence SE’s
Emtricitabine (Emtriva)
HIV treatment NRTI Cytosine analogue Cross-resistance to lamivudine likely Used for HBV SE: diarrhea, nausea, rash (well tolerated)
Abacavir (Ziagen)
Guanasine analogue
NRTI HIV treatment
Used with lamivudine for initial treatment if patient negative for HLA-B5701–leads to serious hypersensitivity
Didanosine; ddI (videx), Stavudine (ddt; Zerit); Zalcitabine (ddC; Hivid)
Older NRTI’s no longer used
inhibit mitochondrial DNA synthesis which may lead to peripheral neuropathy
May cause pancreatitis (esp didanosine)
What are the first and second line drugs for HIV?
1st Tenofovir/Emtricitabine
2nd Abacavir/Lamivudine
MOA of NNRTI’s
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
Efavirenz (Sustiva)
HIV drug
Drug of first choice in NNRTI group
Teratogenic! and decreases effectiveness of oral contraceptives
Penetrates CNS and causes dizziness, drowsiness, insomnia, headache
Rilpivirine (Edurant)
NNRTI HIV drug
Not teratogenic like Efavirenz
SE-depression
Do not use in patients with hepatitis co-infection
What class are the -gravir’s?
Integrase inhibitors for HIV
Dolutegravir (Tivicay)
HIV drug
Integrase inhibitor
Combined with NRTI’s
Increases levels of Metformin so should not be combined
Elvitegravir (Vitekta)
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
Raltegravir (Isentress)
HIV drug
Integrase inhibitor
Resistance develops with use
Rifampin will decrease concentration
Characteristics of HIV protease inhibitors
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
What drugs induce CYP3A4?
rifampin, rifabutin, phenytoin, phenobarbital, carbamazapine
Darunavir (Prezista)
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
Cobicistat (Prezcobix)
Used to inhibit CYP3A4 in order to increase availability of drugs:
Elvitegravir–integrase inhibitor
Protease inhibitors
Atazenavir (Reyataz)
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
Ritonavir (Norvir)
HIV Protease inhibitor
Inhibits CYP3A4 and is used for this purpose to increase availability of other HIV drugs
Saquinavir (Invirase)
HIV Protease inhibitor
Admin with Ritonavir and food
May prolong QT
Indinavir (Crixivan)
HIV Protease inhibitor
Empty stomach admin, good CSF
May cause nephrolithiasis and asymptomatic bilirubinemis
Nelfinavir (Viracept)
HIV Protease inhibitor
Both inhibits and induces CYP3A
Lopinavir /Ritonavir (Kaletra)
HIV Protease inhibitor
Amprenavir (Agenerase)/Fosamprenavir (Lexia)
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
Tipranavir (Aptivus)
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
Enfuvirtide (Fuzeon)
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
Maraviroc (Selzentry)
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
