Fundamentals II: 10:00-11:00am Scribe: Susanna Pischek
Wednesday, December 2, 2009 Proof: Jennifer Grimes
Dr. Jennifer King Antiviral and Antiretroviral Pharmacology Page 1 of 8
I. Objectives [S2]
a. The objectives for today are to first review the Virus Life Cycle and target steps for drug therapy.
b. Briefly explain how antivirals are used to treat different disease states including Herpes Simplex Virus (HSV)/ Varicella Zoster Virus (VZV), Cytomegalovirus (CMV), Influenza Virus, and Hepatitis B and C.
c. Then we will discuss Human Immunodeficiency Virus Life Cycle and the target steps for Drug Therapy and Disease Management.
II. Viral Replication [S3]
a. This first slide represents viral replication. There are various steps in virus replication.
b. First you have a virus that binds to and penetrates a host cell.
c. Then the virus is uncoated to build a nucleic acid. Followed by transcription, translation, and replication.
d. Then finally virus particles assemble and bud out to infect new cells.
e. So, antivirals can work at several of these steps. There are inhibitors of uncoating, which include Amantadine and rimantadine.
f. Inhibitors of transcription, which is interferon.
g. Inhibitors of translation is Fomivirsen.
h. There are numerous drugs that are inhibitors of RNA or DNA genomic replication (Acyclovir, valacyclovir, penciclovir, famciclovir, cidofovir, ganciclovir, valganciclovir, trifluridine, idoxuridine, ribavirin, adefovir, lamivudine, emtricitabine)
i. The last class of drugs that will be discussed are actually inhibitors of virus release. One drug, Oseltamivir, is listed. But when we get to that, another drug will be discussed. The other drug was taken out of the slides because last year nobody used it. However, this year, it has come back into favor because of the swine flu. This drug will be briefly mentioned, in case you come across it in practice.
III. Inhibitors of Uncoating [S4]
a. First let’s talk about inhibitors of uncoating.
IV. Amantadine and Rimantadine [S5]
a. The two drugs are Amantadine and Rimantadine. They both work by interfering with influenza A virus M2 protein, which serves as an ion channel.
b. These drugs are used primarily for Influenza A virus prophylaxis and treatment (~90% protective), so it has no effect on B.
c. Rimantadine is equally as effective as amantadine; however, there are less side effects associated with it, including nausea, vomiting, and diarrhea.
d. The two drugs are 100% cross-resistant to each other; so, if a patient is resistant to one, then the other is not going to work.
e. This was your first class, which was pretty easy.
V. Inhibitors of Transcription [S6]
a. Skipped
VI. Interferon (IFN) [S7]
a. Inhibitors of Transcription include the drugs Interferons. Interferons are a family of cytokines that evoke complex intracellular effects that can be Antiviral, Antiproliferative, or Immunomodulating.
b. There are three major classes of IFNs prepared by recombinant technology. There is interferon alpha, beta, and gamma. Alpha and Beta produce predominantly antiviral effects, whereas Gamma has immunomodulatory effects (which will be discussed tomorrow). The interferon Alpha and Beta are used to primarily treat Hepatitis B and C and Human Pamplona Virus (HPV).
VII. Interferon-Alpha 2b (Interferon A) [S8]
a. The focus of interferons will be on Alpha 2b. Its precise mechanism unknown, but it is thought to stimulate cytokines and proteins causing a state of resistance to virus infection in uninfected cells.
b. It is administered subcutaneously (SC) 3 x/week. It is renally eliminated, so you have to cautious with patients who have renal dysfunction.
c. Alpha 2b is used for the treatment of chronic hepatitis B and hepatitis C infection (in combination with ribavirin).
VIII. Interferon Side Effects [S9]
a. Unfortunately, Interferon has a slue of side effects, which really makes it an awful choice for therapy. Right now, Hepatitis is treated with Interferon and Ribovirin.
b. The side effects of Interferon are predominantly Flu-like syndromes, depression and increased susceptibility to bacterial infections.
IX. Pegylated Interferon [S10]
a. Right now there is a drug called Pegylated Interferon. It is pretty much the chemical attachment of PEG, or polyethyleneglycol, to the therapeutic protein. It has several benefits. It enhances the plasma half-life.
b. How many half-lives does it (the drug) take to get to steady state? 4-5 half-lives
c. It also takes 4-5 half-lives for a drug to be cleared from the body once the medication is stopped.
d. The advantage here is that the Pegylated, or polyethyleneglycol, enhances plasma half-lives. So the regular interferon has to be given three times a week, whereas the pegylated can be given once a week.
e. It also lowers the toxicity, so there is a little less side effects from all those we saw on the previous slide.
f. There is increased drug stability and solubility.
g. Pegylating the protein increases therapeutic efficacy by reducing the ability of the immune system to detect and mount an attack on the compound.
h. Pegylation increases the MW of the protein (or non-protein) molecule, typically reduces excretion rates.
i. Again, the major advantage of the Pegylated Interferon (HINT HINT—If Dr. King helps with the test questions, she usually asks about the pegylated interferon) is that it advances plasma half-lives. It is given once a week in comparison to three times a week. It lowers the toxicity, and it increases the solubility of the medication.
X. Inhibitors of Translation [S11]
a. Next to be talked about are Inhibitors of Translation.
XI. Fomivirsen (Vitravene) [S12]
a. The drug of this class is Fomivirsen. It is a nucleotide sequence similar to a sequence in mRNA that encodes proteins needed for production of infectious cytomegalovirus (CMV).
b. It Inhibits CMV replication by blocking translation through an antisense mechanism.
c. This drug is administered intravitrally (into the vireous). So, the concentrations of the retina in ours are much greater than in systemic exposure.
d. It is used predominantly in patients with CMV retinitis who are HIV infected, or have AIDS, that are resistant to other antivirals such as cidofovir, ganciclovir or foscarnet.
e. The adverse events associated with this are mostly ocular; blurred vision, inflammation, and photophobia.
XII. Inhibitors of RNA or DNA Genomic Replication [S13]
a. Next we will talk about inhibitors of RNA or DNA Genomic Replication. This is the class where the majority of antiviral drugs fall into. When you are trying to organize to memorize these drugs for the test, remember this.
XIII. Acyclovir [S14]
a. Acyclovir is a nucleoside analog of guanosine that is phosphorylated intracellularly to the ACTIVE triphosphate form.
b. So acyclovir itself is useless. It has to get into the cell, be converted to the triphosphate form.
c. It is the acyclic triphosphate that inhibits DNA polymerase kinase. It terminates elongation of the DNA strand.
d. What’s interesting about this drug is that it has a high degree of specificity for the viral thymadine kinase. It needs the enzyme thymadine kinase to be converted to the triphosphate form.
e. Because it is highly specific for the viral thymadine kinase as opposed to the host thymadine kinase, it inhibits replication of HSV and VZV in infected cells.
f. So if the cell is not infected, it doesn’t work. It needs the viral enzyme to work as opposed to the host cell enzyme.
XIV. Nucleoside Analog Mechanism of Action [S15]
a. This slide helps to illustrate this a little bit more for those of you who like pictures. Here is acyclovir. It is converted to the monophosphate, diphosphate, and then the triphosphate. Then it is the triphosphate that is substituted and causes termination of DNA elongation.
XV. Acyclovir (Zovirax) [S16]
a. Unfortunately, acyclovir is poorly absorbed after an oral dose (10-30%), so it has to be taken five times a day.
b. It is used for many cases such as Herpes genitalis, chicken pox, HSV-1 and HSV-2 infections, Shingles.
c. The toxicities are rare. However, nausea and vomiting can occur. Because the drug is poorly absorbed and has to be administered five times a daily, the company came out with a prodrug of acyclovir called Valacyclovir.
XVI. Valacyclovir (Valtrex) [S17]
a. It is an L-valine ester of acyclovir (prodrug of acyclovir)
b. It must be hydrolyzed in the intestine and/or liver to acyclovir and ultimately to the triphosphate form.
c. Because it’s a prodrug, the absorption is significantly enhanced.
d. It can be given once or twice a day as opposed to the acyclovir five times a day.
e. So, where might you see differences? Someone who has no insurance or is on Medicaid will have to take acyclovir for the insurance to pay for it. Someone that has other insurance like Viva or has a lot of money, they will pay for the valacyclovir because it’s easier to take a drug twice a day compared to five times a day. That is where you may see the difference. But they have the same effect; just once/twice a day versus five times a day.
XVII. Vidarabine (Ara-A) [S18]
a. The next drug in this class is vidarabine. It is a nucleoside analog of adenosine.
b. It is activated by cellular enzymes (kinases) as opposed to the viral enzymes to the triphosphate form.
c. It inhibits cellular- and virus-specific DNA polymerases and ribonucleotide.
d. It also directly incorporates into cellular and viral DNA.
e. It can be administered topically or IV.
f. Topically, it is used for HSV keratitis and keratoconjunctivitis.
g. IV form used for HSV encephalitis, but it is much less effective than acyclovir.
h. Acyclovir is the drug of choice.
XVIII. Penciclovir (Denavir) [S19]
a. Penciclovir (Denavir) is a nucleoside analog of guanine that competes with endogenous dGTP for viral DNA polymerase, also preventing viral DNA chain elongation.
b. It has a high affinity for viral-coded thymidine kinase.
c. It is administered topically, so it is an ointment used predominantly for cold sores. You apply within 1 hour of the first sign of a cold sore and every two hours for four days. I’ll explain its use in a couple slides to come.
XIX. Famciclovir (Famvir) [S20]
a. Famciclovir is also in this class. It’s a prodrug of penciclovir.
b. If you go back to the next slide, penciclovir (denavir) is a topical agent, can’t be given orally. Fanciclovir is pretty much the oral agent because it’s a prodrug of penciclovir.
c. Again, it is a guanine analog activated by viral thymidine kinase to triphosphate form, which inhibits virus-induced DNA polymerase.
d. It is administered orally, and it can be used instead of acyclovir. It is administered twice of three times daily for HSV and HZV in immunocompetent and immunocompromised adults.
XX. Trifluridine (Viroptic) and Idoxuridine (Herplex) [S21]
a. The next two agents are ophthalmic solutions: Trifluridine and idoxuridine. They are both used for the treatment of HSV kerititis.
b. Trifluridine is a thymidine analog phosphorylated by cellular thymadine kinase (TK). And the triphosphate form competitively inhibits thymidine triphosphate.
c. Whereas, Idoxuridine is a thymidine analog phosphorylated by cellular TK and produces faulty DNA, which can not infect or destroy tissue.
d. So they have slightly different mechanisms of action.
e. Trifluridine is used more commonly than the idoxuridine.
XXI. Ganciclovir (Cytovene) [S22]
a. The next drug in this class is ganciclovir.
b. It is an analog of guanosine activated by cellular and viral enzymes, specifically UL-97 (phosphotransferase which catalyze the initial phosphorylation enzymes to its triphosphate form).
c. Ganciclovir causes inhibition of CMV DNA polymerase and incorporation into viral DNA. So, a lot of these have a similar mechanism of action. It’s just they work on different enzymes and some need cellular enzymes or others need viral enzymes.
d. Ganciclovir orally is poorly absorbed. It is usually administered IV.
e. It is used for CMV in immunocompromised patients and primary CMV retinitis.
f. Side effects include bone marrow suppression, and it’s been show to be teratogenic.
XXII. Ganciclovir/Valganciclovir Pharmacokinetics [S23]
a. Other adverse effects include myelosuppression and renal impairment and gangciclovir has many drug interactions.
b. Important to know that there are drug interactions in case you have a patient come in whom is on these concominant medications.
c. Like acyclovir, ganciclovir, since it is poorly absorbed, it has a prodrug valganciclovir, which is given orally. A key for when you’re studying, if it is a prodrug, both the prodrugs in the antibody groups have the VAL in front of them. That’s a way to remember.
d. Valganciclovir is pretty benign, other than diarrhea and nausea and vomiting.
XXIII. Foscarnet (Foscavir) [S24]
a. The next drug in this class, Foscarnet, is a pyrophosphate analog.
b. Unlike the other drugs, foscarnet does not need phosphorylation to be active. Probably asked that on a previous question on an exam. (Which one of the following does not need phosphorlyation? Foscarnet, since this sets this drug apart from the other drugs in this class.)
c. It directly inhibit the DNA polymerase by preventing cleavage of the pyrophosphate from nucleoside triphosphates and blocking viral DNA synthesis.
d. Its oral absorption is poor, so it is given by an IV infusion.
e. Its therapeutic uses include predominately CMV retinitis. But it can be used for Herpes zoster in combination with ganciclovir for CMV in patients that relapse on either drug alone.
f. Unfortunately it does have some serious side effects. Predominately nephrotoxicity, but also electrolyte imbalances (decrease calcium), and it can cause seizures.
XXIV. Cidofovir (Vistide) [S25]
a. Cidofovir is a nucelotide analog of cytidine; it’s converted via cellular enzymes to the active diphosphate. So, a lot of the other drugs are converted to triphosphate. This one is only converted to the diphosphate.
b. It competitively inhibits viral DNA polymerase causing chain termination.
c. It is only administered IV.
d. It is administered once a week for 2 weeks and administered with probenecid.
e. Probenecid is an agent used for gout. It blocks active tubular re-absorption of uric acid at the proximal renal tubule thereby promoting urinary excretion. So when probenecid is given with cidofovir, you have increased cidofovir plasma concentrations & decreased renal clearance. It is a synergistic drug interaction.