Anti-HIV Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTI) – Antiviral Drugs

by Pravin Shukle, MD

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    00:00 The next category of medication are the Reverse Transcriptase Inhibitors.

    00:05 These are probably the most famous of the category.

    00:08 And probably the ones that I think will be tested upon most in exams.

    00:13 They are divided into the NRTI's and the NNRTI's.

    00:17 Now they are inhibiting nucleic acid synthesis.

    00:24 Let's take a look at the list of these medications.

    00:27 You can notice that you'll probably recognize some of these agents and I have underlined the ones that I think are probably the most important.

    00:34 The other thing I want to point out on this list of medications is that three letter designation that you see after each of the words or after each of the names.

    00:43 We have started to use three letter designations for medications both in antiviral therapy and in cancer chemotherapy to identify agents with a specific code.

    00:55 That way we don't have to write out the whole name when we are writing out prescriptions.

    01:00 So there you have the list.

    01:02 I think the most famous of these is probably didasosine or DDI.

    01:08 When we take a look at these agents, we'll divide them up into nucleoside based reverse transcriptase agents and the non-nucleoside based reverse transcriptase inhibitors.

    01:21 Now the nucleoside based reverse transcriptase inhibitors are really antimetabolic drugs.

    01:26 So we often use three or more drugs at the same time from different classes.

    01:30 And this is usually used before the symptoms appear.

    01:34 The thing you want to remember about this medication regimen, is we call them HAART regimens or HAART which stands for Highly Active Anti Retroviral Therapy.

    01:46 Now we've shown to reduce significantly CD4 progression in with HAART therapy.

    01:53 And we also have shown that using HAART therapy we could significantly reduce death or morbidity and 5 year mortality rates.

    02:04 The nucleoside based reverse transcriptase inhibitors are different from mammalian reverse transcriptase in the sense that the viral reverse transcriptase is slightly more active and slightly more sensitive to these agents.

    02:17 So this is why we're not as worried about effecting indigenous or mammalian reverse transcriptease with these drugs.

    02:25 NRTIs lack of 3 prime hydroxyl group on the ribose ring.

    02:30 So the next nucleoside cannot bind or bond to the protein that you're making or the plan that you make DNA molecules.

    02:40 NRTIs are converted by host cell kinsase to triphosphates.

    02:45 And they block the binding of nucleosides on the d-site of the reverse transcriptase.

    02:50 So they act as change terminators.

    02:52 You can no longer keep going with production cycle.

    02:56 All NRTIs may cause a lactic acidosis and severe hepatomegaly.

    03:01 And so we watch the aminotransferase levels quite closely and we do clinical exams by examining the liver.

    03:10 Now we have several agents that I'll talk about.

    03:14 Abacavir is good oral availability.

    03:19 It's a guanosine analog.

    03:21 It has a half life about 24 hours.

    03:24 It's resistance to -- the likelihood of resistance is quite low.

    03:28 It causes several point mutations.

    03:31 And because it's several point mutations we think that's why the resistance is unlikely.

    03:35 It is associated with some hyper sensitivity reactions.

    03:39 So you do have to be very careful with them.

    03:41 And they can occur in as many as 5% of HIV positive patients.

    03:46 Now some of these hypersensitive reactions can actually be fatal.

    03:51 So we do want to take these very, very seriously.

    03:56 Didanosine or DDI is also a main stay of therapy.

    04:02 We have to reduce it's dose if there is renal impairment.

    04:05 Resistance once again is unlikely because we think that there is several point mutations that are occurring with this agent.

    04:13 Now there is a high degree of pancreatitis with this drug up to 30%.

    04:18 So watch very carefully on your patients who are on DDI.

    04:23 We have to watch this carefully enough that it becomes a very big concern and we're starting to look for alternatives to DDI in therapy.

    04:32 This will show up on exams I guarantee you.

    04:36 Another adverse event that will show up with DDI is peripheral neuropathies.

    04:43 Emtricitabine or FTC has very good oral bio-availability.

    04:47 It's excreted renally and it's usually once a day dosing.

    04:52 Now this of course is contraindicated in pregnancy and children and in kids, sorry, in patients with hepatic dysfunction.

    05:00 3TC is often used in HAART therapy for HIV and in hepatitis.

    05:05 And the adverse event rates for 3TC are smaller but are definitely there.

    05:11 Usually mild gastric distress.

    05:14 Sometimes we'll get some mild neurological symptoms like headache, insomnia and fatigue.

    05:21 d4T is renally eliminated and we adjust the dose based on renal functions.

    05:26 Peripheral neuropathy can occur with these patients.

    05:30 There is an increased risk of lactic acidosis and hepatitis compared to the other medications.

    05:35 Tenofovir (TAF) also has activity against hepatitis B virus.

    05:41 So it's used in both HIV and hepatitis B.

    05:44 Now it may impede the renal clearance of acyclovir and ganciclovir.

    05:49 So you have to be careful when you're using it in combination.

    05:52 Toxicity associated with this drug are mostly gastric distress.

    05:57 Now something that will show up on exams.

    06:00 And something that you should be aware of, is the development of Fanconi's syndrome.

    06:04 So this is one of the few HIV agents that can result in Fanconi's syndrome.

    06:09 Remember that for your exams.

    06:11 Neurological symptoms are also present.

    06:14 And quite frankly they're present in most of the HIV drugs, headache, insomnia, fatigue.

    06:22 ddC is a commonly used HIV agent.

    06:26 It's distributed to most tissues including the central nervous system.

    06:31 It's renally excreted.

    06:33 There's a dose reduction in renal disease.

    06:35 And it's metabolized through cytochrome P450.

    06:38 So there are going to be issues if you combine it with say rifampin.

    06:43 Remember also that your azole antifungals are going to decrease the clearance of this agent.

    06:48 So you have to be ready to adjust the medication if these patients develop a fungal infection and you put them on azole antifungal agent.

    06:56 Toxicity with these drugs.

    06:58 Pancreatitis is probably the biggest one that you should be aware of.

    07:01 Esophageal ulcerations, stomatitis are often seen as well.

    07:06 Neurological once again it is dose related.

    07:10 It is often seen as a peripheral neuropathy.

    07:12 And other neurological symptoms are the standard ones, headache and fatigue.

    07:20 Zidovudine was formally called AZT.

    07:25 So you've probably have heard about it before as AZT.

    07:28 It's distributed to most tissues and it has dual elimination by both the kidneys and the liver.

    07:34 Now the new three lettered designation is ZDV or Z-D-V.

    07:40 And so it's a little bit confusing.

    07:43 So AZT and ZDV are actually the same thing.

    07:46 In terms toxicity and adverse events there's bone marrow suppression, anemia and neutropenia.

    07:54 GI and GU symptoms include gastric distress and Fanconi's syndrome.

    07:58 Remember that, Fanconi's syndrome, ZDV.

    08:02 And neurological once again headache and insomnia and fatigue.

    About the Lecture

    The lecture Anti-HIV Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTI) – Antiviral Drugs by Pravin Shukle, MD is from the course Antimicrobial Pharmacology.

    Included Quiz Questions

    1. …they should be used once symptoms appear.
    2. …they have been shown to reduce morbidity and 5 year mortality.
    3. …most are anti-metabolic drugs.
    4. …they must be used in combinations of 3 or more drugs.
    5. …they have been shown to reduce or reverse CD4 decreases.
    1. …efavirenz.
    2. …abacavir.
    3. …lamivudine.
    4. …emtricitabine.
    5. …didanosine.
    1. Aminotransferase
    2. Lipase
    3. Reticulocytes
    4. Beta-HCG
    5. Urine pH
    1. Stavudine
    2. Tenofovir
    3. Zidovudine
    4. Abacavir
    5. Didanosine
    1. Emtricitabine
    2. Didanosine
    3. Stavudine
    4. Abacavir
    5. Tenofovir
    1. Fanconi syndrome
    2. Peripheral neuropathy
    3. Esophageal ulcerations
    4. Pancreatitis
    5. Anemia

    Author of lecture Anti-HIV Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTI) – Antiviral Drugs

     Pravin Shukle, MD

    Pravin Shukle, MD

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