Anti-HIV Agents: Protease Inhibitors – Antiviral Drugs

by Pravin Shukle, MD

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    00:00 Let's move on to Protease Inhibitors.

    00:04 Now protease inhibitors are involved in the late stage of protein synthesis and processing.

    00:11 So it's after the nucleic synthesis has already occurred there are other proteins that are being manufactured that are necessary for the next step which is packaging and assembly of the virus quote.

    00:26 Now protease inhibitors are part of the components used in HAART therapy.

    00:31 There are significant disorders in carbohydrate metabolism that are induced by the protease inhibitors.

    00:39 Now we are not sure how these agents work, but we think that there maybe an inhibition of lipid regulating proteins that are site similar to HIV protease.

    00:51 And one of the things that we have to be aware of is that 50% of our patients can actually get a protease inhibitors syndrome or PI syndrome on patients who are taking these PI's for over one year.

    01:05 Now what you see is increased truncal obesity.

    01:09 Kind of that buffalo hump, the Quasimodo hump that we often talk about.

    01:13 And we can see gynecomastia.

    01:15 We also see facial and peripheral lipodystrophy.

    01:20 So there's often some increase fat development in the face and they have a rounder face.

    01:24 Very similar to the kind of changes we see with excess prednisone dosing.

    01:29 We also see hyperglycemia and insulin resistance.

    01:32 And we can see a rise in the serum LDL and tryglyceride values.

    01:42 Now some of the agents are once daily dosing.

    01:45 They require an acidic environment.

    01:47 They can penetrate blood brain barriers.

    01:50 So we sometimes see them in the central nervous system and in the seminal fluid which is quite relevant in terms of sexual activity for our patients.

    01:59 It is also excreted in the bio.

    02:01 So we tend to see the protease inhibitors distribute to most tissues and most fluids.

    02:06 In terms of toxicity and adverse events, we do see GI distress.

    02:12 Now we will see an elevated bilirubin but we actually don't see an elevation in cholesterol and triglycerides.

    02:19 So when you're taking a look at these medications and answering questions, we often see the protease inhibitors thrown into a question about elevated triglyceride as one of the agents that doesn't cause an elevation of cholesterol/triglyceride.

    02:34 So although it's not really relevant from a clinical point of view.

    02:37 You know, we don't care if something doesn't happen.

    02:39 From an exam point of view, they love to put this drug on it as an example of a drug that doesn't cause elevation of triglyceride.

    02:47 So there's a clue there for exam questions.

    02:51 Neurological, you can get peripheral neuropathy.

    02:55 Not listed here is also the fact that you can get headaches and fatigue from this medication.

    03:00 Skin rash can also occur.

    03:02 Although it's much less likely than other agents.

    03:04 Now the other protease inhibitors are probably more popular in terms of sort of the common lexicon.

    03:13 So DRV, DRV/c and DRV/r.

    03:17 There are either ritonavir based or not ritonavir based.

    03:21 They are used in combination with other drugs to boost the effectiveness of the HAART therapy.

    03:26 Now remember that these are sulfa-based moieties.

    03:29 So you want to use it with caution in patients who have a sulfa allergy.

    03:34 Once again, toxicity and adverse events.

    03:36 GI/GU is mostly hepatic toxicity and skin rash.

    03:41 The next of the protease inhibitors that I just want to mention is Fosamprenavir.

    03:46 Now fosamprenavir is the prodrug to amprenavir.

    03:50 So I put them together in one slide.

    03:52 These are used in combination with other drugs.

    03:55 Like ritonavir to boost the effectiveness of your therapy.

    03:59 We use it in caution once again with patients who have a sulfa allergy.

    04:04 The toxicity and adverse events are similar to the other drugs.

    04:07 GI/GU is GI distress.

    04:09 You can get a skin rash.

    04:11 Sometimes you can get paresthesias.

    04:12 And remember that these -- the suspension agent is propeylene glycol.

    04:18 So we tend not to use this agent in pregnancy and in kids.

    04:22 We're not entirely sure that the drug itself is harmful to pregnant women but we know that the suspension agent propylene glycol is.

    04:30 Ritonavir is probably one of the best known of the protease inhibitors.

    04:35 And if my memory serves me correctly, I think it was the first one.

    04:39 I could be wrong at that.

    04:40 Take it with meals, cleared by the liver.

    04:43 It's often used to boost other medications effectiveness due to it's ability to increase, pardon me, inhibit the metabolism of those other drugs.

    04:52 Now at subtherapeutic doses we can still inhibit the metabolism of other protease inhibitors like indinavir and etc.

    05:02 So it is a very useful medication to essentially give us the ability to use less drug to have the same effect.

    05:11 In terms of toxicity and adverse events, GI/GU once again you get GI irritation.

    05:18 You can get a bitter brackish kind of taste in the mouth and patients who often complain about that.

    05:23 In terms of blood work, sometimes you'll get elevation of transaminases values.

    05:28 We also sometimes get an LDL elevation and triglyceride elevation too.

    05:32 As with most HIV drugs, you can get a skin rash from these medications.

    05:37 And you can sometimes get paresthesias, without or with a skin rash.

    05:44 Saquinavir is combined with ritonavir and it is also used both as a substrate and an inhibitor of the cytochrome system.

    05:52 So that once again, it is improving the efficacy of other agents.

    05:56 Toxicity with this is nausea, vomiting, diarrhea and dyspepsia, very similar to other agents.

    06:02 Once again you can get skin rash and paresthesias with this particular PI.

    06:08 Finally, we have this new drug Tipranavir which is combined with ritonavir sometimes.

    06:17 We used it as a substrate and an inducer of cytochrome P450 systems.

    06:21 And we also can induce P glycoprotein.

    06:25 Now there is an increase risk of rhabdomyolysis with HMG-CoA reductase inhibitors or statins.

    06:31 So be very aware that if we're going to be starting patients on this new agent, I think that it's worthwhile just stopping statins, if the patients are on statins already.

    06:41 Toxicity and adverse events, GI/GU is nausea, vomiting and hepatic toxicity.

    06:47 And of course as with most protease inhibitors, skin rash and paresthesias are adverse events.

    About the Lecture

    The lecture Anti-HIV Agents: Protease Inhibitors – Antiviral Drugs by Pravin Shukle, MD is from the course Antimicrobial Pharmacology.

    Included Quiz Questions

    1. …pancreatitis.
    2. …increased truncal obesity.
    3. …hyperglycemia.
    4. …facial lipodystrophy.
    5. …gynecomastia.
    1. Sulfa allergic
    2. Pregnant patients
    3. Children during puberty
    4. Patient with renal dysfunction
    5. Children under 5
    1. Propylene glycol
    2. Sulfa moiety
    3. Methanol
    4. Glycerol
    5. Ethylene glycol
    1. Atazanavir
    2. Ritonavir
    3. Darunavir
    4. Tipranavir
    5. Saquinavir
    1. Saquanivir
    2. Atazanavir
    3. Fosamprenavir
    4. Tipranavir

    Author of lecture Anti-HIV Agents: Protease Inhibitors – Antiviral Drugs

     Pravin Shukle, MD

    Pravin Shukle, MD

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