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Atypical Sedative Drugs

by Pravin Shukle, MD

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    00:00 Let's move on to some atypical drugs. These are drugs that are varied in their classes. They can be acting through something like the benzodiazepine receptor, they can be acting through the melatonin receptor or the serotonin receptor or even the newly discovered orexin receptor. So there are a wide group of drugs that we'll talk about now. So let's take a look at GABA-A macromolecular complex and let's talk about one drug called zolpidem. This causes increased ion flow of chloride ions through that channel. It does so by helping GABA to inhibit the gamma subunit. Now, this drug binds between the alpha and gamma subunits. It's not binding on the gamma subunit, but it acts through only one type of this receptor and specifically it's the alpha-1 receptor. The receptors are containing the alpha-1 subunit that is specific for certain types of syndromes including insomnia. So when we talk about this drug, we actually talk more about treating insomnia than other types of diseases that go through this receptor. Flumazenil also called Anexate is an antagonist to benzodiazepines in general in a drug like zolpidem. It is used as a reversal agent in patients who have had overdoses of benzodiazepines. It binds at a similar site, not the same, but very similar as the benzodiazepines. There are another class of drugs that act through the melatonin receptor.

    01:36 The prototypical drug in this drug class is ramelteon, which is a fairly effective agent. It is a melatonin agonist that acts in receptors that are found in the suprachiasmatic nuclei.

    01:49 They act through the MT1 and MT2 receptors. It is used quite effectively in the treatment of insomnia. There's a relatively low risk of abuse for these medications because they don't typically make patients high. So therefore it has a lower addictive potential than other medications. It is metabolized to an active metabolite by cytochrome P450 system 1A2 and 2C9 so there are potential drug interactions that you can get with this drug although it's not as bad as something that goes through 3A4. I will point out though that this drug will interact with fluvoxamine and with some of the azole antifungals. So you have to be very careful.

    02:33 I want to mention one other melatonin receptor agonist and that's tasimelteon. Now this drug is melatonin agonist as well. It works through the suprachiasmatic nucleus as well. The reason why it's a little bit unique is because of one of the diseases that it choose to treat.

    02:51 There is a syndrome called the non-24-hour sleep-wake disturbance syndrome that you see in blind people. So what does that mean? Now normally we have a circadian rhythm that is modulated through the melatonin system in your brain and when we see sunlight or daytime, we have more stimulation of the system so you have less melatonin. When you're about to go to bed, you have higher levels of melatonin so it initiates that sleep cycle in the sleep-wake circadian rhythm. Blind people don't get the sunlight-mediated stimulation of the system so that it reduces your melatonin levels or raises them depending on the time of day.

    03:36 So they have a disorder where they may not have as good of a circadian rhythm as people who are sighted. So we use this medication to regulate the melatonin levels so that they have more regulated sleep and better sleep. Now let's move on to drugs that act through the orexin receptor and I would argue that most people are a lot less familiar with these drugs. So these are orexin receptor antagonists that have hyptonic properties. Their safety profile is actually quite reasonable. Now, the problem with this class of medications is that we don’t have really good data so our safety profile in specifically addictive risk persons is actually relatively unknown. Same with our safety and pregnancy, we're not advising patients to use this in pregnant patients. We don't have safety data in breastfeeding women. There is some concern that it is secreted in animal breastmilk in some of the animal studies so we're not recommending it for use in those patients. And finally, we know that this particular agent will interact with the CYP 3A4 cytochrome system so it can act with any of those drugs that go through the system and as I've said to you before 3A4 is probably one of the most important and most commonly used pathways for drug degradation so it has an interaction potential that is pretty high. Buspirone is another example of an agent that acts through a different receptor called the serotonin receptor. It's a very commonly used agent. It is a selective anxiolytic, it tends to have minimal sedative effects and it tends to have minimal motor coordination effects. It also has quite a bit less rebound effect as well. So this is a very good drug to use in certain patients who are in, I won't say high risk occupations, but let's say high manual dexterity type of operations where they really rely on their ability to have good motor coordination. It acts on the 1A serotonin receptor. It has a relatively slow onset of action so patients will sometimes start to report improvement in symptoms only after about 10 days. So it takes some time to work. It's used in generalized anxiety disorders, but it is not used in panic disorders. Now, I would recommend that you have a look at the psychiatry lectures in Lecturio.com to see more information on the difference between the 2 syndromes and the treatment regimens that we use. In terms of side effects, there are 3A4 interactions such as drug interactions with say statins for example. You can also get tachycardia. Patients will sometimes complain of miosis. Patients will sometimes complain of GI distress. Interestingly enough, this is relatively safe in pregnancy so we do sometimes use it in our pregnant patients that general rules of pregnancy management do apply. So when we're talking about these drugs, let's just do a quick summary. Bottom line, we used to use a lot of lorazepam and other variants to treat patients with sleep disorders and insomnia. We don't do that so much now because we have these agents like zolpidem and others that are actually a little bit better with fewer side effects and fewer addictive potential issues. The alpha specific atypical agents that act through the benzodiazepine receptor are very effective agents in sleep insomnia management. The newer melatonin agents are rapidly increasing in popularity and there are a lot of people who are expressing a lot of satisfaction with using these medications.

    07:34 With respect to the treatment of anxiety with these atypical drugs, the thing that I want to really point out and really emphasize is buspirone is an excellent agent in patients who have high demand for motor dexterity in their occupations or in their life. So it's a reasonable choice in those patients and it has the advantage of a low risk of addiction. Okay so that's some of the atypical medications. I hope you learn something. If you have any questions, please forward them in and let's move on to do some questions.


    About the Lecture

    The lecture Atypical Sedative Drugs by Pravin Shukle, MD is from the course CNS - Pharmacology.


    Included Quiz Questions

    1. Insomnia
    2. General anxiety disorder
    3. Post-traumatic stress disorder (PTSD)
    4. Anxiety disorder
    5. Agoraphobia
    1. It is a melatonin receptor agonist.
    2. It is most active in the ventromedial hypothalamus.
    3. It is used to induce anesthesia.
    4. It is excreted through the kidneys without metabolism.
    5. It is mainly used to treat trichotillomania.
    1. It is best avoided in patients on medications that strongly inhibit the liver enzyme CYP3A.
    2. Suvorexant is non-addictive and safe to use by patients with substance abuse issues.
    3. Suvorexant is excreted in breast milk and should not be used by nursing women.
    4. Suvorexant is not excreted in breast milk and may be used by nursing women.
    5. Suvorexant is the primary choice for insomnia during pregnancy.
    1. Metabolized by the cytochrome P450 3A4
    2. Used to treat insomnia.
    3. Low risk of abuse
    4. Act in the suprachiasmatic nucleus
    5. Used to treat non-24-hour sleep-wake disorder

    Author of lecture Atypical Sedative Drugs

     Pravin Shukle, MD

    Pravin Shukle, MD


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