Atypical Sedative Drugs

by Pravin Shukle, MD

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    00:00 Let’s take a look at some of the atypical drugs.

    00:04 There are atypical drugs that will act through the benzodiazepine receptor, there are drugs that will act t hrough the melatonin receptor, there are also drugs that will act through the serotonin receptor, and there are drugs that will act through the newly discovered orexin receptor.

    00:25 The atypical drugs that act through the benzodiazepine receptor include drugs like Zolpidem.

    00:30 It causes increased flow through the chloride channel.

    00:35 Once again, it helps GABA by inhibiting the ɣ subunit and it binds between the α and ɣ subunit.

    00:42 You can see that it’s a slightly different binding site than both benzodiazepine and flumazenil.

    00:49 It acts through only one type of receptor and that receptor which contains the α1 type of subunit.

    00:57 More specific actions with this drug, so you get insomnia control without some of the other side effects.

    01:04 Because you’re now acting at a more specific level of the brain, this is why this new drugs seem to be a little bit better for treating insomnia.

    01:13 Flumazenil or Anexate is an antagonist to these types of drugs.

    01:18 And that’s because flumazenil’s binding point is actually very close to drugs like Zolpidem’s binding point.

    01:26 It is used as a reversal agent in overdoses from these medications.

    01:31 And as I said before, it binds at a similar site to both the benzodiazepines and Zolpidem.

    01:40 Let’s talk about the atypical drugs that act through the melatonin receptor.

    01:44 So, Ramelteon is a melatonin agonist.

    01:47 It is active at the suprachiasmatic nuclei.

    01:50 So it’s very, very useful in insomnia treatment.

    01:53 The thing that I like about this class of drugs is that they have a low risk for abuse.

    01:59 They are less addictive than the other medications including benzodiazepines.

    02:05 Now, one of the downsides is that it is metabolized to an active metabolite by cytochrome systems.

    02:12 So in this regard, it will interact with drugs like fluvoxamine and the azole antifungals.

    02:19 So, be aware that you can get drug interactions with this medication.

    02:23 Tasimelteion or Heltioz is a very commonly prescribed medication.

    02:28 Once again, it also is a melatonin agonist.

    02:31 Once again, it also works in the suprachiasmatic nuclei And it is for the strange disorder called the non-24 hour sleep-wake disorder in blind people.

    02:43 So, let me just explain this really quickly, blind people can’t see the sun for obvious reasons.

    02:49 and melatonin is an agent that is naturally made in the brain in response to light.

    02:55 So it helps us with our sleep-wake cycles.

    02:58 Blind people don’t have that cues so they sometimes have altered melatonin levels.

    03:03 This drug is used to help blind people sleep at night and wake during the day.

    03:09 It is the only drug I believe that is currently licensed for use in this particular disorder.

    03:15 And that’s why I do want you to remember this particular melatonin antagonist because it’s probably the only one that will see a long time indicated for the sleep disorder.

    03:28 Let’s move one to the atypical drugs that act through the newly discovered orexin receptor.

    03:34 Suvorexant is an orexin receptor antagonist.

    03:38 It does have very good hypnotic profiles.

    03:42 Let’s take a look at its profile issues now with respect to safety.

    03:46 The safety in addictive risk persons is unknown.

    03:50 So we don’t know if it’s going to be a highly addictive medication or not.

    03:54 The safety in pregnancy is currently unknown and the safety in breastfeeding is currently unknown.

    04:00 So we don’t know a lot of things about this new class of drugs; as time goes on we’ll know more and more.

    04:06 Now, you should be aware that this drug class does interact currently with all cytochrome system drugs.

    04:13 So it’s an important consideration when you have people on multiple medications as to whether or not you’re going to use these medications.

    04:24 Atypical drugs that act through the serotonin receptor include Buspirone or BuSpar.

    04:29 This is a very, very commonly used medication.

    04:34 It is a selective anxiolytic; it has minimal sedative effects and motor effects or rebound.

    04:41 It acts on the 1A serotonin receptor.

    04:45 Now, serotonin receptors are sometimes called serotonin receptors, sometimes they are called 5HT receptors.

    04:52 So just to be clear, 5HT and serotonin are the same thing.

    04:57 This drug has a very slow onset of action.

    05:00 And it’s used in generalized anxiety disorders but not in panic disorders.

    05:06 Generalized anxiety disorders require a long-term treatment; panic disorders are relatively rapid on rapid off kinds of problems so long-term drugs don’t work as well in these types of situations.

    05:21 We’re going to see the psychiatry lectures later on for more information.

    05:26 So I won’t talk about it too much today.

    05:29 Side effects with these medications, the thing I want you to remember is once again, these drugs do have interactions through the cytochrome system.

    05:37 They can cause tachycardia, they can cause miosis and GI distress as well.

    05:42 The thing that you want to remember about this drug and the thing that is important for your exam as well as in practice is that this is one of the few drugs that’s actually safe in pregnancy.

    05:53 So this is where it comes into play.

    05:59 So let’s summarize some of the sleep disorder drugs that we use in modern medicine.

    06:06 We used to use a lot of benzodiazepines like flurazepam but not so much now because they’ve been replaced by these newer drugs.

    06:16 They start with the letter Z.

    06:17 So sometimes it’s easy to remember them; Zolpidem, Zaleplon, Zopiclone, Eszopiclone, they all have Z or zed in their nomenclature.

    06:30 So it’s sometimes easier for us to pick them out.

    06:34 They have α-specific atypical agents acting through the benzodiazepine receptor and these are very effective agents in sleep and insomnia as well; and the newer melatonin–specific agents are rapidly increasing in popularity.

    06:48 There is also a product out in the herbal product world called Melatonin.

    06:53 A lot of people like to by melatonin over the counter as a herbal product.

    06:59 Unfortunately, we don’t really know what’s in these bottles.

    07:02 Some of the bottles that are being sold in herbal product stores have no melatonin specific agents.

    07:08 And some of them have too much.

    07:10 So it’s very hard to predict whether or not these agents are useful or not.

    07:16 There is biological plausibility for them but I say buy or beware and you’re better off just getting something that actually has a US pin number.

    07:25 There’s going to be a specific subset of patients who are unique and these are people who rely heavily on motor skills.

    07:33 So I want you to think of the plastic surgeons and neurosurgeons in your world and think about if they have anxiety.

    07:40 What are we going to treat them with? Well, buspirone or BuSpar has little psychomotor side effects.

    07:47 So, if you have a person who is heavily dependent on motor skills; whether they are an artist or a surgeon, this is a great choice.

    07:54 The other reason why this is a good choice is because it’s safe in pregnancy.

    07:58 A nice thing about these drugs, this particular class of drug is that it has a low risk of addiction.

    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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