Heterocyclic Antidepressants (HCAs)

00:00 Let's continue our discussion about antidepressants.

00:04 First of all, I want to talk about the heterocyclic antidepressants and I want to accentuate that one of them is called Bupropion.

00:12 Now, I want you to understand that we have to know how it is metabolized.

00:18 in order to understand its pharmacology.

00:20 You can't really use this particular drug without understanding the way that it's metabolized.

00:25 Now, let's just remind ourselves of where all of these drugs are acting.

00:28 We're really talking about norepinephrine uptake and serotonin uptake in order to change the concentration of the neurotransmitters in the synaptic cleft.

00:38 The heterocyclic antidepressants act like the tricyclic antidepressants.

00:44 But in general, not always, but in general, they have fewer interactions in the periphery.

00:50 There will be still some other miscellaneous receptors that are affected by heterocyclic antidepressants.

00:57 So, they're not quite as a specific kind of a mechanism as you think they would be.

01:03 Now, let's go back to Bupropion.

01:06 Bupropion is also known as Wellbutrin in the antidepressant world, and Zyban in the anti-smoking world.

01:14 You can see the structure here, it's a relatively simple structure.

01:18 It has two different effects in depression.

01:22 First of all, it's a norepinephrine- dopamine reuptake inhibitor. So it's an NDRI.

01:28 We also know that it's a norepinephrine-dopamine releasing agent or NDRA.

01:35 So there are two mechanisms here that are a little bit complicated.

01:39 And finally, to add a little bit more complexity to this drug, this drug is also a nicotine receptor antagonist.

01:47 With this drug, it's important to understand the metabolism of it.

01:51 Why? Because the metabolites are actually more powerful than the original drug.

01:56 It is converted by Cytochrome P450 System into hydroxybupropion, which is a more active metabolite.

02:06 It is a very potent selective reuptake inhibitor of norepinephrine and it also has an area under the curve that can be as much as 16x higher than the original drug.

02:17 Now, this particular version, or this metabolite of Bupropion was sold once upon a time as a different drug, but it was taken off the market for various reasons.

02:28 The side effects of this particular agent include anxiety, agitation and dry mouth, so very similar to the tricyclics.

02:35 You can get an aggravation of psychosis.

02:38 So you have to be careful using this medication in patients who may have a history of psychosis.

02:42 And you can get seizures at high doses if you're not careful with the agent itself.

02:48 Other drugs are also present in the heterocyclic class.

02:52 And the one that I really want to focus on is something called Mirtazapine.

02:56 Mirtazapine is another drug. It is sold as Remeron, which has a relatively slow onset of action.

03:03 So, you usually have to give it for about four weeks for it to exert its maximal effect.

03:08 Side effects of mirtazapine include weight gain, and that can be sedating in some patients, particularly the elderly.

03:15 You can get a mania, sort of similar to the psychosis with the other drugs, and a low white blood count associated with these drugs.

03:24 One of the concerns that we always have is that using this drug in children may increase their risk of suicide.

03:31 So generally speaking, we're avoiding it in childhood psychiatry.

03:35 It is not commonly used with a monoamine oxidase inhibitor because of interactions.

03:40 And you also have to be aware that when you're stopping this drug, there can be a discontinuation syndrome.

03:47 Another issue with mirtazapine is that it interacts through the cytochrome system.

03:51 And you can see here that it interacts with at least three of the moieties of cytochrome.

03:57 So, you have to be particularly careful with your medications.

04:00 Fluoxetine and paroxetine can increase mirtazapine levels.

04:04 And carbamazepine, also known as Tegretol is an inducer and it can decrease the mirtazapine levels.

04:11 It should not be started within two weeks of monoamine oxidase inhibitor ingestion.

04:17 And it's important to know that sometimes we use it in combination.

04:22 I'm not sure where this name comes from, but we all know that California rocket fuel refers to venlafaxine plus mirtazapine as a combination.

04:32 Again, I'm not sure where that comes from, but we have seen that in combination therapy.

04:38 What's the actions of mirtazapine? We call it a NaSSA.

04:42 A Nonadrenergic and specific seratogenic antidepressant or NaSSA.

04:49 Now it has two enantiomer is the R enantiomer and the S enantiomer.

04:54 And they will have often slightly different charges.

04:57 So, you can see that there's a slight difference in the receptor activity of these two enantiomers.

05:03 So, that's something that you should be aware.

05:05 But trust me, you don't need to know that for your exam.

05:08 But I just want you to remember that there are an enantiomers this drug that can affect the effectiveness of the drug and the side effect profile of this drug.

05:17 It is an inverse agonist of the serotonin receptor.

05:23 What is an inverse agonist? Well, let's talk about what an inverse agonist is.

05:29 An inverse agonist is one that when it binds to the receptor, you actually get a negative activity.

05:36 So you can see here that you have a neutral agonist or antagonist that neither helps nor hinders, you have a partial agonist that gives you a partial response and a full agonist that gives you a full response.

05:48 Antagonist will stop the activity but it doesn't cause a negative activity.

05:55 An inverse agonist actually causes a negative activity.

05:59 So that's what an inverse agonist is.

06:02 The other thing I want to point out is that it is a potent H1 receptor antagonists.

06:10 This medication does not inhibit the reuptake of serotonin, inhibit the uptake of norepinephrine, or inhibit the reuptake of dopamine.

06:22 It does not inhibit monoamine oxidase.

06:27 It does not block sodium, calcium, or potassium channels, and it does not act as an anticholinergic.

06:35 So this is an important distinction between it and many of the other antidepressants.