Pharmacology - ANTIDEPRESSANTS - SSRIs, SNRIs, TCAs, MAOIs, Lithium ( MADE EASY)

in this lecture I'm going to talk about antidepressants so let's get right into it we all experience changes in mood sometimes we feel happy and energetic and other times we feel sad and irritable fortunately these moods usually don't last long and we can go about our normal daily routine however life is not always that simple because there are times when we might experience unusually long periods of sadness guilt and decreased interest in activities this is what we call depression sometimes depression can occur alone and other times it is a part of a larger disorder such as bipolar disorder people with bipolar disorder experience periods of depression alternating with periods of mania in which person feels abnormally optimistic euphoric and energetic now treatment of depression and bipolar disorder often involves use of antidepressant drugs which work by elevating levels of certain neurotransmitters in the brain this led to development of monoamine hypothesis which states that depression results from deficiency in one or more of the three key monoamines namely serotonin norepinephrine and dopamine another hypothesis states that this monoamine depletion could also cause the postsynaptic receptors to upregulate thus leading to depression lastly the monoamine hypothesis of gene expression suggests that there might be an abnormal functioning gene that is responsible for causing depression now all that being said keep in mind that these hypotheses are overly simplistic and they don't accurately explain everything that we observed in research studies however they do give us partial explanation as to why antidepressants work so now let's switch gears and let's talk about antidepressant drugs based on their mechanism of action antidepressants can be divided into five different classes number one selective serotonin reuptake inhibitors SSRIs for short number two serotonin norepinephrine reuptake inhibitors SNRIs for short number three tricyclic antidepressants TCAs for short number four monoamine oxidase inhibitors MAOIs for short and lastly number five atypical antidepressants so now before we start discussing each class let me draw some neurons that will help us understand how these antidepressants differ in the way they work so here we have presynaptic serotonergic neuron or in other words serotonin producing neuron and next to it I'm going to draw a presynaptic noradrenergic neuron or in other words norepinephrine producing neuron now these two neurons interact with their postsynaptic counterparts so as you may have already guessed postsynaptic receptors of noradrenergic neuron are beta and alpha-1 while postsynaptic receptors of serotonergic neuron are serotonin often abbreviated as 5-HT receptors now keep in mind that there's quite a few subtypes of serotonin receptors but for now let's just keep it simple so going back to our two neurons the serotonin is synthesized from an amino acid tryptophan by serotonergic neurons and it is there stored in vesicles awaiting regulated release on the other side norepinephrine is synthesized from an amino acid tyrosine by noradrenergic neurons and it is also stored there in vesicles awaiting release so now what exactly happens when these neurotransmitters are released well there are a few key things to remember when serotonin and norepinephrine get released they begin to stimulate the receptors and at the same time they're transported from the synapse back to their neurons in a process called reuptake now serotonin is reabsorbed by serotonin transporter abbreviated as SERT while norepinephrine is reabsorbed by norepinephrine transporter abbreviated as NET another important thing to remember is that once the serotonin and norepinephrine get reabsorbed back to their neurons they're partially repackaged into synaptic vesicles and partially broken down into inactive metabolites by an enzyme monoamine oxidase abbreviated MAO now let's move on to discussing antidepressant drugs and let's start with selective serotonin reuptake inhibitors so as you can tell from their name SSRIs inhibit reuptake of serotonin and they accomplish that by blocking serotonin transporter this results in increased levels of serotonin available to bind to postsynaptic receptors examples of SSRIs include Citalopram Escitalopram Fluoxetine Fluvoxamine Paroxetine and Sertraline now besides being used for depression SSRIs are also used for other psychiatric disorders such as generalized anxiety post-traumatic stress disorder and obsessive-compulsive disorder okay so this whole mechanism of action looks pretty straightforward but then you may wonder why these antidepressants take weeks to produce maximum benefit well a new research gives us a little insight into why this happens so recently scientists discovered that in people with depression G-proteins tend to cluster in the patches of brain cell membranes rich in cholesterol called lipid rafts now when stuck on these rafts G-proteins lack access to molecule called cyclic AMP which is necessary to work and transmit signals of serotonin however later on it was discovered that SSRIs also tend to build up in these lipid rafts which resulted in the gradual movement of G-proteins out of the rafts toward regions of membrane where they are able to function better so here we have a possible reason why antidepressants take so long to produce maximum benefit now when it comes to side effects excessive stimulation of serotonin receptors in the brain may lead to insomnia increase anxiety and irritability next excessive stimulation of spinal serotonin receptors may lead to sexual side effects including erectile dysfunction and stimulation of serotonin receptors in the gastrointestinal tract as well as in the CNS may lead to nausea vomiting and diarrhea lastly abrupt withdrawal of an SSRI can result in temporary deficiency of synaptic serotonin which in turn may lead to unpleasant symptoms such as headache nausea vomiting agitation and sleep disturbances now let's move on to serotonin norepinephrine reuptake inhibitors so SNRIs just like SSRIs work by inhibiting reuptake of serotonin via inhibition of serotonin transporter but what makes them different is their ability to additionally inhibit norepinephrine transporter this results in increased levels of both serotonin and norepinephrine which can then bind to the postsynaptic receptors examples of SNRIs include Venlafaxine Desvenlafaxine Duloxetine and Levomilnacipran now similarly to SSRIs SNRIs are also used for depression anxiety and panic disorders however unlike SSRIs SNRIs have been shown to be also effective in reducing pain associated fibromyalgia as well as other pain caused by neuropathy this unique pharmacological action of SNRIs is thought to be related to enhanced noradrenergic activity within the central nervous system now when it comes to side effects they are very similar to those of SSRIs however because of additional noradrenergic activity SNRIs may increase blood pressure and heart rate now let's move on to tricyclic antidepressants so this class of antidepressants was named after their core chemical structure which contains three rings connected together unlike the other classes of antidepressants TCA's mechanism of action is not as straight forward so just like SNRIs TCAs were found to primarily inhibit reuptake of both serotonin and norepinephrine by blocking both of their transporters however different tricyclic agents do this with different level of selectivity in other words some TCAs such as Desipramine are more selective inhibitors of norepinephrine transporter then serotonin transporter furthermore TCAs also block many other receptors such as alpha receptors histamine receptors and muscarinic receptors however blockade of these other receptors is thought to be responsible for their side effects more than their antidepressant activity examples of TCAs include Amitriptyline Amoxapine Clomipramine Desipramine Doxepin Imipramine Maprotiline Nortriptyline and Protriptyline now TCAs are mainly used for depression however due to their broad mechanism of action they also proved to be beneficial in treatment of other medical problems for example Amitriptyline and Nortriptyline have been used for migraine prevention as well as treatment of neuropathic pain on the other hand TCAs such as Doxepin have been used for insomnia now when it comes to side effects inhibition of alpha receptors leads to orthostatic hypotension and dizziness inhibition of histamine receptors leads to sedation and inhibition of muscarinic receptors leads to anticholinergic effects such as blurred vision dry mouth constipation and urinary retention lastly TCAs block cardiac sodium channels and produce effects similar to antiarrhythmic agents such as Quinidine this ultimately can lead to cardiac conduction abnormalities now let's move on to monoamine oxidase inhibitors so monoamine oxidase is a mitochondrial enzyme that degrades monoamines such as serotonin and norepinephrine MAO exists in two subtypes A and B which are differently distributed in tissues such as brain gut and liver now MAO subtype A preferentially metabolizes serotonin but will also metabolize norepinephrine and dopamine while MAO subtype B preferentially metabolizes dopamine this is why the inhibition of MAO subtype A is thought to be responsible for antidepressant effects of majority of MAOIs so the primary mechanism of action is pretty straightforward MAOIs inhibit the activity of MAO enzymes preventing breakdown of monoamine neurotransmitters ultimately increasing their availability now examples of MAOIs include Isocarboxazid Phenelzine and Tranylcypromine which are all irreversible inhibitors of both MAO subtype A and MAO subtype B which in turn makes them effective for treatment of depression another example of MAOI which is a bit different from the rest is Selegiline which is a selective inhibitor of MAO subtype B and therefore has been shown to be effective in reducing symptoms of Parkinson's disease which results from depletion of dopamine so now on the surface it seems like MAOIs could be a good choice for the first or the second line antidepressant however in practice there are usually a very last choice and the reason is that MAOIs show not only high incidence of drug-drug interactions but also drug-food interactions as I mentioned earlier MAO enzymes are present in the gut there they play important role in breakdown of monoamines ingested in food the problem arises when inhibited MAO enzymes can't metabolize tyramine which is contained in foods that have been aged or fermented now built-up tyramine is taken up into the synaptic nerve terminals where it acts as a catecholamine releasing agent the release of large amount of catecholamines caused by tyramine leads to hypertensive crisis and potentially a stroke this is why patients that are prescribed MAOIs due to lack of other options must be educated about avoiding tyramine-rich foods okay so now finally we can move on to atypical antidepressants this class includes agents that have actions at several different sites and thus don't exactly fit into the other classes examples of atypical antidepressants include Bupropion Mirtazapine Trazodone Nefazodone Vilazodone and Vortioxetine now each of these drugs has a little different mechanism of action so Bupropion is a weak norepinephrine and dopamine reuptake inhibitor besides being used for depression Bupropion was found to be effective in reducing nicotine cravings and withdrawal symptoms next Mirtazapine is an alpha-2 receptor antagonist so by blocking presynaptic alpha-2 receptors Mirtazapine increases noradrenergic and serotonergic neurotransmission additionally Mirtazapine is thought to have some postsynaptic serotonin receptor blocking activity as well as antihistaminic activity which explains its sedating effects next we have Trazodone and Nefazodone their therapeutic effect is thought to be related to their ability to inhibit reuptake of serotonin as well as block postsynaptic serotonin receptors of subtype 2a which are the bad serotonin receptors activation of these serotonin 2a receptors is thought to contribute to depression additionally both of these agents antagonize histaminic H1 and adrenergic alpha-1 receptors which may account for their sedative effects next we have Vilazodone which has similar sounding name to Trazodone and Nefazodone but again it has its own unique mechanism of action so Vilazodone is a serotonin partial agonist reuptake inhibitor meaning it partially stimulates serotonin receptors and it inhibits reuptake of serotonin finally we have Vortioxetine which has a mechanism of action that is still a little unclear but it is believed to be related to its ability to inhibit serotonin reuptake as well as activate and block different subtypes of serotonin receptors involved in mood regulation and now before we end I just wanted to briefly discuss Lithium which is a mood stabilizing drug in its own class Lithium has been used in medicine for a very long time initially for depression but currently for bipolar disorders unfortunately Lithium has a fairly narrow therapeutic index which means that minor changes in dose or its blood levels can lead to toxicity now despite years of research the exact mechanism of action of Lithium as a mood stabilizer is still not entirely known however a few mechanisms of action have been proposed one in particular that has been extensively studied states that Lithium inhibits the recycling of neuronal membrane inositol lipids okay so this may get a little complicated but bear with me so in the inositol lipid pathway G-protein coupled receptors such as serotonin receptors activate phospholipase-C PLC for short which cleaves phosphatidylinositol 4,5-bisphosphate PIP2 for short to the signaling molecules diacylglycerol DAG for short and inositol 1,4,5-trisphosphate IP3 for short next IP3's action is terminated by conversion to inositol 4,5-bisphosphate IP2 for short and at this point the enzyme inositol phosphatase comes around and dephosphorylates IP2 to inositol phosphate IP1 for short and lastly another inositol phosphatase dephosphorylates IP1 to free inositol which is necessary for the regeneration of PIP2 so now what Lithium does is it inhibits both inositol phosphatase enzymes and thus decreases cellular responses to neurotransmitters that are linked to this second messenger system now Lithium also was found to inhibit glycogen-synthase-kinase-3 GSK3 for short mimicking the Wnt protein signaling pathway so basically we have this Wnt proteins which are secreted glycoproteins acting as a signaling molecules when they bind to receptors of the so called frizzled family they induce certain reactions which ultimately result in inhibition of GSK3 now GSK3 regulates critical processes such as axon remodelling synapse formation plasticity and neurogenesis what the research has found though is that the abnormal activation of GSK3 seems to be associated with several neurological and psychiatric disorders such as bipolar disorder so because Lithium inhibits GSK3 directly and non-directly it's likely that this particular mechanism contributes to its therapeutic effect unfortunately this doesn't end here Lithium brings about changes in all of the major neurotransmitter systems in the brain and I think at this point you had enough so we're not gonna dig further and with that I wanted to thank you for watching I hope you enjoyed this video and as always stay tuned for more

Channel: Speed Pharmacology

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Keywords: antidepressant drugs, tricyclic antidepressants, antidepressants pharmacology, tricyclic antidepressant (drug class), antidepressants, ssri, ssri mechanism of action, snri, how antidepressants work, serotonin pharmacology, monoamine, selective serotonin reuptake inhibitor (drug class), lithium, depression medication, serotonin receptors pharmacology, atypical antidepressants, cns pharmacology, inhibitors, serotonin, antidepressants side effects, mental health, depression treatment

Id: T25jvLC6X0w

Length: 19min 23sec (1163 seconds)

Published: Thu Nov 10 2016