NSG 502 Discuss the medication‘s classification, pharmacodynamics, pharmacokinetics, neurotransmitters and receptor sites involved

NSG 502 Discuss the medication‘s classification, pharmacodynamics, pharmacokinetics, neurotransmitters and receptor sites involved

NSG 502 Discuss the medication‘s classification, pharmacodynamics, pharmacokinetics, neurotransmitters and receptor sites involved

Venlafaxine (Effexor) is a selective serotonin-norepinephrine reuptake inhibitor with FDA approved indications for the treatment of major depressive disorder, generalized anxiety disorder, and social anxiety disorder (Schatzberg & DeBattista, 2015). Off label uses of venlafaxine include posttraumatic stress disorder, premenstrual dysphoric disorder, and chronic pain (Schatzberg & DeBattista, 2015).

Venlafaxine has unique pharmacokinetic and pharmacodynamic properties that differ from selective serotonin reuptake inhibitors (SSRI’s). Venlafaxine blocks 5HT or the serotonin transport (SERT) even at lose doses, increasing serotonin availability at the synaptic cleft (Schatzberg & DeBattista, 2015). In addition, venlafaxine works on B-adrenergic receptors, coupled cyclic adenosine monophosphate, accounting for why it’s onset of effectiveness is faster than other antidepressants (Schatzberg & DeBattista, 2015). An important feature of venlafaxine is that it works on norepinephrine reuptake, increasing norepinephrine and dopamine in the prefrontal cortex (Stahl, 2013). However, the effect of norepinephrine reuptake is observed at higher doses, at 150mg or more per day (Stahl, 2013). The blockage of norepinephrine transporter (NET), also blocks the reuptake of dopamine, explaining venlafaxine’s effect of increasing dopamine in the prefrontal cortex (Stahl, 2013).  Increased levels of available dopamine can account for venlafaxine’s effect on cognition (Schatzberg & DeBattista, 2015).

Venlafaxine has weak protein binding, is not a potent inhibitor of cytochrome P450, and is a substrate for CYP2D6, accounting for a low risk of drug interactions and protein binding to medications such as digoxin. Furthermore, when looking at the metabolism of venlafaxine, there is a very low level of hepatic metabolism (Schatzberg & DeBattista, 2015).

Venlafaxine side effects include gastrointestinal such as nausea due to working on SERT and increased serotonin that usually improve around weeks two to three of taking (Schatzberg & DeBattista, 2015). Increased serotonin can also cause central nervous system side effects including headache and insomnia (Stahl, 2020). Due to NET blockade, at higher doses increased norepinephrine can also raise heart rate and blood pressure (Schatzberg & DeBattista, 2015). Moreover, actions on NET can impact norepinephrine and acetycholine release, resulting in constipation and dry mouth (Stahl, 2020).

Dosing of venlafaxine should be started at 37.5 mg once a day and extended release is preferred with a maximum dose of 225 mg per day. In individuals who have been on venlafaxine for more than a week, it must be tapered due to concern for discontinuation syndrome, including symptoms of dizziness and paresthesia’s (Schatzberg & DeBattista, 2015).

Interestingly, one study supports that venlafaxine can be utilized off label for migraine prophylaxis (Bulut et al., 2004).  Venlafaxine was found to be comparable to amitriptyline in effectiveness for headache reduction (Bulut et al., 2004). For individuals who suffer from migraines and depression, venlafaxine may be a beneficial medication option for treatment.

 

References

Bulut, S., Berilgen, M.S, Baran, A. Tekatas, A., Atmaca, M., Mungen, B. (2004). Venlafaxine versus amitriptyline in the prophylactic treatment of migraine: randomized, double-blind, crossover study. Clin Neurol Neurosurg, 107 (1): 44-48. Doi: 10.1016/i.clinneuro.2004.03.004.

Schatzberg, A. F. & DeBattista, A.F. (2015). Manual of Clinical Psychopharmacology (8th Ed.). American Psychiatric Publishing.

Stahl, S.M. (2020). Stahl’s Essential Psychopharmacology Prescriber’s Guide (7th Ed.).   Cambridge University Press: New York, NY.  ISBN-10: 1108926010.

Stahl, S.M. (2013). Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications (4th Ed.). Cambridge University Press: New York, NY. ISBN 10:  9781107686465.

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Fluvoxamine (Luvox) is a well-tolerated and widely available medication belonging to a class of medications known

NSG 502 Discuss the medication‘s classification, pharmacodynamics, pharmacokinetics, neurotransmitters and receptor sites involved
NSG 502 Discuss the medication‘s classification, pharmacodynamics, pharmacokinetics, neurotransmitters and receptor sites involved

as selective serotonin reuptake inhibitors, or SSRIs (Sukhatme et al., 2021). It has not been approved for the treatment of depression in the United States, however, the U.S. Food and Drug Administration did authorize it for treatment of obsessive-compulsive disorder and social anxiety disorder, with off-label uses for depression, panic disorder, generalized anxiety disorder, binge eating disorder and post-traumatic stress disorder. It is available in both immediate and controlled-release formulas making once-daily administration possible and advantageous for medication adherence (Stahl, 2013; Stahl et al., 2021).

Therapeutic actions of SSRIs are largely rooted in the monoamine theory of depression, whereby increasing deficient serotonin likely results in the improvement of depressive symptoms (Chu, 2021). As with all SSRIs, fluvoxamine exerts action by selectively inhibiting serotonin reuptake through inhibition of the serotonin reuptake transporter (SERT) at the presynaptic axon terminal (Stahl, 2013). Upon fluvoxamine administration, serotonin levels rise within the somatodendritic area in the midbrain raphe and stimulate nearby 5HT1A autoreceptors. Over time, the 5HT1A autoreceptors desensitize and downregulate due to the increased concentration of serotonin, which simultaneously augments the amount of serotonin remaining in the synaptic cleft (Stahl, 2013). In turn, this mechanism causes postsynaptic serotonin receptors to desensitize, which then stimulates postsynaptic receptors for an extended period (Chu, 2021). This cascade of reactions causes delayed but powerful “disinhibition of serotonin release in key pathways throughout the brain” (Stahl, 2013, p. 296), thus inhibiting the neuronal uptake of serotonin. Additionally, and uniquely so, secondary properties of fluvoxamine include potential agonist actions at the sigma-1 binding receptors (Stahl, 2013). In fact, “fluvoxamine (FLV) has been shown to have the strongest activity of all SSRIs at the sigma-1 receptor” (Sukhatme et al., 2021, p. 1) which may not only contribute to its anxiolytic effect but may also prove beneficial for psychotic depression (Stahl, 2013).

Another critical factor involved in the anti-depressive effects of SSRIs worth mentioning is the brain-derived neurotrophic factor or BDNF. BDNF is a growth factor that serves many key functions of the central nervous system and has been implicated in several psychiatric disorders, including depression (Björkholm & Monteggia, 2016). Accumulating evidence indicates BDNF serves as a transducer between the antidepressant medication and neuroplastic changes in the brain that ensue, suggesting that BDNF is a crucial facilitator of standard antidepressant responses. In short, the neuroplastic changes that occur due to antidepressant pharmacotherapy are thought to result in the improvement of depressive symptoms (Björkholm & Monteggia, 2016).

Following oral administration, fluvoxamine is rapidly absorbed with an absolute bioavailability of 53%, largely unaffected by food (Teva, 2019). Studies have demonstrated little to no significant affinity for muscarinic, alpha or beta-adrenergic, histaminergic, or dopaminergic receptors, which likely explains the tolerable side effect profile of this medication. Roughly 80% of fluvoxamine is bound to plasma protein, namely albumin, and the medication is extensively metabolized by the liver through oxidative demethylation and deamination by CYP2D6 and CYP1A2 isoenzymes (Teva, 2019). Fluvoxamine has no pharmacologically active metabolites and is a strong inhibitor of four CYP450 isoenzymes including CYP1A2, CYP2C19, CYP3A4, and CYP2D6 (Stahl et al., 2021; Zastrozhin et al., 2018). It is noteworthy to mention regarding CYP450 interactions that fluvoxamine can therefore reduce the clearance of Pimozide, Thioridazine, alprazolam, diazepam, and carbamazepine, as well as increase levels of clozapine, theophylline, and tizanidine (Teva, 2019). Fluvoxamine is excreted in the urine with a half-life ranging between 9-28 hours, averaging approximately 15 hours (Stahl et al., 2021).

Common side effects of fluvoxamine include insomnia and gastrointestinal upset, and are likely yet theoretically due to increases in serotonin concentration at receptor sites other than those that are targeted to produce therapeutic effects. Additionally, the increase in serotonin can potentially reduce dopamine release which may contribute to cognitive slowing, emotional flattening, and even apathy in some patients (Teva, 2019). Fluvoxamine’s sigma-1 binding properties can further add to symptoms of sedation and fatigue experienced by some patients (Stahl et al., 2021). A general list of side effects as highlighted by Stahl et al. (2021) includes sexual dysfunction, decreased appetite, nausea, constipation, dry mouth, insomnia, sedation, agitation, tremors, headache, dizziness, sweating, bruising, rare hyponatremia, and rare bleeding. It is important to mention that side effects usually improve over time, becoming more tolerable and often disappearing altogether (Stahl, 2013). To note, any adverse reactions should prompt ongoing assessment and monitoring by the primary provider. Life-threatening but rare side effects include seizures, induction of mania, and suicidal ideation (Stahl et al., 2021). Lastly, SSRIs are contraindicated with concurrent use of MAOIs, linezolid, and any medication that increases serotonin levels as this poses an increased risk of developing serotonin syndrome, a life-threatening condition (Chu, 2021).

The usual dosage range for treatment of obsessive-compulsive disorder in adults is 100-300 mg/day, beginning between 50 and 100mg daily until maximum therapeutic effects are reached (Stahl et al., 2021). As a general principle, full therapeutic effects of SSRIs, including fluvoxamine, are not usually experienced until 2-4 weeks of treatment (Stahl, 2013). Overdoses of fluvoxamine are rare, and the medication is safe for long-term use. Though fluvoxamine is not habit forming, tapering is still required when discontinuing to avoid symptoms of withdrawal (Stahl et al., 2021).

 

References

Björkholm, C., & Monteggia, L. M. (2016). BDNF – a key transducer of antidepressant effects. Neuropharmacology, 102, 72–79. https://doi.org/10.1016/j.neuropharm.2015.10.034

Chu, A. (2021, May 10). Selective serotonin reuptake inhibitors. StatPearls [Internet]. Retrieved September 13, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK554406/.

Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications. Cambridge University Press.

Stahl, S. M., Grady, M. M., & Muntner, N. (2021). Stahl’s essential psychopharmacology: Prescriber’s Guide. Cambridge University Press.

Sukhatme, V. P., Reiersen, A. M., Vayttaden, S. J., & Sukhatme, V. V. (2021). Fluvoxamine: A review of its mechanism of action and its role in covid-19. Frontiers in Pharmacology, 12. https://doi.org/10.3389/fphar.2021.652688

Teva Canada Limited (2019). Act fluvoxamine. (Fluvoxamine Maleate Tablets). https://pdf.hres.ca/dpd_pm/00054136.PDF

Zastrozhin, M. S., Grishina, E. A., Denisenko, N. P., Skryabin, V. Y., Markov, D. D., Savchenko, L. M., Bryun, E. A., & Sychev, D. A. (2018). Effects of CYP2D6 genetic polymorphisms on the efficacy and safety of fluvoxamine in patients with depressive