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Generalized Anxiety Disorder
The term “generalized” refers to people who suffer from GAD and are afraid of many different things rather than just one or two specific things or sets of circumstances. This can have an emotional and physical impact on the daily living of someone, including fatigue, muscle tension, and increased heart rate. Anxiety can be debilitating, but there are many methods to bring it down to bearable levels. Therefore, symptoms like excessive worrying about various things are characteristic of GAD, making it the most prevalent kind of anxiety disorder. Different therapy approaches for GAD are compared, and the pharmacokinetics and pharmacodynamics of the anxiolytic drugs used to treat the disease will be discussed.
Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin-norepinephrine reuptake inhibitors (SNRIs)
Because of their relatively low risk, SSRIs and SNRIs are recommended as first-line treatments for depression. Patients should be informed that they can take these antidepressants from 2 weeks to 6 weeks to start significantly reducing anxiety (Leshem et al., 2021). The first two weeks are when adverse reactions could be potentially at their worst. Increased anxiety or unease at first can make patients less likely to stick with their treatment plan. Some of these symptoms may go away if you start on a lower dose of the antidepressant. However, clinical data suggests that tolerance varies by patient and that a given patient may experience fewer side effects by moving from an SSRI to an SNRI. Several SSRIs and SNRIs are cytochrome P450 enzyme inhibitors, which raises the possibility of drug interactions with other psychopharmacological medications and medical treatment (Leshem et al., 2021). Sudden discontinuation of SSR medications can result in withdrawal symptoms. While unpleasant, these symptoms pale in comparison to those of benzodiazepine withdrawal. These adverse effects may be more familiar with paroxetine than with sertraline or fluoxetine.
Tricyclic Antidepressants (TCAs)
The classic tricyclic antidepressants (TCAs), imipramine and clomipramine, are as effective as second-generation antidepressants in treating anxiety disorders. However, on average, TCAs have more side effects than SSRIs or SNRIs (Schneider, Patterson, & Jimenez, 2019). As a result, these medications should be tried first before using TCAs. The dosage should be gradually increased until it reaches the levels recommended for depression treatment. TCAs should be used with caution in patients at risk of suicide due to the possibility of lethal toxicity following an overdose. All TCAs are rapidly absorbed after oral administration and bind to plasma albumin with a high affinity of 90-95 percent at therapeutic plasma concentrations. Because of their ability to bind to extravascular tissues, they have enormous distribution volumes (10-50 l kg1) (Schneider, Patterson, & Jimenez, 2019). The main mechanisms of inactivation by CYP450 enzymes are the demethylation of tertiary TCAs to their secondary amine metabolites, hydroxylation, then glucuronidation, and excretion in the urine. Plasma concentrations with a therapeutic impact of 50 to 300 ng ml1 (molecular weights ranging from 263 to 314) are commonly used (Schneider, Patterson, & Jimenez, 2019).
Benzodiazepines are a class of medications with a highly personalized chemical structure and consistent pharmacological properties. Their pharmacokinetics and metabolism distinguish them to a large extent, so they must be used with caution. These are weak acids with high lipophilicity and variable constant dissociation, which allows for rapid passage through membranes (blood-brain and placental barriers, as well as the path in breast milk) (Ogawa et al., 2019). Except for chlordiazepoxide, dipotassium clorazepate, and midazolam, almost all benzodiazepines are insoluble in water, necessitating the use of organic solutions for parenterally administrable versions. These sedatives are frequently used only for the relief of acute anxiety. If you have a history of alcohol or drug abuse, these medications are not a good choice because they can become habit-forming. In extreme cases (e.g., severe heart disease, contraindications to conventional medications, suicidality, and other disorders), benzodiazepines can be used for a limited time (Ogawa et al., 2019). Patients with a history of the benzodiazepine or other substance abuse should not be treated with this class of medication. Benzodiazepines can be combined with SSRIs/SNRIs in the weeks preceding the antidepressant’s onset of efficacy.
Buspirone, an azapirone-classified partial agonist of 5-HT1A, is FDA-approved for anxiety treatment and is frequently used in conjunction with SSRIs or SNRIs, primarily for GAD. It is the only azapirone that has been approved in the United States. In a Cochrane study, Buspirone was superior to a placebo but had a more minor effect on GAD than benzodiazepines and antidepressants (Wilson & Tripp, 2020). Furthermore, those who had previously used benzodiazepines found them less effective and well-tolerated (nausea and dizziness). Buspirone has a significant first-pass effect and is almost well absorbed orally. The plasma peak for a 10 mg dose is reached in less than an hour. 95% of the time, it binds to plasma proteins (Wilson & Tripp, 2020). Buspirone metabolism involves hydroxylation and oxidative breakdown, which results in the formation of inactive metabolites, and Buspirone is excreted via the urinary and biliary systems. The apparent elimination half-life is typically 2 to 4 hours (Wilson & Tripp, 2020). Repeated doses demonstrate a linear relationship between plasma concentrations and the dose administered
Leshem, R., Bar-Oz, B., Diav-Citrin, O., Gbaly, S., Soliman, J., Renoux, C., & Matok, I. (2021). Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) during pregnancy and the risk for autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) in the offspring: a true effect or a bias? A systematic review & meta-analysis. Current Neuropharmacology, 19(6), 896-906.
Ogawa, Y., Takeshima, N., Hayasaka, Y., Tajika, A., Watanabe, N., Streiner, D., & Furukawa, T. A. (2019). Antidepressants plus benzodiazepines for adults with major depression. Cochrane Database of Systematic Reviews, (6).
Schneider, J., Patterson, M., & Jimenez, X. F. (2019). Beyond depression: Other uses for tricyclic antidepressants. Cleveland Clinic Journal of Medicine, 86(12), 807-814.
Wilson, T. K., & Tripp, J. (2018). Buspirone. Objectives: Describe the mechanism of action of buspirone Outline the indications for initiating buspirone. Summarize the