Gabapentin And Pregabalin Discussion Paper

Gabapentin And Pregabalin Discussion Paper

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1.
Besty Sheldon
Gabapentin and Pregabalin

Gabapentin and pregabalin are considered a gabapentinoid and they are an antiepileptic drug used in the management of neuropathic pain (Chincholkar, 2020). Both can be useful in off-label conditions as well like, bipolar disorder, complex regional pain syndrome, attention deficit disorder, restless legs syndrome, sleep disorder, headaches, anxiety, chronic pain, and fibromyalgia (Chincholkar, 2020)Gabapentin And Pregabalin Discussion Paper. However, using it off-label needs to be studied further to fully understand.

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Furthermore, oral bioavailability for pregabalin is more than 90%, while gabapentin is 30-60%, meaning that it takes less pregabalin to reach the required pharmacological effect than gabapentin (Chincholkar, 2020). Thus, decreasing the risk of side effects and harmfulness. Also, gabapentin relies only on L-amino acid transporters (LAT) which are easily saturable, meaning it is dependent on dose pharmacokinetics (Chincholkar, 2020)Gabapentin And Pregabalin Discussion Paper. While pregabalin has non-saturable absorption, along with less bioavailability (Chincholkar, 2020).

Pharmacokinetics

Actions of gabapentin are at an intracellular site and require active uptake, with facilitated transport across cell membranes through system LAT which gabapentin is solely dependent on LAT for absorption (Chincholkar, 2020). Gabapentin is not absorbed by the liver and elimination is done by the kidneys, but like all drugs which are filtered through the kidney’s, buildup can cause renal failure causing in adverse effects (Chincholkar, 2020). Additionally, it is important to understand the pharmacodynamics as well.

Pharmacodynamics

GABA receptors are neurons in the nervous system which send chemical messages that help to reduce nerve impulses (Ghit et al.,2021). Interestingly, gabapentin and pregabalin do not bind to GABA receptors. “Although gabapentin’s mechanism of action is unclear, it does block voltage-gated calcium channels by binding to the α2 -δ subunit, 23 thereby reducing calcium influx. By blocking calcium influx, gabapentin reduces the release of glutamate and substance P from primary nociceptive afferents, thereby modulating nociceptive transmission” (Gropper, 2016, para. 1). Also, it is important to think about which patients are right for these medications.

Because gabapentin’s mechanism is unknown, Fukada et al., (2012) is concerned that it may be come a ‘catch all’ for prescribing, potentially increasing the risk of adverse effects, side effects, and ineffectiveness. Additionally, there have been limited research on off-label use related to ethnicity, weight, and gender. There is useful information however on the absorption in milligrams related to weight, when talking about the bioavailability Gabapentin And Pregabalin Discussion Paper

Conclusion

At the clinic I work in, both gabapentin and pregabalin are prescribed. The patient I have in mind, has found gabapentin to be very useful, stating that his pain is better (taking less opioids), his mood is better (less short), and anxiety is better. Also, on a clinical note his (undiagnosed) bipolar is also more stable resulting in healthier relationships and increased satisfaction with his work.

References

Fukada, C., Kohler, J. C., Boon, H., Austin, Z., & Krahn, M. (2012). Prescribing

gabapentin off label: Perspectives from psychiatry, pain and neurology specialists. Canadian pharmacists journal : CPJ = Revue des pharmaciens du Canada : RPC, 145(6), 280–284.e1. https://doi.org/10.3821/145.6.cpj280

Ghit, A., Assal, D., Al-Shami, A. S., & Hussein, D. (2021). GABAA receptors: structure,

function, pharmacology, and related disorders. Journal, genetic engineering & biotechnology, 19(1), 123. https://doi.org/10.1186/s43141-021-00224-0

Gropper, M. (2016). Gabapentin (J. K. Aronson, Ed.). ScienceDirect; Elsevier. https://www.sciencedirect.com/science/article/pii/B9780444537171007897 Gabapentin And Pregabalin Discussion Paper

2.
Maggie Etukeni
Pharmacologic Options (Initial posting)

Comparing and Contrasting Pharmacologic Options for the Treatment of Generalized Anxiety Disorder

Generalized anxiety disorder (GAD), is a psychiatric condition that is characterized by excessive, persistent, and unrealistic worry about everyday things. Several types of medications are used in the management of GAD including antidepressants, benzodiazepines, antipsychotics and buspirone (Munir & Takov, 2022). According to the FDA (2017) the specific medications that are approved GAD treatment include benzodiazepine (Alprazolam (Xanax), Clonazepam (Klonopin), and antidepressants (Paroxetine (Paxil), Escitalopram (Lexapro), Duloxetine (Cymbalta), Venlafaxine (Effexor)

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Pharmacodynamics

Benzodiazepines act as positive allosteric modulators on the GABA-A receptors (gamma amino butyric acid-A receptor). GABA is the most common neurotransmitter in the CNS. There are three GABA receptors designated A, B, and C. GABA is an inhibitory neurotransmitter, producing a calming effect on the brain. Benzodiazepines bind and interact with the GABA-A receptors. Once they bind the GABA-A receptor, they result in a conformational change of the receptor. The conformational change in the GABA-A receptor’s chloride channel hyperpolarizes the cell and accounts for the benzodiazepine inhibitory effect throughout the central nervous system (Griffin et al., 2013)Gabapentin And Pregabalin Discussion Paper.

On the contrary, antidepressants such as paroxetine exact their effect via a different mechanism. For instance, paroxetine is categorized as a selective serotonin reuptake inhibitor (SSRI). Therapeutic actions of SSRIs emanate from their capacity to inhibit the presynaptic neuronal uptake of serotonin, thereby increasing serotonin activity in the CNS, which presents as alleviation of anxiety symptoms (Chu & Wadhwa, 2022)Gabapentin And Pregabalin Discussion Paper

On the other hand, antidepressant such as duloxetine and venlafaxine exert their effect via a different mechanism. They are categorized as serotonin-norepinephrine reuptake inhibitors (SNRIs). SNRI therapeutic effect results from their ability to inhibit the presynaptic neuronal uptake of serotonin and norepinephrine in the CNS, therefore increasing their activity. The increase in activity is associated with alleviating anxiety symptoms in GAD (Sheffler & Abdijadid, 2021).

Pharmacokinetics

Pharmacokinetic properties determine a drug’s onset of action and the duration of its effects. It includes the properties of absorption depending on the route of administration, distribution, metabolism, and excretion of a drug. Usually, benzodiazepines are well absorbed in the gastrointestinal tract after oral administration. They are quirkily distributed to the central nervous system and preferentially accumulate in lipid-rich areas. They are subject to cytochrome P450 enzyme metabolism and undergo conjugation. Most metabolites are highly protein bound. They are excreted almost entirely in the urine (Griffin et al., 2013). For instance, Alprazolam oral absorption is not affected by food, is metabolized by CYP450 3A4, has inactive metabolites, and has an elimination half-life of 12–15 hours (Stahl, 2017)Gabapentin And Pregabalin Discussion Paper.

SSRIs are only available orally and administered as tablets, capsules, or liquid suspensions or solutions (Chu and Wadhwa, 2022). They have a large volume of distribution and are highly bound to plasma proteins. The Peak plasma levels are reached in two to ten hours. SSRIs are metabolized by the cytochrome P450 system enzymes and preferentially excreted via the kidneys (Edinoff et al, 2021). For instance, it is administered orally, has a high distribution volume, and is highly plasma bound (95%). It may displace other highly protein-bound drugs such as warfarin. Paroxetine is eliminated after transformation in the liver by cytochrome P450 isoenzyme CYP2D6 into pharmacologically inactive metabolites (Stahl, 2017).

Similar to SSRIs, SNRIs are available in oral dosage forms in different formulations, such as immediate, extended, or sustained-released formulations. They also have a high volume of distribution, primarily metabolized by the liver by the cytochrome P450 CYP2D6 enzyme before excretion. For instance, for duloxetine, food does not affect absorption; metabolized mainly by CYP450 2D6 and CYP450 1A2. It is an inhibitor of CYP450 2D6. It has an elimination half-life of 12 hours (Stahl, 2017)Gabapentin And Pregabalin Discussion Paper.

References

Chu, A., & Wadhwa, R. (2022). Selective serotonin reuptake inhibitors – StatPearls – NCBI bookshelf. National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/books/NBK554406/

Edinoff, A. N., Akuly, H. A., Hanna, T. A., Ochoa, C. O., Patti, S. J., Ghaffar, Y. A., Kaye, A. D., Viswanath, O., Urits, I., Boyer, A. G., Cornett, E. M., & Kaye, A. M. (2021). Selective serotonin reuptake inhibitors and adverse effects: A narrative review. Neurology International, 13(3), 387-401. https://doi.org/10.3390/neurolint13030038

Food and Drug Administration. (2017, January 19). FDA-approved GAD (Generalized anxiety disorder) medications. Promises Behavioral Health. https://www.promises.com/addiction-blog/fda-approved-gad-generalized-anxiety-disorder-medications/

Griffin, C. E., 3rd, Kaye, A. M., Bueno, F. R., & Kaye, A. D. (2013). Benzodiazepine pharmacology and central nervous system-mediated effects. The Ochsner journal, 13(2), 214–223. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3684331/

Munir, S., & Takov, V. (2022). Generalized Anxiety Disorder. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK441870/

Sheffler, Z. M., & Abdijadid, S. (2021). Antidepressants – StatPearls – NCBI bookshelf. National Center for Biotechnology Information. https://www.ncbi.nlm.nih.gov/books/NBK538182/

Stahl, S. M. (2017). Prescriber’s guide: Stahl’s essential psychopharmacology. Cambridge University Press Gabapentin And Pregabalin Discussion Paper

NURS 6521 Discussion response

Gabapentin and Pregabalin

Sheldon thanks for bring forth this discussion of pregabalin and gabapentin which has gained popularity recently in management of chronic neuropathic pains, both are gabapentinoids that works mainly at an intracellular site and require active uptake. They undergo facilitated transport across cell membranes through system l-amino acid transporters (LAT) as both drugs are structurally similar to the amino acid leucine they exert their effect by inhibiting calcium influx and subsequent release of excitatory neurotransmitters; with slight difference in their pharmacokinetics, Chincholkar (2020) elucidates that pregabalin  has some distinct pharmacokinetic advantages over gabapentin that may translate into an improved pharmacodynamic effect; due to the following, Gabapentin is slowly  & partially absorbed  after oral administration, with maximum plasma concentrations attained within 3-4 hours, its plasma concentrations do not increase proportionally with increasing dose and its bioavailability of drops from 60% to 33% as the dosage increases from 900 to 3600 mg/day it is available in two extended-release formulations in addition to the immediate release: a gastric retentive formulation (GBP-GR) given as once daily dose and a gastro-retentive prodrug gabapentin enacarbil given in two divided doses, while in contrast, orally administered pregabalin is rapidly and completely absorbed, with maximum plasma concentrations attained within 1 hour, the absolute bioavailability of pregabalin remains more than or equal to 90% irrespective of the dosage. Both drugs can be given without regard to meals, they don’t bind to plasma proteins, no hepatic metabolism or inhibition of hepatic enzymes, are excreted renally, with elimination half-lives of approximately 6 hours, are available in liquid formulation, for children and patients who are unable to take solid food, capsules can be opened and their contents dissolved in water and administered via a feeding tube.

Their pharmacodynamics is similar, work by binding to α2δ-1 subunit of voltage-gated calcium channels (VGCCs) involved in nociception, inhibiting calcium currents thereby inhibiting release of neurotransmitters, inhibit the accumulation of α2δ-1 in the pre-synaptic terminals in the dorsal horn, thus providing analgesia, Analgesic effects are mediated by the facilitation of descending noradrenergic inhibition, inhibition of descending serotonergic facilitation and by cortical mechanisms affecting the limbic system,  Robertson, Marshman, Plummer and Downs  (2019)Gabapentin And Pregabalin Discussion Paper.

Adverse effects are common with gabapentinoids resulting in a discontinuation rate of at least 11%, but serious adverse events are uncommon, weight gain, dizziness, somnolescence; patients must be warned about the potential to impact the ability to perform tasks that need concentration such as driving, and they stimulate feelings of sociability, euphoria, calm and relaxation and can enhance psychoactive effects of other drugs which has lead gabapentinoids being abused.

References

Chincholkar M. Gabapentinoids: pharmacokinetics, pharmacodynamics and considerations for clinical practice. Br J Pain. 2020 May;14(2):104-114. doi: 10.1177/2049463720912496. Epub 2020 Mar 13. PMID: 32537149; PMCID: PMC7265598.

Robertson K, Marshman LAG, Plummer D, Downs E. Effect of Gabapentin vs Pregabalin on Pain Intensity in Adults With Chronic Sciatica: A Randomized Clinical Trial. JAMA Neurol. 2019 Jan 1;76(1):28-34. doi: 10.1001/jamaneurol.2018.3077. Erratum in: JAMA Neurol. 2019 Jan 1;76(1):117. PMID: 30326006; PMCID: PMC6439871. Gabapentin And Pregabalin Discussion Paper

Pharmacologic Options for the Treatment of Generalized Anxiety Disorder

Generalized anxiety disorder (GAD), a chronic mental illness, often begins during adolescence or early adulthood and persists throughout the lifespan characterized excessive persistent & unrealistic worry about everyday things. Scientific sound studies has supported the efficacy of selective serotonin (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), benzodiazepines, azapirones, anti-adrenergic medications, melatonin analogues, second-generation antipsychotics, kava and lavender oil in as pharmacological active agents to treat GAD.

SSRIs & SNRIs classes are described by Munir and Takov (2022) as the first-line agents with a response rate of 30% to 50%.  SSRIs examples, fluoxetine, dapoxetine and citalopram, are more selectively inhibiters of serotonin (5-HT) reuptake transporter and weakly inhibiter of dopamine and norepinephrine reuptake mechanisms. Inhibition of 5-HT reuptake increases the concentrations of synaptic 5-HT, which in turn increases in the brain a rise in serotonin levels improves symptoms and make people more responsive to other types of treatment, such as CBT, serotonin is a neurotransmitter thought to have a good influence on mood, emotion and sleep. SSRIs have broad spectrum efficacy in both short-term and long-term treatment, and are generally well tolerated; and for these reasons are widely considered to be the first-line pharmacological approach in patients with anxiety disorders in combination with cognitive behavioural therapy (CBT)Gabapentin And Pregabalin Discussion Paper.

SNRIs examples desvenlafaxine, duloxetine, levomilnacipran are also called dual reuptake inhibitors or dual-acting antidepressants because it inhibit two neurotransmitters, Bandelow at el. (2017) acknowledges SNRIs as second line treatment to patient not responding to SSRIs, they work by increasing Nor-epinephrine and serotonin in the brain thus stabilizing the mood, alertness and energy, They do this by stopping serotonin and norepinephrine from going back into the cells that released them

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References

Munir S, Takov V. Generalized Anxiety Disorder. [Updated 2022 Jan 9]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK441870/

Bandelow B, Michaelis S, Wedekind D. Treatment of anxiety disorders. Dialogues Clin Neurosci. 2017 Jun;19(2):93-107. doi: 10.31887/DCNS.2017.19.2/bbandelow. PMID: 28867934; PMCID: PMC5573566 Gabapentin And Pregabalin Discussion Paper