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Week 2 Main Discussion

COLLAPSE

                                                              Agonist-to-Antagonist Spectrum of Action

Communication within neurons with their targeted tissues at synapses causes their release of chemical substances called neurotransmitters (ligands) (Vaskovic, 2022). According to Berg and Clarke (2018), all receptors are all in a state of inactivity unless activated by a neurotransmitter (ligand). Ligands could act as agonists with various degrees of intrinsic efficacy, or as antagonists with zero intrinsic efficacy. Inverse agonism and biased agonism are 2 concepts in contemporary pharmacology that have major implications for the use of drugs in medicine. Nevertheless, it has been researched that receptors can be active without an activating ligand and thus display “constitutive” activity. A new class of ligands was discovered that can reduce the constitutive activity of a receptor and these ligands produce the opposite effect of an agonist and are called inverse agonists. Drugs can behave as agonists or antagonists. Agonists are drugs with both affinities (they bind to the target receptor) and intrinsic efficacy (they change receptor activity to produce a response). Antagonists have affinity but zero intrinsic efficacy; therefore, they bind to the target receptor but do not produce a response. As intrinsic efficacy differs with drug structure, agonists can have different intrinsic efficacies and consequently be characterized as full or partial agonists. A full agonist typically produces the maximal response a system is capable of, whereas a partial agonist produces a submaximal response. Between agonists and antagonists are partial agonists, which increase the degree and frequency of ion-channel opening as compared to the resting state, but not as much as a full agonist. Many important psychopharmacological drugs target ion channels to effect change. For example, Clozapine and several putatively ‘atypical’ antipsychotic agents, including ziprasidone, quetiapine, and tiospirone, exhibited partial agonist activity and marked affinity at h5-HT1A receptors, similar to their affinity at hD2 dopamine receptors. In contrast, risperidone and sertindole displayed low affinity at h5-HT1A receptors and behaved as ‘neutral’ antagonists, inhibiting 5-HT-stimulated [35S]GTPgammaS binding (Newman-Tancredi et al., 1998).

                                                         G Couple Proteins and Ion Gated Channels

G couple proteins (GPCRs), also called metabotropic receptors, are membrane-bound proteins that activate G-proteins after binding to neurotransmitters. Each has seven transmembranes in its structure which contain binding sites for neurotransmitters. They contain receptors for hormones such as calcitonin, and neurotransmitters such as dopamine and serotonin, and are often the target of drugs. Ion gated channels also called the inotropic receptor serve as regulators controlling cellular excitability which allow flow into or out of the cell in response to the binding of a chemical messenger to their respective receptors. These ion channels contain sodium, potassium, and calcium channels, They are usually classified by gating i.e. the stimulus that ‘opens’ the channel, be it chemical or mechanical stimuli based on the actions of the neurotransmitter, drug, or hormone. Ion channels are opened and closed by the actions of neurotransmitter ligands at receptors acting as gatekeepers.

GPCRs have slower effects than ionotropic receptors. Like ionotropic receptors, which are present in the plasma membrane and membranes of intracellular organelles of all cells, metabotropic receptors are primarily located along the dendrites or cell body, but they can be present anywhere along the neuron if there is a synapse. They are also important for receiving incoming information from other neurons (Henley, 2021).

                                                                                                      The Role of Epigenetics.

Epigenetics can be defined as the study of how human behaviors and the environment can cause changes that affect the way their genes work. Epigenetic changes are reversible and do not change our DNA sequence, but they can change how the body reads a DNA sequence. Epigenetic changes affect gene expression to turn genes “on” and “off.” Since your environment and behaviors, such as diet and exercise, can result in epigenetic changes, it is easy to see the connection between your genes and your behaviors and environment. Epigenetic alterations are considered to be very influential in both the normal and disease states of an organism. These alterations include methylation, acetylation, phosphorylation, and ubiquitylation of DNA and histone proteins (nucleosomes) as well as chromatin remodeling. Many diseases, such as cancers and neurodegenerative disorders, are often associated with epigenetic alterations (Rasool et al., 2015). DNA Methylation is by adding a chemical group to DNA and this group is added to specific places on the DNA, where it blocks the proteins that attach to DNA to “read” the gene. This chemical group can be removed through a process called demethylation. Drugs may alter epigenetic homeostasis by direct or indirect mechanisms. Direct effects may be caused by drugs that affect chromatin architecture or DNA methylation. For example, the antihypertensive hydralazine inhibits DNA methylation. Most drug trials investigating the use of epigenetic drugs for treating anxiety disorder (Ads) have used histone deacetylase inhibitors (HDACi). HDACi is showing favorable results in both preclinical and clinical drug trials for treating ADs. However, the mode of action of HDACi in ADs is not clear on how epigenetic dysregulation contributes to the pathogenesis of Ads (Peedicayil, 2020).

                                     Implications of Findings to Prescribing

 As a psychiatric mental health nurse practitioner, it is very key to know a specific action of a drug and the underlying molecular basis behind the disease to ensure a proper prescription. The acts of knowing the mechanisms of action, dosage, route, and side effects of medications that we are prescribing are important to provide excellent care to the patient. For example, prescription of sertraline (Zoloft), (a selective serotonin reuptake inhibitor (SSRI)) in the treatment of a patient with a diagnosis of major depressive disorder, there are some issues to be addressed with the patient while taking the medication to allay any concern. The length of time the medication takes to begin to become effective, the expected side effects, and the required dosage for effectiveness should be discussed with the patient because Zoloft is expected to start working in about two to six weeks. Serotonin in the central nervous system plays a role in regulating mood, personality, and wakefulness, which is why blocking serotonin reuptake is thought to be beneficial in treating a disorder such as major depression.

                                                                                          References

Berg, K. A., & Clarke, W. P. (2018). Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity. The international journal of neuropsychopharmacology, 21(10), 962–977. https://doi.org/10.1093/ijnp/pyy071

Center for disease control and prevention. (2020). What is Epigenetics? Retrieved from https://www.cdc.gov/genomics/disease/epigenetics.htm

Csoka, A.B., & Szyf, M. (2009). Epigenetic side-effects of common pharmaceuticals: a potential new field in medicine and pharmacology. Medical Hypotheses:73(5):770-80. doi: 10.1016/j.mehy.2008.10.039.

Henley Casey. (2021). Foundations of Neuroscience. Retrieved from https://openbooks.lib.msu.edu/neuroscience/

Newman-Tancredi, A., Gavaudan, S., Conte, C., Chaput, C., Touzard, M., Verrièle, L., Audinot, V., & Millan, M.J. (1998). Agonist and antagonist actions of antipsychotic agents at 5-HT1A receptors: a [35S]GTPgammaS binding study. Eur J Pharmacol. 355(2-3):245-56. doi: 10.1016/s0014-2999(98)00483-x. PMID: 9760039.

Peedicayil J.(2020). The Potential Role of Epigenetic Drugs in the Treatment of Anxiety Disorders. Neuropsychiatric Disease and Treatment. 16:597-606. doi: 10.2147/NDT.S242040. PMID: 32184601; PMCID: PMC7060022.

Stahl, S.M. (2013). Stahl’s Essential Psychopharmacology: Neuroscientific basis and practical applications. (4th ed.). New York, NY: Cambridge University Press.

Singh, H.K., & Saadabadi, A. (2020). Sertraline. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547689

Stefanska, B., & MacEwan, D.J. (2015). Epigenetics and pharmacology. British Journal of Pharmacology;172(11):2701-4. doi: 10.1111/bph.13136.

Rasool, M., Malik, A., Naseer, M. I., Manan, A., Ansari, S., Begum, I., Qazi, M. H., Pushparaj, P., Abuzenadah, A. M., Al-Qahtani, M. H., Kamal, M. A., & Gan, S. (2015). The role of epigenetics in personalized medicine: challenges and opportunities. BMC medical genomics, 8 Suppl 1(Suppl 1), S5. https://doi.org/10.1186/1755-8794-8-S1-S5

Vaskovic, J. (2022). Neurotransmitter. Retrieved from https://www.kenhub.com/en/library/anatomy/neurotransmitters

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