The Agonist-to-Antagonist Action of Psychopharmacologic Agents
The Agonist-to-Antagonist Action of Psychopharmacologic Agents
The use of pharmacological treatments for opioid use disorders, including methadone, buprenorphine, and naltrexone, has been associated with a reduction in mortality compared with illicit opioid use. The opioid agonist methadone and buprenorphine achieve clinical efficacy in patients with an opioid use disorder by suppressing craving and diminishing the effectiveness of illicit opioid doses. At the same time, the antagonist naltrexone blocks the action of opioids (Kelty et al., 2020). Beyond drug-related mortality, these pharmacotherapies can impact a participant’s risk of death.
According to Kelty et al. (2020), methadone is a long-acting synthetic mu-opioid agonist used primarily as management or opioid replacement therapy. Buprenorphine is a partial agonist of the mu-opioid receptor and an antagonist of the kappa-opioid receptor, with high receptor affinity, which reduces the likelihood of poisoning. Partial action at the mu-opioid receptor limits the maximal opioid effect compared with full agonists such as methadone. High affinity for the mu-opioid receptor results in the binding of buprenorphine in preference to other opioids, also providing some protection from the toxicity of other opioids. Naltrexone is an opioid antagonist with action on the mu-, kappa- and delta-opioid receptors. While pharmacologically an ideal treatment for opioid dependence, naltrexone is unpopular in its initial oral formulation. Unlike methadone and buprenorphine, patients are required to undergo opioid detoxification before induction onto naltrexone.
Compare and contrast the actions of g-couple proteins and ion gated channels.
According to Wicher et al. (2008), the binding of volatile ligands perceives many odorant signals to odorant receptors that belong to the G-protein-coupled receptor (GPCR) family. They couple to G-proteins, most of which induce cAMP production. The second messenger activates cyclic-nucleotide-gated ion channels during this process to depolarize the olfactory receptor neuron, thus providing a signal for further neuronal processing.
Wicher et al. (2008) added that in comparing and contrasting the actions of G-couple proteins and ion gated channels, a test is done to determine which G-proteins are involved in metabotropic odorant signaling. In comparison, testing putative G- protein coupling was co-expressed with human HCN2 (hyperpolarization-activated cyclic-nucleotide-gated potassium channel 2) channels, which report changes in cyclic nucleotide concentrations. Increasing intracellular cAMP concentration due to G- protein activation causes a depolarizing shift of the steady-state activation curve and activation acceleration.
In contrast, testing putative G- protein coupling was again co-expressed with human KCNQ4 (potassium voltage-gated channel, KQT-like subfamily, member 4) channels are inhibited on activation of endogenous G- proteins. The application of ethyl butyrate at various concentrations did not affect the human KCNQ4 current, although ethyl butyrate produced olfactory receptor currents. This indicates that odorant receptor activation by ethyl butyrate does not lead to G- protein activation (Wicher et al., 2008).
Explain how the role of epigenetics may contribute to pharmacologic action
According to Abdolmaleky et al. (2005), epigenetic interaction is another overlooked issue in psychiatric genetic studies. Epigenetics refers to modifications in gene expression that are controlled by heritable but potentially reversible changes in DNA methylation and chromatin structure. According to Peedicayil (2012), the role of epigenetics in the pharmacotherapy of idiopathic mental disorders is an ongoing research process. Epigenetic therapy is a new development in pharmacology involving epigenetic drugs to correct epigenetic defects. Epigenetic therapy may apply to the treatment of mental disorders. Although several classes of epigenetic drugs are being investigated, most attention is being given to the clinical use of two drug classes. These drugs are DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors. These epigenetic drugs have shown promising results in preclinical studies of idiopathic mental disorders. Such therapies may fulfill the need for newer and more effective medications for treating these disorders.
Impact of a psychiatric Mental Health Nurse Practitioner
According to DeSocio (2019), epigenetics has been described as a framework for integrating a relationship-based practice with psychoeducation, psychotherapy, and psychopharmacology in advanced practice psychiatric nursing. Psychiatric nurses are taught the value of three-generational genograms in identifying family processes across generations. A Generational Stress Genogram could be completed during nurse-patient encounters, providing a framework for discussing the impact and generational transmission of the epigenetic signatures of stress. More research is needed to achieve this translation from science to integrated, evidence-based practice. For example, future pharmacological agents that reverse stress-induced epigenetics are currently being tested in animal research. These reports foretell an exciting evolution in epigenetically-informed, evidence-based practice for nursing and other healthcare disciplines.
References
Abdolmaleky, H. M., Thiagalingam, S., & Wilcox, M. (2005). Genetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope. American Journal of Pharmacogenomics : Genomics-Related Research in Drug Development and Clinical Practice, 5(3), 149–160. https://doi.org/10.2165/00129785-200505030-00002
DeSocio, J. E. (2019). Reprint of “Epigenetics, maternal prenatal psychosocial stress, and infant mental health”…DeSocio JE. Epigenetics, maternal prenatal psychosocial stress, and infant mental health. Archives of Psychiatric Nursing. 2018. 32(6): 901-906. Archives of Psychiatric Nursing, 33(3), 232–237. https://doi.org/10.1016/j.apnu.2019.05.001
Kelty, E., Hulse, G., Joyce, D., & Preen, D. B. (2020). Impact of Pharmacological Treatments for Opioid Use Disorder on Mortality. CNS Drugs, 34(6), 629–642. https://doi.org/10.1007/s40263-020-00719-3
Peedicayil, J. (2012). Role of epigenetics in pharmacotherapy, psychotherapy and nutritional management of mental disorders. Journal of Clinical Pharmacy & Therapeutics, 37(5), 499–501. https://doi.org/10.1111/j.1365-2710.2012.01346.x
Wicher, D., Schäfer, R., Bauernfeind, R., Stensmyr, M. C., Heller, R., Heinemann, S. H., & Hansson, B. S. (2008). Drosophila odorant receptors are both ligand-gated and cyclic-nucleotide-activated cation channels. Nature, 452(7190), 1007–1011. https://doi.org/10.1038/nature06861
SECOND POST
Foundational Neuroscience
Psychopharmacology has developed significantly over the last decades; however, research on treatments is continuously searching to improve their effectiveness. The biological mechanism of brain function and dysfunction is quite detailed and challenging to understand fully. The future prescriber needs to seek and absorb a greater understanding of the pathological process for psychotropic treatment interventions.
For cells to receive a signal from other cells, a ligand (a natural neurotransmitter or drug) must diffuse to the receptor of the surface of the receiving cell and temporarily occupy it (Kowalski, Dowben, & Keltner, 2017). The interaction between the neurotransmitter, drug, or a combination of the two will affect the receptor, and its physical structure will change (Kowalski et al., 2017). The neurotransmitter ligand or drug ligand on the receptor is one of four types: agonist, antagonist, partial agonist, or inverse agonist, and each will differently impact the efficacy of psychopharmacological treatments (Kowalski et al., 2017).
Agonists and Antagonists
Agonists are drugs that can bind to the receptor to facilitate or change receptor activity to produce a maximal response (Berg & Clark, 2018). For example, lorazepam acts as an agonist at the benzodiazepine receptor and expedites the effect of the inhibitory neurotransmitter GABA and causes the cell to reduce its activity (Kowalski et al., 2017). Lorazepam’s impact on the receptor causes a reduction in agitation and excitement, inducing relaxation. Antagonists block the effect of the agonist on the cell, allowing no signal transduction to occur (Kowalski et al., 2017). For example, when the antagonist drug flumazenil binds to the benzodiazepine receptor and lorazepam is present, the flumazenil will reverse the activity of the lorazepam and return the cell to a resting state, blocking the effect that would occur if only the agonist were present (Kowalski et al., 2017).
Partial Agonists
Partial agonists, acting by themselves, will slightly increase the receptor signal transduction producing a weak biological response. However, in the presence of an agonist, a partial agonist will work as an antagonist to block the complete signal transduction and is helpful for the treatment of opioid addiction and acute opioid withdrawal (Kowalski et al., 2017). An example of a partial agonist is buprenorphine which binds to mu-opioid receptors but only allows partial activation (Kumar, Viswanath, & Saadabadi, 2022). Buprenorphine’s partial agonism produces analgesic effects that plateau at high doses, and then its effects become antagonistic (Kumar et al., 2022).
Inverse Agonists
Inverse agonists are drugs that bind to the same receptor site as the agonist but produce an opposite response to the agonist (Berg & Clarke, 2018). The inverse agonist will block the agonist present, causing a negative effect on signal transduction (Kowalski et al., 2017). Naloxone is an inverse agonist at the mu-opioid receptor and is the preferred antidote for treating opioid overdose (Kowalski et al., 2017).
Ion Gated Channels and G Couple Proteins
Neurotransmitter receptor activation results in either a rapid or slow conversion of chemical messages to electrical impulses. Ion gated channels respond to a specific stimulus that causes the neurotransmitter receptor to open and allows a rapid influx of selectively permeable ions, including sodium, potassium, calcium, and chloride, altering the neuron membrane and activity (Camprodon & Roffman, 2019). The influx of ions causes post-synaptic depolarization, and neurons will fire (Camprodon & Roffman, 2019). The G-coupled-protein-receptors (GCPRs) are slower transmissions activated by a second messenger system (Camprodon & Roffman, 2019). These messenger systems include cellular cytoplasmic enzymes and proteins within the cellular membrane that, when activated, influence a gradual intra-cellular process (Camprodon & Roffman, 2019).
Epigenetics and Pharmacologic Action
Genetic variations in the serotonin transporter (SERT) may contribute to a higher risk of depression in individuals exposed to stressful life events (Camprodon & Roffman, 2019). According to Camprodon and Roffman (2019), a study indicated that individuals with one or two copies of the low active form of the gene, the S-variant allele, experienced more depression and suicidal tendencies than individuals with two copies of the L-variant allele. Research also indicates that epigenetic changes occur in the brain of individuals with bipolar disorder, including decreased brain-derived neurotrophic factor (BDNF) and increased cumulative damage from free radicals (Lockwood & Youssef, 2017). By combining the knowledge of epigenetics on the effects of disease with the epigenetic effects of psychotropic medications, prescribers can offer better patient-centered treatments.
Impact on Prescribing
There are many psychotropic treatment choices for different disorders, but current literature suggests they are only partially effective (Camprodon & Roffman, 2019). Understanding the agonist to antagonist mechanisms can greatly influence specific drug interventions. The psychiatric mental health practitioner (PMHNP) must be aware of medication actions. Consider the situation in which a patient receiving levodopa to treat Parkinson’s disease requires an antipsychotic medication. Due to the dopamine receptor blockade actions of most antipsychotics, the drug will likely interfere with levodopa, and the patient will have worsening parkinsonism (Camprodon & Rothman, 2019).
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
Camprodon, J.A., & Roffman, J.L. (2016). Psychiatric neuroscience: Incorporating pathophysiology into clinical case formulation.
In T.A. Stern, M. Favo, T.E.Wilens, & J.F. Rosenbaum. (Eds.), Massachusetts General Hospital psychopharmacology and
neurotherapeutics (pp. 1-19). Elsevier.
Kowalski, P.C., Dowben, J.S., & Keltner, N.L. (2017). My dad can beat your dad: Agonists,
antagonists, partial agonists, and inverse agonists. Perspectives in Psychiatric Care,
53(2), 76. https://doi.org/10.1111/ppc.12208
Kumar, R., Viswanath, O., Saadabadi, A. (2022). Buprenorphine. In: StatPearls [Internet].
Treasure Island (FL): StatPearls Publishing; 2022 Jan-, Available from
https://www.ncbi.nlm.nih.gov/books/NBK459126
Lockwood, L., & Youssef, N.A. (2017). Systematic review of epigenetic effects of
pharmacological agents for bipolar disorders. Brain Sciences, 7(11), 154.
https://doi.org/10.3390/brainsci7110154
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