Posted: July 14th, 2022

Explain the agonist-to-antagonist spectrum of action of psychopharmacologic agents

FYI HERE RESPOND TO TWO COLLEAGUES: Please include 2 in test citations and references in each response
By Day 3 of Week 2
Post a response to each of the following:

1-Explain the agonist-to-antagonist spectrum of action of psychopharmacologic agents, including how partial and inverse agonist functionality may impact the efficacy of psychopharmacologic treatments.
2-Compare and contrast the actions of g couple proteins and ion gated channels.
3-Explain how the role of epigenetics may contribute to pharmacologic action.
4-Explain how this information may impact the way you prescribe medications to patients. Include a specific example of a situation or case with a patient in which the psychiatric mental health nurse practitioner must be aware of the medication’s action.
By Day 6 of Week 2
Respond to at least two of your colleagues on two different days in one of the following ways:
If your colleagues’ posts influenced your understanding of these concepts, be sure to share how and why. Include additional insights you gained.
If you think your colleagues might have misunderstood these concepts, offer your alternative perspective and be sure to provide an explanation for them. Include resources to support your perspective.

Colleague 1
There is growing optimism about the potential role that epigenetics will play in the future in the understanding and treatment of mental disease. It will provide clinicians with not only a deeper knowledge of the biologic reaction of the human brain to stressful or noxious stimuli across its lifespan, but it will also improve medications that specifically target these complex biological reactions. This is because of its direct role on gene behavior (Szyf, 2019). This will be of particular benefit to the developing brain beginning in pregnancy and continuing into early adulthood, a time in a person’s life when continual maturation of the central nervous system (CNS) makes it especially susceptible to the negative effects of unfavorable occurrences (Barker, 2018; Szyf, 2019). DNA methylation is a subject that receives a lot of attention in the field of epigenetics study (DNAm). This is a chemical process that involves changes in genetic material as a response to stimuli, and it is this process that can then produce “behavioral phenotypes” (Szyf, 2019, p 369). Barker (2018) provides additional clarification by stating that “…if adversity-related DNAm is a causative connection in the aetiology of a mental health disorder – then correcting epigentic markings might help in remission of these problems” (p. 3).
Cannabis use is a good illustration of the outcomes that can result from epigenetic processes like those described above. According to Hurd et al. (2019), prenatal, perinatal, and adolescent exposure to the chemical tetrahydrocannabinol (THC), the substance responsible for psychoactive results, can lead to changes in gene expression that can affect mental health throughout the lifespan. These changes can have an impact on the development of psychosis. During the period of prenatal development, maternal exposure to THC can cause changes in receptors in the brain known as cannabinoid 1 receptors (CB1Rs). These receptors are located in the mesocorticolimbic brain, which is the region of the brain where it is believed that high concentrations of dopamine, glutamate, and GABA significantly contribute to addiction and psychiatric disorders (Hurd et al, 2019). These compounds can also be transferred to nursing infants by their moms who are breast-feeding them. One consequence of this exposure is the influence these compounds have throughout the process of neurotransmitter development, specifically GABA (Hurd et al., 2019). In the brain of a developing child, GABA begins as an excitatory neurotransmitter and does not become an inhibitory neurotransmitter until the brain gradually matures (Hurd et al., 2019). “The timing of this change is a pivotal juncture in the neurodevelopmental trajectory,” write Hurd et al. (2019), and “pertubations during this critical era are linked to numerous diseases” (p. 8252). The development of the central nervous system continues throughout adolescence; in particular, the reward system, which is located in the mesolimbic dopamine pathway and is accessed via the endocannabinoid (eCB) ligands, continues to mature (Hurd et al., 2019). When the development of this part of the brain is hampered by a chemical like THC, it can raise the risk of developing an addiction to drugs (Hurd et al., 2019).
There are constraints on the epigenetic research being done. Access to living human tissue of the central nervous system, for instance, is not feasible despite the fact that such access would be ideal for this area of research. Instead, information is extrapolated from saliva, buccal epithelial cells, and blood, which are all locations where peripheral inflammation and changes in the immune response can be observed. This is done in order to gain a better understanding of how the alterations correspond to mental illness (Barker, 2018). In spite of this constraint, the information that was gained from these peripheral tissues, particularly blood, holds promise information for the future of epigenetic studies of mental disease (Barker, 2018). Barker (2018) goes on to say, “Moreover, there is solid evidence from animal research, and emerging evidence in humans, that peripheral inflammatory indicators can impact brain areas implicated in some psychiatric disorders. This is supported by increasing data in human studies.” As a consequence of this, immunological processes and DNAm that are associated to adversity may be well assessed in blood samples (p. 5).

Ion channels and G couple proteins are the two primary types of communication pathways that are used by neuron cells in the central nervous system to communicate with one another. Because of their significance in preserving homeostasis in the central nervous system and, by extension, mental health, both processes have been the subject of intensive research to determine whether or not they play a role in psychiatric and neurological disorders. As a result, numerous drug developments have been made that target the structures of these processes in an effort to treat disease (Pluimer et al., 2020; Held & Toth, 2021).
The communication between interneurons is regulated by the central nervous system, which has hundreds of ion channels, each of which, along with the proteins that they are associated with, acts directly on the cell membrane (Held & Toth, 2021). When an electrical impulse in a neuron cell reaches the cell’s membrane, that synaptic activity, which is tightly regulated by ion channel, increases the permeability of the cell membrane (membrane potential) to the influx of ion proteins. This causes the permeability of the cell membrane to increase, which allows more ions to enter the cell (Held & Toth, 2021). Communication through ion channels happens far more quickly than it does through the G couple protein mechanism (Stern et al., 2016). TRP channels, also known as transient receptor potential channels, are a group of 28 cation channels that are responsible for perceiving both internal and external stimulus (Held & Toth, 2021). For instance, the channel TRPM2 is selective for calcium ions that are critical for healthy brain functioning and is thought to be involved in ‘oxidative stress’ that occurs with aging and neurodegenerative diseases (Held & Toth, 2021). Another type of TRP ion channel that has received a lot of attention is the TRPM3, which is abundant in the choroid plexus, the cerebellum, the forebrain, and the dentate gyrus of the hippocampus. This channel helps to control movement, cerebral spinal fluid, and memory, and it has been the subject of a lot of research (Held & Toth, 2021). Dysregulation of TRPM3 has also been implicated in certain brain pathologies involving learning disabilities including Kabuki Syndrome and autism suggesting its critical role in early brain development (Held & Toft, 2021). Other areas of TRPM3 involvement include mood and anxiety disorders, including post-partum depression and seizures (Held & Taft, 2021).
Neuron signaling is also performed by the G-protein-coupled receptors (GPCRs). According to Pluimer et al. (2020), “GPCRs constitute the largest superfamily of membrane proteins in eukaryotes. Their capacity to bind a wide variety of ligands and diverse signaling profiles position them as ideal candidates for drug-target therapies” (p. 139). In fact, the Food and Drug Administration has approved between 20% – 30% of all the current drugs on the market, including opioids, anti-psychotics, and anti-histamines, to target GPCRs (Pluimer et al., 2020; Vedel et al., 2020). Unlike ion channels, GPCRs, of which there are five (Glutamate, Rhodospsin, Adhesion, Frizzled and Secretin), exert their influence through a complex slower process of chain reactions involving second-messenger systems (Stern et al., 2016). According to the International Union for Basic and Clinical Pharmacology Committee of Receptor Nomenclature and Drug Classification, (NC-IUPHAR) there are, at present, 121 ‘orphan GPCR’ receptors, meaning an ‘endogenous ligand’ has not yet been identified for that receptor, including one for GPR 139, which is thought to have a role in Parkinson’s Disease, alcohol addiction, hyperalgesia, phenylketonuria schizophrenia, attention deficit hyperactivity disorder, depression and fetal development (Vedel et al., 2020).

Colleague 2

1-Explain the agonist-to-antagonist spectrum of action of psychopharmacologic agents, including how partial and inverse agonist functionality may impact the efficacy of psychopharmacologic treatments.

Paul Ehrlich (1854–1915) is credited with being the first person to suggest the notion of highly precise interactions between medications and receptors. corpora non agunt nisi fixata (drugs do not act unless they are bound) (Weir, 2020). However, before moving on to talk about how different drugs interact with one another, it is necessary to define what exactly a receptor is. A neurotransmitter, hormone, or inflammatory mediator are all examples of endogenous chemical mediators that may be recognized by receptors, which are proteins. Pharmacologists define a receptor as a protein that identifies one of these endogenous chemical mediators (Weir, 2020). Following the binding of the mediator (agonist) to the receptor, a cascade of events takes place, which eventually results in a change in the function of the host cell. For instance, the binding of GABA to GABAA receptors inhibits neuronal activity by causing an inward flow of chloride ions (Cl) via an integral ion channel. This flow of chloride ions (Cl) is responsible for the inhibition of neuronal function. When referring to a target whose function is changed by an external drug rather than an endogenous mediator, it is common practice to use the word “receptor” in a more general sense (Weir, 2020).
An agonist is a substance that binds to a receptor, which then causes the receptor to become activated and causes the function of the receptor’s host cell to change. Agonists are characterized by having both affinity and efficacy. The ability of an agonist (or drug) to bind to a receptor is referred to as its affinity (Weir, 2020). Affinity is defined as the ratio of the binding rate (k + 1) to the dissociation rate (k 1), which is to say that affinity (kA) = k + 1/k 1. Affinity is frequently measured experimentally through the utilization of radioactive binding techniques. On the other hand, efficacy is a term that refers to the capability of the medication to activate the receptor once it has successfully attached to the receptor (Weir, 2020). Full agonists are capable of producing a maximal response or maximal efficacy (this may occur when only a fraction of receptors are occupied, hence the concept of’spare’ receptors), whereas partial agonists are not capable of producing a full response even in the presence of high concentrations of agonist (Weir, 2020).
Competitive receptor antagonists are classed as either reversible or irreversible. Competitive antagonists bind to the receptor and therefore possess affinity, but they are unable to produce a response and thus lack efficacy (Weir, 2020). Furthermore, they prevent the agonist from binding and so block its ability to activate the receptor. It is possible to overcome irreversible competitive antagonism. To put it another way, the effects of an antagonist attaching to an agonist binding site may be neutralized by raising the concentration of a competing agonist. In contrast, irreversible competitive antagonists form a covalent bond with the receptor, and it is not possible to circumvent the receptor blockage by raising the concentration of the agonist (i.e. the effect is insurmountable). Because of this, the agonist has less of an opportunity to exert its full impact when there is an irreversible antagonist present (Weir, 2020).
Inverse agonists are substances that, according to their name, have the opposite impact of agonists on the body. This recently discovered phenomenon is only conceivable in the event that the receptor is capable of action in the absence of an agonist (i.e. it has constitutive activity). In this circumstance, a competitive antagonist by itself will not have any impact on constitutive activity (since there is no agonist present), but an inverse agonist will create a concentration-dependent drop in receptor activity. This will occur because an agonist is not present (Weir, 2020).

2- Compare and contrast the actions of g couple proteins and ion gated channels.

Ion channel receptors are an essential part of the signaling process that occurs in the nervous system. They make it possible for a chemical neurotransmitter message to be rapidly and directly converted into an electrical current. Ionotropic receptors are known to be controlled by protein-protein interactions with other ion channels, G-protein coupled receptors, and intracellular proteins (Li et al., 2014). This has become abundantly clear over the course of the last several decades. The interactions between ion channel receptors and these other proteins have the potential to regulate these other proteins as well. This bidirectional functional cross-talk is necessary for key cellular processes like as excitotoxicity in pathological and disease states like stroke, and it is also vital for the fundamental dynamics of activity-dependent synaptic plasticity. Protein interactions with ion channel receptors constitute a potential target for therapeutic intervention in neuropsychiatric disorder (Li et al., 2019). As a result, protein interactions with ion channel receptors may boost the computational capacity of neuronal signaling cascades (Li et al., 2014).
In order for there to be effective neurotransmission, there must be a specific interaction between the many different types of neurotransmitter receptors that are present in the pre- and post-synaptic compartments. In the neurological system, ligand-gated ion channels are an extremely important part of the process of intercellular communication. Ion channels are the cell’s mechanism for transporting ions across membranes, and as such, they are the fundamental component of the electrical activity that neurons undergo. G protein coupled receptors, also known as GPCRs, are integral membrane proteins that are utilized by cells to translate extracellular information into intracellular responses. These responses may include reactions to hormones and neurotransmitters, as well as reactions to taste, smell, and vision cues (Li et al., 2014).
3-Explain how the role of epigenetics may contribute to pharmacologic action.
Epigenetics may be defined in a number of different ways, but it generally refers to the concept that the function of a gene can be altered without a corresponding change in the genetic code, and that this variation in gene function may also be heritable. This may often take place as a result of a change in the structure of the DNA molecule, such as the formation of chromatin around a gene, which modifies the expression of that gene. The human genome contains many genes, but only few of them are ever used. Through the study of epigenetics, one may decide whether a gene will be translated into its corresponding RNA and protein, or if it will be ignored or silenced (Mahgoub & Monteggia, 2013). Epigenetic processes allow for the modification of the structure of chromatin found in the nucleus of a cell, which in turn allows for the activation or silencing of genes. This may take place as a result of methylation, acetylation, phosphorylation, or any one of a number of other activities that are controlled by neurotransmission, medicines, and the surrounding environment (Mahgoub & Monteggia, 2013).
It was formerly believed that genes did not alter throughout the course of a person’s lifespan; nevertheless, it is now recognized that epigenetics may change in adult neurons that have differentiated. Neurons are able to be altered by a variety of factors, including child maltreatment, nutritional inadequacies, psychotherapy, drug misuse, and other similar situations; as a result of these events, genes may either be activated or silenced. These results may sometimes be favorable, but more often than not, they are not. Increasing amounts of evidence point to the possibility that epigenetic mechanisms, which are able to cause changes in gene expression that are both stable and long-lasting in response to environmental occurrences and behavioral experiences, may play a role in the processes that contribute to the pathophysiology of psychiatric disorders (Mahgoub & Monteggia, 2013).
The goal is that with a greater knowledge of how epigenetic processes underlie mental diseases, it will be possible to better identify how individual genes that may contribute to these disorders are impacted by epigenetic alterations. Researchers will discover new pathways of treatment approaches to satisfy the demands of people who are suffering from mental disease if they have a better grasp of how epigenetic processes carry out long-lasting and adaptive alterations in gene activity and expression (Mahgoub & Monteggia, 2013)
4-Explain how this information may impact the way you prescribe medications to patients. Include a specific example of a situation or case with a patient in which the psychiatric mental health nurse practitioner must be aware of the medication’s action.
This information plays a critical role in determining how medicine is recommended to patients, making it very important. When a practitioner has a thorough awareness of the agonist-to-antagonist spectrum of action, they are in a better position to accurately anticipate the clinical effects of psychopharmacologic drugs. Providers may benefit from having knowledge about the activity of certain neurotransmitters and where these neurotransmitters fall on the spectrum of agonists to antagonists, as this can help them choose the most effective therapy to deliver the desired therapeutic result. An illustration of this can be found in the treatment for substance abuse. If medical professionals have a better understanding of the mechanism by which a partial agonist can inhibit the use of a full agonist by occupying receptor sites, they will be better able to explain why drugs like Suboxone are used to treat addiction.
When a patient presents with anxiety that will require both short-term and long-term management, the psychiatric mental health nurse practitioner must be aware of the action of the medication. This is an additional specific example of a situation in which the psychiatric mental health nurse practitioner must be aware of the action of a medication. The knowledge that benzodiazepines alter ion flow and begin working nearly instantly, but the effects of an SSRI for long-term use will be delayed, has the potential to impact the prescription choices made by medical professionals. In this circumstance, it may be reasonable to prescribe a benzodiazepine as an initial treatment until the effects of the SSRI begin to take hold.

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