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

Posted: May 5th, 2020

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.
The spectrum of action for psychopharmacologic agents can be categorized into agonists, antagonists, and partial agonists. Agonists bind to receptors, activate them, and produce a biological response. On the other hand, antagonists block the action of agonists and produce the opposite effect in the body (Stahl, 2013). Agonists can vary in their efficacy and can be classified as full or partial agonists. A full agonist elicits the maximum possible response, while a partial agonist produces a lesser agonist effect on the receptor (Berg & Clarke, 2018).

For example, aripiprazole is a partial agonist that lowers dopaminergic neurotransmission in the mesolimbic pathway while enhancing dopaminergic activity in the mesocortical pathway (Berg & Clarke, 2018). When administered, aripiprazole occupies brain receptors where dopamine levels are elevated and partially blocks the effects of dopamine, thus reducing psychosis. However, if dopamine levels are low, aripiprazole acts as an agonist to increase dopamine transmission in those regions. This dual effect of partial agonists is why they are sometimes referred to as agonist-antagonists. Aripiprazole produces fewer extrapyramidal effects because it is a weak agonist and does not block dopamine function as much as an antagonist (Ghaemi, 2019). On the other hand, an inverse agonist binds to the same receptor sites as an agonist but not only antagonizes the effects of an agonist but also suppresses spontaneous receptor signaling (Ghaemi, 2019).

Now let’s compare and contrast the actions of G-coupled proteins and ion-gated channels. There are two types of receptor proteins involved in the opening and closing of postsynaptic ion channels. The first type is ionotropic receptors, which are directly linked to ion channels. These receptors have two functions: an extracellular site for binding neurotransmitters and a membrane-spanning domain to form an ion channel (Jiang et al., 2023). In other words, ionotropic receptors combine the functions of transmitter binding and channel opening into a single molecular entity and are known as ligand-gated ion channels. These receptors are composed of multiple subunits, usually four or five, and each subunit forms an independent pore channel (Jiang et al., 2023).

The second type of receptor is metabotropic receptors. These receptors do not have ion channels themselves, but their activation affects the channels through intermediate molecules called G-proteins. As a result, metabotropic receptors are also referred to as G-protein-coupled receptors (Jiang et al., 2023). Metabotropic receptors are single proteins with an extracellular domain for neurotransmitter binding and an intracellular domain for binding to G-proteins. When a neurotransmitter binds to a metabotropic receptor, it activates G-proteins, which then dissociate from the receptor and directly interact with ion channels or bind to other effector proteins such as enzymes to generate intracellular messengers that can open or close ion channels. Therefore, G-proteins function as transducers that couple neurotransmitter binding to the regulation of postsynaptic ion channels (Jiang et al., 2023).

Moving on to the role of epigenetics in pharmacologic action, epigenetics refers to changes in gene expression caused by environmental or behavioral factors. Understanding the function of the entire genome and considering epigenetic regulatory mechanisms can lead to the development of drugs that act on broad epigenetic events rather than being designed for specific genes or proteins (Stefanska & MacEwan, 2015). Epigenetic variations can be responsible for the development of certain diseases, such as cancer, and can also influence the response to pharmacologic treatments.

Epigenetic modifications, such as DNA methylation and histone modifications, play a crucial role in regulating gene expression. These modifications can be influenced by various factors, including lifestyle, environmental exposures, and medications. Pharmacologic agents have the potential to directly or indirectly modulate epigenetic processes, thereby affecting gene expression and cellular function.

Understanding the impact of epigenetics on pharmacologic action is essential for prescribing medications to patients. By considering epigenetic factors, healthcare providers can personalize treatment approaches and optimize therapeutic outcomes. For example, in the case of psychiatric medication prescribing, epigenetic alterations in the elderly population can affect the metabolism and clearance of drugs, as well as alter the efficacy and side effect profile (McClarty et al., 2018). Therefore, healthcare providers must be aware of these age-related epigenetic changes and adjust medication dosages accordingly to ensure safety and efficacy in elderly patients.

Let’s consider a specific example: A psychiatric mental health nurse practitioner is treating an elderly patient with psychosis. The patient is prescribed an antipsychotic medication to manage their symptoms. However, due to age-related epigenetic alterations, the efficacy of the medication may be affected, and the patient may experience increased side effects. The nurse practitioner should take into account the patient’s age, assess their individual response to the medication, and consider dose adjustments based on the patient’s specific needs and epigenetic profile (McClarty et al., 2018). By considering the impact of epigenetics on pharmacologic action, the nurse practitioner can optimize treatment outcomes and minimize potential adverse effects.

In summary, understanding the agonist-to-antagonist spectrum of action of psychopharmacologic agents, as well as the influence of partial and inverse agonist functionality, is important for tailoring treatments to individual patients. Additionally, recognizing the roles of G-coupled proteins and ion-gated channels in neurotransmission helps elucidate the mechanisms of drug action. Moreover, considering the impact of epigenetics on pharmacologic action enables healthcare providers to personalize treatments and optimize therapeutic outcomes, particularly in populations with age-related epigenetic alterations.

References
Berg, K. A., & Clarke, W. P. (2018). Making sense of pharmacology: inverse agonism and functional selectivity. International Journal of Neuropsychopharmacology, 21(10), 962-977.
Ghaemi, N. (2019). Clinical psychopharmacology: Principles and practice. Oxford University Press, USA. Kew, J. N., & Davies, C. H. (Eds.). (2010). Ion channels: from structure to function. Oxford University Press, USA.
Jiang, C., He, X., Wang, Y., Chen, C. J., Othman, Y., Hao, Y., Yuan, J., Xie, X. Q., & Feng, Z. (2023). Molecular Modeling Study of a Receptor-Orthosteric Ligand-Allosteric Modulator Signaling Complex. ACS chemical neuroscience, 14(3), 418–434. https://doi.org/10.1021/acschemneuro.2c00554Links to an external site.
McClarty, B. M., Fisher, D. W., & Dong, H. (2018). Epigenetic alterations impact on antipsychotic treatment in elderly patients. Current treatment options in psychiatry, 5(1), 17- 29.
Stahl, S. M. (2013). Ion Channels as Targets of Psychopharmacologic Drug Action. In Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (3rd ed.). New York, NY: Cambridge University Press.
Stefanska, B., & MacEwan, D. J. (2015). Epigenetics and pharmacology.