Please provide feedback on this case study answer Q1. Pharmacological

Please provide feedback on this case study answer Q1. Pharmacological Mechanism of Action (MOA) of Aspirin and Morphine Aspirin Aspirin which comes under the class of non-steroidal anti-inflammatory drugs (NSAID), works by inhibiting the COX enzymes namely COX1 and COX2. This leads to the inhibition and decreased synthesis of prostaglandins which mediate the inflammation, pain, and fever. Going into the cellular level, aspirin acetylates the serine residue that is present on the COX enzyme, which further prevents the arachidonic acid from binding which leads to the inhibition of prostaglandin synthesis. This is mainly useful in cases of reducing pain and inflammation. Moving on to the receptor level, Aspirin is also known for its activity on the Cox enzymes that are present in the platelets and lead to the reduction in the production of thromboxane A2. This is significant in cases to reduce platelet aggregation as it exerts an antiplatelet effect and prevents major cardiovascular occurrences Aspirin does not directly have any connection to the nervous system however as discussed before it reduces the perception of pain by lowering the peripheral sensitization and central nervous system inflammation mediated by prostaglandins but does not affect any neuronal action potential. Morphine Morphine is categorized under the class of opioid agonists and shows its action on the mu-opioid receptors that are present in the brain and spinal cord. looking into the receptor level, morphine binds to the G-protein coupled receptors which are mu, delta, and kappa receptors, and leads to the inhibition of the adenylyl cyclase and further decreases the cAMP levels. This further results in the closure of voltage- gated calcium channels and the opening of potassium channels, which cause the hyperpolarisation of the neuron and the inhibition of neurotransmitter release. Morphine’s therapeutic significance is that it is an analgesic when it acts on the mu- opioid receptors as it directly reduces the transmission of pain signals to the central nervous system by inhibiting the neurotransmitter release. This happens because the neuron reaches a hyperpolarised state where the threshold of the signal is high which further decreases the pain perception. Q2. Explanation of John’s Complaints about His Medications Stomach Pain (Possible Ulcer) Aspiring might be the reason for John’s stomach pain. Aspirin acts by inhibiting COX 1 which regulates the synthesis of prostaglandins that play a crucial role in producing mucus that acts as a protective layer in the stomach from the Hcl produced. Inhibiting COX 1 leads to low production of mucous and bicarbonate secretion, which will expose the stomach to the highly acidic pH which is caused by HCL and lead to the formation of ulcers and gastric irritation. Fatigue and Shortness of Breath (Possible Anaemia) John fatigue can be because of anaemia deficiency, this can be related to aspirin as if it is chronically taken it leads to GI bleeding and causes less absorption of iron. The other symptoms include dizziness, and shortness of breath due to blood loss and low haemoglobin, and lesser oxygen capacity. Constipation Morphine might be responsible for John’s constipation. Morphine which comes under the class of opioids binds to the mu-opioid receptor that is present in the gastrointestinal tract which leads to the decrease in bowel motility. This leads to the slowing of the passage of stool which further leads to constipation. the reduced gut mobility is mainly because of the inhibition of acetylcholine release that occurs in the myenteric plexus, which is the cause of decreased peristalsis. Q3. Mechanism of Action of Alcohol and Interactions with John’s Medications A) Mechanism of Action of Alcohol Alcohol mainly shows its effects by interacting with these 2 receptors namely gamma-aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors which are present in the central nervous system. Alcohol strengthens the inhibitory effects of GABA by increasing gab aminergic-mediated activity which leads to sedation and also relaxation of the body. Along with this, it is also proven to inhibit excitatory glutamate transmission by acting as an antagonist to the NMDA receptors. The addictive aspects of alcohol are mainly linked to its dopaminergic effect. B) Interactions Between Alcohol, Aspirin, and Morphine Alcohol can exacerbate the gastrointestinal side effects of aspirin by increasing gastric acid secretion and reducing the mucosal barrier, further increasing the risk of ulcers and bleeding. Additionally, alcohol impairs liver function, which can reduce the metabolism of aspirin and increase the risk of toxicity. B) Interactions Between Alcohol, Aspirin, and Morphine Alcohol can lead to more adverse reactions when combined with aspirin as it increases gastric acid secretion and also reduces the mucosal barrier this will further increase the severity of ulcers and bleeding. Also, alcohol impairs liver function which will lead to a lower metabolism of aspiring and a lesser elimination rate which accumulates and increases the toxicity in the body. when alcohol is combined with morphine it potentiates the depression and also leads to respiratory depression and sedation to a greater extent which can increase the risk of overdose. both have an impact on the brainstem activity that is responsible for controlling critical functions like breathing. Q4. Recommendations for John A) Immediate Actions to Prevent Further Complications with His Ulcer John should with immediate effect stop or reduce the usage of aspirin mainly in combination with alcohol as it will exacerbate the risk of gastrointestinal bleeding. He should also consult for medical help regarding his ulcers and preferably start a prescription of a proton pump inhibitor or an H2 antagonist which would reduce the stomach acid secretion and heal the ulcer. B) Recommendations for Managing Side Effects Due to Medication Interactions John’s doctor would probably recommend changing his medicine from aspirin to an alternative like acetaminophen which would help in relieving him of gastrointestinal risks in the future and would be continuously monitored. Also for his osteoarthritis and chronic pain physical therapy should be considered. Also for the management of morphine-induced constipation, the doctor might prescribe him laxatives or mu- opioid receptor antagonist. References: ï‚· Christiansen, M., Grove, E. L., & Hvas, A. (2021). Contemporary clinical use of aspirin: mechanisms of action, current concepts, unresolved questions, and future perspectives. Seminars in Thrombosis and Hemostasis, 47(07), 800- 814. https://doi.org/10.1055/s-0041-1726096 ï‚· Colafella, K. M. M., Neuman, R. I., Visser, W., Danser, A. H. J., & Versmissen, J. (2019). Aspirin for the prevention and treatment of pre‐eclampsia: A matter of COX‐1 and/or COX‐2 inhibition? Basic & Clinical Pharmacology & Toxicology, 127(2), 132-141. https://doi.org/10.1111/bcpt.13308 ï‚· Eacret, D., Manduchi, E., Noreck, J., Tyner, E., Fenik, P., Dunn, A. D., Schug, J., Veasey, S. C., & Blendy, J. A. (2023). Mu-opioid receptor-expressing neurons in the paraventricular thalamus modulate chronic morphine-induced wake alterations. Translational Psychiatry, 13(1). https://doi.org/10.1038/s41398-023-02382-w ï‚· Esch, T., Kream, R. M., & Stefano, G. B. (2020). Emerging regulatory roles of opioid peptides, endogenous morphine, and opioid receptor subtypes in immunomodulatory processes: Metabolic, behavioral, and evolutionary perspectives. Immunology Letters, 227, 28-33. https://doi.org/10.1016/j.imlet.2020.08.007 ï‚· Li, J., Wang, H., Li, M., Shen, Q., Li, X., Zhang, Y., Peng, J., Rong, X., & Peng, Y. (2020). Effect of alcohol use disorders and alcohol intake on the risk of subsequent depressive symptoms: a systematic review and meta‐analysis of cohort studies. Addiction, 115(7), 1224-1243. https://doi.org/10.1111/add.14935 ï‚· Patrono, C. (2022). Fifty years with aspirin and platelets. British Journal of Pharmacology, 180(1), 25-43. https://doi.org/10.1111/bph.15966 ï‚· Pervin, Z., & Stephen, J. M. (2021). Effect of alcohol on the central nervous system to develop neurological disorder: pathophysiological and lifestyle modulation can be potential therapeutic options for alcohol-induced neurotoxication. AIMS Neuroscience, 8(3), 390-413. https://doi.org/10.3934/neuroscience.2021021 ï‚· Reiss, D., Maduna, T., Maurin, H., Audouard, E., & Gaveriaux‐Ruff, C. (2020). Mu opioid receptor in microglia contributes to morphine analgesic tolerance, hyperalgesia, and withdrawal in mice. Journal of Neuroscience Research, 100(1), 203-219. https://doi.org/10.1002/jnr.24626 ï‚· Vane, J. R., & Botting, R. M. (2003). The mechanism of action of aspirin. Thrombosis Research, 110(5-6), 255-258. https://doi.org/10.1016/s0049- 3848(03)00379-7 ï‚· Wang, Z., Jiang, C., Yao, H., Chen, O., Rahman, S., Gu, Y., Zhao, J., Huh, Y., & Ji, R. (2020). Central opioid receptors mediate morphine-induced itch and chronic itch via disinhibition. Brain, 144(2), 665-681. https://doi.org/10.1093/brain/awaa430

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