Pharmacology
Summary
Glucocorticoids, such as dexamethasone, fludrocortisone, and prednisone, emulate the effects of cortisol and exert a range of physiological impacts on multiple systems, including metabolism and immune regulation. When released into the circulation, they exert potent anti-inflammatory effects by interacting with specific DNA sequences in gene promoter regions, known as glucocorticoid receptor elements (GREs), which affect gene transcription. This mechanism involves regulation of the production of phospholipase A2 or PLA2, the enzyme that catalyzes the arachidonic acid pathway, which sets off a cascade of inflammatory events.
Glucocorticoids also exert effects on the concentration, distribution, and function of leukocytes, including inhibiting the recruitment and activation of lymphocytes. At the cellular level, they interact with transcription factors such as nuclear factor Kappa-B or NF-KB, which controls the transcription of genes involved in the production of pro-inflammatory cytokines. This results in the reduced recruitment and activation of T and B lymphocytes.
Consequently, glucocorticoids are useful in treating inflammatory disorders such as gout, rheumatoid arthritis, asthma, and inflammatory bowel diseases, among others. However, the adverse effects of glucocorticoids, due to their catabolic properties, include muscle weakness, skin thinning, osteoporosis, and immunosuppression. And lastly, long-term glucocorticoid use results in adrenal cortical atrophy, leading to acute adrenal insufficiency during times of trauma or stress.
Lesson Outline
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FAQs
Gout originates from the accumulation of uric acid crystals in the joints, a byproduct of purine metabolism. When blood levels of uric acid rise, a condition known as hyperuricemia, it often leads to gout. Gout medications manage this through different strategies: xanthine oxidase inhibitors, such as allopurinol limit uric acid production, uricosurics like probenecid facilitate uric acid excretion through the kidneys, and other drugs such as NSAIDs and cholchicine work through various mechanisms to alleviate gout symptoms and reduce the frequency of acute gout attacks.
Acute gouty attacks, characterized by sudden and severe joint pain with redness and swelling, arise from the accumulation of uric acid crystals in the joint linings. Nonsteroidal anti-inflammatory drugs (NSAIDs) are generally the first line of treatment. Should NSAIDs be ineffective or contraindicated, glucocorticoids or colchicine may be prescribed. Additionally, long-term management with drugs like allopurinol or probenecid is often implemented to prevent future episodes.
Pseudogout, characterized by calcium pyrophosphate crystal deposition, is a chronic condition in which the goal of treatment is symptom management. Nonsteroidal anti-inflammatory drugs (NSAIDs) are often first-line agents to alleviate pain and inflammation. In cases where NSAIDs are contraindicated or ineffective, corticosteroids (either oral or injected directly into the affected joint) can be employed. Colchicine, also used in gout management, can be effective for acute pseudogout attacks and as prophylaxis. Gout treatments aim to reduce uric acid levels using medications like allopurinol or probenecid, while pseudogout focuses more on symptom management since there's no specific drug to dissolve calcium pyrophosphate crystals.
Tumor lysis syndrome (TLS) is a life-threatening condition that occurs when large numbers of cancer cells are killed rapidly, leading to the a surge of potassium, phosphate, and uric acid released into the bloodstream, which can lead to acute kidney injury, arrhythmias, and seizures. Allopurinol or febuxostat can be administered to inhibit xanthine oxidase, reducing the production of uric acid from purines released during cell lysis.
Pegloticase is a recombinant uricase enzyme that converts uric acid into a more easily excreted substance, allantoin. It typically reserved for severe, refractory gout where standard treatments such as xanthine oxidase inhibitors or uricosurics are ineffective or inappropriate. By lowering uric acid levels in the blood, pegloticase helps to relieve gout symptoms, decrease the occurrence of gout attacks and preventing related complications, such as urate nephrolithiasis.
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