Mechanism of action of metoprolol
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Mechanism of Action of Metoprolol
Beta-Adrenergic Receptor Blockade
Metoprolol is a selective beta-1 adrenergic receptor antagonist, which means it primarily blocks the beta-1 receptors found in the heart. This action reduces the effects of adrenaline and noradrenaline, leading to a decrease in heart rate, cardiac output, and blood pressure . By inhibiting these receptors, metoprolol reduces the cardiac response to stress hormones, which is beneficial in conditions like hypertension, angina, and heart failure .
Impact on Myocardial Function and Energetics
In patients with nonischemic dilated cardiomyopathy, metoprolol has been shown to improve left ventricular performance and myocardial efficiency. This improvement is achieved without increasing myocardial oxygen consumption, suggesting that metoprolol enhances the heart's efficiency in using oxygen . Additionally, metoprolol alters substrate utilization in the heart, shifting from fatty acid to carbohydrate metabolism, which is more oxygen-efficient .
Repression of PGC1alpha-Mediated CPT-1B Expression
Metoprolol decreases the expression of carnitine palmitoyltransferase-1B (CPT-1B) in diabetic hearts by repressing the activity of PGC1alpha, a transcriptional coactivator. This repression is mediated through increased binding of upstream stimulatory factor-2 (USF-2) to PGC1alpha, which reduces the coactivation of PPAR-alpha and MEF-2A, key regulators of CPT-1B expression . This mechanism helps in reducing fatty acid oxidation, which is beneficial in heart failure management.
Diuretic Effect
Metoprolol has been observed to increase urine output significantly, which is likely due to an increase in renal blood flow and glomerular filtration rate. This diuretic effect can help in managing fluid overload conditions often seen in heart failure .
Neutrophil Modulation and Infarct Size Reduction
Metoprolol also exerts effects on the haematopoietic system, particularly by inhibiting neutrophil migration. This action reduces reperfusion injury during acute myocardial infarction by preventing excessive inflammation and microvascular obstruction. The drug achieves this by impairing the structural and functional rearrangements necessary for neutrophil-platelet interactions .
Peripheral Beta-2 Adrenoreceptor Mechanisms
While metoprolol is primarily a beta-1 selective blocker, it also has some effects on beta-2 receptors, which are found in the vasculature. This can lead to impaired vasodilation in response to beta-2 adrenergic agonists, potentially increasing systemic vascular resistance and reducing tissue oxygen delivery . This effect might contribute to the increased mortality observed with acute administration in certain patient populations.
Clinical Implications
Metoprolol is widely used for treating hypertension, angina, and heart failure due to its ability to reduce heart rate, blood pressure, and myocardial oxygen demand. It is also beneficial in post-myocardial infarction patients by reducing mortality rates over long-term use . However, its use in acute settings, particularly perioperative periods, requires caution due to potential adverse effects on microvascular function and tissue oxygenation .
Conclusion
Metoprolol's primary mechanism of action involves selective beta-1 adrenergic receptor blockade, leading to reduced cardiac workload and improved myocardial efficiency. It also modulates metabolic pathways, exerts diuretic effects, and influences inflammatory responses, making it a versatile drug in cardiovascular therapy. However, its impact on peripheral beta-2 receptors and microvascular function necessitates careful consideration in acute clinical settings.
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