Explore chapters and articles related to this topic
Advanced Therapeutic Options in Acute Heart Failure
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Tiffany Dong, Aditi Nayak, Alanna Morris
Milrinone inhibits phosphodiesterase 3, ultimately preventing breakdown of cyclic adenosine monophosphate (cAMP). This increases myocardial inotropy and diastolic compliance, while reducing systemic and pulmonary vascular resistance, and thus improves cardiac index, filling pressures, and afterload.21 Milrinone can also be used for right ventricular (RV) failure.22 Doses range from 0.125 to 0.75 mcg/kg/min. There is a synergistic effect with dobutamine as both increase cAMP. Compared with dobutamine, milrinone may be appropriate in patients who have downregulation of their adrenergic receptors. Side effects include hypotension, cardiac ischemia due to increased myocardial demand, and arrhythmias. Caution should be used in patients with renal dysfunction, as milrinone is renally cleared.3
Effects of Calcium Channel Antagonists on The Myometrium
Published in Gabor Huszar, The Physiology and Biochemistry of the Uterus in Pregnancy and Labor, 2020
Ronald A. Janis, David J. Triggle
Other possible sites of action of these drugs include the following: (1) a site of action involved with excitation-contraction coupling other than Ca2+-channels; (2) calmodulin or a protein with a calmodulin-like surface similar to that on phosphodiesterase, such that phosphodiesterase is inhibited and cyclic AMP and/or cyclic GMP levels are elevated in smooth muscle. It was proposed that nicardipine inhibits OT-induced contraction of rat uterus by inhibiting cyclic AMP phosphodiesterase.146 Although some Ca2+ channel antagonists bind to calmodulin and inhibit phosphodiesterases, the effects are usually seen only at high concentrations,147,150 and elevations of the cyclic nucleotide levels are not consistently associated with smooth muscle relaxation caused by these drugs24,151 as might be expected for inhibition of calmodulin-dependent phosphodiesterase; (3) some evidence supports the possibility that these drugs may stimulate Ca2+ or Na+ pumps,152,154 but an electrophysiological study did not find evidence for stimulation of the Na+ pump in intact cerebrovascular smooth muscle cells.155
Vascular smooth muscle: excitation, contraction and relaxation
Published in Neil Herring, David J. Paterson, Levick's Introduction to Cardiovascular Physiology, 2018
Neil Herring, David J. Paterson
The PKA activator, cAMP, is continuously degraded by the enzyme phosphodiesterase 3 (PDE3; Figure 12.10). Drugs that inhibit PDE3, such as milrinone and cilostazol, raise intracellular cAMP, leading to vasodilatation.
A randomized open label, parallel-group study to evaluate the hemodynamic effects of Cafedrine/Theodrenaline vs Noradrenaline in the treatment of intraoperative hypotension after induction of general anesthesia: the “HERO” study design and rationale
Published in Current Medical Research and Opinion, 2023
Benjamin Vojnar, Götz Geldner, Susanne Huljic-Lankinen, Melanie Murst, Thomas Keller, Stephan Weber, Christine Gaik, Tilo Koch, Andreas Weyland, Peter Kranke, Sascha Kreuer, Daniel Chappell, Leopold Eberhart
The 20:1 C/T is a mixture of Noradrenaline and Norephedrine, both covalently bound to Theophylline7. Previous data indicate that the rapid onset of action seems to be based on Noradrenaline-mediated vasoconstriction, which is subsequently reduced by the delayed effect of Cafedrine, while Norephedrine leads to a positive inotropic effect, which is enhanced and prolonged by phosphodiesterase 3 inhibition mediated by Theophylline7. In sum, C/T exerts inotropic and moderate vasopressor effects, meaning the term “inopressor” best describes its mechanism of action and differentiates this medicinal product from other sympathomimetic agents. Inopressors may be particularly suitable for treatment of hypotension that occurs in association with Propofol use as they counteract both cardiac impairment and vasodilation14,15,18. The effect of C/T is long-lasting7. Noradrenaline, a well-established alternative agent for the treatment of acute hypotension8 with a short elimination half-life, has potent alpha-adrenergic and slight beta-adrenergic effects, resulting in potent vasoconstriction and less potent inotropy. Reflex bradycardia can occur16,17. The effect of NA on cardiac output has been shown to be highly variable23. In summary, the pharmacodynamic and -kinetic profiles of C/T compared to NA are described to be different.
Clinical pharmacology of antiplatelet drugs
Published in Expert Review of Clinical Pharmacology, 2022
Georg Gelbenegger, Bernd Jilma
Substances that increase the intraplatelet concentration of cAMP and cGMP inhibit platelet aggregation, regardless of the agonist employed [42,43]. Phosphodiesterases 3 and 5 degrade cAMP and cGMP to 5’-AMP and 5’-GMP, respectively, and thereby regulate two critical second messenger platelet signaling pathways, leading to increased concentrations of adenosine, cAMP and cGMP [44]. In addition to its inhibitory effect on phosphodiesterases, dipyridamole inhibits adenosine uptake of red blood cells, resulting in increased adenosine levels. Via A2 receptors, adenosine leads to cAMP-dependent inhibition of platelet aggregation. Cilostazol is a reversible phosphodiesterase 3 inhibitor. Phosphodiesterase inhibitors are used rarely and almost exclusively for secondary prevention of ischemic stroke [45].
Current status of drug repositioning in hematology
Published in Expert Review of Hematology, 2021
Cilostazol is a phosphodiesterase 3 inhibitor that was originally developed as an antiplatelet agent. Its action mechanism is multifaceted. It not only inhibits platelet function but also improves endothelial cell function. In the context, cilostazol used for the prevention of ischemic stroke is a representative example of DR. In a Japanese multicenter randomized trial, patients at high risk of non-cardioembolic ischemic stroke were assigned to two treatment groups (oral aspirin or clopidogrel alone and cilostazol combined with aspirin or clopidogrel), and the rate of the first recurrence of symptomatic ischemic stroke was compared between the two groups [19]. Ischemic stroke recurrence was observed in 7% of patients in the former group and 3% in the latter, and the risk was significantly lower in the combination treatment group (HR: 0 · 49, P = 0 · 001). Meanwhile, the incidence of severe or life-threatening bleeding was similar between the two groups. A systematic review and meta-analysis of cilostazol for the secondary prevention of ischemic or hemorrhagic stroke showed decreased rates of ischemic stroke (odds ratio [OR] 0 · 68, P < 0 · 0001), hemorrhagic stroke (OR 0 · 43, P = 0 · 0001), and systemic bleeding (OR 0 · 73, P = 0 · 04) compared to the corresponding rates associated with placebo, aspirin, or clopidogrel [20]. Cilostazol was initially used in the Asia-Pacific region, and its utility for patients in Western countries whose epidemiology and risk factors may differ from those in the Asia-Pacific region is discussed [21].