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PHM142 Fall 2016 Instructor: Dr. Jeffrey Henderson Cardiac Glycosides http://www.livescience.com/45201-tech-makes-animal-organsviable-for-transplant.html By: Golsa Bahari-kashani Lamis Khadir Sukhpreet Sidhu Namra Minhas What are cardiac glycosides? • Originate from the foxglove plant (Digitalis purpurea) • Have been used for at least 3000 years by Ancient Egyptians, Romans, and Early Europeans • Treat heart conditions: congestive heart failure and arrhythmias • May be used to treat cancer Diederich, M., Muller, F., & Cerella, C. (2016). Cardiac glycosides: From molecular targets to immunogenic cell death. Biochemical Pharmacology. doi:10.1016/j.bcp.2016.08.017 Structure Structure includes : • A glycoside (sugar) • An aglycone [non-sugar] part which is a steroidal moiety • A lactone http://www.people.vcu.edu/~urdesai/car.htm Types of Cardiac Glycosides Prassas, I., & Diamandis, E. P. (2008). Novel therapeutic applications of cardiac glycosides. Nature Reviews Drug Discovery, 7(11), 926-935. doi:10.1038/nrd2682 THERAPEUTIC USES Congestive Heart Failure Failure of the heart in functioning as a pump Causes: • • • Ischemic disease Chronic long-term untreated hypertension Chronic emphysema and bronchitis CGs increase force of cardiac contraction by increasing intracellular Ca2+ Effects on the heart • • • • Heart rate slowed Contraction is greater Slower AV node conduction velocity Increase in AV nodal refractory period https://emergencymedicinecases.com/wp-content/uploads/2010/03/Ep4Acute-Heart-Failure.jpg Atrial Fibrillation and Flutter • Quivering or irregular heartbeat (arrhythmia) • Occurs when electrical signalling in the heart is disrupted • Lead to rapid ventricular rate that can impair ventricular filling • Digitalis compounds, such as digoxin reduce the ventricular rate through the parasympathomimetic effect • Vagal activation reduces conduction of electrical impulses within the AV node • Digoxin also increases the effective refractory period within the AV node atrial-fibrillation-s1-photo-of-atrial-fibrillation.jpg MECHANISM Mechanism ● inhibits Na+/K+ ATPase in cardiomyocytes by binding to α subunit → ↑[Na+] inside cell (not pumped out) ● Na+ pumped in via Na+-Ca2+ exchanger (NCX) and Ca2+ pumped out. ● ↑[Na+] inside cell inhibits NCX (lose concentration gradient driving Na+ in): Ca2+not pumped out ● ↑ intracellular [Na+] → block NCX → ↑ intracellular [Ca2+] → ↑Ca2+ reuptake by sarcoplasmic reticulum → ↑Ca2+ release on contraction → ↑ contractility ● Bind cardiac muscle with 10 - 1000 times higher affinity than skeletal muscle Bodemann, H. H. (1981). The current concept for the cardiac glycoside receptor. Clin Cardiol Clinical Cardiology, 4(5), 223-228. doi:10.1002/clc.4960040502 Digitalis Mechanism • Na+-K+ ATPase exists in different conformational states • Glycoside binding site in E2P (phosphorylated) conformation state • Binding freezes the enzyme to stop conformation changes and ion transport • Phosphorylation on inner surface of the membrane, glycoside bound on outside Testa, B., & Meyer, U. A. (1995). Advances in drug research (Vol. 19). London: Academic Press. Haviv, H., & Karlish, S. (2013). P-Type Pumps: Na ,K -ATPase. Encyclopedia of Biological Chemistry, 681-687. ADVERSE EFFECTS Adverse Effects • Majority are dose-related • More marked in women than in men • Cardiac arrhythmia especially tachycardia and AV block • Toxicity common in patients with impaired renal function, lean and elderly patients Digestive Disorders Neurosensory Disorders Cardiac Manifestations Endocrine Effects Anorexia, nausea, vomiting, salivations Headache, insomnia, confusion, depression, dizziness, seizures Beginning with bradycardia then extrasystole, tachycardia or fibrillation Related to steroid structure of CGs high can have metabolites with an estrogen effect causing gynecomastia in men Anti-cancer Activity ● Traditionally used to treat cardiac conditions ● CGs such as peruvoside are promising in targeting cancers i.e. leukemia and ovarian cancers ● digitoxin, digoxin, bufalin, and ouabain can stop cancer cells from proliferating and inhibit growth of tumours by inducing cell death Patel, S. (2016). Plant-derived cardiac glycosides: Role in heart ailments and cancer management. Biomedicine & Pharmacotherapy, 84, 1036-1041. doi:10.1016/j.biopha.2016.10.030 Summary ● Structure: steroid nucleus + sugar moiety + lactone moiety ● 2 types: cardenolides - (5-membered ring) + bufadienolides (6-membered ring) ● Therapeutic uses: mainly used to treat congestive heart failure, atrial fibrillation and flutter, and potential uses in cancer ● Widely accepted mechanism: Inhibit Na+/K+ ATPase in cardiomyocytes by binding to its α subunit → increased [Na+] inside cell ● ↑ intracellular [Na+] → block Na+-Ca@+ exchanger → ↑ intracellular [Ca2+] → ↑Ca2+ reuptake by sarcoplasmic reticulum → ↑Ca2+ release on contraction → ↑ contractility ● Glycoside binding site in the Na+-Ca2+ ATPase E2P (phosphorylated) conformation state → binding freezes the enzyme to stop conformation changes and ion transport ● Adverse effects: digestive, neurosensory, cardiac and endocrine systems ● digitoxin, digoxin, bufalin, and ouabain can stop cancer cells from proliferating and inhibit growth of tumours by inducing cell death through the immune system Summary Role of CGs in cardiac disorders and cancer Patel, S. (2016). Plant-derived cardiac glycosides: Role in heart ailments and cancer management. Biomedicine & Pharmacotherapy, 84, 10361041. doi:10.1016/j.biopha.2016.10.030 References Diederich, M., Muller, F., & Cerella, C. (2016). Cardiac glycosides: From molecular targets to immunogenic cell death. Biochemical Pharmacology. doi:10.1016/j.bcp.2016.08.017 Prassas, I., & Diamandis, E. P. (2008). Novel therapeutic applications of cardiac glycosides. Nature Reviews Drug Discovery, 7(11), 926-935. doi:10.1038/nrd2682 Testa, B., & Meyer, U. A. (1995). Advances in drug research (Vol. 19). London: Academic Press. Erdmann, E., Greeff, K., & Skou, J. (2013). Springer Science & Business Media. Bodemann, H. H. (1981). The current concept for the cardiac glycoside receptor. Clin Cardiol Clinical Cardiology, 4(5), 223-228. doi:10.1002/clc.4960040502 Patel, S. (2016). Plant-derived cardiac glycosides: Role in heart ailments and cancer management. Biomedicine & Pharmacotherapy, 84, 1036-1041. doi:10.1016/j.biopha.2016.10.030 Schwinger, R. (2003). The Na, K-ATPase in the failing human heart. Cardiovascular Research, 57(4), 913-920. doi:10.1016/s0008-6363(02)00767-8 Haviv, H., & Karlish, S. (2013). P-Type Pumps: Na ,K -ATPase. Encyclopedia of Biological Chemistry, 681-687. Congestive Heart Failure Medications. (n.d.). Retrieved from https://www2.nau.edu/~daa/lecture/chfmeds.htm Cardiac glycosides - Therapeutic use, adverse effects and interactions - Pharmacorama. (n.d.). Retrieved from http://www.pharmacorama.com/en/Sections/NAK-ATPase-Digoxin-3.php Atrial Fibrillation and Flutter Retrieved from http://www.cvpharmacology.com/cardiostimulatory/digitalis