1. PHARMACOLGY OF CARDIAC GLYCOSIDES Tishaan Singh, (Jason) Song Chio, Eugene Choi PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

2. Outline Introduction of Cardiac Glycosides Pharmacokinetics Pharmacodynamics Applications

3. Introduction – Sources Found: secondary metabolities in plants and insects Foxglove plant (Digitalis purpurea), Strophanthus gratus, Lily of the Valley, milkweed butterflies

4. Introduction – Structure, Action, Uses Structure: organic compounds containing Glycoside (sugar) Aglycone (non-sugar) – steroid, active part Action: 2 prominent effects Increased inotropic effect Decreased chronotropic effect Uses: Ancient times: arrow coatings, homicidal or suicidal aids, rat poisons, heart tonics, diuretics, emetics Modern times: heart failure, atrial fibrillation, supraventricular tachycardia Digoxin

5. Pharmacokinetics Digoxin t 1/2 = 36 – 48 hours Would require several days to reach steady-state Special dosing regimen: “digitalization” Therapeutic range: 0.5 – 1.5 ng/mL >2.0 ng/mL can lead to toxicity (arrhythmias) – life-threatening Digibind: rapidly reduces plasma digoxin levels

6. Cardiac Glycosides

7. Cardenolides and Bufadienolides

8. Increased Intracellular Calcium

9. Na + /K + -ATPase Signal Transducer

10. Cellular Effects

11. Applications Digitalis Slowing of rapid ventricular rate in atrial fibrillation Returns heart to normal sinus rhythm Patients with the tachycardia-bradycardia syndrome should receive maintenance doses of digitalis after pacemaker implantation Digitalis has a low toxic-therapeutic ratio Contraindicated: ventricular fibrillation Digoxin Indicated for treatment of mild to moderate heart failure Increases left ventricular ejection fraction and improves heart failure symptoms Contraindicated: ventricular fibrillation

12. Applications Digitoxin Similar to Digoxin; effects are longer lasting Eliminated in the liver, while Digoxin is eliminated in the kidney; Digitoxin can be used in patients with poor kidney function Ouabain Small doses can be used to treat hypotension and cardiac arrhythmias Treatment of heart failure

13. Alternative Applications Cancer therapies Due to signal cascade after cardiac glycoside binds to Na + -K + - ATPase. Increased expression of cell cycle inhibitor p21 Cip1 Inhibition of transcription factors (NF-κβ) Initiation of receptor-mediated apoptosis Evidence for selectivity of cardiac glycosides to malignant but not normal cell proliferation

14. Alternative Applications Contraceptive – decreases sperm motility Sperm motility heavily dependent on α4 isoform of the sodium pump Indirectly involved in pH maintenance (Na gradient for NHEs) Rodent α4 isoform found to be highly sensitive to ouabain @ ~ 1 μM

15. Summary of Cardiac Glycosides Common structural motifs: steroid (pharmacophore), sugar, unsaturated lactone Causes increased inotropic and decreased chronotropic effects Used for heart failure, atrial fibrillation, supraventricular tachycardia Long half-lives – require special dosing regimen (digitalization) Narrow therapeutic window, toxicity can lead to arrthymias, but can be reversed using Digibind Cardiac glycosides (CG) inhibits Na + /K + -ATPase activity, increases intracellular [Na + ], reduces activity of Na + /Ca 2+ exchanger, therefore increases intracellular [Ca 2+ ] CG induced Na + /K + -ATPase signaling: [Ca 2+ ] oscillation mediates cellular proliferation, differentiation, and apoptosis Digitalis, Digoxin, Digoxin, Ouabain Slows heart rate, returns to normal rhythm Treatment for heart failure Alternative Applications Cancer therapies Contraceptives

16. References Singh, B. and Rastogi, R.P. 1970. Cardenolides-glycosides and genins. Phytochemistry 9: 315-331. Prassas, I., Diamondis, E. P., Novel therapeutic applications of cardiac glycosides, Nat. Rev. 2008, 7, 926-935. Schoner, W., Scheiner-Bobis, G., Endogenous Cardiac Glycosides: Hormones using the sodium pump as signal transducer, Sem Nephrol. 2005, 25, 343-351. Schwinger, R. et al., The Na, K-ATPase in the failing human heart, Cardiovasc Res, 2003, 57, 913- 920. Fürstenwerth, Hauke. "Ouabain–the insulin of the heart." International journal of clinical practice 64.12 (2010): 1591-1594. Prassas, Ioannis, and Eleftherios P. Diamandis. "Novel therapeutic applications of cardiac glycosides." Nature Reviews Drug Discovery 7.11 (2008): 926-935. Woo, Alison L., Paul F. James, and Jerry B. Lingrel. "Roles of the Na, K ‐ ATPase α4 isoform and the Na+/H+ exchanger in sperm motility." Molecular reproduction and development 62.3 (2002): 348- 356. Akera, T., and TM T. Brody. "The role of Na+, K+-ATPase in the inotropic action of digitalis." Pharmacological reviews 29.3 (1977): 187-220. Digitoxin, Antibody Hapten Source Digoxin. "Naturally occurring cardiac glycosides." Med J Aust 144 (1986): 540-544.