PHARMACOLGY OF CARDIAC GLYCOSIDESTishaan Singh, (Jason) Song Chio, Eugene Choi

PHM142 Fall 2015Coordinator: Dr. Jeffrey HendersonInstructor: Dr. David Hampson

Outline• Introduction of Cardiac Glycosides

• Pharmacokinetics

• Pharmacodynamics

• Applications

Introduction – Sources• Found: secondary metabolities in plants and insects

• Foxglove plant (Digitalis purpurea), Strophanthus gratus, Lily of the Valley, milkweed butterflies

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

Pharmacokinetics

• Digoxin t1/2 = 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

Cardiac Glycosides

Cardenolides and Bufadienolides

Increased Intracellular Calcium

Na+/K+-ATPase Signal Transducer

Cellular Effects

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

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

Alternative Applications• Cancer therapies

• Due to signal cascade after cardiac glycoside binds to Na+-K+-ATPase.• Increased expression of cell cycle inhibitor p21Cip1 • Inhibition of transcription factors (NF-κβ)• Initiation of receptor-mediated apoptosis

• Evidence for selectivity of cardiac glycosides to malignant but not normal cell proliferation

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

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+/Ca2+ exchanger, therefore increases intracellular [Ca2+]• CG induced Na+/K+-ATPase signaling: [Ca2+] 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

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.