PHM142 Fall 2012 Instructor: Dr.

Jeffrey Henderson

Cardiac Glycosides
October 17, 2012
Sarah Johnson Maya Hamam Barret Barr Divya Prajapati

What are Cardiac Glycosides?

Family of compounds derived from the Digitalis plant (Digitalis purpurea or Digitalis lanata)

What are Cardiac Glycosides?

Contain a polysaccharide chain, a steroid portion and a lactone ring

Types

Two main types: Bufadienolides and Cardenolides

What are they used for?

Cardiac glycosides are cardiotonic drugs Used in the treatment of congestive heart failure and cardiac arrhythmia

Digitoxin

Digoxin

Also known as Lanoxin

Why use Cardiac Glycosides?

Starling Curve

Decompensation contractions get weaker In heart failure: - Decompensation occurs well below the pericardium limit

Increase contractile strength of failing heart by 50-100% Drugs have little effect on a healthy heart

Mechanism of Action

Digitalis acts on Na+/K+ ATPase to inhibit it

Keeping the pump phosphorylated state

Mechanism of Action

Partial Inhibition of Na+/K+ ATPase

Electrochemical driving force for Na+ disappears CICR from SR Result: - Increase in the strength of contraction

Toxicity- Digitalis Overdose

Signs: Biphasic / inversions of T-wave in ECG Uneven depolarization in parts of the ventricle

Adverse Reactions of Digoxin

Cardiac Related Adverse Effects Gastrointestinal Related Adverse Effects

Central Nervous System Related Adverse Effects

Tx for Adverse Reactions

Removal from drug therapy Pacemaker

DIGIBIND

Drug-Drug Interactions

Quinidine

Inhibits P-glycoprotein mediated glycoside transporter in the kidney

Digitalis clearance is decreased and bioavailability is increased Serum levels of Digitalis can reach potentially toxic concentrations

Itraconazole

Propafenone Verapamil

Amiodarone Indomethacin

Drug- Drug Interactions

Antibiotics:

Azithromycin
Telithromycin Erythromycin Clarithromycin Tetracycline

Decreased renal clearance and increased bioavailability due to Pglycoprotein inhibition Destruction of gut bacteria capable of metabolizing Digitalis Inhibition of CYP3a4 metabolism in liver

All 3 mechanisms increase Digitalis serum levels to potentially toxic concentrations

Summary

Cardiac glycosides are a family of compounds derived from the digitalis plant Digitalis consists of two major cardiac glycosides: Digitoxin and Digoxin. Cardiac Glycosides partially inhibit the E2 Na+/K+ ATPase by preventing dephosphorylation. This causes Na+ to accumulate inside the cell, inhibiting NCX and causes VOCC to open. The rise in Ca+2 induces SR to release Ca+2 which results in a stronger contraction of the ventricle. Overdose results in complete inhibition of the Na+/K+ pump no membrane repolarization no muscle relaxation heart stops beating! Adverse reactions of Digoxin normally only occur at doses higher than those needed to achieve a therapeutic effects. Massive overdoses of Digoxin can be reversed using DIGIBIND, a drug that binds to Digoxin molecules making them unavailable for biding at their site of action in the body There are three main mechanisms that can make Digitalis concentrations potentially toxic. 1) inhibition of P-glycoprotein transporter in the kidneys 2) eradication of gut bacteria that metabolize Digitalis 3) inhibition of Cyp3A metabolism in the liver.

References
eCPS

Guyton, A.C. and J.E. Hall. 2006. Electrocardiographic Interpretation of Cardiac Muscle and Coronary Blood Flow Abnormalities: Vectorial Analysis., p. 146, 261-263. In W. Schmitt and R. Gruliow, Textbook of Medical Physiology, Elsevier Saunders, Philadelphia.
Schwartz, A., Whitner, K., Grupp, G., Grupp, I., Adams, R., and S. Lee. 1982. Mechanism of Action Digitalis: Is the Na,K-ATPase The Pharmacological Receptor?. Annals New York Academy of Sciences, 82, 253-271. Winnicka K., Belawski K., Bielawska A., 2006. Cardiac Glycosides in Cancer Research and Cancer Therapy. Acta Poloniae Pharmaceutica n Drug Research. Vol. 63 No. 2 pp. 109-115 Wood, C. and C. Nurse. 2011. Bio 3U03 Animal Physiology:Homeostasis Term I. Cardiac Physiology., Lecture 5 p. 4. McMaster Uni.