Congestive Heart Failure-Pharmacological approach I (Cardiac Glycosides-Digoxin)

Drug classes that can be used to treat chronic heart failure:

1. ACE inhibitors

2. ARBs

3. Non-selective alpha antagonists

4. Selective alpha agonists

5. B-blockers

6. Calcium channel blockers

7. Diuretics (Loop diuretics and Spironolactone)

8. Digoxin (Cardiac Glycoside)

9. Direct K+ channel acting antagonists

10. Phosphodiesterase inhibitors

11. Nitric Oxides donors

12. Organic Nitrates

Part 1.1: Digoxin and Cardiac Glycosides

1.1 Mechanisms of Cardiac Glycosides in general:

1. Positive inotropic effect (increases force of contraction)

-Digoxin has a positive inotropic effect and thus helps the frail myocardium to pump by increasing contractility.

Mechanisms of action:

-Cardiac glycosides are potent inhibitors of active transport of sodium and potassium ions across the membrane.

-They reversibly bind to a subunit of the Na+/K+ ATPase.

-Both sodium and calcium ions enter the cardiac myocytes during each depolarisation.

-Calcium ion entry triggers contraction and the concentration within the cytoplasm increases.

-To restore original calcium concentrations, calcium ions are taken back into the sarcoplasmic reticulum via Ca2+ ATPase (SERCA-2).

-Also, it is removed from the cell by Na+/Ca2+ exchanger (NCX)

-Inhibition of Na+/K+ ATPase by cardiac glycosides results in a reduction in the rate of sodium extrusion and thus sodium ion conc. within cytoplasm increases.

-This leads to more Na+ removed via the NCX exchanger and Ca2+ is less effectively removed.

-With less Ca2+ efflux and repeated entry of calcium ions, calcium ions accumulate in the myocyte.

-This results in a few effects:

(a) Ca2+ uptake into the SR is increased via SERCA

(b) Increased Ca2+ is available for release from the SR during the next EC-coupling.

This leads to enhanced myocardial contractility.

2. Controls ventricular rate response to atrial filbrillation

-Atrial filbrillation (cardiac arrhythmia, associated with CHF). Indicated for atrial filbrilation and heart flutters.

3. Modulate nervous system activity

-This contributes to efficacy in managing heart failure.

4. Alters automaticity and diastolic RP of Digoxin (Electrophysiological actions)

-Decreases automaticity and increases diastolic resting membrane potential in atrial and AV nodal tissues.

-This is achieved by an increase in vagal tone (via m2 receptors) and a decrease in sympathetic nervous activity.

-This can cause sinus bradycardia and/or prolongation of AV conduction, higher-grade sinus arrest or AV block.

Definition of AV block: impairment of the conduction between the atria and ventricles of the heart 

Therpeutic Point and Take Note: At high concentrations, cardiac glycosides can directly increase automaticity in cardiac tissue, which contributes to atrial and ventricular arrhythmias.

-The simultaneous non-uniform increase in automaticity and depression of conduction in the Purkinje fibres and Ventricle muscle fibres can cause serious ventricular arrhythmias.

1.2 Pharmacokinetics

-t1/2 for digoxin is 36 hours in patients with normal renal function.

-Dosing issues: Loading doses (An initial higher dose of digoxin may be given at the beginning of a course of treatment before dropping to a lower maintenance dose)

Why use a loading dose?

-It is most useful for drugs that are eliminated from the body relatively slowly, i.e. have a long systemic half-life. Such drugs need only a low maintenance dose in order to keep the amount of the drug in the body at the appropriate therapeutic level (i.e. without an initial higher dose, it would take a long time for the amount of the drug in the body to reach that level)

*Definition of Maintenance dose: maintenance rate [mg/hr] of drug administration equal to the rate of elimination at steady state 

Steady state (in general occurs after 5-7 half-lives of drug):

Steady state levels

-This permits a once a day dosing (steady state blood levels are achieved one week after initiation of maintenance therapy).

-Excretion issues: The amount of digoxin excreted by kidney is denoted by clearance rate that is proportional to the glomerular filtration rate (GFR).

-Thus any issues with renal function (affecting GFR), will affect the half life in the body significantly (esp advanced renal insufficiency) [half life~3.5-5 days]

-The volume of distribution and clearance rate of the drug are decreased in the elderly.

1.3 Side effects/Adverse effects (Take extra caution in elderly or renal-impaired)

*Digoxin has a narrow therapeutic index/window (which means it is therapeutic dose and toxic dose is small).

Thus, digoxin MUST BE USED with caution in patients with renal insufficiency and in the elderly.

1. Blurred vision (with xanthopsia-yellow vision)

***2. Arrhythmias/Ventricular tachycardia or fibrillation

3. Nightmares

4. Confusion

5. Depression

6. Psychosis (abnormal condition of the mind)

1.4 Drug interactions

-Care with CYP3A4 inhibitors

-Other anti-arrhythmic drugs (e.g. amiodarone-sodium channel blocker)

-Many others (Check AMH 13 for complete list)

-Care with drugs that lower K+ levels in the blood (insufficient blood potassium to cause repolarisation) [e.g. loop diuretics-furosemide]  or lower Mg2+ levels (Affects Mg2+ dependent-ATPase)

-K+ and Mg2+ level changes will cause an increased risk of TOXICITY

***The advent/implementation of alternative therapies that palliate (lessen) the symptoms and improval of survival rates has led to more limited roles of cardiac glycosides for CHF treatment.

***Now only digoxin is widely used today

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