Epidemiology -- Approximately 2,000,000 patients in the U.S.A. are diagnosed with congestive heart failure (CHF).  It is primarily a disease of the older adult with an incidence in 60 y/o's four times that seen in 50 y/o's.  Additionally, males (60% of cases) are affected slightly more than females (40% of cases) according to the Framingham study of 1971, a landmark clinical study of cardiovascular health.

CHF may be characterised by the specific onset of the disease, the portion of the heart affected, or the results of the failure.

Acute vs. Chronic Failure
Acute heart failure often occurs post-myocardial infarction.  Damage to the myocardium, resultant from the ischaemia of the MI, will decrease the contractility and consequently decrease the cardiac output.  The more common manifestations of acute failure include a dramatic drop in CO with increased venous pressure, due to damming of blood in the large veins.

Chronic heart failure may also present post-MI or as the result of congenital cardiomyopathies, infection, hypertension, or nutritional deficits, among other etiologies.  Chronic CHF is more insidious, with the decreased CO less noticeable (acutely), and is often accompanied by fluid retention and increased blood volume.
 

Left vs. Right Sided Failure
Left sided failure (involving only the left ventricle) is often accompanied by a decrease in CO.  It may result from hypertension (increased afterload which increases the workload on the heart), coronary artery disease, and rheumatic heart disease (involving valvular dysfunction).

Right sided failure (in which the right ventricle fails) is often secondary to left sided failure.  However it may also be secondary to valvular stenosis or pulmonary disease such as pulmonary hypertension (in which the right ventricle will hypertrophy, resulting in cor pulmonale -- this is the consequence that precipitated the removal of certain legend anorexiants from the market.)

Both sides of the heart may fail simultaneously, as with cardiomyopathies of congenital, viral, or alcoholic origin.
 

High vs. Low Output Failure
Low output failure is much the more common type of heart failure.  It is the "classic" heart failure characterised by a decrease in cardiac output.

However, the heart may fail and, either through rapid compensation or through the etiology of the failure, not cause a significant drop in CO.  This may occur with sudden, sustained increases in peripheral resistance, beriberi, arteriovenous fistulae, or thyrotoxicosis.

Ventricular dilatation may occur.  As the CO falls, more blood is left in the chamber (an increase in end diastolic volume, EDV).  This increase in volume will stretch the ventricle, increasing its tension (or preload).  Recall that, according to the Frank-Starling law of the heart, an increase in preload will increase the force of contraction, thereby ejecting more blood and increasing the CO.

Ventricular hypertrophy also may occur.  As the ventricle contracts harder and more often (discussed below), the muscle receives more work.  Just as with other muscles of the body, the greater the workout myocardium receives, the greater the muscle mass.  This also will result in greater contractile strength.
 

NOTE that both ventricular dilatation and hypertrophy are self-limiting.  The chamber wall can only stretch so much before it will loose its ability to stretch (loose its elasticity -- recall Young's modulus from physics) and will no longer be able to contract.  Additionally, the ventricle can only hypertrophy to a certain point.  If the muscle continued to enlarge it would loose much of its rapid contractile response that is required to maintain appropriate CO.
Sympathetic reflex control also contributes to compensation in CHF.  As the CO begins to drop, the pressure, as detected by baroreceptors, is less.  Therefore, the cardioacceleratory centre is activated and CNS sympathetic outflow is increased.  This increase in sympathetic tone will increase both heart rate and force of contraction and consequently increase the CO.  This is also a self-limiting compensatory reflex.  If heart rate increases too much (to the point of tachycardia) each beat generated is ejecting less blood, decreasing CO.

The kidney also contributes to the reflex compensation of CHF.  As with the sympathetic system noted above, the drop in CO will be interpreted by baroreceptors in the kidney as a drop in pressure.  The kidney, in response, will attempt to increase blood pressure and renal blood flow through the release of renin and all of its subsequent actions.  RECALL that renin will lead to the release and activation of angiotensin II, aldosterone, and ADH (also recall that these hormones are intimately associated with one another).  Also recall that the the overall effects of these hormones are

angiotensin II -- vasoconstriction (increased peripheral resistance, afterload)
aldosterone -- sodium and water retention (increased blood volume, increased PR, afterload)
ADH -- water retention and vasoconstriction (increased blood volume, increased PR, afterload)
Early in failure these reflex actions could be beneficial, by increasing venous return, increasing preload, and therefore, increasing CO.  HOWEVER since the PRIMARY problem is the inability of  the heart to force blood out, the detrimental effects (noted parenthetically above) will contribute further to the heart failure in what is described by Guyton as a vicious cycle (as the heart fails more, more water is retained causing the heart to fail more et c.).

Fatigue is common with CHF patients.  As CO drops, blood flow to muscles decreases.  Therefore when demand for oxygenated blood increases, the supply has been decreased, and the patient will tire very easily.

As the CO decreases and the pumping ability of the heart fails, blood will begin to pool gravimetrically.  Since this results in increased capillary pressure wherever the blood is pooling, an increase in capillary filtration will occur, therefore resulting in various forms of oedema.  The specific oedema and its consequence is dependent upon the site of formation.

In left sided failure, the blood will back up into the pulmonary circulation.  Chronically, this pulmonary oedema will manifest as
dyspnea (pain or difficulty in breathing)

orthopnea (difficulty in breathing especially when recumbent -- the more advanced the CHF, the worse  the orthopnea.  Often the patients must prop themselves up with pillows to ease breathing just so they can sleep.  This gives rise to a rough estimate of  the severity of CHF, one-, two-, or three-pillow CHF.)

cough (due to pulmonary congestion)

As pulmonary oedema progresses the patient may exhibit Cheyne-Stokes respiration, characterised by 10-60 sec periods of apnea.

If failure is very rapid, acute pulmonary oedema may ensue with resultant death.
 

In right sided failure, the blood backs up along the venous system.
Hepatomegaly results from hepatic congestion due to the increased pressure within the hepatic vein.  The liver will enlarge and exhibit extensive sinusoidal congestion.

Ascites (oedema of  the abdominal cavity) will also occur as the blood continues to pool in the inferiour vena cava.

Pitting oedema will also occur, as venous pressures increase (especially in the feet and ankles -- pedal oedema), increases in extracellular fluid, resultant from increased capillary filtration, will cause an oedema that may be "pushed" aside, creating a pit that takes several minutes to disappear as that the ECF redistributes itself.

History of digitalis glycosides

Withering first described the potential benefit of digitalis in his 1785 paper An Account of the Foxglove and Some of Its Medical Uses: With Practical Remarks on Dropsy and Other Diseases.  Withering stated that "It has a power over the motion of the heart to a degree yet unobserved in any other medicine, and this power may be converted to salutary ends."  However, this is not the first recorded use of this class of drugs.  Chemical relatives of digitalis were used in ancient Egypt, Rome, and 13th century Wales.  Additionally, bufonalides (which have almost identical properties) have been collected from the skins of toads and used as arrow poisons, probably since pre-history.

Digitalis species
D. purpurea -- the common foxglove; digoxin, digitoxin
D. lanata -- the primary source of digoxin in the U.S.A.
Strophanthus sp.
S. hispidus -- strophanthine
S. gratus -- ouabain
Urginia (Scilla) maritima -- the sea onion, squill

The mechanism, illustrated and discussed above, is responsible for the beneficial pharmacodynamic response of positive inotropy.  However, cardiac glycosides possess other pharmacodynamic actions that contribute other effects that may also influence cardiac function.

These agents will stimulate both the adrenergic and vagal neurones that control cardiac function.  Stimulation of these nerves is presumed to result from a similar action on the neurone (inhibition of ATPase).  These effects are somewhat dose dependent, with myocardial tissues affected at low doses, the vagus nerve affected at slightly higher doses, and sympathetic stimulation not clinical evident until toxic doses are attained.

Recalling the normal physiology of cardiac control, it is evident that stimulation of the vagus nerve at therapeutic doses of digoxin can result in a negative chronotropic effect, slowing heart rate (bradycardia).  Excessive action by this mechanism can ultimately result in second or third degree heart block that may be characterisic of digoxin toxicity.  (Another contributor to this bradycardia is the effect of digoxin at the AV node specifically, where the refractory period may be prolonged, delaying impusle conduction from the AV node to the ventricle.)

Overstimulation of the sympathetic input can increase the firing rate of the SA and AV nodes and cause tachycardia, but this is often off-set by the vagal effects.  HOWEVER, recall that the myocardium received sympathetic input directly.  The direct sympathetic stimulation of myocardial tissues in digoxin toxicity may cause the development of ventricular arrhythmias.

Additionally, the increase in intracellular calcium (resultant from the mechanism of digoxin) will also predispose cardiac conduction tissues (SA node, bundles of His, and Purkinje fibres) to premature firing (by making more positive their respective resting membrane potentials).  This will contribute to the arrhythmogenic (pro-arrhythmic) effects of digoxin.

In summary, the overall effects of digoxin that may be observed include at

Therapeutic doses
positive inotropy -- myocardial effect
bradycardia -- vagal effect
pro-arrhythmia (increased abnormal automaticity) -- sympathetic effect
Supratherapeutic (toxic) doses
heart block -- vagal
premature atrial beats, fibrillation, flutter -- sympathetic
bigeminy, trigeminiy, ventricular fibrillation and flutter -- sympathetic

NOTE that digoxin produces differential effects in the normal vs. failing heart.  While it may produce some slight increase in force of contraction, digoxin does not greatly increase CO in the healthy heart.  However, its toxic effects (AV block and ventricular arrhythmias, or the vagomimetic and sympathomimetic effects) may produce lethality in healthy patients.  The reason for this differential action is not known.

Absorption -- digoxin has less bioavailability (70%) than digitoxin (95%).

Distribution -- both drugs have a relatively large volume of distribution.  This is attributable in part to their degree of plasma protein binding (digoxin, 50%; digitoxin, >90%).

Metabolism and Elimination -- Digitoxin is metabolised hepatically to digoxin (this is one factor in its long half-life) and may undergo enterohepatic cycling (another factor in the half-life).  Digoxin is eliminated renally (60% of digoxin elimination).  Therefore renal function may play a role in digoxin dosing.  The half-life of digoxin is 1.6 days while that of digitoxin is 7 days.

In the case of severe heart failure, the primary goal may be the rapid attainment of therapeutic digoxin plasma levels.  Due to the long half-life, this may be shortened by digitalisation of the patient.
Fast Digitalisation begins with 0.25 mg IV or PO q.i.d. for one day, followed by standard dosing.
Slow Digitalisation follows a 0.25 mg stat, then b.i.d. for 3 days, followed by standard dosing.
The goal in both cases is a therapeutic plasma level of 0.5-2.0 mcg/L (or 0.5-2.0 ng.ml).
Dosage forms of digoxin include solid tablets, liquid capsules, elixir, and parenteral preparations.

Note that many clinicians are re-evaluating the potential benefit of digitoxin over digoxin.  Digitoxin, which fell out of favour some 20-30 years ago, may soon become a treatment option again, based upon its longer half-life and more "steady" steady-state control of congestion heart failure.  Additionally, movement is being observed toward individualised digoxin/digitoxin dosing that may produce a serum level outside of the "accepted" therapeutic range.

Digoxin toxicity affects a wide variety of organ systems, as summarised below:

Cardiac Effects -- Digoxin toxicity presents primarily as arrhythmias, SA and AV block, bigeminy and trigeminy that proceeds to V-tach and V-fib as discussed above.

Gastrointestinal Effects -- Anorexia and nausea/vomiting/diarrhoea are early signs and symptoms of digoxin toxicity.

Neurological Effects -- include headache, fatigue, and drowsiness.

Visual Effects -- These effects are classic to severe digoxin toxicity.  They include blurred vision and chromotopsia, a primarily yellow-green (but may be red, brown, or blue) halo that appears around lights.

Complicating factors of digoxin toxicity include hypokalaemia (recall that digoxin competitively inhibites the Na/K pump by binding at the K site.  Therefore if there is less K present, more digoxin will bind.), hypercalcaemia, and hypomagnesaemia.

Digoxin toxicity may be treated with

Potassium -- which may be helpful in treating mild digoxin toxicity.  However, hyperkalemia may reduce the efficacy of digoxin and compound the heart failure.  Care should be taken in monitoring potassium levels to prevent this occurance.

Lidocaine (lignocaine) or Phenytoin are useful in digoxin-induced arrhythmias.

Digibind® -- may be used in cases where plasma levels of digoxin are high.  These are fab fragments of digoxin specific antibodies that bind to and prevent the action of digoxin.

Amrinone (inamrinone) and Milrinone -- These drugs are used in emergencies of heart failure.  They are bipyridine derivatives that produce and increase in the force of contraction of the heart.

Mechanistically, these agents inhibit the enzyme phosphodiesterase (PDE), specifically the 3 subtype isozyme.  Recall that PDE₃ is responsible for the degradation of cAMP.  Also recall that beta-1 receptor activation (which results in the contractile process) is mediated by adenylyl cyclase and generation of cAMP.  Therefore, by preventing the metabolism of cAMP, its action is prolonged, hence a positive inotropic effect.  Note that since it is acting by a different mechanism, the actions of these agents are additive to those of digoxin.

Additionally, these agents act as vasodilators (discussed in subsequent sections of the course).  This will also be beneficial in the treatment of emergent cardiac failure.

Milrinone is the preferred phosphodiesterase inhibitor due to its greater potency, shorter half-life, and lower incidence of side effects (especially arrhythmias), relative to inamrinone.

The chronic administration of phosphodiesterase inhibitors has been correlated to a decrease in the survival rate on patients with congestive heart failure.  Therefore these agents are only used in the acute management of emergent cardiac failure.

Dobutamine is the preferred sympathomimetic due less tachycardia and fewer arrhythmias, relative to other beta adrenergic agonists.  Additionally, it act as a partial agonist/antagonist at alpha receptors with an overall effect of renal vasodilatation.  This is beneficial in maintaining renal blood flow.  (Dopamine and other sympathomimetics may decrease renal blood flow and cause subsequent, ischaemia-induced renal damage.)

Tolerance develops rapidly to the beneficial effects of the direct sympathomimetics.  Therefore they are only used short term and continued infusion may require a "drug holiday" to maintain efficacy.

Diuretics will increase fluid loss, thereby decreasing peripheral resistance and afterload, and therefore increasing cardiac performance.  The specific class of diuretic should be chosen with care, since thiazide and loop diuretics will cause potassium loss, potentially increasing the risk of digoxin toxicity, while K sparing diuretics may cause hyperkalemia and decrease the efficacy of digoxin.  These agents are often employed first, before the addition of digoxin to the therapeutic regimen.

Vasodilators may also be beneficial in the treatment of CHF.  Pharmacodynamically, they may either decrease preload or afterload.  This will decrease the workload on the heart and improve cardiac performance.  Specific agents used in CHF include the alpha-1 antagonists prazosin, doxazosin, and terazosin; organic nitrates/nitrites, and hydralazine.

ACE Inhibitors may also be useful in the treatment of CHF.  Their actions will decrease ATII induced vasoconstriction (reducing the afterload) and also prevent aldosterone and ADH mediated water retention (thus reducing blood volume).  By this dual mechanisms, many CHF patients respond well to ACE inhibition as a first line therapy in early CHF.

Beta Adrenergic Antagonists are also recommended for early to mid congestive heart failure (Class II -III failure).  Several drugs in the class have been examined for use in CHF and those that are most beneficial are drugs that possess  both beta antagonist and alpha-1 antagonist activity (e.g. carvedilol).  Second most effective agents are those with beta-1 selective antagonist features.

Recall that these agents are negative inotropes.  Therefore, on the surface, they would appear to be detrimental to a patient with a failing heart.  The theory as to the efficacy of beta blockade is as follows.  The beta blockade produced in the mid-failure stage will decrease cardiac workload and slow the progression of the heart failure (the heart has to work less hard and/or it will not fail as fast) by blocking both direct cardiac effects and peripheral actions mediated by circulating catecholamines (noradrenaline).  This may be assisted by decreases in peripheral resistance both directly (by the alpha antagonist activity) and indirectly (by non-selective beta-mediated decreases in renin-angiotensin-aldosterone release and function).

Digoxin -- Increases myocardial contractility to increase force of contraction and CO

Direct action on myocardial cells through inhibition of Na/K ATPase
Increase IC Ca -- increase contractility
Positive inotropic agent
Toxicity may increase with hypokalemia, characterised by diverse direct and indirect cardiac effects and additional systemic effects

Stimulate G-coupled proteins to activate adenylyl cyclase
Increase IC levels of cAMP
Ultimate myocardial effect -- contraction
Positive inotropic agent
Used primarily in emergencies

Increases IC levels of cAMP
Sustains myocardial contraction
Positive inotropic agent
Used primarily in emergencies

Thiazide and Loops often lead to hypokalemia and digoxin toxicity
Potassium sparers avoid this to some extent although hyperkalemia could reduce digoxin efficacy
Patients on thiazide, loops, or even digoxin alone are often placed on potassium supplements to avoid digoxin toxicity

Arteriodilators -- dilate primarily the arterial system to decrease afterload and thereby decrease myocardial workload, increasing CO.  These agents work well with left-sided only failure.

Venodilators -- dilate primarily the venous system, allowing greater capacitance in the vessels, decreasing preload.  These agents work well with right-sided only failure.

Less vasoconstriction -- decreased afterload (see arteriodilators)
Less aldosterone/ADH, therefore less water and Na retention (see diuretics)

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