1. Na/Ca2+ exchange reaction that exchanges Ca2+ ions for Na+ ions across the cell membrane.

2. Uptake of Ca2A+ by the sarcoplasmic reticulum and mitochondria

Yes r/t increased heart rate, greater force of contraction. Also, increased venous return secondary to vasoconstriction which leads to increased cardiac preload

The heart dilates and becomes more globular as a result of an increase in blood volume related to compensatory mechanism that the heart evokes to enhance cardiac output. Initially stretching of the heart muscle causes a stronger contraction however excessive elongation of the fibers results in weaker contractions and the geometry diminishes the ability to eject blood effectively. This is termed systolic failure. The structural changes (hypertrophy) that occur due to systolic failure can lead to impairment in the ability of the ventricles to relax and accept blood during diastole. This is termed diastolic heart failure and is a particularly common feature of heart failure in elderly women.

A fall in cardiac output causes a decrease in blood flow to the kidney. When blood volume is low, juxtaglomerular cells in the kidneys secrete renin. Renin stimulates the production of angiotensin I, which is then converted to angiotensin II. Angiotensin II causes blood vessels to constrict, resulting in increased blood pressure. Angiotensin II also stimulates the secretion of the hormone aldosterone from the adrenal cortex. Aldosterone causes the tubules of the kidneys to increase the reabsorption of sodium and water into the blood. This increases the volume of fluid in the body, which increases peripheral resistance and an increase in blood pressure. Blood volume increases and more blood is returned to the heart. If the heart is unable to pump this extra volume, venous pressure increases and peripheral edema and pulmonary edema occur. These compensatory responses increase the work of the heart, and can contribute to further decline in cardiac function.

 Angiotensin-converting enzyme (ACE) inhibitors are the agents of choice in heart failure. They block the enzyme that cleaves angiotensin I to form the potent vasoconstrictor angiotensin II. These agents also diminish the rate of bradykinin inactivation. Vasodilation occurs as a result of the combined effects of lower vasoconstriction caused by the diminished level of angiotensin II and the potent vasodilating effect of increased bradykinin. By reducing circulating angiotensin II levels, ACE inhibitors also decrease the secretion of aldosterone, resulting in decreased sodium and water retention. ACE inhibitors decrease vascular resistance, venous tone, and blood pressure, resulting in an increased cardiac output. ACE inhibitors also blunt the usual angiotensin II-mediated increase in epinephrine. They improve clinical signs and symptoms in patients also receiving thiazide or loop diuretics and/or digoxin. The use of ACE inhibitors in the treatment of heart failure has significantly decreased both morbidity and mortality.

Angiotensin receptor blockers-These substances block the activation of angiotensin II AT1 receptors. Blockade of AT1 receptors directly causes vasodilation, reduces secretion of vasopressin, reduces production and secretion of aldosterone, amongst other actions – the combined effect of which is reduction of blood pressure. Angiotensin II receptor antagonists are primarily used for the treatment of hypertension where the patient is intolerant of ACE inhibitor therapy. They do not inhibit the breakdown of bradykinin or other kinins, and are thus only rarely associated with the persistent dry cough and/or angioedema that limit ACE inhibitor therapy. More recently, they have been used for the treatment of heart failure in patients intolerant of ACE inhibitor therapy.

ACE inhibitors-ACE inhibitors are used primarily in the treatment of hypertension, though they are also sometimes used in patients with cardiac failure, renal disease or systemic sclerosis ACEIs can also be used to treat diabetic nephropathy and left ventricular hypertrophy. ACE inhibitors block the conversion of angiotensin I to angiotensin II. They, therefore, lower arteriolar resistance and increase venous capacity; increase cardiac output, cardiac index, stroke work, and volume; lower renovascular resistance; and lead to increased natriuresis (excretion of sodium in the urine). Renin will increase in concentration in the blood due to negative feedback of conversion of Angiotensin I to Angiotensin II. Angiotensin I will increase for the same reason. Angiotensin II will decrease. Aldosterone will decrease. Bradykinin will increase due to less inactivation that is done by ACE enzyme.

Both groups have adverse effects which include postural hypotension, renal insufficiency, hyperkalemia, and angioedema. ACE inhibitors can cause a persistent dry cough believed to be associated with the increases in bradykinin levels produced by ACE inhibitors, although the role of bradykinin in producing these symptoms remains disputed by some authors. Patients who experience this cough are often switched to angiotensin II receptor blockers. ARB’s have the advantage of more complete blockade of angiotensin action, because ACE inhibitors inhibit only one enzyme responsible for the production of angiotensin II and they do not affect bradykinin levels.

TRUE

“Calcium channel blockers are of no value in heart failure”, Lange, 2010. Calcium channel blockers are also known as calcium entry blockers and calcium antagonists. They selectively interfere with inward calcium ion movement across myocardial and vascular smooth muscle cells. They are classified according to structure:

1) phenylalkylamines

2) 1,4 dihydropyridines 

3) benzothiazepines.

These drugs block calcium entry at the alpha1 subunit of the L-voltage gated calcium ion channels (slow channels).

They produce decreased myocardial contractility, decreased heart rate, decreased activity of the sinoatrial node, decreased conduction of cardiac impulses through the AV node and vascular smooth muscle relaxation with associated vasodilation and decrease in systemic blood pressure. The fundamental physiologic defect in heart failure is a decrease in cardiac output relative to the needs of the body. Calcium channel blockers are effective for the treatment of coronary artery spasm. Thus, there is NO direct role for these drugs in the management of HF. 

TRUE

Heart failure results when cardiac output is inadequate for the needs of the body. A defect in cardiac contractility is complicated by the multiple compensatory processes that further weaken the failing heart. The drugs used in HF fall into 3 major groups with varying targets and actions.

Positive inotropic drugs: cardiac glycosides (digoxin), beta agonists (dobutamine) PDE inhibitors (amrinone, milrinone)

Vasodilators: nitroprusside, nitrates, hydralazine

Misc: Loop diuretics, ACE inhibitors, beta blockers, spironolactone, thiazides

The homeostatic responses of the body to depressed cardiac output are mediated mainly by the SNS and the renin-angiotension-aldosterone system.

Major responses are:

1)tachycardia (early sign of increased sympathetic tone)

2) increased PVR (another early response also mediated by increased sympathetic tone)

3) retention of salt and water by the kidney-an early compensatory response, mediated by the renin-angiotension-aldosterone system and facilitated by increased sympathetic outflow.

Increased blood volume results in edema and pulmonary congestion and contributes to increased end diastolic fiber length. Pharmacologic therapies for heart failure include removing the retained salt and water with diuretics, reduction of afterload and salt and water retention by means of ACE inhibitors, reduction of sympathetic stimulation by means of B blockers; reduction of preload or afterload with vasodilators; and in systolic failure, direct augmentation of depressed cardiac contractility with positive inotropic drugs such as digitalis. Considerable evidence suggests that angiotensin antagonists, some B adrenoceptor blockers and the aldosterone antagonists spironolactone also have long term beneficial effects, Acute HF should be treated with a loop diuretic; if very severe, a prompt acting positive inotropic agent such as a B agonist or phosphodiesterase inhibitor and vasodilators should be used as required to optimize filling pressures and blood pressure. Chronic failure is best treated with diuretics (often a loop diuretic with spironolactone) plus an ACE inhibitor and, if tolerated, a B blocker. Digitalis is helpful if systolic dysfunction is prominent.

Inhibition of Na/K ATPase of the cell membrane is considered to be the primary biochemical mechanism of action. Inhibition of Na/K ATPase results in a small increase in intracellular sodium. The increased sodium alters the driving force for sodium-calcium exchange by the exchanger NCX, so that less calcium is removed from the cell. The increased intracellular calcium is stored in the sarcoplasmic reticulum and upon release increases contractile force. These consequences are seen in both the electrical and the mechanical function of the heart. Digitalis also modifies autonomic outflow and this action has effects on the electrical properties of the heart.

Mechanical effects: electrical effects include early cardiac parasympathomimetic responses and later arrhythmogenic actions.

Electrical effects: increased PR interval caused by a decrease in AV conduction velocity and flattening of the T wave. The increase in the AV nodal refractory period is important when Atrial flutter?Fib is present because the refractoriness of the AV node determines the ventricular rate in these arrhythmias. The effect of digitalis is to slow the rate. Shortened QT, inversion of the T and ST depression may occur later.

Note that hypokalemia will aggravate dig toxicity. If extracellular K+ is low, the function of the Na-K ATPase will be impaired and will be more sensitive to the inhibiting effects of digoxin (ie, the effects of digoxin will be exagerated).

How is this clinically important? First, if someone is taking digitalis, make sure you check their K+ preoperatively and consider checking K+ after giving a loop diuretic intraoperatively. Also, beware hypokalemia +/- hyperventilation in patients taking digoxin. Example: If you hyperventilate someone 33% more than normal, their PaCO2 will decrease to 30 mm Hg. This will cause their pH to increase from 7.40 to about 7.48, which in turn will drive potassium intracellularly (serum K+ will decrease by about 0.5 meq).

The zona glomerulosa of the adrenal cortex. (Aldosterone is the principal mineralcortocoid) Aldosterone is metabolized by several mechanisms. A portion of it is excreted unchanged in the urine, while the rest is converted to inactive metabolites in the liver. Its release can be directly stimulated by hyperkalemia. It is clinically beneficial in the treatment of HTN and CHF.

Heart failure, a syndrome which manifests as the hearts inability to fill or eject blood efficiently can cause decreased perfusion to the kidneys. This decreased perfusion can activate the RAAS hormone system. When blood volume to the kidneys is low, the juxtaglomerular cells in the kidneys secrete renin. The renin then stimulates the production of angiotensin I, which is then converted to angiotensin II. Angiotensin II causes the blood vessels to constrict which increases blood pressure. Angiotensin II also stimulates the secretion of the hormone aldosterone from the adrenal cortex. Aldosterone causes the tubules in the kidneys to increase the reabsorption of sodium and water back into the blood.

True. High serum aldosterone will increase reabsorption of sodium and water and will release or secrete potassium ions in the distal convoluted tubules and collecting ducts of the kidneys.

An aldosterone antagonist – potassium sparing medication that has a close structural resemblance to aldosterone. Binds to the cytoplasmic mineralcorticoid receptors on the collecting ducts and acts as a competitive antagonist to aldosterone. This will decrease the reabsorption of sodium and water while decreasing the secretion of potassium.

Correct.

Note spironolactone produces a diuretic effect when aldosterone levels are elevated (in contrast to triamterene which does not require elevated aldosterone levels).

 Be prepared to discuss figures 16.4 and 16.5

See opposite side:

Digitalis has a profound effect on myocyte intracellullar concentrations of Na+, K+, and Ca2+. These effects are caused by digitalis inhibiting:

A. Ca2+ adenosine triphosphatose (ATPase) of the sarcoplasmic reticulum.

B. Na+/K+ ATPase of the myocyte membrane.

C. Cardiac phosphodiesterase

D. Cardiac B1 receptors

E. Juxtaglomerular renin release

B. The cardiac glycosides bind to and block the action of the Na+/K+ ATPase. This leads to increased intracellular Sodium. The diminished sodium gradient results in less CA2+ being extruded from the cell via the Na+/Ca2+ exchanger.

Cardiac glycosides do not bind to the Ca2+ ATPase. They have no direct effect on phosphodiesterase, B1 receptors, or renin release.

Compensatory increases in heart rate and renin release that occur in heart failure may be alleviated by which of the following drugs?

A. Milrinone

B. Digoxin

C. Dobutamine

D. Enalapril

E. Metoprolol

E. Metoprolol, a B1 selective antagonist, prevents the increased heart rate and renin release that result from sympathetic stimulation, which occurs as compensation for reduced cardiac output of heart failure.

Enalapril is an ACE inhibitor that actually increases renin release. Dobutamine increases cardiac contractility but does not slow the heart rate or interfere with renin release. Digoxin decreased the heart rate because of its vagomimetic effects, but does not decrease renin release.

A 58yo man is admitted to the hospital with acute heart failure and pulmonary edema. Which one of the following drugs would be most useful in treating the pulmonary edema?

A. Digoxin

B. Dobutamine

C. Furosemide

D. Minoxidil

E. Spironolactone

C. Furosemide has the ability to dilate vessels in the context of acute heart failure. It also mobilizes the edematous fluid and promotes its excretion.

Dobutamine increased contractility but does not appreciably improve pulmonary edema. Digoxin acts too slowly and has no vasodilating effects. Minoxidil decreases arterial pressure and causes reflex tachycardia. Spironolactone does not alleviate acute pulmonary edema.

A 46yo man is admitted to the ER. He has taken more than 90 digoxin tablets (0.25mg each), ingesting them about 3hrs before admission. His pulse is 50-60 and his electrocardiogram shows third-degree heart block. Whic one of the following is the most important therapy to initiate in this patient?

A. Digoxin immune Fab

B. Potassium salts

C. Lidocaine

D. Phenytoin

E. DC cardioversion

A. Digoxin immune Fab

In the severely poisoned patient, reduction of digoxin plasma concentrations is paramount and can be accomplished with administration of antidigoxin antibodies.