PHA 824

1) The underlying hemodynamic abnormalities in heart failure and the therapeutic approaches to its treatment.

2) The properties of angiotensin converting enzyme inhibitors, angiotensin II receptor blockers and vasodilators used to treat heart failure and the rationale behind their use.

3) The actions of beta blockers and the rationale for their use in the treatment of heart failure.

5) The properties of intravenous agents (dobutamine, dopamine and PDE inhibitors) used in the treatment of heart failure.

1) Heart failure, the inability of the circulatory system to meet the metabolic demands of the body, is a multifaceted disease state involving several organ systems and neurohumoral factors including the heart, kidney, vascular system and the brain.There are several forms of heart failure with multiple etiologies.

2) Signs and symptoms of heart failure include tachycardia, decrease in exercise tolerance, shortness of breath and edema (peripheral pulmonary) and increase in heart size.

3) The treatment of heart failure is a particularly difficult therapeutic problem with no single drug or drug class adequate to provide complete relief from the signs and symptoms of heart failure.

4) The drugs used and their specific therapeutic approaches depend on the underlying pathophysiology and severity of the disease. While drug therapy is capable of symptomatic relief, it does not correct the underlying pathology.

5) Regardless of the treatment, 50 % of individuals die within 5 years of developing CHF. In an era where morbidity and mortality from other cardiovascular diseases are decreasing, deaths from CHF are increasing.

6) An overview of heart failure and its treatment can be found in Chapter 13 of Katzung’s Basic and Clinical Pharmacology

a) The major vasodilators used are ACE inhibitors and angiotensin II receptor antagonists, organic nitrates, hydralazine and nitroprusside.

b) Arterial selective vasodilators decrease peripheral vascular resistance and afterload on the failing myocardium. The reduction in afterload leads to an increased cardiac output and improved tissue perfusion.

c) Venous selective vasodilators increase venous capacitance, thus decreasing preload. A small reduction in venous tone can result in a pooling of large amounts of blood. This would decrease left ventricular filling pressure and pulmonary congestion.

2) Diuretics -promote the elimination of edematous fluid, improving tissue perfusion and pulmonary function. Noteworthy are loop diuretics and aldosterone receptor antagonists.

3) Beta blockers-These agents reverse many of the deleterious effects of activation of the sympathetic nervous system on the failing heart.

4) Positive Inotropic Agents- Drugs that increase contractile force; beta₁ receptor agonists, cAMP PDE inhibitors, cardiac glycosides.

Many ACE inhibitors have been developed. Captopril was the first agent developed and hence is the prototype. Enalapril is a prodrug that is de-esterified by plasma esterases to enalaprilat. Most of the ACIs are activated in this fashion.

Benazepril - Metabolized to benazeprilat

Captopril

Enalapril - Metabolized to enalaprilat

Fosinopril - Metabolized to fosinoprilat

Lisinopril

Moexipril- Metabolized to moexiprilat

Quinapril - Metabolized to quinaprilat

Ramipril - Metabolized to ramiprilat

Trandolapril-Metabolized to tandolaprilat

Perindopril - metabolized to perindoprilat

Effects on the Cardiovascular System

1) ACE inhibitors decrease circulating levels of angiotensin II and aldosterone.

2) These agents decrease peripheral vascular resistance.

3) Despite this fall in peripheral resistance, there is little effect on heart rate.

4) Angiotensin II (acting at the AT1-receptor) is a stimulus for cardiac remodeling and hypertrophic growth. ACE inhibitors block these deleterious effects.

5) ACE inhibitors are effective regardless of the circulating renin levels.

6) In addition to heart failure, ACE inhibitors are also widely used to treat hypertension.

7) While there are many ACE-inhibitor products available, their mechanisms of action are the same. The differences are in the requirement for metabolic activation and/or duration of action and plasma half life.

8) In addition to ACE there are other enzymes, such as chymase, that can form angiotensin II. Therefore, ACE inhibitors cannot completely block the generation and biological activity of angiotensin II.

Side Effects

1) Persistent cough

2) Can decrease renal function in certain patients; should not be used in patients with renal artery stenosis.

3) Can cause a modest elevation in serum K+. This can be more significant in patients with renal insufficiency or when used with other drugs (K+ sparing diuretics) that also elevate serum K+ levels.

4) Angioedema

5) Loss of taste

6) Hypotension

Status in Cardiovascular Medicine

1) ACE-inhibitors are first line medications in the treatment of heart failure. Numerous clinical trials have shown that these drugs decrease the risk of death, improve outcomes and decrease symptoms of patients with heart failure.

2) ACE-inhibitors have been shown to be effective in reducing morbidity and mortality in patients following myocardial infarction.

3) ACE-inhibitors are also drugs of first choice in the treatment of hypertension and are especially useful in patients with co-existing heart failure or post MI.

ANGIOTENSIN II RECEPTOR ANTAGONISTS

1) Many of the effects of angiotensin II are a result of interaction at angiotensin₁ receptor (AT₁), typical G-protein coupled receptors.

2) By blocking AT₁ receptors, angiotensin II receptor antagonists directly block the ability of angiotensin II to stimulate vascular smooth muscle contraction, aldosterone release, cardiac remodeling and hypertrophic growth.

3) Losartan, Irbesartan, Eprosartan, Candesartan, Telmisartan and Valsartan are antagonists at AT₁ receptors.

4) The binding of Irbesartan, Candesartan and Valsartan is such that they do not readily dissociate from the receptor. However, they do not covalently modify the receptor. Therefore, antagonism with these compounds is not overcome with increasing amounts of angiotensin II. The reason for these binding kinetics is not clear. However, the insurmountable antagonism has advantages if the physiologic concentration of angiotensin II increases.

5) Losartan and Eprosartan are competitive receptor antagonists. Losartan has a metabolite, EXP 3174 that has a higher affinity for the AT₁ receptors than the parent molecule.

6) Like ACE inhibitors, AT₁ receptor antagonists are effective for the chronic treatment of congestive heart failure. They are also widely used to treat hypertension. There is evidence that these agents increase survival following myocardial infarction.

Side Effects

Side effects are related to the decrease in the effects of angiotensin II. These would include hypotension and the elevation of K+ and use in patients with renal artery stenosis. Effects related to inhibition of ACE (angioedema or persistent cough) are less likely to occur.

Status in Cardiovascular Medicine

1) AT₁ receptor antagonists are effective in the treatment of heart failure. Clinical trials have shown that these drugs decrease the risk, improve outcomes and decrease symptoms of patients with heart failure.

2) Similarly, AT₁ receptor antagonists are alternatives to ACE-inhibitors in reducing morbidity and mortality in patients following myocardial infarction.

3) AT₁ receptor antagonists are also first line agents in the treatment of hypertension.

4) There is no evidence that AT₁ receptor antagonists are superior to ACE-inhibitors. Therefore, the drugs should be considered as alternative choices in treating cardiovascular disease.

VASODILATORS WITH VARIOUS MECHANISMS OF ACTION

NITRATES- Previously discussed

HYDRALAZINE

1) One of the first orally active, arterial selective vasodilators

2) Hydralazine works by poorly understood mechanisms with the predominant action to decrease peripheral vascular resistance.

3) In heart failure the decrease in peripheral vascular resistance decreases the afterload leading to an increase in cardiac output.

4) However, when used alone sympathetic reflexes can be activated as a result of the decrease in peripheral vascular resistance resulting in a reflex acceleration of heart rate.

Status in Cardiovascular Medicine

1) The use of hydralazine has decreased due to the introduction of drugs such as ACE inhibitors, AT₁ receptor antagonists and beta blockers.

2) A recent report has shown that a combination of an isosorbide dinitrate and hydralazine had significant benefit when given to African Americans.

This combination product BiDil (20 mg isosorbide dinitrate and 37.5 mg hydralazine). This is the first example of a drug product being developed to treat a specific racial group. African-Americans have a greater response to isosorbide and hydralazine in the therapy of heart failure. Clinical trials have shown that BiDil when added to a standard treatment regime significantly improved outcomes more than when placebo was added.

3) Hydralazine is also used to treat hypertension. However, it is not a drug of first choice nor can it be used as monotherapy due to the reflex tachycardia and increase in fluid retention seen when the drug is used alone.

Side effects

Two types of side effects can be seen with hydralazine. One is genetically based and is an immunologic response to the drug. The others are side effects typical of a vasodilator

1) Hydralazine is inactivated by N-acetylation and can produce a lupus-like syndrome. The likelihood of the lupus-like syndrome is increased in the slow acetylator population.

2) Headache, tachycardia. The tachycardia can be blocked by co-administration of beta blockers. Water and salt retention occurs as a result of the fall in blood pressure. This problem can be alleviated by diuretics.

SODIUM NITROPRUSSIDE

1) A balanced vasodilator that produces its effects by activating guanylate cyclase increasing the smooth muscle levels of cGMP.

2) These actions result in a decrease in preload and afterload that can contribute to an increase in cardiac output and decreases pulmonary congestion.

3) It is unstable in solution and has an ultra short duration of action.

4) The very short duration of action also makes nitroprusside useful in treating hypertensive emergencies which require a rapid reduction in blood pressure.

5) Nitroprusside must be reconstituted prior to use and given via infusion. It is also light sensitive and solutions must be protected from light.

Status in Cardiovascular Medicine

1) Nitroprusside is a very potent vasodilator.

2) It is used in the acute management of congestive heart failure and hypertensive emergencies.

Side Effects

1) Hypotension

2) Nitroprusside is metabolized to cyanide and thiocyanate. The body can buffer some of this cyanide with thiosulfate, cysteine or cystine. However, large blood concentrations or prolonged infusions of nitroprusside can overwhelm the ability to buffer the cyanide and increase the risk of cyanide poisoning.

NESIRITIDE

Nesiritide is human B-type natriuretic peptide (hBNP), a hormone produced by the heart ventricles. This peptide is produced as a drug product by recombinant DNA technology and was approved for clinical use by the FDA in August 2001. BNP is a different molecular entity than atrial natriuretic peptide (ANP) which is produced in heart atria. As a natural consequence of heart failure, circulating levels of endogenous BNP are elevated. Nesiritide usage further increase these levels. Nesiritide stimulates soluble guanylate cyclase and increases vascular levels of cyclic GMP. This results in a dilation of arterial and venous smooth muscle. Hence, nesiritide is considered a balanced vasodilator. This results in a decrease in total peripheral vascular resistance, mean arterial blood pressure, pulmonary arterial blood pressure and right atrial blood pressure. As a result, cardiac output and stroke volume are increased without an increase in heart rate. Natriuresis and diuresis also occur. Unlike the nitrates, tolerance does not develop with this drug. Nesiritide is given by intravenous administration. It is recommended for use in decompensated congestive heart failure to produce a rapid decrease in peripheral vascular resistance and blood pressure. This decreases pulmonary arterial blood pressure and improves the symptoms of heart failure. Recent clinical trials have suggested that Nesiritide may not be as efficacious as previously thought following the initial approval of the drug.

The major side effect associated with nesiritide is prolonged hypotension.

CIRCULATORY EFFECTS OF VASODILATORS

Clinical trials have shown bisoprolol, bucindolol carvedilol and metoprolol to be effective in treating heart failure . ***REFER TO SYMPATHOLYTICS FOR A REVIEW IF NEEDED***

Cardiac glycosides are one of the oldest groups of drugs used in cardiovascular therapeutics. There is evidence of use in Egyptian and Roman times. William Withering published medical accounts of the use of the “foxglove” for the treatment of “dropsy.” Originally, extracts of d. purpurea were used. Two active principals, digoxin and digitoxin, are now used in cardiovascular therapeutics. The uses of these drugs are in heart failure and supraventricular tachyarrhythmias. These agents have a limited therapeutic index.

2) This enzyme is responsible for maintaining the ionic gradient of the myocardial cell.

3) The inhibition of the Na⁺, K⁺, ATPase results in an increase in intracellular Na⁺. The decrease in the Na⁺ gradient diminishes the exchange of Na⁺ for Ca²⁺

4) The increase in intracellular Ca²⁺ is responsible for the positive inotropic action.

Status in Cardiovascular Medicine

At one time cardiac glycosides were considered the mainstays of heart failure therapy. However, with the evolution of therapeutic approaches and understanding of the disease state the status of the cardiac glycosides and usage has been altered. These drugs are now added to therapeutic regimes if necessary to provide inotropic support in patients who do not adequately respond to ACEI, AT1 blockers or beta blockers. In addition, cardiac glycosides can be used in heart failure patients who have atrial fibrillation (see below for reasons).

Antiarrhythmic Actions

1) The blockade of the cardiomyocyte Na+,K+ ATPase and subsequent alterations in Ca levels also affect cardiac conduction and electrical activity. In addition, cardiac glycosides act at sites extrinsic to the heart to affect cardiac conduction.

2) These drugs penetrate the carotid arch and baroreceptors and increase the sensitivity of these sites to the ambient level of blood pressure. This is the same reflex arc that is activated when blood pressure is elevated. Therefore, there is an increase in neural traffic from the baroreceptors and carotid arch to CNS cardiovascular centers. This results in an enhanced level of vagal outflow from the CNS to the myocardium.

3) Thus by enhancing vagal tone, cardiac glyosides slow cardiac conduction in the AV and SA nodes. It is this activity which imparts antiarrhythmic actions on cardiac glycosides. It is this action that imparts antiarrhythmic activity on these drugs.

At the SA node this increase in vagal tone:

1) Increases SA nodal refractory period

2) Slows SA nodal conduction velocity

At the AV node (major site of antiarrhythmic action) the increase in vagal tone:

1) Increases AV nodal refractory period

2) Slows AV nodal conduction velocity

Pharmacokinetics

AGENT	GASTRO INTESTINAL ABSORPTION	ONSET OF ACTION (MIN)	PEAK EFFECT (HR)	AVERAGE HALF LIFE	PRINCIPAL METABOLIC ROUTE (EXCRETORY PATHWAY)	AVERAGE DIGITALIZING DOSES		USUAL DAILY ORAL MAINTENANCE DOSES
AGENT	GASTRO INTESTINAL ABSORPTION	ONSET OF ACTION (MIN)	PEAK EFFECT (HR)	AVERAGE HALF LIFE	PRINCIPAL METABOLIC ROUTE (EXCRETORY PATHWAY)	oral	intravenous	USUAL DAILY ORAL MAINTENANCE DOSES
Digoxin	30 to 100%	15 to 30	1 ½ to 5	36 to 48 hours	Renal; some gastrointestinal excretion	1.25 to 1.5 mg	0.75 to 1.00 mg	0.25 to 0.5 mg
Digitoxin	90 to 100%	25 to 120	4 to 12	4 to 6 days	Hepatic; renal excretion of metabolites	0.7 to 1.2 mg	1.00 mg	0.1 mg

Special Considerations That Can Alter the Therapeutic Response to Cardiac Glycosides

1) Renal disease-decreased renal clearance of digoxin

2) Drug Interactions that:

a) Decrease bioavailability

Cholestyramine

b) Decrease renal clearance

Amiodarone

Verapamil

Quinidine

3) Hypokalemia and Electrolytes

a) Hypokalemia increases the likelihood of toxicity. Alterations in potassium levels could be exacerbated by co-administration of diuretics.

4) Age

5) The elderly are more sensitive to cardiac glycosides.

6) Hypoxia

a) Hypoxia increases the likelihood of toxicity.

Signs of Toxicity

Cardiac glycosides have a limited margin of safety. It has been reported that increasing plasma concentrations to levels greater than around 1 ng/ul IS NOT associated with a greater therapeutic effect. The major concern with these drugs is the generation of arrhythmias.

1) Nausea, vomiting

2) Central nervous system-visual disturbances

3) Arrhythmias - These actions would result from direct effects on cardiomyocytes due to a significant inhibition of the Na+, K+ ATPase and increases in cardiomyocyte calcium levels as well as via the vagally mediated increase in parasympathetic tone. The first signs of toxicity are ectopic beats and first degree AV block. More serious arrhythmias would be AV block, ventricular tachycardia and ventricular fibrillation.

Treatment

1) Potassium

2) Lidocaine

3) Atropine

4) Fab Fragments

1) Review actions from sympathomimetics handout. These drugs are given by IV infusion in the management of decompensated heart failure. A noteworthy point is that dobutamine can decrease peripheral vascular resistance while dopamine does not have this effect. In the setting of decompensated heart failure, this could lead to an increase in cardiac output.

2) Because of their short plasma half lives, these drugs must be given by intravenous infusion. As a consequence, the beta₁ receptors can be further down-regulated by infusion with these agonists.

3) Recall that there is a concern of inducing arrhythmias with these drugs. This concern is even greater in the setting of a damaged, poorly perfused heart.

Milrinone and Inamrinone (formerly known as amrinone, name change, July 1, 2000)

These compounds are orally active inhibitors of cAMP phosphodiesterase. This enzyme breaks down cAMP thus terminating its actions. The cardiovascular effects of increasing intracellular cAMP are similar to those seen following activation of beta₁ and beta₂ receptors. PDE inhibitors were designed to replace cardiac glycosides as orally active positive inotropic agents for the treatment of congestive heart failure. These PDE inhibitors were shown to increase cardiac output and decrease peripheral vascular resistance. However, clinical trials showed oral dosing with these agents was not effective in decreasing the morbidity and mortality in heart failure. These drugs are second line agents reserved for the intravenous treatment of decompensated heart failure.

1) There are isoforms of cAMP phosphodiesterase. Inamrinone and milrinone inhibit the cAMP phosphodiesterase isoform (PDE III) that is present in the heart and blood vessels.

2) Inhibition of cardiac PDE results in an increased force of contraction and cardiac output.

3) Inhibition of vascular PDE produces vasodilation and a decrease in peripheral vascular resistance.

2) Thrombocytopenia -less likely to occur with milrinone compared to inamrinone.

1) These agents are reserved for the short term treatment of congestive heart failure and are used in patients who have not responded well to other positive inotropic agents.

2) As more patients are receiving beta blockers for the chronic treatment of heart failure, this makes treatment of decompensated heart failure more problematic. Thus, PDE inhibitors could be particularly effective in treating these patients.