The students should:

1. Understand the underlying hemodynamic abnormalities in heart failure and the therapeutic approaches to its treatment.
   
2. Understand 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. Understand the actions of beta blockers and the rationale for their use in the treatment of heart failure.
   
4. Know the pharmacologic action, toxcities and uses of cardiac glycosides.
   
5. Understand the properties of intravenous agents (dobutamine, dopamine and PDE inhibitors) used in the treatment of heart failure.

Captopril
Enalapril
Losartan
Hydralazine
Nitroprusside
Carvedilol
Milrinone
Digoxin
Dopamine
Dobutamine

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 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. ACE inhibitors also have beneficial effects on elevated serum lipids.
   
7. In addition to heart failure, ACE inhibitors are also widely used to treat hypertension.
   
8. While there are many ACE-inhibitor products available, their mechanisms of action are the same. The differences are in the requirement of activation and/or duration of action and plasma half life.
   
9. 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.

1. Persistent cough
   
2. Can decrease renal function in certain patients.
   
3. Angioedema
   
4. Loss of taste

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.

1. 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. These agents all bind in a reversible fashion. However, 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 antagonist 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.
   

Side Effects

Fewer side effects have been reported with AT₁ receptors antagonists. They less likey cause cough or angioedema.

Status in Cardiovascular Medicine

1. AT₁ receptors 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 receptors antagonists are alternatives to ACE-inhibitors in reducing morbidity and mortality in patients following myocardial infarction.
   
3. AT₁ receptors antagonists are also first line agents in the treatment of hypertension.
   
4. There is no evidence that AT₁ receptors antagonists are superior to ACE-inhibitors. Therefore, the drugs should be considered as alternative choices in treating cardiovascular disease.

1. An arterial selective vasodilator that works by poorly understood mechanisms that may increase the levels of smooth muscle cGMP and a decrease in intracellular calcium.
   
2. The predominant activity is 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.

1. The use of hydralazine has decreased due to the introduction of safer more effective agents such as ACE inhibitors and AT₁ receptor antagonists.
   
2. A recent report has show that a combination of an isosorbide dinitrate and hydralazine had significant benefit when given to African Americans. http://content.nejm.org/cgi/reprint/351/20/2049.pdf
   
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.

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. Typical arterial vasodilator side effects, headache, tachycardia. The tachycardia can be blocked by co-administration of beta blockers
   
3. Water and salt retention occur as a result in the fall of blood pressure. This problem can be alleviated by diuretics

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 increases 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.
   
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 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 used 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.

The major side effect associated with nesiritide is prolonged hypotension.

The beta blockers that clinical trials have been shown to be effective in treating heart failure include; bisoprolol, bucindolol carvedilol and metoprolol. At first glance, this seems paradoxical to use a drug that has a negative inotropic effect to be effective in treating heart failure. Indeed, beta blockers would not be used to treat severe heart failure. The mechanisms for this efficacy are not completely understood. It is known that norepinephrine acting at the beta1-receptor can stimulate hypertrophic growth responses. Recall that norepinephrine and epinephrine levels are increased in heart failure. The presence of an antagonist might also up-regulate the beta₁ receptor that have been down-regulated by the pathophysiology of heart failure. One pathophysiology of heart failure is that the heart increases dimensions. This increase result in a hypertrophied heart with decreased contractile performance. Beta blockers reverses these changes.

The side effects of carvedilol are typical for a drug with alpha and beta blocking properties.

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.

Mechanism of Positive Inotropic Action

1. Cardiac glycosides inhibit the myocardial cell Na⁺, K⁺, ATPase.
   
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.

DOPAMINE AND DOBUTAMINE

1. Review actions from sympathomimetics handout. They 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.

PHOSPHODIESTERASE INHIBITORS

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 were 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.

Cardiovascular Actions

1. There are isoforms of cAMP phosphodiesterase. Inamrinone and milrinone inhibit the cAMP phosphodiesterase isoform 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.
   
4. These agents have the potential to induce arrhythmias.
   
5. Tolerance does not develop to the cardiovascular actions of PDE inhibitors.

1. Arrhythmias
   
2. Thrombocytopenia
   
3. Gastrointestinal-nausea, vomiting, etc
   
4. Less toxicity with milrinone when compared to Inamrinone

Status in Cardiovascular Medicine

1. These agents are reserved for the short term treatment of congestive heart failure.
   
2. These agents are given by intravenous infusion and are used in patients who have not responded well to other positive inotropic agents.
   
3. 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 this setting.

An outline of treatment approaches recommended can be found in Goodman and Gilman and in Circulation 112:1825-1852,2005.