Drug treatment for Heart Failure

Pharmacology

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Drug treatment for Heart Failure:
Heart failure (HF) is a complex, progressive disorder in which the heart is unable to pump sufficient blood to meet the needs of the body. Patients with HF complain of dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, fatigue, and dependent edema.

Figure (1): Drug classes of heart failure

Goals of pharmacologic intervention in HF:
The goals are to alleviate symptoms, slow disease progression, and improve survival. Accordingly, six classes of drugs have been shown to be effective (Figure 1):
1) inhibitors of the renin-angiotensin system,
2) β-adrenoreceptor blockers,
3) diuretics,
4) inotropic agents (Digoxin)
5) direct vasodilators, and
6) aldosterone antagonists

Angiotensin-converting enzyme inhibitors:

Figure (2): Mechanism of action of ACE inhibitors in Heart failure


Angiotensin-receptor blockers
ARBs have the advantage of more complete blockade of angiotensin action, because ACE inhibitors inhibit only one enzyme responsible for the production of angiotensin II. Further, the ARBs do not affect bradykinin levels. Even so, ARBs are a substitute for ACE inhibitors in those patients who cannot tolerate the latter.

Β-Blockers:

Although it may seem counterintuitive to administer drugs with negative inotropic activity to a patient with HF, several clinical studies have clearly demonstrated improved systolic functioning and reverse cardiac remodeling in patients receiving Β -blockers.

The benefit of Β -blockers is attributed to:

1. Ability to prevent the changes that occur because of the chronic activation of the sympathetic nervous system, including decreasing the heart rate and inhibiting the release of renin.
2. Β -blockers also prevent the direct deleterious effects of norepinephrine on the cardiac muscle fibers, decreasing remodeling, hypertrophy and cell death.
Two B-blockers have been approved for use in HF: carvedilol , and long-acting metoprolol.

Digitalis:

The cardiac glycosides are often called digitalis or digitalis glycosides, because most of the drugs come from the digitalis (foxglove) plant.

Mechanism of action: (Figure 3)

Figure (3): Mechanism of action of Digoxin
Therapeutic uses:
1. Digoxin therapy is indicated in patients with severe left ventricular systolic dysfunction after initiation of ACE inhibitor and diuretic therapy.
2. Digoxin's major indication is HF with atrial fibrillation.
Pharmacokinetics:
1. Digoxin is very potent, with a narrow margin of safety and long half-life of around 36 hours.
2. Digoxin is mainly eliminated intact by the kidney, requiring dose adjustment based on creatinine clearance.
3. Digoxin has a large volume of distribution, because it accumulates in muscle.
Adverse effects:
Digitalis toxicity is one of the most commonly encountered adverse drug reactions. Decreased serum levels of potassium predispose a patient to digoxin toxicity.
Factors predisposing to digitalis toxicity:
1. Electrolytic disturbances: Hypokalemia can precipitate serious arrhythmia. Hypercalcemia and hypomagnesemia also predispose to digitalis toxicity.
2. Drugs: Quinidine, verapamil, and amiodarone
Types of adverse effects include:
1. Cardiac effects: The common cardiac side effect is arrhythmia, characterized by slowing of atrioventricular conduction associated with atrial arrhythmias. A decrease in intracellular potassium is the primary predisposing factor in these effects.
2. Gastrointestinal effects: Anorexia, nausea, and vomiting are commonly encountered adverse effects.
3. Central nervous system effects: These include headache, fatigue, confusion, blurred vision, alteration of color perception, and halos on dark object


Antianginal Drugs:

Angina pectoris is a characteristic sudden, severe, pressing chest pain radiating to the neck, jaw, back, and arms. It is caused by coronary blood flow that is insufficient to meet the oxygen demands of the myocardium, leading to ischemia.
Three classes of drugs, used either alone or in combination, are effective in treating patients with stable angina: organic nitrates, β-blockers, and calcium-channel blockers. Figure (4)

Figure (4): Classes of Antianginal drugs

Organic Nitrates:
1. Isosorbide dinitrate and isosorbide mononitrate.
2. Nitroglycerin.
3. Amyl nitrite.

Mechanism of action:

Organic nitrates, such as glyceryl trinitrate, are thought to relax vascular smooth muscle by their intracellular conversion to nitrite ions, and then to nitric oxide, which in turn activates guanylate cyclase and increases the cells' cyclic guanosine monophosphate (GMP). Elevated cGMP ultimately leads to dephosphorylation of the myosin light chain, resulting in vascular smooth muscle relaxation. Figure (5)
Pharmacokinetics:
The time to onset of action varies from 1 minute for nitroglycerin to more than 1 hour for isosorbide mononitrate. Significant first-pass metabolism of nitroglycerin occurs in the liver. Therefore, it is common to take the drug either sublingually or via a transdermal patch, thereby avoiding this route of elimination.
Adverse effects:
1. The most common adverse effect of nitroglycerin, as well as of the other nitrates, is headache.
2. High doses of organic nitrates can also cause postural hypotension, facial flushing, and tachycardia.
3. Methaemoglobinaemia can occur with heavy dosage
4. Tolerance: Tolerance to the actions of nitrates develops rapidly. The blood vessels become desensitized to vasodilatation. Tolerance can be overcome by providing a daily nitrate-free interval to restore sensitivity to the drug. This interval is typically 10 to 12 hours, usually at night, because demand on the heart is decreased at that time.
Interactions
1.An important footnote to the use of nitrate has been the marked potentiation of their vasodilator effects observed in patients taking phosphodiesterase (PDE) inhibitors, such as sildenafil and tadalafil .
2. Other methylaxanthine PDE inhibitors, such as theophylline, do not cause a similar interaction because they are rather weak inhibitors of PDE-5, even at the doses effective in asthma.


Figure (5): Mechanism of action of Organic nitrate