Pharmacology I, Chapter 13: CHF

Pharmacology I, Chapter 13: CHF

• Case Study 1: A 65-year-old man presents with shortness of breath, edema in feet/ankles, and crackles in the lungs following a viral illness. Blood pressure is 110/70 mmHg, pulse is 105 bpm, and left ventricular ejection fraction is 20% (normal ~60%). The diagnosis is Stage C, Class III heart failure, with cardiomyopathy secondary to viral infection. What treatment?

• Case Study Treatments: Initial treatment includes a low-sodium diet and a diuretic (furosemide). An ACE inhibitor (enalapril) is added, followed by digoxin to manage continued shortness of breath. Beta blockers and eplerenone (aldosterone antagonist) are potential additional treatments.

• CHF Overview: CHF affects approximately 5 million patients in the US. It's characterized by decreased cardiac contractility and inadequate cardiac output to meet body needs. Coronary artery disease is the most common cause in the US.

• Homeostatic Response to CHF:

  • Tachycardia: Increased sympathetic tone.
  • Increased peripheral vascular resistance: Resulting from increased sympathetic tone.
  • Salt and water retention: Mediated by the renin-angiotensin-aldosterone system, causing blood volume increases and edema.
  • Cardiomegaly: A compensatory response to sympathetic discharge.

• Drug Treatments for CHF:

  • (1) Positive Inotropic Drugs:
    • Cardiac glycosides.
    • PDE inhibitors.
  • (2) Vasodilators:
    • Nitrates (nitroprusside).
    • Loop diuretics.
    • Angio antagonists.
    • Nesiritide (BNP).
  • (3) Miscellaneous:
    • Beta blockers.
    • Spironolactone.
    • Thiazides.

• Normal Cardiac Contractility: Involves decreased sensitivity of contractile proteins to calcium, amount of calcium released from the SR (sarcoplasmic reticulum), amount of trigger calcium, movement of calcium against its sodium gradient, and alteration of sodium/potassium ATPase (digoxin).

Digoxin

• Description: Digoxin (Lanoxin®), a cardiac glycoside, is the most commonly used glycoside derived from foxglove.

• Mechanism of Action: Digoxin inhibits the Na+/K+ ATPase pump, increasing intracellular calcium, thus strengthening cardiac muscle contractions.

• Pharmacological Effects: Specifically, it increases cardiac contractility, ventricular ejection volume, cardiac output, and renal perfusion. Additionally, it can cause early and toxic responses, as seen in the electrical effects.

• Clinical Uses: Digoxin is used to reduce symptoms of CHF and atrial fibrillation.

• Drug Interactions: Quinidine displaces digoxin from tissue binding sites, increasing digoxin levels. Itraconazole inhibits the P-glycoprotein pump, leading to an increased risk of digoxin toxicity.

• Toxicity: Digoxin toxicity includes nausea, vomiting, diarrhea, visual disturbances (color changes), arrhythmias, and potentially life-threatening CNS effects.

• Overdose Treatment: Includes correction of any potassium deficiency, use of digoxin antibodies (Digibind®) to bind digoxin, and close monitoring of serum digoxin concentrations.

Digoxin in the Body

• Forms of Digoxin:
  • Free form (70%): Active form.
  • Inactive bound to albumin: Not pharmacologically active.
  • Bound to tissue receptors (Na+/K+ ATPase pumps): Where Digibind® antibodies bind.

PDE Inhibitors

• Description: These drugs are inotropic agents used in CHF. Milrinone is a specific example of an IV-only PDE inhibitor that can be used in acute heart failure. Examples include theophylline, amrinone, and milrinone.

• Mechanism of Action: PDE inhibitors inhibit the phosphodiesterase (PDE) enzyme, resulting in increased intracellular calcium and improved contractility.

ACE Inhibitors

• Mechanism of Action: ACE inhibitors decrease blood pressure by blocking the conversion of angiotensin I to angiotensin II. This reduces vasoconstriction and aldosterone secretion. They also increase renal blood flow.

• Examples: Examples include captopril, enalapril, and benazepril.

• Clinical Significance: Approximately 30% of patients experience a cough, and they are contraindicated during pregnancy due to potential fetal renal damage.

Angiotensin Antagonists

• Mechanism of Action: A second class of drugs used in CHF, acting antagonistically to the renin-angiotensin system. This can be accomplished by two different types of drugs:
• block Angio II formation (ACE inhibitors)
• Block Angio II receptor

Angio II Receptor Blockers

• Mechanism of Action: Specifically block the receptor for Angio II, reducing its effects.

• Examples: Losartan is an example.

• Clinical Significance: Similar clinical effects to ACE inhibitors, but with a lower incidence of cough. Fetal kidney damage is still a risk, and these agents should never be used during pregnancy.

BNP Agonist

• Description: BNP is a naturally occurring peptide hormone synthesized in the ventricles that counteracts the renin-angiotensin-aldosterone system and lowers blood pressure. ANP is a similar, but the atria synthesizes this peptide hormone.

• Function: These hormones are natriuretic, meaning they increase sodium excretion.

• Examples: Nesiritide (Natrecor®)

• Clinical Significance: The drug form, nesiritide, is used intravenously (IV) in acute heart failure cases. Serum levels of the natural BNP are often utilized as a screening tool to detect cardiac disease.

Beta Receptors

• Mechanism of Action: Beta-1 receptors in the heart increase heart rate, blood pressure, and oxygen demand. Beta-2 receptors in the periphery trigger vasoconstriction. When NE binds to beta 1 receptors, Ca++ flows into the cardiac cells, strengthening their contractions.

• Examples: NE (norepinephrine), metoprolol (Lopressor®), bisoprolol, and carvedilol.

• Clinical Significance: Beta blockers are used to slow down the heart rate in patients with heart issues. By blocking the stimulation of beta receptors by catecholamines, these medications offer a different mechanism of action to manage patients with congestive heart failure (CHF).

Case Study Treatment summary

• Drug treatments are tailored in CHF depending on disease severity (mild, moderate, severe).
• This case involves a moderate presentation of the disorder.
• For the moderate case detailed in the example case study, the treatment involves digoxin and ACE inhibitors, and diuretics.
• Use of beta blockers and other medications such as vasodilators may be added to moderate CHF management based on disease progression and the specific condition of the patient.