Drugs for Lipid Disorders, Heart Failure, and Diuresis

Overview of the Cardiovascular System

• Components and Structure

  • The heart consists of 4 distinct chambers.
  • Pulmonary Circulation: Operates in conjunction with the pulmonary system for gas exchange.
  • Systemic Circulation: Facilitates the movement of blood throughout the body systems.

• Primary Functions

  • Pumps blood to the lungs for $O_2$ repletion and $CO_2$ release.
  • Supplies organs and tissues with oxygen-rich blood via arteries.
  • Returns deoxygenated blood to the heart via veins.

Understanding Lipids and Lipoproteins

• Lipid Composition

  • Lipids consist of cholesterol and triglycerides.
  • These are normal, necessary components of plasma but require lipoproteins for transport through the bloodstream.
  • Types of Lipoproteins:
    • Chylomicron.
    • High-density lipoprotein (HDL).
    • Low-density lipoprotein (LDL).
    • Very-low-density lipoprotein (VLDL).

• Functions of Cholesterol

  • Production of steroids and hormones.
  • Building of cell membranes.
  • Building of bile acids.

• Functions and Characteristics of Triglycerides

  • Serve as an energy source.
  • Derived from dietary fats and formed in the small intestine.
  • Excess amounts are stored in adipose tissue.

• Sources of Cholesterol

  • Exogenous: Dietary intake absorbed in the intestines.
  • Endogenous: Produced internally by the liver.

• The Role of the Liver in Lipid Management

  • Produces LDL and HDL via both intrinsic and exogenous pathways.
  • Uses the HMG-CoA enzyme in the production process.
  • LDL and VLDL are responsible for transporting cholesterol to the periphery for utilization.
  • HDL pulls excess cholesterol back to the liver for recycling.
  • Triglycerides are utilized in the hepatic production of cholesterol.

Hyperlipidemia and Atherosclerosis

• Hyperlipidemia Definitions and Labs

  • Refers to elevated blood lipid levels, often associated with Metabolic Syndrome.
  • Normal Lab Values:
    • Total Cholesterol: <$200\,mg/dL$.
    • LDL: <$100\,mg/dL$ (optimal is <$70\,mg/dL$).
    • HDL: >$40\,mg/dL$.
    • Triglycerides: <$150\,mg/dL$.
    • Non-HDL Cholesterol: <$130\,mg/dL$.

• Pathology of Atherosclerosis

  • Involves the build-up of cholesterol and other debris on the arterial endothelium.
  • Mechanism: Cholesterol deposits on the endothelium; macrophages migrate to the lesion and stimulate abnormal smooth muscle growth.
  • Consequences: Gradually occludes vessels and impairs contractility.
  • Related Conditions:
    • Atherosclerotic Cardiovascular Disease (ASCVD).
    • Coronary Artery Disease (CAD).
    • Cerebral Vascular Attack (CVA).
    • Peripheral Vascular Disease (PVD).
    • Metabolic Syndrome (characterized by high triglycerides and/or low HDL).

• ACC/AHA Guidelines 2019

  • Treatment is determined by age and risk factors.
  • Primary Prevention: Focuses on lifestyle modification.
  • Hypercholesterolemia Therapy: Initiated when LDL is $≥ 190\,mg/dL$.
  • ASCVD/High Risk/Diabetes: Goal LDL is <$70\,mg/dL$.
  • Statins remain the therapy of choice.

• Demographic Considerations

  • South Asian Descent: Higher rates of ASCVD.
  • East Asian Descent: Increased sensitivity to statin therapy.
  • Metabolic Risk (DM/ASCVD): Increased in Mexican Americans, Native Americans, and Alaskans compared to non-Hispanic whites.
  • Gender: Females show lower rates of ASCVD prior to menopause.
  • Pediatrics: Lifestyle changes should be the first intervention for children.

HMG-CoA Reductase Inhibitors (Statins)

• Key Drug: atorvastatin (Lipitor).
• Classification: Considered a "high-intensity" statin and first-line therapy for hyperlipidemia.
• Mechanism of Action: Works in the liver to inhibit the HMG-CoA Reductase enzyme, leading to an increase in hepatic LDL receptors.
• Therapeutic Effects:
  • Decrease in LDL.
  • Mild decrease in triglycerides.
  • Mild increase in HDL.
• Interactions:
  • Grapefruit juice.
  • "Azole" antifungals.
  • Erythromycin.
  • Amiodarone.
• Nursing Considerations:
  • Route: PO (Oral).
  • Assessment: Check Liver Function Tests (LFTs).
  • Implementation: Administer in the evening or at bedtime with $H_2O$ to improve tolerance.
  • Contraindications: Pregnancy, end-stage liver disease.
  • Side Effects: Myalgias/myopathy, Rhabdomyolysis, liver dysfunction.
  • Teaching: Therapy requires $4$ to $6$ weeks for effect. Patients must report muscle pain or changes in urine color.

Fibric Acid Derivatives (Fibrates)

• Key Drug: gemfibrozil (Lopid).
• Indications: Hypertriglyceridemia and mixed dyslipidemias.
• Mechanism of Action: Activates the lipase enzyme to decrease triglyceride production and increase cholesterol secretion into bile acid.
• Therapeutic Effects:
  • Significant decrease in triglycerides.
  • Mild decrease in LDL.
  • Mild increase in HDL.
• Nursing Considerations:
  • Interactions: Enhances anticoagulant action (warfarin); increased risk of rhabdomyolysis when paired with statins.
  • Contraindications: Pregnancy, gallbladder disease, liver disease.
  • Side Effects: Increased risk for gallstones, GI disturbances.
  • Implementation: Administer PO in the evening/bedtime with $H_2O$.
  • Teaching: Requires $6$ to $8$ weeks for maximal effect. Report abdominal or flank pain.

Bile Acid Sequestrants

• Key Drug: cholestyramine (Questran).
• Mechanism of Action: Binds bile and prevents the resorption of cholesterol in the intestines; increases hepatic LDL receptors.
• Therapeutic Effects:
  • Decrease in LDL.
  • Mild increase in HDL.
  • May cause an increase in triglycerides.
• Nursing Considerations:
  • Route: PO (powder form).
  • Interactions: Affects almost all other medications. Other drugs must be taken $1$ hour before or $4$ to $6$ hours after the sequestrant.
  • Administration: Must be diluted in $4$ to $6\,ml$ of non-carbonated liquid to avoid choking.
  • Contraindications: Bowel or biliary obstruction, Phenylketonuria (PKU).
  • Side Effects: GI disturbances, constipation.
  • Assessment: Monitor fat-soluble vitamin levels, especially in pregnant women.
  • Teaching: Increase fiber and fluid in the diet.

Nicotinic Acid (Niacin)

• Classification: Vitamin $B_3$.
• Mechanism of Action: Inhibits LDL production, promotes LDL clearance, and prevents HDL clearance.
• Therapeutic Effects:
  • Decrease in LDL and triglycerides.
  • Increase in HDL.
• Nursing Considerations:
  • Interactions: Statins (increases risk of myopathies).
  • Implementation: Up-titrate slowly. Administer NSAIDs $30$ minutes prior to dosing to reduce side effects.
  • Side Effects: Facial flushing, pruritis, increased bleeding (due to effects on intrinsic TPA).
  • Contraindications: Active bleeding, Peptic Ulcer Disease (PUD), liver disease.

Selective Cholesterol Absorption Inhibitors

• Key Drug: ezetimibe (Zetia).
• Mechanism of Action: Inhibits the absorption of cholesterol within the small intestines.
• Therapeutic Effects: Decrease in LDL and triglycerides; increase in HDL.
• Interactions: Fibric acid derivatives, bile acid sequestrants. May increase warfarin levels.
• Contraindications: Liver disease.

PCSK9 Inhibitors

• Key Drug: evolocumab (Repatha).
• Classification: Monoclonal antibodies.
• Mechanism of Action: Binds to the liver to improve LDL clearance.
• Administration: Subcutaneous (SC) injection every $2$ weeks or once a month.
• Side Effects: Mild reactions; may increase infection risk.
• Contraindications: Pregnancy.

OTC and Other Agents

• Omega-3 Fatty Acids:
  • Fish/Krill oil: No clinical evidence for OTC versions.
  • Lovaza (Rx strength): Research supports lower triglycerides and increased HDL (though may increase LDL).
  • Side effects: GI disturbances, dyspepsia (fishy taste).
  • Risk: Presumed increase in bleeding risk.

Heart Failure Pathophysiology and Goals

• Definition: The heart's inability to fill and pump blood to meet metabolic needs.
• Causes:
  • Untreated systemic hypertension (increases workload).
  • Impaired contraction (infarct, cardiomyopathies, myocarditis).
  • Structural changes (valve disorders, congenital defects).
• Clinical Culmination: Fluid overload, dyspnea, impaired perfusion, and activity intolerance.
• Therapeutic Goals:
  • Preserve Renin-Angiotensin-Aldosterone System (RAAS) function.
  • Improve myocardial contraction.
  • Reduce preload and afterload.
  • Reduce fluid overload.

Heart Failure Pharmacologic Classes

• RAAS Focus (ARNI/ACE/ARB): Prevent sodium/water reabsorption and lower systemic vascular resistance (SVR).

• Beta Blockers: Cardioprotective when used with ACE inhibitors; slows heart to allow better filling/pumping.

• Phosphodiesterase Inhibitors (PDIs): Positive inotropes used in intensive care; reduce SVR via vasodilation.

• Cardiac Glycosides:

  • Key Drug: digoxin (Lanoxin).
  • Mechanism: Inhibits sodium-potassium ATPase pump; augments vagal tone.
  • Effects: Positive inotrope (pumping), negative chronotrope (slowing), improved circulation, promotes diuresis.
  • Interactions: Amiodarone, Verapamil, Foxglove plant.
  • Digoxin Toxicity: Signs include headache, N/V/D, anorexia, visual changes (yellow/blurred vision), and bradycardia. Treated with Digibind. Therapeutic level is $0.5$ to $2.0\,ng/mL$.

• HCN Blockers:

  • Key Drug: ivabridine.
  • Mechanism: Slows conduction through the SA node.
  • Indication: Stable HF with Ejection Fraction (EF) < $35\%$ and HR > $70$.
  • Adverse Effects: Bradycardia, light sensitivity, atrial fibrillation, hypertension.

• ARNIs (Angiotensin Receptor Neprilysin Inhibitor):

  • Key Drug: valsartan-sacubitril (Entresto).
  • Mechanism: Prevents breakdown of natriuretic peptides and inhibits RAAS.
  • Contraindications: History of angioedema with ACEI/ARB. Cannot be used within $36$ hours of an ACE inhibitor.
  • Side Effects: Hypotension, hyperkalemia, dizziness, cough, angioedema.

Diuretics

• General Purpose: Used for HTN, HF, glaucoma, kidney injury, cerebral edema, and liver failure.

• Nursing Considerations: Monitor I&O, weight, BP, and electrolyte levels (Sodium, Potassium, GFR, BUN, Creatinine). Administer during the day.

• Carbonic Anhydrase Inhibitors (Acetazolamide):

  • Inhibits sodium resorption at proximal tubule; reduces aqueous humor in eyes.
  • Side effects include metabolic acidosis and hypokalemia.

• Loop Diuretics (Furosemide):

  • Blocks sodium/water resorption in the Loop of Henle.
  • Administration: IV push must be slow ($1$ to $2$ minutes per $40\,mg$).
  • Side Effects: Ototoxicity (tinnitus), hypokalemia, hypotension.
  • Interactions: NSAIDs, Vancomycin/Aminoglycosides (increases ototoxicity).

• Osmotic Diuretics (Mannitol):

  • Increases osmotic pressure to pull water into the nephron.
  • Use: Early acute renal failure, cerebral edema.
  • Note: Warm vials and assess for crystals before IV administration.

• Potassium-Sparing Diuretics (Spironolactone):

  • Competes with aldosterone in distal tubules.
  • Side Effects: Gynecomastia, hyperkalemia.
  • Interaction: ACE inhibitors, ARBs (additive potassium effect).

• Thiazide Diuretics (Hydrochlorothiazide):

  • Prevents sodium/potassium/chloride resorption in distal tubule.
  • Use: First-line HTN therapy for black patients.
  • Side Effects: Hypokalemia, hyperglycemia, elevated uric acid.