Pharmacotherapy for Advanced Practice Nurses and Physician Assistants

Diuretics

Overview of Diuretics

Diuretics are defined as drugs that induce a state of increased urine flow, commonly referred to as "water pills." They act primarily as ion transport inhibitors, which decrease the reabsorption of sodium ions (Na+) at various sites within the nephron, thereby leading to increased Na+ excretion along with water, as water "chases" sodium.

Types of Diuretics

1. Acetazolamide

  • Classification: Carbonic anhydrase inhibitor.

  • Mechanism of Action: Acetazolamide inhibits the reabsorption of bicarbonate (HCO3-) in the proximal convoluted tubule.

  • Properties: Demonstrates weak diuretic properties.

2. Thiazide Diuretics

  • Examples: Hydrochlorothiazide, chlorthalidone, etc.

  • Site of Action: Distal convoluted tubule.

  • Mechanism of Action: Inhibit the reabsorption of Na+ and Cl- in the distal convoluted tubule, leading to retention of water.

  • Usage: These are among the most commonly used diuretics.

3. Potassium-Sparing Diuretics

  • Examples: Spironolactone, Amiloride, Triamterene.

  • Mechanism of Action:

    • Spironolactone: An aldosterone antagonist that inhibits the aldosterone-mediated reabsorption of Na+ and secretion of K+.

    • Amiloride and Triamterene: Block sodium channels, preventing K+ loss that can occur with thiazide or loop diuretics.

4. Loop Diuretics

  • Examples: Furosemide, Bumetanide, Torsemide, Ethacrynic Acid.

  • Site of Action: Ascending loop of Henle.

  • Mechanism of Action: Inhibit the Na+/K+/2Cl− cotransport in the ascending loop of Henle, resulting in the retention of Na+, Cl-, and water in the tubule.

  • Efficacy: These drugs are the most efficacious among diuretics.

Mechanism of Action for Specific Diuretics

Acetazolamide

  • Mechanism: Increases Na+ excretion via Na+/H+ exchange.

Thiazide Diuretics

  • Major Effects:

    • Increased NaCl excretion.

    • Increased K+ excretion.

    • Decreased Ca++ excretion, which can be beneficial in treating calcium stone formation.

  • Side Effects: May include hypokalemia, hyponatremia, hypercalcemia, and hyperuricemia.

Loop Diuretics

  • Major Effects:

    • Enhanced NaCl excretion, increased K+ excretion, and increased Ca++ excretion, useful in treating hypercalcemia.

  • Side Effects: Ototoxicity (causing tinnitus), hypokalemia, hyperuricemia, hypomagnesemia, and hypotension.

Potassium-Sparing Diuretics

  • Major Effects:

    • Reduced K+ excretion, leading to the risk of hyperkalemia.

  • Side Effects: Hyperkalemia, which can result in significant cardiac issues.

Renal Regulation of Arterial Pressure

Mechanisms of Regulation

  1. Acute Hemorrhage: Causes a decrease in arterial pressure leading to renal perfusion pressure reduction.

  2. Renin Production: Low blood pressure triggers kidney cells to secrete renin.

  3. Renin-Angiotensin-Aldosterone System (RAAS):

    • Renin catalyzes the conversion of angiotensinogen to angiotensin I in plasma, which is subsequently converted to angiotensin II by ACE in the lungs. Angiotensin II is a potent vasoconstrictor that stimulates aldosterone secretion, enhances Na+ reabsorption, and prompts thirst.

    • Effects of Angiotensin II:

      • Increased aldosterone secretion leading to Na+ reabsorption and increased blood volume and pressure.

      • Increased Na+-H+ exchange causing contraction alkalosis.

      • Stimulation of thirst and vasoconstriction of arterioles.

Angiotensin-Converting Enzyme (ACE) Inhibitors

Mechanism of Action

  • ACE inhibitors block the conversion of angiotensin I to angiotensin II, thus lowering blood pressure (BP) by reducing vasoconstriction and promoting Na+ and water excretion.

  • Adverse Effects: Include dry cough (due to increased bradykinin), hyperkalemia, hypotension, rash, and fever.

Calcium Channel Blockers

Mechanism of Action

  1. Block voltage-dependent L-type Ca²+ channels in cardiac and smooth muscle cells, reducing contractility of the heart and causing vasodilation.

  2. Classes:

    • Nifedipine: More effective in vascular smooth muscle.

    • Verapamil and Diltiazem: More effective in cardiac muscles.

Clinical Uses

  • Hypertension, angina, arrhythmias, Prinzmetal's angina, and Raynaud’s disease.

Adverse Effects

  • Includes flushing, dizziness, fatigue, hypotension, and constipation.

Cardiac Glycosides

Overview

  1. Inotropic Effects: Increase heart contraction force and also slow heart rate.

  2. Example: Digoxin.

Mechanism of Action

  1. Digitalis inhibits the Na+/K+ ATPase pump, leading to increased intracellular Na+, which in turn increases intracellular Ca++ through the Na+/Ca++ exchange mechanism.

  2. Higher intracellular Ca++ levels lead to more forceful contractions.

Pharmacokinetics

  • Absorption varies based on form and route, and some is metabolized through the liver, with elimination via urine.

Uses

  • Primarily for heart failure and certain arrhythmias (e.g., atrial fibrillation).

Adverse Reactions

  • Narrow therapeutic index, leading to toxicity risk especially in hypokalemia, nausea, vomiting, and arrhythmias.

Phosphodiesterase (PDE) Inhibitors

General Action

  • Short-term management of heart failure.

  • Examples: Amrinone, milrinone.

Mechanism of Action

  • Inhibit phosphodiesterase, leading to an increase in cAMP, increased Ca++, and stronger heart contractions. In smooth muscle, increased cAMP causes decreased Ca++ entry, resulting in relaxation and vasodilation.

Antiarrhythmic Drugs

Classifications

  1. Class I: Na+ channel blockers (e.g., Disopyramide, Lidocaine, Flecainide).

  2. Class II: Beta-adrenergic blockers (e.g., Metoprolol, Propranolol).

  3. Class III: K+ channel blockers (e.g., Amiodarone).

  4. Class IV: Ca²+ channel blockers (e.g., Diltiazem).

Mechanisms and Effects

  • Class I drugs alter action potentials and refractory periods.

  • Class II reduce automaticity due to decreased cAMP and Ca++.

  • Class III drugs prolong action potential duration and refractory period, affecting ventricular arrhythmias.

  • Class IV drugs mainly reduce conduction velocity and contractility.

Adverse Effects

  • Common side effects across classes include arrhythmias, CNS effects, and gastrointestinal disturbances, with specific class-related adverse effects such as hypotension or QT prolongation.

Antianginal Drugs

Overview and Classes

  • Focus on reducing myocardial demand through three major classes: nitrates, beta-adrenergic blockers, and calcium channel blockers.

Nitrates

  • Mechanism: Cause dilation of veins and arteries, primarily reducing preload and afterload.

  • Examples: Isosorbide, nitroglycerin.

  • Side Effects: Include headache, hypotension, dizziness.

Beta Blockers

  • Mechanism: Decrease heart rate and contractility by blocking beta-adrenergic receptors.

  • Use: For long-term prevention of angina.

Calcium Channel Blockers

  • Mechanism: Decrease Ca2+ entry into cells, reducing contractility and arterial contraction.

  • Use: For the long-term prevention of angina.

Antihypertensive Agents

Categories and Adverse Reactions

  • Physiological mechanisms of various drug classes used in hypertension management.

  • Notable adverse reactions can include hypotension, bradycardia, and others relevant to specific drug classes.

Antilipemic Drugs

General Effects and Classes

  • Aim to lower serum cholesterol and triglyceride levels through multiple action mechanisms, including inhibiting absorption, production, or altering metabolism.

  • Common classes include bile acid-binding resins, statins, fibrates, and cholesterol absorption inhibitors.

Pharmacodynamics

  • Specific mechanisms for each class leading to lipid profile changes, with side effects to consider.