Pharmacology of ACE Inhibitors and ARBs
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Questions and Answers

What is a potential adverse effect of captopril, especially at high doses in renal patients?

  • Angioedema
  • Hyperkalemia
  • Neutropenia (correct)
  • Dysgeusia

Which medication class can lead to reduced bioavailability when taken together with antacids?

  • Angiotensin receptor blockers
  • ACE inhibitors (correct)
  • Potassium-sparing diuretics
  • Nonsteroidal anti-inflammatory drugs

What is a key distinguishing factor between ACE inhibitors and angiotensin receptor blockers (ARBs) regarding adverse effects?

  • ACE inhibitors have a higher incidence of angioedema (correct)
  • ACE inhibitors have fewer gastrointestinal manifestations
  • ARBs cause more dry cough
  • ARBs are less likely to cause renal failure

In which trimester is the use of ACE inhibitors especially concerning due to teratogenicity?

<p>First trimester (A)</p> Signup and view all the answers

What mechanism do angiotensin receptor blockers primarily employ to produce their effects?

<p>Blocking AT1 receptors (D)</p> Signup and view all the answers

What cardiovascular effect do ARBs NOT induce?

<p>Increased heart rate (A)</p> Signup and view all the answers

What condition may potentially be exacerbated in patients taking potassium supplements along with certain medications?

<p>Hyperkalemia (C)</p> Signup and view all the answers

Which aspect of the pharmacodynamics of angiotensin receptor blockers contributes to decreased platelet aggregation?

<p>Inhibition of thromboxane A2 activity (D)</p> Signup and view all the answers

What is the primary mechanism by which Sacubitril exerts its effects in heart failure?

<p>Inhibiting neprilysin, leading to increased levels of natriuretic peptides (A)</p> Signup and view all the answers

Which adverse reaction is most commonly associated with the use of Sacubitril/Valsartan?

<p>Hyperkalemia (D)</p> Signup and view all the answers

How should β-blockers like Metoprolol be administered to patients with compensated heart failure?

<p>Administered in a staggered approach with gradually increasing doses (C)</p> Signup and view all the answers

When might thiazide diuretics be beneficial in heart failure management?

<p>When combined with loop diuretics in refractory cases (D)</p> Signup and view all the answers

What is the potential consequence of excessive diuresis in heart failure patients?

<p>Reduced cardiac output leading to complications (D)</p> Signup and view all the answers

Which of the following statements is true regarding the combination of hydralazine and isosorbide dinitrate?

<p>This combination is useful in treating chronic heart failure (D)</p> Signup and view all the answers

What is the role of aldosterone antagonists in heart failure treatment?

<p>To reduce mortality in severe heart failure by preventing myocardial fibrosis (C)</p> Signup and view all the answers

What is the primary effect of ACE inhibitors on angiotensin II levels?

<p>Inhibits conversion of Angiotensin I to Angiotensin II (C)</p> Signup and view all the answers

What is a key effect of neprilysin inhibition in heart failure management?

<p>Increased vasodilating peptides and reduced vasoconstrictors (A)</p> Signup and view all the answers

Which of the following is NOT one of the therapeutic uses of ACE inhibitors?

<p>Asthma management (A)</p> Signup and view all the answers

What is a significant pharmacological effect of ACE inhibitors?

<p>Has a vasodilatory effect (D)</p> Signup and view all the answers

Which ACE inhibitor is uniquely cleared by both bile and urine?

<p>Fosinopril (D)</p> Signup and view all the answers

What is the consequence of ACE inhibitors on bradykinin levels?

<p>Inhibits degradation of bradykinin (A)</p> Signup and view all the answers

First-dose hypotension related to ACE inhibitors is most likely to occur in which population?

<p>Hypovolemic patients (B)</p> Signup and view all the answers

What is a common gastrointestinal effect caused by digoxin?

<p>Diarrhea (D)</p> Signup and view all the answers

How do ACE inhibitors provide cardioprotective effects in chronic heart failure (CHF)?

<p>By inhibiting degradation of substance P (A)</p> Signup and view all the answers

Which of the following outcomes is NOT associated with the use of ACE inhibitors?

<p>Increase in sodium retention (C)</p> Signup and view all the answers

Which therapeutic use of digoxin is indicated for patients with normal sinus rhythm who remain symptomatic?

<p>Congestive heart failure (D)</p> Signup and view all the answers

What condition contraindicates the use of digoxin?

<p>Wolf-Parkinson-White syndrome (D)</p> Signup and view all the answers

What is a potential severe adverse effect of digoxin treatment?

<p>Visual disturbances (D)</p> Signup and view all the answers

Which drug may increase digoxin levels by inhibiting P-glycoprotein?

<p>Amiodarone (C)</p> Signup and view all the answers

What is the mechanism of action of phosphodiesterase inhibitors like Milrinone?

<p>Increase cAMP levels (D)</p> Signup and view all the answers

Which of the following interactions can decrease the effect of digoxin?

<p>Antacids (B)</p> Signup and view all the answers

What is the specific antidote used for treating digoxin toxicity?

<p>Digoxin immune fab (D)</p> Signup and view all the answers

What is the mechanism by which digoxin exerts its positive inotropic effect?

<p>Binds and inhibits Na+/K+ ATPase (D)</p> Signup and view all the answers

How long does it take to achieve steady state after initiating the maintenance dose of digoxin?

<p>7 days (A)</p> Signup and view all the answers

Which electrolyte can enhance the effect of digoxin on Na+/K+ ATPase?

<p>Calcium (Ca+) (D)</p> Signup and view all the answers

What is the typical half-life of digoxin in normal renal function?

<p>36-40 hours (B)</p> Signup and view all the answers

Which of the following conditions can result from high concentrations of digoxin?

<p>Self-sustained tachycardia (D)</p> Signup and view all the answers

What percentage of oral bioavailability does digoxin typically achieve?

<p>65-80% (B)</p> Signup and view all the answers

What is the therapeutic range for digoxin concentrations in the blood?

<p>0.8-2.0 ng/ml (C)</p> Signup and view all the answers

What effect does digoxin have at low therapeutic doses on the cardiac electrical conduction system?

<p>Decreased conduction through the AV node (C)</p> Signup and view all the answers

Flashcards

ACEIs Mechanism of Action

ACEIs block the enzyme ACE, inhibiting the conversion of Angiotensin I to Angiotensin II. This reduces vasoconstriction, aldosterone release, and noradrenaline release.

ACEI effect on Bradykinin

ACEIs inhibit the breakdown of bradykinin, leading to increased vasodilation.

ACEI Hypertension

ACEIs treat hypertension alone or in combination with other drugs like calcium channel blockers or diuretics.

ACEI Effects on Heart

ACEIs decrease vascular remodeling/hypertrophy, prevent heart failure progression, and reduce mortality.

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ACEI Renal Protection

ACEIs help protect kidneys by reducing intraglomerular pressure and mesangial cell growth. This is very beneficial for diabetic nephropathy.

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ACEI Renal Clearance

Most ACEIs are cleared by the kidney, but fosinopril is cleared by both bile and urine.

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ACEI First-Dose Hypotension

ACEIs can cause a sudden drop in blood pressure, especially in patients with low blood volume or already using multiple blood pressure medications.

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ACEIn Myocardial Infarction

ACEIs can be used in acute myocardial infarction, especially in hypertensive or diabetic patients, to help reduce cardiovascular events.

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Bradykinin accumulation

Increased buildup of bradykinin in the body.

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Hyperkalemia

High potassium levels in the blood.

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Acute renal failure

Sudden kidney failure.

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Angioedema

Rapid swelling of the throat, mouth, lips and tongue.

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ACE inhibitors (ACEIs)

Drugs that block the formation of angiotensin II, lowering blood pressure.

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Angiotensin receptor blockers (ARBs)

Block angiotensin II receptors, lowering blood pressure.

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Teratogenicity (first trimester)

Risk of birth defects from drug use during pregnancy's first trimester.

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Drug Interactions (ACEIs/ARBs)

NSAIDs impair ACEI hypotensive effect, while antacids reduce bio-availability, and K+ supplements/diuretics can lead to hyperkalemia.

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Sacubitril/Valsartan Mechanism

Inhibits neprilysin, increasing natriuretic peptides and reducing angiotensin II, resulting in decreased vascular resistance and blood pressure.

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Natriuretic Peptides

Released under atrial and ventricle stress, causing vasodilation, natriuresis, and diuresis (e.g., ANP, BNP).

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Loop Diuretics (e.g., Furosemide)

Counteract salt and water retention, edema, and symptoms in heart failure by reducing preload.

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Aldosterone Antagonists (e.g., Spironolactone)

Reduce mortality in severe heart failure by reducing myocardial and vascular fibrosis.

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Beta-Blockers (e.g., Metoprolol)

Reduce harmful sympathetic activation, preventing adverse effects, and helping to slow the progression of heart failure. Start low and titrate slowly.

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Vasodilators (e.g., Hydralazine/Isosorbide Dinitrate)

Lower blood pressure by reducing afterload (Hydralazine) and preload (Isosorbide Dinitrate), beneficial in chronic heart failure.

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ACEIs Adverse Effects

Similar to Sacubitril/Valsartan, but with a higher incidence of cough and angioedema.

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Thiazide Diuretics (e.g., Hydrochlorothiazide)

Limited role in heart failure, but may be used in combination with loop diuretics for refractory heart failure patients.

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Digoxin Source

Digoxin is derived from the plant source, Digitalis lanata.

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Digoxin Absorption

Digoxin is absorbed orally with a bioavailability of 65-80% or administered intravenously (IV).

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Digoxin Distribution

Digoxin distributes widely throughout the body, with a large volume of distribution (Vd) of 4-7 L/kg. Skeletal muscle is its primary storage site.

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Digoxin Elimination

Digoxin is excreted unchanged by the kidneys. Its half-life is 36-40 hours in individuals with normal kidney function.

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Digoxin Therapeutic Range

The therapeutic range for Digoxin is narrow, between 0.8-2.0 ng/ml.

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Digoxin Positive Inotropic Effect

Digoxin increases heart contractility by binding and partially inhibiting the Na+/K+ ATPase in cardiac muscle cells.

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Digoxin Electrical Effects: Low Doses

At low therapeutic doses, digoxin has cardio-selective vagal effects, slowing down the heart rate and affecting the conduction system.

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Digoxin Electrical Effects: High Concentration

At high concentrations, digoxin can disrupt heart rhythm, leading to dangerous arrhythmias.

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Digoxin's Effect on GIT

Digoxin can cause nausea, vomiting, anorexia, and diarrhea due to direct stimulation of the chemoreceptor trigger zone (CTZ) in the brain.

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Digoxin's Effect on CNS

Digoxin can stimulate the CTZ and vagal center in the brain, leading to disorientation and hallucinations, especially in older adults.

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Digoxin's Visual Disturbances

Digoxin can cause visual disturbances like blurry vision or seeing halos around lights due to its steroid nucleus.

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Digoxin's Use in Heart Failure

Digoxin is used for congestive heart failure in atrial fibrillation and in patients with normal sinus rhythm who are not adequately controlled with other therapies.

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Digoxin's Limitations in Heart Failure

Digoxin does not reduce mortality in heart failure; it only alleviates signs and symptoms. It's ineffective when heart failure is due to exhausted energy stores, like in high-output failure.

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Digoxin's Use in Atrial Arrhythmia

Digoxin is used for atrial flutter, fibrillation, and paroxysmal tachycardia by controlling ventricular rate through reduced conduction in the AV node.

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Digoxin's Contraindication in Wolf-Parkinson-White Syndrome

Digoxin is contraindicated in patients with Wolf-Parkinson-White syndrome, as it can worsen arrhythmias in this condition.

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Digoxin's Adverse Effects and Dose Reduction

Digoxin's adverse effects, such as GIT disturbances and visual problems, may necessitate a dose reduction to manage the side effects.

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Study Notes

ACE Inhibitors (ACEIs)

  • ACEIs are primarily cleared by the kidneys, except for fosinopril, which also uses bile elimination. Dosage adjustment is necessary in patients with renal impairment.

Pharmacodynamics of ACEIs

  • Mode of Action: ACEIs competitively inhibit ACE (kininase II), leading to several effects:

    • Inhibition of Angiotensin I to Angiotensin II conversion, reducing the vasoconstrictor and aldosterone-releasing effects of Angiotensin II. This also increases renin release as a compensatory mechanism.
    • Increasing bradykinin levels due to inhibition of its degradation, which has a vasodilating effect.
    • Inhibiting the degradation of substance P and stem cell regulator peptides, which contributes to the cardioprotective effects in heart failure (CHF)

  • Pharmacological Effects:

    • Lowering blood pressure by reducing peripheral resistance
    • Reduced salt and water retention due to decreased aldosterone release and increased sodium excretion.
    • No significant effect on heart rate or cardiac output.
    • No reflex sympathetic activation (safe for ischemic heart disease)
    • Reduced intraglomerular capillary pressure, potentially decreasing proteinuria.

Therapeutic Uses of ACEIs

  • Hypertension (alone or combined with other agents like calcium channel blockers, beta-blockers, or diuretics)
  • Left ventricular systolic dysfunction
  • Acute myocardial infarction, especially in hypertensive or diabetic patients.
  • Patients at high risk for cardiovascular events (reducing myocardial infarction and stroke).
  • Diabetic nephropathy (via reduction of increased glomerular pressures and mesangial cell growth)
  • Scleroderma crisis (Angiotensin II plays a role in this, and ACE inhibitors can be life-saving)

Adverse Effects of ACEIs

  • First-dose hypotension, especially in patients with hypovolemia, multiple antihypertensives, or heart failure.
  • Dry cough due to increased bradykinin levels.
  • Hyperkalemia (increased potassium levels), especially in renal impairment or diabetes
  • Acute renal failure, particularly in bilateral renal artery stenosis or stenosis of solitary kidney.
  • Angioedema (swelling of the face, tongue, and throat).

Drug Interactions with ACEIs

  • Antacids: reduced bioavailability
  • NSAIDs: impaired hypotensive effect (by blocking bradykinin).
  • Potassium supplements, beta-blockers, and potassium-sparing diuretics: potential for hyperkalemia.

Angiotensin Receptor Blockers (ARBs)

  • Pharmacokinetics: Oral bioavailability ranges from <50% to 70%, with plasma protein binding above 90%.
  • Mode of Action: Competitive antagonists for AT1 receptors, resulting in:
    • Vasodilation
    • Reduced sympathetic stimulation
    • Decreased aldosterone release and increase potassium levels
    • Reduced salt and water retention
    • Inhibited cardiac hypertrophy and remodeling
    • Blocking of thromboxane A2 receptors, which is antiplatelet
    • Vasodilation due to activation of the unblocked AT2 receptors, followed by inhibition of hypertrophy and remodeling
  • Adverse Effects: Similar to ACEIs but typically with less incidence of cough and angioedema.
  • Therapeutic Uses: Similar to ACEIs.

Sacubitril/Valsartan (Neprilysin Inhibitor)

  • Inhibition of neprilysin prevents the degradation of natriuretic peptides (ANP, BNP), promoting vasodilation, natriuresis, and diuresis.
  • This results in a decrease in vasoconstriction via reduced breakdown of angiotensin II.
  • Adverse effects are similar to ACE inhibitors.

Diuretics

  • Loop diuretics (e.g., furosemide) are important but can cause salt and water loss; the dose should thus be minimal to maintain euvolemia (normal blood fluid levels.)
  • Thiazide (e.g., hydrochlorothiazide) diuretics have limited use in heart failure. They may be combined with loop diuretics in refractory cases.
  • Avoid diuretics in asymptomatic left ventricular dysfunction.
  • Aldosterone blockers (e.g., spironolactone) reduce mortality in severe heart failure, reducing myocardial and vascular fibrosis.

Beta-Blockers

  • Used with low dose and slow titration in compensated heart failure to counteract harmful sympathetic activation.
  • Examples: metoprolol, carvedilol, bisoprolol.

Vasodilators

  • Hydralazine (arterial vasodilation) and isosorbide dinitrate (venodilation) are beneficial in chronic heart failure. Combinations are often used.

Other Positive Inotropic Drugs

  • Digoxin

    • Chemistry: Plant-derived steroid, linked to a lactone ring and a sugar moiety.
    • Pharmacokinetics: Oral absorption, with 65-80% bioavailability; widely distributed; excreted unchanged by kidneys; half-life of 36-40 hours in normal renal function. Dose must be reduced in renal dysfunction and elderly persons.
    • Pharmacodynamics: Inhibits Na+/K+ ATPase in cardiac myocytes, causing increased intracellular calcium and thereby enhancing contractility.

  • Phosphodiesterase inhibitors: Examples include milrinone.

  • Dobutamine: IV used for rapid response in acute decompensated heart failure to increase contractility and cardiac output, with minimal effect on heart rate; recent beta-blocker therapy can cause resistance to the effects.

Additional Information

  • Other adverse effects of various antihypertensive drugs are mentioned, including gastrointestinal disturbances, visual disturbances, and arrhythmias, along with possible drug-drug interactions.

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Test your knowledge on the pharmacological effects, side effects, and mechanisms of action of ACE inhibitors and angiotensin receptor blockers (ARBs). This quiz covers important concepts related to their use, especially in renal patients, and highlights critical distinctions between the two medication classes. Perfect for medical students and healthcare professionals.

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