L8.3 Drugs for Heart Failure and Dysarrhythmias

Question 1

PNS mechanism

Answer 1

• SA & AV nodes
• M2 receptors in heart
• Gi decreases cAMP → increases K channels → hyperpolarises → decreases HR

Question 2

SNS mechanism

Answer 2

• SA, conducting tissues and myocardial cells
• Gas → increase cAMP → increases Ca → increase HR & contractility
  
  • Potential for dysrhythmia

Question 3

How does dysrhythmia arise?

Answer 3

• Altered automaticity in SA node
• Generation of AP at sites other than the SA node
  
  • Conduction block

Question 4

Why should the no treatment option be always considered first?

Answer 4

• Antiarrhythmic drugs often have proarrhythmic activity which may worsen the condition and even cause sudden death

Question 5

Classes of antidysrhythmics

Answer 5

• 1: Na channel block (a = moderate; b = weak; c = strong)
• 2: ß-adrenoceptor agonist + PDEi
• 3: K channel blockers
• 4: Ca channel blockers
• Unclassified: Atropine, adenosine, cardiac glycosides, electrolyte supplements

Question 6

Unclassified agents

Answer 6

• Adenosine: similar effects to PNS stimulation
• Atropine: inhibits PNS activation (for bradyarrhythmia)
• ß-adrenoceptor agonist: mimics sympathetic activation
• Cardiac glycosides (digoxin)
  
  • Slows AV conduction → increase PNS input to heart via CNS effect
  • Improves contractility
    
    • Inhibits Na/K ATPase → overload of Ca inside cell
  • Useful in atrial fibrillation → slows ventricular rate → improve filling
  • May worsen ventricular fibrillation

Question 7

Glycosides in heart failure

Answer 7

• Narrow margin of safety, low therapeutic index (needs to be used carefully)
  
  • Affects all tissues
    
    • GUT: Anorexia, nausea
    • CNS (crosses BBB): Drowsiness, confusion
    • Cardiac: Ventricular dysrhythmias
• Toxicity
  
  • Low K (low competition for binding)
  • High Ca (decrease gradient for Ca efflux)
  • Renal impairment
• Oral absorption, LONG 1/2 life → ~40hrs
• Vd ~ 400L due to high affinity binding to muscles

Question 8

b-agonist and PDE inhibitors

Answer 8

• I.v. and short term support for acute heart failure
• ß-agonist:
  
  • Dobutamine → selective ß1-agonist
    
    • AE: Increases cradiac work, O2 demand
    • Risk of dysrhythmias
• Phosphodiesterase (PDE is responsible for cAMP → AMP) inhibitors
  
  • Milrinone
    
    • Same issues as ß agonist

Question 9

Effects of inotropes on heart failures

Answer 9

• Only symptomatic relief (Short term benefit)
• Cardiac remodelling not improved

Question 10

Definition and causes of heart failure

Answer 10

• insufficient CO to meet tissue perfusion needs
• Causes:
  
  • Loss of myocardial muscles
    
    • MI/cardiomyopathy
  • Pressure overload
    
    • Aortic stenosis/hypertension
  • Volume overload
    
    • Valve regurgitation/Shunts

Question 11

How is preload reduced

Answer 11

• Venodilators:
• Nitrates
  
  • Angina, venous dilation > arterial dilation
  • Decrease preload and work
• Diuretics
  
  • Furosemid - for hypertension
• Aldosterone receptor antagonists

Question 12

Aldosterone receptor antagonists

Answer 12

• Spironolactone
• Inhibits aldosterone
• Improves survival with combination therapy in severe heart failure
• Requires close monitoring of hyperkalaemia and renal function

Question 13

How is afterload reduced?

Answer 13

• Arterial vasodilators
• ACE inhibitors (First line therapy)
• AT1 antagonist
• ß-blockers

Question 14

Targeting ANGII with ACEi

Answer 14

• Decrease vasoconstriction (which is more potent than NA) → decrease afterload
• Decreased fluid rentention from aldosterone action → decrease preload
• Decrease ventricular remodeling → decrease hypertrophy

Question 15

Effects of ACEi on morbidites and mortality

Answer 15

• Effective at all grades of heart failure including asymptomatic
• Improve symptoms and delay progression
• Maintain at tolerated dose and combined with other therapies

Question 16

B-blockers

Answer 16

• (metoprolol - ß1 blocker)
• Despite ß1 blockade → SV increases (bad)
  
  • Care needed at start of treatment (titrate to maintenance dose)
• Inhibits the RAS
  
  • Also protects against receptor downregulation
• Mixed a&b blocker (Carvedilol)
  
  • Vasodilation reducing afterload and cardiac work
  • Improve ejection fraction
• Benefits/detriment depending on where you are on the frank-starling curve

Question 17

Overview of all the drugs

Answer 17