Drugs Affecting Cardiac Structure and Function

Question 1

What are the symptoms of a failing heart?

Answer 1

Symptoms of a Failing Heart:

• Fatigue
• Oedema
• Shortness of breath
• Palpitations

Question 2

What are the general actions of digoxin?

Answer 2

Digoxin:

• inhibit Na+/K+ATPase
• increased [Na]i decreases Ca2+ extrusion
• increase Ca2+ in sarcoplasmic reticulum
• increase Ca2+ release with each action potential

Question 3

Explain the role of glycosides in heart failure?

Answer 3

• narrow margin of safety, low therapeutic index
• affect all excitable tissues
  
  • gut - anorexia, nausea, diarrhoea
  • CNS - drowsiness, confusion, psychosis
  • cardiac - ventricular dysrhythmias (but used to treat atrial dysrhythmias)
• increased toxicity with
  
  • low K+ (↓ competition for binding)
  • high Ca2+ (↓ gradient for Ca2+ efflux)
  • renal impairment
• oral absorption, t1/2 ~ 40 hr
• Vd ~ 400 L due to high affinity binding to muscle

Question 4

Explain the mechanism of β-Adrenoceptors Agonists and PDE Inhibitors in heart failure.

Answer 4

• Intravenous, short term support for acute heart failure, cardiogenic shock
• β-adrenoceptor agonists
  –  noradrenaline, adrenaline
  - activate both α- & β-adrenoceptors
  –  dobutamine
  - selective β1-adrenoceptor agonist
  –  Adverse effects
  - Increase cardiac work, O2 demand
  - Risk of arrythmias
• Phosphodiesterase inhibitors
  –  Amrinone
  - issues as for β-adrenoceptor agonists

Question 5

What can happen to beta1 cells in heart failure?

Answer 5

chronic overactivation of β1-adrenoceptors with sympathetic compensation for reduced CO

• ->reduced β1-adrenoceptor expression & impaired β1-adrenoceptor coupling
• -> reduced sensitivity to β1-adrenoceptor agonists or sympathetic drive

Question 6

What are some progressive elements of heart failure?

Answer 6

- Inotropes 
	–  Increase contractile force of cardiomyocytes 
	–  Symptomatic relief 
		- Increase work on the heart 
- Symptoms progress 
	–  Chest pain 
	–  Fainting 
	–  Death
- Cardiac remodelling 
- More than loss of cardiac pump function 
	–  Other strategies needed 
		-Increase long-term survival

Question 7

What are some Mechanisms of heart failure?

Answer 7

• insufficient CO to meet tissue perfusion needs
• multiple causes for acute and chronic heart failure
  
  • Loss of myocardial muscle
    –  Ischaemic heart disease
    –  Cardiomyopathy
• Pressure overload
  –  Aortic stenosis
  –  Hypertension
• Volume overload
  –  Valve regurgitation
  –  Shunts (eg septal defects)

Question 8

What are some drugs to reduce preload?

Answer 8

• Venodilators
  –  Nitrates
  - Angina, venous dilation > arterial dilation
  - 1st pass metabolism, tolerance
• Diuretics
  –  Furosemide / Frusemide
  - Loop of Henle
• Aldosterone receptor antagonists e.g. spironolactone
  
  • Inhibit aldosterone action on cortical and distal tubules
    
    • K+ sparing diuretic
    • improves survival with combination therapy in severe heart failure
  • require close monitoring of hyperkalaemia and renal function
    - Aquaretics
    –  Vasopressin receptor antagonists

Question 9

What are some drugs to reduce afterload?

Answer 9

- Arterial vasodilators 
	–  Reflex tachycardia 
- ACE inhibitors 
	–  First line therapy 
	–  Decrease constriction 
	–  Also 
		-  decrease fluid retention  
		-  slow progression of hypertrophy 
- AT1 antagonist 
        –  Alternative to ACEI 
- β-adrenoceptor antagonists

Question 10

Explain Ace inhibitors in the treatment of heart failure?

Answer 10

• effective at all grades of heart failure
• improve symptoms, delay progression
• proven survival benefits, titrate dosage because:
  –  First-dose hypotension
  –  Dry cough
  –  Loss of taste
  –  Hyperkalaemia (+ thiazide diuretic)
  –  Acute renal failure
  –  Itching, rash, angio-oedema
  –  Foetal malformations
• maintain at tolerated dose and combine with other therapies (diuretics, glycosides, β-adrenoceptor antagonists,)
• Contraindicated in:
  
  • bilateral renal stenosis
  • angioneurotic oedema
  • pregnancy

Question 11

What is the mechanism, side effects and contraindications for beta blockers in heart failure?

Answer 11

• despite β1 blockade, stroke volume increases
• care needed at start of treatment (titrate to maintenance dose)

Side effects:

• hypotension, fatigue (cardiac and β2-mediated)
• bronchoconstriction (β2 block – so not in asthma)
• cold extremities (α1-mediated reflex – so not in PVD)
• may cause and/or mask signs of hypoglycaemia (so not in diabetes)
• counter-intuitive therapy
• attempts to inhibit the disease process in early stages
• β1 blockade (cardiac) metoprolol
  
  • reduces tachycardia, cardiac work
  • inhibits renin release and subsequent AII effects
  • protects against receptor downregulation
• β1 & α1 blockade (vascular, carvedilol only)
  
  • vasodilation reduces afterload, cardiac work

Question 12

What is the aim of heart failure treatment?

Answer 12

• Decrease cardiac work and improve cardiac function
  – preload, afterload, contractility
• Reduce signs and symptoms
  
  • oedema, fatigue, arrhythmias, ventricular remodelling
• Increase survival
  
  • one-year mortality rate ~ 10% for mild and moderate HF

Question 13

What are some drugs that affect contractility, preload and afterload?

Answer 13

Drugs Affecting Contractility
- Symptomatic relief 
	– Inotropes 
		- acute: β -adrenoceptor agonists, PDE inhibitors 
		- chronic: glycosides
Drugs Affecting Preload
- Symptomatic relief 
	– Diuretics, venodilators
- Reduced mortality	
	– aldosterone antagonists
Drugs Affecting Afterload
- Reduced mortality
	– Angiotensin inhibitors,
	‒ β -adrenoceptor antagonists

Question 14

What are some alternative treatments for heart failure to drugs?

Answer 14

Surgical
–  Pacemaker, defibrillator, valve replacement
–  Heart Transplant
Pharmacological & Surgical approaches complemented with
–  Reduce salt, fluid, alcohol
–  Stop smoking
–  Undertake appropriate exercise