Drugs Used in Heart Failure & Cardiac Arrhythmia Management

• Drugs commonly used for heart failure:

  • Inotropes (increase the force of the contraction of the heart)
  • Diuretics (cause passage of increased amounts of urine)
  • Beta blockers (stabilise the heart rhythm)
  • ACE inhibitors (cause dilation of blood vessels and reduce work of contraction of the heart)
  • Angiotensin receptor blockers (same as ACE inhibitors)
• Inotropes - adrenoreceptor agonists:

  • Increase force of contraction of the heart by stimulating cardiac β1 receptors (+ve inotropic)
  • Ancillary (providing support for primary operations/activities) effects depend on interactions with other adrenergic receptors
  • Used in cardiogenic shock in ITU/CCU (intensive therapy unit/critical care unit)
  • Short half life - intravenous infusion via central line
  • May cause arrhythmias and increase myocardial oxygen demand

  
• Cardiac glycosides - digoxin:

  • Actions:
  • Antiarrhythmic: vagolytic effect reduces rate and conduction velocity in sinus and AV nodes
  • Inotropic: increases intracellular Ca++ (required for excitation-contraction coupling in the heart)
• Cardiac glycosides - digoxin:

  • Indications:
  • Supraventricular arrhythmias
  • Chronic atrial fibrillation
  • Heart failure (improves symptoms but not mortality)
• Cardiac glycosides - digoxin:

  • Pharmacology:
  • Renal >> hepatic elimination
  • Therefore pts with renal problems will need lower doses or they'll end up with high amounts in the blood
  • Half life 36 hours - longer in renal failure
  • Narrow therapeutic index (amount needed to produce therapeutic effect v close to amount needed to produce toxic effect) - need to monitor plasma concentrations when
  • Possible toxic symptoms
  • Lack of efficacy
• Cardiac glycosides - action:

  • Diagram shows how digoxin effects extracellular and intracellular electrolytes, and how we get to the stage that intracellular calcium is increased.

  
• Cardiac glycosides - digoxin - adverse effects (caused when concentrations in the blood are too high):

  • Cardiac
  • Heart block (overstimulation of vagus nerve)
  • Supraventricular and ventricular arrhythmias (all parts of heart may become unstable and cause tachycardias)
  • Non-cardiac
  • Nausea, constipation, vomiting
  • Confusion
  • Visual disturbances
• Cardiac glycosides action: sodium-potassium-ATPase = digoxin's primary site of action. It usually pumps K from outside to inside the cell, in exchange for Na, which moves inside from outside. When digoxin inhibits the pump, K outside increases & Na inside increases. Another pump = sodium-calcium exchanger - usually pumps Na into cell, in exchange for Ca. But under digoxin treatment, there's more Na inside due to sodium-potassium-ATPase. So more difficult to exchange for Ca, so Ca accumulates inside & causes inotropic effect. High Na in the cell causes cardiac instability, and arrhythmias.

  
• Action of diuretics:

  • Diagram shows nephron from glomerulus to collecting duct.
  • In a normal person, glomerular filtration rate = 120ml/min.
  • The production of urine depends on the hydration status of the patient, but is typically around 1ml/min.
  • Therefore, more than 99% of the fluid which enters he nephron is reabsorbed.
  • Diuretics inhibit that absorption to a limited degree, and that increases the amount of urine that flows. Different subtypes of diuretics have different sites of action and different potencies.

  
• Types of diuretics:

  • K⁺ losing (cause loss of potassium along with the loss of water)
  • K⁺ sparing (retain potassium despite losing water)
• K⁺ losing diuretics (cause loss of potassium along with the loss of water):

  • Loop diuretics (powerful, can increase urine production ten fold)
  • Furosemide - most common one to come across
  • Bumetanide
  • Thiazide diuretics (mostly used to treat high blood pressure, only increase urine production 2-3 fold)
  • Bendroflumethiazide
  • Carbonic anhydrase inhibitors - used to treat glaucoma, not heart failure
  • Acetazolamide
• K⁺ sparing diuretics (retain potassium despite losing water):

  • Aldosterone antagonists
  • Spironolactone
  • Aldosterone independent
  • Amiloride
• Adverse effects of thiazide and loop diuretics - mostly loops:

  • Hypovolaemia (loss of sodium)
  • Hyponatraemia
  • Renal dysfunction
  • Ototoxicity
  • Hypomagnesaemia
  • Urinary retention
  • Precipitation of hepatic encephalopathy
• Adverse effects of thiazide and loop diuretics - either:

  • Hypokalaemia (loss of potassium)
  • Gout (retention of uric acid)
  • Interstitial nephritis
  • Hypomagnesaemia
  • Thrombocytopenia (loss of platelets in the blood)
  • Pancreatitis
• Adverse effects of thiazide and loop diuretics - either:

  • Hypokalaemia (loss of potassium)
  • Gout (retention of uric acid)
  • Interstitial nephritis
  • Hypomagnesaemia
  • Thrombocytopenia (loss of platelets in the blood)
  • Pancreatitis
• Adverse effects of thiazide and loop diuretics - mostly thiazides:

  • Impaired glucose tolerance
  • Increased LDL cholesterol
  • Hypercalcaemia
  • Erectile impotence
• K⁺ sparing diuretics - spironolactone:

  • Pro-drug
  • Steroid structure
  • Inhibits aldosterone
  • Improves survival in chronic heart failure
  • Oestrogenic adverse effects (because structure similar to oestrogen): gynaecomastia, menstrual disturbances, reduced libido, testicular atrophy
  • Other adverse effects include hyperkalaemia (high amounts of potassium in the blood), GI disturbances
• Renin-angiotensin system:

  • Reduced glomerular filtration rate leads to the release of renin, which converts angiotensinogen to angiotensin I. Angiotensin I is converted by ACE to Angiotensin II.
  • ACE inhibitors inhibit this and prevent production of angiotensin II.
  • Angiotensin II stimulates release of aldosterone, which causes salt and water retention and potassium loss. So, if you inhibit the production of aldosterone by inhibiting the production of angiotensin II then you'll get the reverse effect - salt and water loss and potassium retention.
  • Angiotensin II also causes vasoconstriction.

  
• Renin-Angiotensin system:

  AIIRA = Angiotensin II Receptor Antagonists - these drugs inhibit the action of Angiotensin II on blood vessels, so they prevent vasoconstriction as well as the release of aldosterone.

  
• ACE inhibitors - lisinopril mechanisms of action:

  • Inhibit conversion of Ang I to Ang II
  • Inhibit degradation of bradykinin which produces vasodilation by release of vascular NO and prostaglandins - bradykinin is an irritant though and can induce coughing in the lungs
  • Reduces aldosterone secretion
  • Renal vasodilation
  • Commonly used in heart failure - improve survival
• ACE inhibitors - lisinopril adverse effects:

  • Renal failure especially in renal artery stenosis
  • Cough (10-15%) - possibly related to increased tissue bradykinin levels
  • Hyperkalaemia
  • Angioedema - tongue swelling, anaphylaxis - ACE inhibitors are one of the most common drug related causes of angioedema
  • Urticaria, skin rashes
  • Altered taste - captopril
  • Congenital malformations (don't use in pregnancy)
• ACE inhibitors - lisinopril adverse effects:

  • Renal failure especially in renal artery stenosis
  • Cough (10-15%) - possibly related to increased tissue bradykinin levels
  • Hyperkalaemia
  • Angioedema - tongue swelling, anaphylaxis - ACE inhibitors are one of the most common drug related causes of angioedema
  • Urticaria, skin rashes
  • Altered taste - captopril
  • Congenital malformations (don't use in pregnancy)
• Angiotensin receptor blockers (antagonists) - Losartan - mechanism of action:

  • Inhibit action of endogenous Ang II at Angiotensin II subtype 1 receptor
  • Vasodilation, decreased SNS activity
  • Do not produce cough unlike ACE inhibitors
  • AT1 blockers do not block AT2 receptor, which is exposed to high concentration Angiotensin - may have beneficial effects
• The cardiac action potetial - Phase 0:

  • Fast sodium entry (Na⁺ channels)
  • Essentially the same process which causes depolarisation of nerve cells
• The cardiac action potetial - Phase 1:

  • Inactivation of sodium channels
• The cardiac action potetial - Phase 2:

  • Slow calcium influx (L-Ca⁺⁺ channel)
  • Calcium influx is important because calcium is central to excitation-contraction coupling within the myocardium
  • Slow calcium influx is unique to cardiac muscle
• The cardiac action potetial - Phase 3:

  • Efflux of K⁺
  • Repolarisation happens by potassium moving out of the cell
• The cardiac action potetial - Phase 3:

  • Efflux of K⁺
  • Repolarisation happens by potassium moving out of the cell
• The cardiac action potetial - Phase 4:

  • Spontaneous diastolic drift (Na⁺ and Ca⁺⁺ entry)
  • Between contractions
  • Membrane potential may become progressively less negative until it reaches a threshold at which the cell fires off again
  • The spontaneous diastolic drift towards a threshold potential is responsible for the innate pacemaker activity of the heart
• For SA and AV nodes, the action potentials arising from them don't show a phase 0 - they depolarise almost exclusively by the slow entry of calcium, that's why they have slower action potentials. This is important for pharmacology; drugs which affect calcium entry are going to have a profound effect on nodal tissue, and less of an effect of tissue that depolarises by sodium. Conversely, drugs which act on sodium channels are going to affect Purkinje and ventricular tissue more cause they're dependent on sodium for their depolarisation.

  
• Types of arrhythmias:

  • Too fast - tachy-arrhythmias
  • Too slow - brady-arrhythmias
  • Not at all - cardiac arrest
• A normal ECG complex starts with a P wave (caused by atrial activation), then a QRS complex (caused by ventricular depolarisation), and then a T wave (caused by ventricular repolarisation)

  
• Brady-arrhythmias - types:

  • Sinus bradycardia - occurs from slow rate of the sinus node (SA node) - relatively common in fit, young, healthy people
  • Nodal/junctional bradycardia - occur from AV node
  • Heart block - means there's a delay in the impulse being conducted through the AV node/some impulses that reach the AV node are not conducted through the ventricles
  • First degree
  • Second degree
  • Third degree (complete) - none of the impulses that reach the AV node are conducted through the ventricles
• In a complete heart block the atria are firing off, and the ventricles are firing off, but they're unconnected. The atria are firing off at their own rate, which is faster than that of the ventricles (also firing at their own rate). The heart rate underlying here (the rate that the ventricles are contracting) is only around 20 per minute. When the heart beats that slowly, it can't maintain an adequate cardiac output & the pt may develop low blood pressure, dizziness, renal failure and failure of other organs - therefore necessity to speed heart up.

  
• Atropine:

  • Antimuscarinic anticholinergic drug
  • Blocks vagal inhibition of Sinus and AV node
  • Intravenous bolus administration
  • Anticholinergic adverse effects
  • Dry mouth
  • Mydriasis - dilation of pupils
  • Postural hypotension
  • Urinary retention
• Isoproterenol (Isoprenaline):

  • β₁/β₂ adrenoceptor agonist drug
  • Positive chronotropic effect, especially on Sinus node (increases SA node rate)
  • Short half life requiring intravenous infusion
  • Sympathomimetic adverse effects
  • Tachycardia
  • Arrhythmias (cardiac instability)
• So it may be possible in a patient with an extreme bradycardia to reverse that by a bolus dose of atropine, or by a bolus dose of isoproterenol, followed by an infusion, or perhaps a combination of both. If that doesn't work, could possibly increase patient's heart rate using mechanical means, eg temporary/permanent pacemaker.
• Tachyarrhythmias - types:

  • Supraventricular tachycardia (SVT)
  • Ventricular tachycardia (VT)
• Supraventricular tachycardia (SVT):

  • Arise from somewhere above Bundle of His (SA node, AV node or atria)
  • Generally symptomatic but not life-threatening
  • Sinus or nodal tachycardia
  • Accessory pathway re-entrant tachycardias
  • Atrial fibrillation or flutter
• Ventricular tachycardia:

  • Arise in Bundle of His or ventricular tissue itself
  • Symptomatic and may lead to cardiac arrest -  so have a worse prognosis than SVT
  • Monomorphic
  • Polymorphic - torsade de pointes