L65: Positive Inotropic Drugs

Question 1

Cause of heart failure

Answer 1

Pump failure

1. ↓ HR
2. ↓ force

Volume failure
3. ↓ Blood volume

Question 2

Drugs used in heart failure

Answer 2

Acute use:
1. Positive inotropic drugs
- β agonist: Dopamine, Dobutamine
- PDE-III inhibitor: Amrinone
- cardiac glycoside: Digoxin
- calcium sensitiser: Levosimendan 
—> ↑ CO but also ↑ cardiac workload, enhance heart remodelling

Long term management:
1. ACE inhibitor
2. Diuretics
3. Vasodilator
4. β blocker
—> ↓ CO but preserve cardiac function for longer

Question 3

β agonist: Dopamine, Dobutamine (Inodilator)

Answer 3

Activate β1 in heart —> ↑ cAMP —> PKA —> ↑ intracellular Ca

1. Dobutamine: (Inodilator)
   Both: non-selective agonist of β receptor
   (-) enantiomer: agonist of α receptor
   (+) enantiomer: partial agonist for α receptor

Heart (β1): positive inotropic effect
Vasculature (β2): activation of β2 receptor and (+) offset (-) α1 effect —> vasodilation
Overall: Inodilation

2. Dopamine: (Inodilator)
   - concentration-dependent effect
   - Low dose:
   —> Vasodilation (D1 receptor activation)
   —> ↓ Vasoconstriction (D2 receptor activation —> inhibit NE release —> ↓ α1 effect)

• Intermediate dose:
  —> Positive inotropy (β1 activation)
• High dose: (bad)
  —> Arterial and venous constriction (α1 activation) —> ↑ afterload —> further ↓ CO

Advantages:

• Fast onset
• Short duration

Limitations:

• Tolerance development, tachyphylaxis (↓ beyond 4 days)
• Effects blunted by use of β blocker
• **- Pro-arrhythmic (DAD)
• Pro-angina

Question 4

Phosphodiesterase-III inhibitor: Amrinone, Milrinone (Inodilator)

Answer 4

Heart effect:
Inhibit PDE-III —> ↓ breakdown of cAMP —> ↑ PKA —> ↑ intracellular Ca —> Positive inotropy

Vascular effect:
↓ breakdown of cAMP —> inhibit Myosin Light Chain Kinase (MLCK) —> Vasodilation

Advantage:
- Inodilator

SE:

• **- Pro-arrhythmic
• Hypotension
• GI disturbance

Question 5

Cardiac glycosides: Digoxin

Answer 5

Two effects:
1. Inhibit Na/K-ATPase —> ↑ intracellular Na —> shift Na/Ca exchanger expel Na + move Ca in (normally Na in Ca out)—> ↑ Ca storage —> ↑ Ca release during contraction —> ↑ intracellular Ca

2. Parasympathetic activation —> anti-arrhythmic (anti-arrhythmic drug)

Advantage:
- Anti-arrhythmic

Adverse effects:

• **- Pro-arrhythmic
• GI disturbance
• CNS disturbance
• narrow therapeutic index

Use: NOT 1st line, opposed by ↑ K (activate Na/K-ATPase), opposed by ↑ Mg

Question 6

Calcium sensitizer: Levosimendan (IV)

Answer 6

Two effects:
1. Stabilise binding between Troponin C and Ca —> ↑ affinity of Troponin C to Ca —> ↑ Contractility without ↑ intracellular Ca

2. Stimulate K channel —> ↑ Repolarisation / Hyperpolaristaion —> ↓ Ca pumping in —> vasodilation —> coronary and systemic vasodilator

Advantage:
- Coronary and systemic vasodilator

Adverse effects:

• Hypotension
• Headache

Question 7

***Comparison of positive inotropic drugs

Answer 7

β agonist: Dopamine, Dobutamine:
- Inodilator, IV, ***Pro-arrhythmic

Phosphodiesterase-III inhibitor: Amrinone, Milrinone
- Inodilator (Peripheral), IV, ***Pro-arrhythmic

Cardiac glycosides: Digoxin
- Anti-arrhythmic, Oral, ***Pro-arrhythmic

Calcium sensitizer: Levosimendan
- Coronary and systemic vasodilator, IV, Hypotension

Question 8

Management of chronic heart failure

Answer 8

Asymptomatic (stage A, B):

• Reduce risk factor
• ACE inhibitor
• β blocker

Previous/current symptoms (stage C) or Refractory (stage D):

• Restrict salt intake
• ACE inhibitor
• β blocker
• • Diuretics
• • Cardiac glycoside (if arrhythmia present, not good choice usually since ↑ cardiac workload, long term ventricular remodelling)

Question 9

Compensatory mechanism to restore CO in heart failure

Answer 9

1. ↑ Sympathetic activity —> ↑ HR, ↑ Force, ↑ TPR (which may ↓ CO) —> ↑ cardiac workload —> Hypertrophy
2. ↑ RAAS system —> ↑ salt, water retention —> ↑ blood volume —> ↑ cardiac workload —> Hypertrophy + Oedema (water retention)