Inotropic Drugs-Limitations in Heart Failure

Question 1

Central dogma of intotropic agents

Answer 1

Postive inotropy = increased effective [Ca++]

Question 2

The two generally accepted major indications for the use of digitalis are:

Answer 2

1) treatment of chronic CHF in the presence of atrial fibrillation
2) treatment of chronic CHF when there is confirmed S3 gallop

Question 3

What are the positive inotropic agents?

Answer 3

• Cardiac glycosides
• Beta adrenergic receptor agonists
• Phosphodiesterase inhibitors
• Calcium sensitizing agents

Question 4

Positive effects of digitalis

Answer 4

– Positive inotropic effect decreases sympathetic tone by resolving the symptoms of CHF
– Increase parasympathetic (vagal) tone
– Increase renal blood flow thereby decreasing circulating blood volume

Question 5

Digitoxin route of elimination

Answer 5

hepatic degradation with renal excretion of metabolites

Question 6

Digitalis DDIs

Answer 6

• ACE-I increase K+ which affects “Dig” binding
• Diuretics can increase or decrease K+
• Ca++ blockers also slow AV nodal conduction
• Beta-blockers also slow AV nodal conduction

Question 7

Drugs That Alter Digoxin Absorption or Bioavailability

Answer 7

-Erythromycin or tetracycline: increased bioavailability due to inactivation of gut flora

Question 8

The two generally accepted major indications for the use of digitalis are:

Answer 8

1) treatment of chronic CHF in the presence of atrial fibrillation
2) treatment of chronic CHF when there is confirmed S3 gallop

Question 9

Issues with positive inotropic agents:

Answer 9

1. Tachyphylaxis (desensitization, tolerance)
2. Substantially increased MVO2
3. Increased risk of sudden death (proarrhythmic) 4. Generally not orally active
4. Very short plasma half-life

Question 10

The two generally accepted major indications for the use of digitalis are:

Answer 10

1) treatment of chronic CHF in the presence of atrial fibrillation
2) treatment of chronic CHF when there is confirmed S3 gallop

Question 11

What is the DIG trial?

Answer 11

The first large, prospective, placebo-controlled clinical
trial with morbidity and mortality endpoints for
digitalis, 1997

Question 12

Outcomes of the DIG trial

Answer 12

> treatment with digitalis had no effect on overall mortality
modest reduction in deaths due to worsening of HF
higher incidence of sudden death (arrhythmias).
One notable outcome was a modest reduction in the number of hospitalizations. Thus, at a minimum, there appears to be a medical- economic rationale for the use of cardiac glycosides.

Question 13

T or F: use of digitalis is dose dependent

Answer 13

True, USE A LOW(er) DOSE

Question 14

Digitalis mechanism of action

Answer 14

Inhibits the sodium-potassium ATPase, increases intracellular Na+, causes the Na/Ca exchanger to reverse potential, increasing intracellular Ca2+ and thus improving inotropy

Question 15

Negative effects of digitalis

Answer 15

– Increase intravascular Ca++ too
– Decrease NE reuptake
– Increase sympathetic tone by activation of CNS descending pathways

Question 16

Positive effects of digitalis

Answer 16

– Positive inotropic effect decreases sympathetic tone by resolving the symptoms of CHF
– Increase parasympathetic (vagal) tone
– Increase renal blood flow thereby decreasing circulating blood volume

Question 17

Half life of Digoxin

Answer 17

1.7 (1.1 to 1.9) days

Question 18

half life of Digitoxin

Answer 18

7 (5 to 10) days

Question 19

Digoxin route of elimination

Answer 19

renal excretion of unchanged drug;

limited hepatic metabolism

Question 20

Digitoxin route of elimination

Answer 20

hepatic degradation with renal excretion of metabolites

Question 21

Digitalis DDIs

Answer 21

• ACE-I increase K+ which affects “Dig” binding
• Diuretics can increase or decrease K+
• Ca++ blockers also slow AV nodal conduction
• Beta-blockers also slow AV nodal conduction

Question 22

Drugs That Alter Digoxin Absorption or Bioavailability

Answer 22

-Erythromycin or tetracycline: increased bioavailability due to inactivation of gut flora

Question 23

Dopamine effect on NE

Answer 23

Dopamine is both a direct and indirect agonist; that is, it can cause the release of synaptic NE as well as blocking its reuptake

Question 24

Issues with positive inotropic agents:

Answer 24

1. Tachyphylaxis (desensitization, tolerance)
2. Substantially increased MVO2
3. Increased risk of sudden death (proarrhythmic) 4. Generally not orally active
4. Very short plasma half-life

Question 25

How do PDE inhibitors work?

Answer 25

prevents the breakdown of cAMP to AMP by phosphodiesterases (how coffee works)

Question 26

Potential uses of PDEs?

Answer 26

• some evidence for the use of Type III PDE-I’s in the presence of beta blockers.
• Recent evidence that PDE V inhibitors (e.g., sildenafil (Viagra)), may be useful in pressure overload HF or with PPH.

Question 27

New Directions in HF Therapeutics:

Answer 27

• Cytokine inhibitors (TNFα)
• Peptide antagonists (ET-1); only in PPH (so far)
• New diuretics (BNP), Natrecor
• Metabolic modifiers, lipid vs glucose
• Cardiac Resyncronization Therapy (electrical, BV pacing)
• Pharmacogenomics, personalized medicine (beta blockers, ACE-I, others TBD), an example of which is…