Inotropic Drugs-Limitations in Heart Failure Flashcards Preview

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Flashcards in Inotropic Drugs-Limitations in Heart Failure Deck (27):
1

Central dogma of intotropic agents

Postive inotropy = increased effective [Ca++]

2

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

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

3

What are the positive inotropic agents?

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

4

Positive effects of digitalis

– 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

5

Digitoxin route of elimination

hepatic degradation with renal excretion of metabolites

6

Digitalis DDIs

• 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

7

Drugs That Alter Digoxin Absorption or Bioavailability

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

8

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

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

9

Issues with positive inotropic agents:

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

10

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

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

11

What is the DIG trial?

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

12

Outcomes of the DIG trial

> 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.

13

T or F: use of digitalis is dose dependent

True, USE A LOW(er) DOSE

14

Digitalis mechanism of action

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

15

Negative effects of digitalis

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

16

Positive effects of digitalis

– 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

17

Half life of Digoxin

1.7 (1.1 to 1.9) days

18

half life of Digitoxin

7 (5 to 10) days

19

Digoxin route of elimination

renal excretion of unchanged drug;
limited hepatic metabolism

20

Digitoxin route of elimination

hepatic degradation with renal excretion of metabolites

21

Digitalis DDIs

• 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

22

Drugs That Alter Digoxin Absorption or Bioavailability

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

23

Dopamine effect on NE

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

24

Issues with positive inotropic agents:

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

25

How do PDE inhibitors work?

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

26

Potential uses of PDEs?

• 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.

27

New Directions in HF Therapeutics:

• 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...