Inotropic agents-uses and limitations

Question 1

Name the general classes of positive inotropic agents

Answer 1

cardiac glycosides, B-adrenergic receptor agonists, phosphodiesterase inhibitors, Ca sensitizing agents

Question 2

In general, what do positive inotropic agents do?

Answer 2

increase effective Ca conc

Question 3

Examples of Cardiac glycosides

Answer 3

Digitalis (digoxin and digitoxin)

Question 4

What are two accepted indications for use of digitalis?

Answer 4

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

Question 5

Describe the use of digitalis in CHF with normal sinus rhythm.

Answer 5

Class II and II HF limited to systolic dysfunction show reduced probability of worsening HF, maintenance of exercise capacity and better quality of life.

Question 6

Describe the results of the prospective, controlled trial with morbidity and mortality endpoints for digitalis

Answer 6

treatment with digitalis had no effect on overall mortality, modest reduction in deaths due to worsening of heart failure, higher incidence of sudden death (arrhythmias). Reduction in number of hospitalizations

Question 7

Do patients with normal systolic function benefit from digitalis

Answer 7

No

Question 8

Compare the chemical structure of digoxin from digitoxin

Answer 8

Digoxin has a hydroxyl at C12, where digitoxin does not

Question 9

dosing of digitalis

Answer 9

effects are dose dependent and lower doses are much safer/more effective than higher doses

Question 10

MOA of cardiac glycosides

Answer 10

Blocks Na/K pump, causing an increase in intracellular Na which leads to an increase in intracellular Ca b/c the Na/Ca exchanger is activated. Intracellular Ca is then reduced by the SERCA2 in the SR, the Na/Ca exchanger and a Ca pump in plasma membrane

Question 11

Negative effects of digitalis

Answer 11

Increases intravascular Ca (can cause vasoconstriction), increases SNS, decreases NE reuptake

Question 12

Positive effects of digitalis

Answer 12

increased PNS (vagal) tone, increased renal blood flow (thus decreasing blood volume) and positive inotropic effect decreases sympathetic tone by resolving symptoms of CHF

Question 13

Relaxation of cardiac muscle is facilitated by?

Answer 13

Ca pump in SR, Na/Ca exchanger and active Ca pump

Question 14

Effects of digitalis on myocardial conductions

Answer 14

Decreased conduction velocity in AV node and SA node with increased effective refractory period in AV node, enhanced excitability of Purkinje fibers, decreased refractory period and increased automaticity in ventricular muscle.

Question 15

Explain how digitalis toxicity can produce premature ventricular contractions

Answer 15

Digitalis toxicity can lead to excess Ca in SR, thus the normal oscillatory release/uptake of Ca by SR is amplified by the overload. If the Ca oscillation is large enough to depolarize cell past threshold, it can lead to an inward current resulting in after-depolarization resulting in PVCs and other forms of ectopy.

Question 16

EKG effects of digitalis

Answer 16

Increased PR interval, decreased QT interval, inverted T wave, ST segment depression

Question 17

Pharmacokinetics of Digoxin and digitoxin

Answer 17

digoxin: 1.7day half life, renal excretion of unchanged drug (limited use if compromised renal function), limited hepatic metabolism. Digitoxin: 7 day half life, hepatic degradation with renal excretion of metabolites. Both are available orally

Question 18

What is a digitalizing dose?

Answer 18

Steady state is not rapidly achieved for digitalis, so a loading dose is sometimes use

Question 19

Digitalis toxicity

Answer 19

low therapeutic index, thus toxic side effects are common, especially if given with non-K sparing diuretics. Hypokalemia leads to increased intracellular Na and thus intracellular Ca. AV-block, premature ventricular contractions, bradyarrhythmias, ventricular fibrillations, anorexia, nausea, vomiting, etc

Question 20

Treatment of digitalis toxicity

Answer 20

discontinue drug, slow infusion of K (if hypokalemia) will displace digitalis from bidning sites. If life threatening, digitalis specific antibody fragments

Question 21

Digitalis drug interaction

Answer 21

ACEI increase K which prevents digitalis from binding. Diuretics can increase or decrease K. Ca blockers and beta blockers also slow AV nodal conduction. Erythromycin/tetracyclin decreases bioavailability. Amiodarone, quinidine decrease renal elimination

Question 22

stimulation of B1 adrenergic receptors results in what? B2? A1?

Answer 22

B1= positive intotropy. B2= positive inotropy + vasodilator/ bronchodilator. A1= vasoconstriction

Question 23

Name classes of positive inotropic agents other than cardiac glycosides

Answer 23

B adrenergic agonist (+/- alpha adrenergic activity) and phosphodiesterase inhibitors

Question 24

Name Beta agonists and their functions

Answer 24

Norepinephrine has strong A1 and B1, with minimal B2 actions. Epinephrine has strong A1, B1 and B2 adrenergic actions. Dopamine has strong A1, slight B1 and minimal B2, with strong dopaminergic activity. Isoproterenol has NO A1, strong B1 and strong B2. Dobutamine has strong B1 and slight B2 activity.

Question 25

What are dopaminergic actions relevant to HF

Answer 25

enhanced renal circulation producing diuresis

Question 26

How is dopamine a direct and indirect agonist

Answer 26

it can cause release of synaptic NE as well as blocking its reuptake

Question 27

compare low dose to high dose dopamine

Answer 27

low dose: vasodilatory. High dose: vasoconstrictor due to release of NE

Question 28

Problems with positive inotropic agents

Answer 28

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

Question 29

Phosphodiesterase inhibitors MOA

Answer 29

Prevents breakdown of cAMP to AMP by phosphodiesterases and increases affinity of troponin-C for Ca, increases reuptake of Ca by SR and competitively inhibits adenosine receptors.

Question 30

Evidence for use of PDEs

Answer 30

Type III PDEI in presence of beta blockers may be helpful and PDE V inhibitors may be useful in pressure overload HF. Overall, increase in mortality secondary to sudden death.