Pharmacology Of Positive Inotropic Agents

Question 1

What are some potential causes of heart failure? (7)

Answer 1

1. MI
2. Chronic, untreated HTN
3. Chronic dysrhythmia
4. CAD
5. Valvular disease
6. Viral cardiomyopathy
7. Aortic stenosis

Question 2

Heart failure is characterized by what?

Answer 2

A reduction in SV (and CO) at any given EDV.

Question 3

The Frank-Starling Relationship in Cardiac Dynamics represents what?

Answer 3

Ventricular contraction (tension = SV) varies directly with muscle fiber length (EDV, preload).

Question 4

Positive inotropic influences ________ the contractile force at any given EDV.

Answer 4

Increase

Question 5

Negative inotropic influences ________ the contractile force at any given EDV.

Answer 5

Decrease

Question 6

Low cardiac output from CHF results from ________ ________ ________.

Answer 6

Decreased contractile capacity.

Question 7

What are the 3 major clinical symptoms of CHF?

Answer 7

1. Ventricular hypertrophy (cardiomegaly)
2. Edema (pulmonary and/or peripheral)
3. Weak, rapid pulse (baroreflex activation)

Question 8

The goal of CHF treatment is to ________ ________.

Answer 8

Reverse symptoms

Question 9

Clinical treatment of CHF (4)

Answer 9

Includes both pharmacological and non-pharmacological modes of treatment:

1. Diet and Na+ restriction
2. Exercise
3. Diuretics, ACE-I, and vasodilators
4. Positive inotropic agents

Question 10

One clinical treatment of CHF, ________, is derived from ________ ________ _________.

Answer 10

Digitalis; foxglove plant extract

Question 11

Cardiac glycosides (General and MOA)

Answer 11

General: Used in CHF, atrial fibrillation, and others.

MOA: Inhibits Na+/K+-ATPase. Increases intracellular Na+, which forces an increase in Na+/Ca2+ exchange, thereby providing more Ca2+ for muscle fiber contraction and increasing cardiac output.
Increased contraction promotes decreased EDV and ESV, which decreases pulmonary and systemic venous pressure, produces reflex decreased SNA and positive vagal effect (preload, afterload, and HR decrease), increases coronary flow (decreases hypertrophy), and decreases renal artery resistance.
Increases vagal tone. Increases PR interval. Decreases action potential duration. Depresses ST segment.

Question 12

Cardiac glycosides (Considerations)

Answer 12

Monitor electrolytes: changes in plasma K+ and Ca2+ may lead to dysrhythmia.
Cardiac glycosides augment prodysrhythmic effects.

Question 13

Cardiac glycosides (PK and ADRs)

Answer 13

PK: Discussed in antidysrhythmic agents. Several PO venues. Lanoxicaps formulation allows for 100% bioavailability.

ADRs:

1. Low margin of safety
2. Poor compliance
3. Enhanced morbidity/mortality when combined with diuretics that deplete K+
4. Dysrhythmia
5. Visual and neurological disturbances
6. CTZ stimulation induces anorexia, nausea, vomiting

Question 14

Correction for adverse elevations in plasma digoxin (2)

Answer 14

1. Cholestyramine
2. Digoxin immune Fab (des-IgG) [Digibind]: antibodies bind to both bound and free cardiac glycoside where it is sequestered in EC fluid and renally eliminated; administered IV with immediate onset of action; toxicity reversal within minutes; clinical effects also reversed.

Question 15

Isoproterenol (General, MOA, and considerations)

Answer 15

General: Increases both contractility and heart rate.

MOA: Beta-1 receptor-mediated increases in intracellular cAMP promotes elevation in Ca2+ for membrane excitation and contraction.

Considerations: Acute use only.

Question 16

Dopamine (General, MOA, and PK)

Answer 16

General: A parenteral adrenergic agonist acting at various peripheral receptors (dose-dependent).

MOA: Low dose - stimulates DA1 and DA2 on peripheral vasculature, resulting in vasodilation. Moderate dose - additional stimulation of beta-1 receptors, resulting in increased contraction and slight increased HR. High dose - additional stimulation of alpha-1 receptors produces peripheral vasoconstriction.

PK: Rapid action onset, metabolism by MAO/COMT.

Question 17

Dobutamine (Dobutrex) [General, Considerations, MOA, and PK]

Answer 17

General: Structurally similar to dopamine.

MOA: Less alpha-1 effects and less beta-1 tachycardia. Preferential increase in cardiac contractility.

Considerations: Indicated for short-term management of heart failure following MI or during glycoside titration.

PK: Continuous, short-term IV infusion. Half-life = 2 minutes. Hepatic metabolism (COMT) with renal elimination of metabolites.

Question 18

Phosphodiesterase inhibitors (Inamrinone and milrinone) [MOA and PK]

Answer 18

MOA: Inhibits the enzyme responsible for cAMP metabolism. Results in elevated intracellular cAMP and an ensuing increase in intracellular Ca2+ (compare beta-1 agonists). Improves myocardial contractility. Also a beneficial direct vasodilator.

PK: IV. Rapid onset of action (2-5 minutes). Acute use only.

Question 19

CHF Pharmacotherapy Adjuncts (3)

Answer 19

1. Vasodilators: ACE-I (also improve cardiomegaly), alpha-1 antagonists, nitrates, and other direct-acting smooth muscle relaxants.
2. Diuretics: Reduce blood volume (decreased preload and increased edema mobilization).
3. CCBs: Not widely used in CHF due to cardiodepressant action. Afterload-reducing effects may be beneficial, but produces reflex tachycardia (compare verapamil and nifedipine).