Inotropic Drugs

Question 1

Positive inotropes

Answer 1

Increase the force of contraction of the heart, whereas negative inotropes weaken it. Goal is to increase the ejection fraction in patients with reduced EF due to systolic dysfunction.

_Positive inotrope drug classes_
Cardiac glycosides (digoxin)
Beta-adrenergic agonists (dopamine; dobutamine)
Phosphodiesterase Type 3 inhibitors (amrinone; milrinone)

Question 2

Cardiac glycosides (Digoxin) Mechanism of Action

Answer 2

1. Positive inotropic action:
   Bind to extracellular surface of a subunit of myocardial Na/K/ATPase and inactivate this enzyme. Overall, this increases myocardial contractility and decreases ventricular pressures.
2. Parasympathetic (Vagal mediated effects):
   Therapeutic doses, heart rate will decrease. Utilized in reducing ventricular rate in patients with atrial fibrillation or atrial flutter

Question 3

What does the inhibition of the Na/K/ATPase result in?

Answer 3

1. A rise in the concentration of intracellular sodium
2. Rise in concentration of intracellular calcium because of the consequential inhibition of the Na/Ca pump that normally pumps Ca out of the cell, disabling it makes more calcium stay inside the cell

Question 4

What are the main clinical uses for Digoxin?

Answer 4

Atrial fibrillation and flutter

• Great for reducing ventricuar rate when it is being driven by a high atrial rate
• A_ctivates vagal efferent nerves_ to the heart that reduce conduction of electrical impulses within the AV node, fewer impulses reach the ventricles and ventricular rate drops
• Also, increases the effective refractory period within the AV node

Question 5

Adverse side effects from digoxin?

Answer 5

Irregular heart beat (multiple PVCs, T wave changes), bradycardia, hazy or yellow-green vision, non-specific abdominal pain and bloating, anorexia and nausea, confusion or hallucination

Other factors that can affect cardiac glycosides:
Hypokalemia -> results in a decreased amount of digoxin to achieve toxic arrhythmias
Hyperkalemia -> antagonizes the effects thus increased doses are needed
Magnesium -> hypomagnesemia is unknown, but may enhance digoxin binding to the myocardium
Calcium -> hypercalcemia has synergistic effects, so IV calcium usually avoided
Metabolic alkalosis -> may cause hypokalemia, thus increasing the effects of digoxin
Renal dysfunction -> since it is renally cleared, may lead to accumulation

Question 6

Digoxin contraindications?

Answer 6

Cardiac glycoside toxicity
Idiopathic hypertrophic subaortic stenosis (IHSS)
Myocardial infarction
AV block

Antidote for digoxin toxicity: Digoxin Immune Fab (Digifab)

• consists of antigen binding fragments derived from anti-digoxin antibodies
• improves symptoms usually less than 30 minutes

Question 7

Beta-adrenergic agonists indications

Answer 7

Dobutamine, Dopamine

• IV inotropes may be necessary for short-term therapy
• Short-term administration produces sustained improvement of cardiac function in patients with congestive heart failure; however, increased mortality when dobutamine is infused over 72 hours due to down regulation of B1 receptors
• Investigational agents are B1 agonists (xamoterol, prenalterol) and B2 agonists (pirbuterol, terbutaline) and dopamine analog ibopamine

Uses: currently used in acute situations to stabilize patients with acute exacerbations of CHF (cardiogenic shock) or as bridge to sustain patients who may be candidates for other types of therapy (cardiac transplant for ex.)

Question 8

B-adrenergic agonists mechanism of action

Answer 8

Act directly on B1 or a2 receptors to produce positive inotropic effect

Stimulates adenyl cyclase -> increased cAMP -> stimulates calcium influx via slow Ca channels -> activation of protein kinases result in phosphorylation of Ca channel.

Question 9

MOA of B-agonists in CHF

Answer 9

Remember: prolonged stimulation can lead to receptor down regulation due to internalization of the receptor

Question 10

Drug selection of pressor agents

Answer 10

Epinephrine/Norepinephrine: Usually selected for pressor effects due to vasoconstriction

Dopamine/Dobutamine*: Primarily B receptor agonists used for their inotropic effects
*Dobutamine has more inotropic effects than chronotropic (B1 only)

Question 11

Dopamine uses and side effects

Answer 11

Dopaminergic, B1 and a1 effects and acts as a precursor to norepinephrine

Uses: shock, oliguria, cardiogenic or septic shock, hypotension

Side effects: nausea, vomiting, tachycardia, arrhythmias, headache, hypertension, vasoconstriction. Avoid in patients receiving MAO inhibitors or use 1/10 of the dose

Question 12

Dobutamine uses and side effects

Answer 12

Synthetic anaolog of dopamine, predominant B1 stimulating agent. Exerts potent inotropic effect wthout affecting heart rate and blood pressure

Uses: cardiogenic shock, refractory CHF

Side effects: Facilitate AV conduction, A-fib patients may have increased ventricular response, tachycardia, increased blood pressure, local reactions, nausea, headache and angina

Question 13

Mechanisms of action of dopamine and dobutamine

Answer 13

Question 14

Comparing dopamine and dobutamine

Answer 14

Question 15

Phosphodiesterase inhibitors MOA

Answer 15

Inhibit phosphodiesterase (PDE), specifically the 3 subtype isozyme
Amrinone and Milrinone

PDE₃ is responsible for the degradation of cAMP, so inhibiting this enzyme results in more cAMP -> resulting in a positive inotropic effect

• Can be additive to digoxin because different mechanism
• Originally to replace cardiac glycosides, they are NOT effective in decreasing morbidity and mortality associated with HF

Question 16

Milrinone uses and side effects

Answer 16

Is the preferred phosphodiesterase inhibitor due to greater potency, and lower incidence of side effects relative to inamrinone.

Uses: May be effective in patients who do not respond to dobutamine, in patients with depressed myocardial function, used for short term treatment of CHF

Adverse side effects: ventricular arrhythmias (12.1%), supraventricular arrhythmias (3.8%), headaches, hypokalemia, tremor, bronchospasm

Question 17

Amrinone (Inocor) uses and side effects

Answer 17

Used to shorten atrial effective and AV nodal functional refractory periods, enhancing AC conduction by 10%. Decreases afterload by relaxing effect of smooth muscle. PCWP and SVR, MAP and DBP are reduced. Heart rate unchanged.

Side effects: precaution in A-fib patients (digitalis recommended prior to treatment), thrombocytopenia, nausea, vomiting, abdominal pain, liver dysfunction, arrhythmias, hypersensitivity (sulfite sensitivity)