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Cardio Week 2 > Lecture 23: Pharmacology Myocardial Inotropic Agents > Flashcards

Lecture 23: Pharmacology Myocardial Inotropic Agents Flashcards

1
Q

What are the key characteristics of contractility?

A

Intrinsic property of cardiac muscle that determines the strength of contraction
Independent of external loading, valvular loading and function, or filling pressure
NOT equal to CO or cardiac performance

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2
Q

What is stroke volume?

A

Blood volume ejected per beat

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3
Q

What are the determinants of cardiac output?

A
  1. preload, contractility and afterload affect STROKE VOLUME
  2. Synergistic LV contraction, LV wall integrity, valvular competence
  3. Heart rate
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4
Q

Where does calcium bind?

A

Binds to Troponin C (TnC) and changes conformation of TnI, TnT and myosin

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5
Q

What is SERCA?

A

SR Ca ATPase, one of two mechanisms to remove calcium from cell

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6
Q

What is the role of the sodium calcium exchanger?

A

The second method to remove calcium from the cell (3 Na in for 1 Ca out)

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7
Q

What is the Ltype calcium channel?

A

Allows calcium to flow inward and activates the ryanodine receptor (stimulated by AP)

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8
Q

What is the role of the Ryanodine receptor?

A

Once it binds to Ca from L-type calcium channel, it releases calcium from the SR

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9
Q

What are couplons?

A

L-type calcium channels + Ryanodine receptors as a functional unit

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10
Q

What is the role of phospholamban?

A

Inhibits SERCA when dephosphorylated

Will activate SERCA when phosphorylated (detaches)

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11
Q

What are the sites of action of inotropes?

A
  1. Beta receptor agonist = increases cAMP
  2. PDE inhibitors = blocks the breakdown of AMP which leads to more cAMP
  3. Ca sensitizers = muscle is more sensitized to Ca
  4. Digitalis = blocks Na/K ATPase
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12
Q

What characteristic do all FDA approved inotropes share?

A

Increasing intracellular calcium (and cAMP)

It is the mechanism by which calcium is released by SR that varies among different inotropes

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13
Q

What do inotropes do to the Frank-Starling Curve? Diuretics? Vasodilators?

A

Shifts it up but change volume
To the left without increasing contractility
Vasodilator shifts curve up and to the left (decrease volume and increase contractility)

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14
Q

What is digitalis?

A

A type of cardiac glycosides

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15
Q

What are key characteristics of digitalis?

A

Extract of the foxglove plant and the first drug used to treat chronic heart failure
MoA: Binds Na/K ATPase
High levels of extracellular potassium competitively decreases digoxin binding, and therefore may be protective in digoxin toxicity

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16
Q

What are the CV effects of digoxin?

A
  1. causes an upward and leftward shift of the Starling curve
  2. no desensitization or tolerance = advantage which is NOT true of other drugs
  3. Increases intracellular calcium causing increased inotropy WITHOUT increased heart rate
  4. can induce morality in HIGH doses
    INCREASED cardiac output
    INCREASED LV ejection fraction
    decreased LVEDP
    INCREASED exercise tolerance
    INCREASED natriuresis
    decreased Neurohormonal activation
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17
Q

What is the MoA of digoxin?

A

Inhibits Na/K atpase
More Na intracellulary means that the Na-Ca exchange will compensate and push more Na out of the cell
This therefore takes more Ca into the cell and increases contractility

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18
Q

What types of patients are contraindicated for digoxin?

A

Patients with RENAL failure

This is because digoxin is eliminated through the kidney

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19
Q

What are the neurohormonal effects of digoxin?

A
  1. Decreases plasma NE
  2. Decreases peripheral nervous system activity (because it binds to Na/K pump)
  3. Decreases RAAS activity
  4. Increases Vagal tone
    Normalizes arterial barorecptors
    So you want to give digitalis as an early treatment to heart failure patients because it decreases both NE and RAAS, which are the two factors in contributing to downward spiral
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20
Q

Are the effects of digoxin the same for atrial and ventricular myocytes?

A

No they are different

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21
Q

What are the atrial and AV nodal effects of digoxin?

A

Increase in vagal tone and decrease in sympathetic activity
BRADYCARDIA, so it does slow heart rate
Increases risk of heart block because of increased refractory period of AV node
i. depolarization of resting potential (which allows inactivation gates of sodium to stay on, so sodium channels are inactivated)
ii. Delayed After-Depolarization’s (DAD’s)

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22
Q

What are delayed after-depolarizations (DAD’s)?

A

Too much [Ca]i = SR takes up too much Ca = SR malfunctions and releases boluses of Ca randomly
Boluses of Ca released by SR will spontaneously fluctuate intracellular Ca level
Fluctuation = transient contraction and change in membrane potential
Change in membrane potential/contraction = ectopic beats, bigeminy, tachycardia

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23
Q

What is bigeminy?

A

The state of having a pulse characterized by two beats close together with pause following each pair of beats

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24
Q

What are the ventricular effects of digoxin?

A

At therapeutic doses, digoxin increases inotropy
At toxic doses, dig can increase sympathetic tone, automaticity and delayed after depolarizations
-most ppl who die from dig are due to arrhythmia

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25
Q

What are the cardiac toxicities associated with digoxin?

A
  1. 1st, 2nd and 3rd degree AV conduction block (caused by increased vagal tone or decreased AV node conduction)
  2. Ventricular arrhythmias (extrasystoles, bigeminy, ventricular tachycardia…caused by delayed after depolarizations, DAD’s)
  3. ECG changes (increased PR, ST depression, inverted T wave, decreased QT and P wave changes)
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26
Q

Are there mortality benefits between giving a placebo and giving digoxin (digitalis)?

A

No mortality benefits, but may be caused by lack of dosing with respect to cardiac index
According to NEJM 1997 study
Women had higher mortality but that was because BSA was not taken into account

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27
Q

What are the current clinical uses of digoxin?

A
  1. atrial fibrillation with rapid ventricular response
  2. CHF symptoms DESPITE medical therapy
    • balance risk benefit
  3. can be combined with other drugs
    • caution with concomitant beta blocker just given risk of bradycardia and heart block
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28
Q

How does hypokalemia interact with digoxin?

A

Hypokalemia INCREASES digoxin affinity, so lower digoxin levels will have greater effects
That’s why you need to make sure digoxin patients are not hypokalemia

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29
Q

What must you do when prescribing digoxin?

A

KEEP LEVELS LOW, even if “subtherapeutic”

Use only in those with symptomatic heart failure (NYHA from II-IV)

30
Q

What are the factors that predispose towards digoxin toxicity?

A
  1. hypokalemia (because potassium counteracts digoxin effect on Na/K, so you need potassium to guard against dig toxicity)
  2. hypomagnesemia
  3. hypothyroidism
  4. hypoxia and acidosis
  5. A SHITLOAD OF DRUG INTERACTIONS
31
Q

What are risk factors for digoxin toxicity outside of physiologic content?

A

Absolute contraindications = digoxin toxicity
Relative:
i. advanced AV block without a pacemaker
ii. bradycardia or sick sinus syndrome
iii. ventricular tachycardia/arrhythmia
iv. marked hypokalemia
v. Wolf-Parkinson-White with atrial fibrillation (increases conduction through bypass tract)

32
Q

What are the CARDIAC toxicities associated with digoxin?

A
  1. Arrhythmias
  2. Blocks (SA and aV block)
  3. Heart failure exacerbation due to heart block/bradycardia
    • so that’s why you need to be careful about managing treatment
33
Q

What are the EXTRAcardiac digoxin toxicity?

A
  1. GI (nausea, vomiting, diarrhea)
  2. Nervous (Depression, disorientation, paresthesis)
  3. Visual (blurred vision, scotomas, yellow-green vision)
  4. Hyperestrogenism (gyneocmastia, galactorrhea, even at therapeutic doses)
34
Q

What is the treatment for digoxin toxicity?

A

Specific antibody that binds digoxin toxicity

Avoidance of hypo or hyperkalemia (need normal potassium levels in order to decrease digoxin binding to receptor)

35
Q

What are the actions of catecholamines?

A
  1. Peripheral excitatory action on smooth muscle in skin and mucous membrane
  2. Peripheral inhibitory action in gut, bronchial and blood vessels in skeletal muscle
36
Q

What happens when beta1 receptor is bound by NE?

A

Activates Gstimulatory protein
Increase cAMP levels
Increases PKA which leads to calcium sensitivity and phosphorylation of phospholamban (to take up more Ca in SR and allow for more release)

37
Q

What is the function of beta 1?

A 
Increases contractility
Increases heart rate
Increases conduction
Located in the 
	i. myocardium
	ii. SA node
	iii. AV node
38
Q

What is the function of Beta2?

A
  1. vasodilation
  2. bronchodilation
    Located in arterioles and lungs
39
Q

What is the function of alpha receptors?

A

Vasoconstriction

Located in the peripheral arteries

40
Q

What are the 3 major catecholamines/

A
  1. NE
  2. Epinephrine
  3. Dopamine
41
Q

Which adrenergic agents are always used?

A
  1. Dobutamine
  2. Dopamine
  3. Phenylephrine (Pressor)
42
Q

What adrenergic agents are occasionally used?

A
  1. Epinephrine

2. Norepinephrine

43
Q

What adrenergic agents are RARELY used?

A

Isopreterenol, only for cardiac transplant patients

44
Q

What are the key characteristics of Dopamine?

A

i. DA1 receptor (post-synaptic) = vasodilation of renal, mesenteric, coronary and cerebral
ii. DA2 receptor (pre-synaptic) = inhibits re-uptake of NE (indirect beta stimulation)…low doses
iii. B1 and alpha receptors stimulated directly at HIGH doses = vasoconstriction, a lot like norepinephrine

45
Q

What are the side effects of dopamine?

A
  1. tachycardia (as dose increases)
  2. HTN
  3. Nausea/vomiting
  4. Infiltration of IV site can lead to necrosis of skin or gangrene of fingers/toes
    i. alpha stimulation = extreme vasoconstriction
    Give drug centrally to avoid IV infiltration
46
Q

What is the purpose of phentolamine?

A

Alpha blocker

Antidote for IV dopamine administration (because IV dopamine leads to picture below)

47
Q

What are the key characteristics of dobutamine?

A

MoA = B1 receptor agonist
Increase inotropy
Decrease afterload by vasodilation

48
Q

What is danger of continuous infusions of dobutamine?

A

Can lead to desensitization

Short-acting of 2 minutes

49
Q

What are side effects of dobutamine?

A
  1. arrhythmia
  2. ischemia/angina
  3. hypotension
  4. tachycardia
  5. rapid ventricular response in atrial fibrillation due to increase in AV conduction
  6. Nausea, headache, palpitations
50
Q

What are the diagnostic uses of dobutamine?

A

Takes advantage of ischemic potential of dobutamine

Used for stress test in place of exercise test (for patients who cant run on treadmill)

51
Q

What are the key characteristics of epinephrine as cardiac therapy?

A

Less selective, stimulates both alpha and beta 1 and 2 receptors
Can cause Tachyphylaxis, platelet aggreagation, infarction
Used as an emergency resuscitation drug rather than as a treatment drug

52
Q

What is tachyphylaxis?

A

Describes acute decrease in response to a drug after its administration

53
Q

What are the key characteristics of norepinephrine?

A

MoA: Alpha and Beta1 Receptor agonist with little Beta2 receptor ativity
Powerful vasoconstrictor, modest inotrope
Slows heart rate

54
Q

What are the key characteristics of Isoproterenol?

A

MoA: Beta1 and Beta 2 agonist
Increases heart rate
Decreases pulmonary vascular resistance
Used exclusively after heart transplant to drive heart rate

55
Q

What are the phosphodiesterase inhibitors used for cardiac therapy?

A

Phosphodiesterase Type III inhibitors
Can increase contractility through increase in intracellular calcium, without an increase in heart rate especially at low dose
Act independently of beta receptors
Potent vasodilators for peripheral arterial system, venous capacitance vessels and pulmonary vascular beds
In arterioles, cAMP is used to inhibit contraction…therefore increase cAMP leads to vasodilation

56
Q

What is the MoA of Phosphodiesterase?

A

Break down of cyclic AMP and less SR Ca is released

57
Q

How do phosphodiesterase inhibitors benefit patients with decompensated heart failure?

A
  1. Inhibits platelet aggregation
  2. Inhibits pro-inflammatory cytokine formation
  3. Improved systolic and diastolic function
  4. improved exercise tolerance
  5. Excellent venodilator and pulmonary vasodilator
58
Q

What are the hemodynamic effects of PDE inhibition?

A
  1. increased cardiac index
  2. decreased SVR/MAP (because of vasodilation)
  3. decreased PAWP/LVEDP
  4. minimal change in heart rate
  5. increased ventricular dP/dT = rate of ventricular contraction
59
Q

What are the available PDE inhibitor?

A

Amrinone

Milrinone

60
Q

What is Amrinone?

A

A PDE inhibitor
Can cause thrombocytopenia
First one that came out but is not used anymore

61
Q

What is Milrinone?

A

Re-engineered amirinone molecule (w/o issue of thrombocytopenia)
Long half life of 2.3 hours (so bad if you want to get rid of it fast)
80% eliminated by the kidney so contraindicated in kidney
Avoid acute hypotension by not giving bolus (since there is long half-life)

62
Q

What are oral PDE inhibitors?

A
  1. oral milrinone
  2. Oral Enoximone
  3. Oral Vesnarinone
    All of which increases mortality
63
Q

What are the key characteristics of Vesnarinone?

A

Improved quality of life
INCREASED MORTALITY
Increased risk of torsade de pointes
A PDE inhibitor and a type III anti-arrhythmic

64
Q

What are the key characteristics of Enoximone?

A

Low doses of PDE III inhibitor does not help people
Doesn’t work
Shows that mortality effect of PDE inhibitor is dose dependent (smaller dose = less mortality)
Safe but does not help heart failure patients

65
Q

What are the pros of beta-adrenergic inotropic therapy in heart failure?

A
  1. Increased contractility
66
Q

What are the cons of beta-adrenergic inotropic therapy in heart failure?

A
  1. Desensitization and tachyphylaxis (bad for transplant patients)
  2. tachycardia
  3. pro-arrhythmia potential
  4. worsens diastolic function
  5. weak vasodilator properties
    Excess mortality
67
Q

What are the pros for PDEI inotropic therapy in heart failure?

A
  1. No tachyphylaxis
  2. increased contractility
  3. Improved diastolic function
  4. Veno/vasodilator
  5. Effective in setting of beta-blocker therapy
68
Q

What are the cons of PDEI inotropic therapy in heart failure?

A
  1. Hypotension (due to vasodilator effects in arteriole, venules and pulmonary capillary beds
  2. thrombocytopenia (with Amrinon but rare with Milrinone)
  3. Pro-arrhythmia potential, tachycardia
    Excess mortality
69
Q

What are considerations we need to make when giving beta AGONISTS and PDEI inotropes (and to a certain extent digoxin)?

A

Increased mortality rates for beta blockers/PDE III inhibitors
Quality of life improvement more important than longevity?
Is a good death an acceptable endpoint for a patient with heart failure?

70
Q

When are IV inotropic therapy indicated?

A

Acute therapy
1. decompensated patient with volume overload and impaired perfusion
2. Volume overload with diuretic resistance
Chronic therapy
1. transplant listed recipients (used as a bridge)
2. Refractory heart failure symptoms after maximal medical therapy (palliation)

71
Q

Can Milrinone be given safely?

A

Yes if given at small doses for heart transplant

Also use of ICD (implantable cardioverter defibrillator)

Cardio Week 2 (11 decks)

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