L 29-30 Flashcards
Causes of low output CHF
CAD HT MI Persistent Arrhythmias Rheumatic HD General Cardiomyopathy
CHF and RAAS
Poor CO => poor renal perfusion=> production of Renin and activation of RAAS to increase blood volume
CHF and SNS
Poor CO=> decreased systolic BP=> neurohumoral response=> increase in HR
CHF and preload
In CHF preload on the heart is increased due to increased blood volume from the RAAS system and increased SNS tone.
CHF and afterload
In CHF afterload rises from RAAS and increased SNS tone
CHF and contractility
Contractility is decreased as ventricles dilate and stretch farther than normal.
Contractility increased by positive inotropic agents and worsened by Beta blockers.
Equation for CO
CO= HR x SV
CHF and HR
Heart Rate is generally increased because reduced CO=> baroreflex=> increased SNS tone causing increased HR.
Factors controlling contractility
Sensitivity of contractility proteins to Ca
Amount of Ca released from SR
Amount of Ca stored in SR
Amount of trigger Ca
Activity of Na-Ca exchanger
Intracellular Na concentration and activity of Na-K ATPase
Explain cardiac myocyte electrolyte transport and activity at the cell membrane
Na/K ATPase maintains a high Na concentration outside the cell. This gradient is used to exchange Na into the cell for Ca out of the cell.
Ca is allowed into the cell and to act as trigger Ca by L-type voltage-gated Ca channels.
Site of action for cardiac glycosides
NA/K–ATPase in the cardiac myocyte
Describe Ca channels in the SR of the heart
SERCA: A Ca ATPase that transports Ca into the SR
RyR: (ryanodine receptor) Ca gated Ca channel that releases Ca from the SR
Main goals of drug treatment in CHF and drug classes used for each
1) Reduce preload with diuretics and venodilators
2) Reduce afterload with arteriodilators
3) Improve contractility with positive inotropic drugs
4) Decrease HR and energy expenditure of the heart with Beta blockers
What are cardiac glycosides?
Positive inotropic agents commonly called Digitalis.
Only version of this drug in the US is Digoxin.
These act on the Na/K–ATPase in the cell membrane of cardiac myocyte
Mechanism of action for cardiac glycosides
Digitalis (Digoxin) is a positive inotropic agent that increases contractility by increasing rate of contraction and relaxation.
Digitalis binds to the K+ site of the NA/K–ATPase and prevents function
=> increased intracellular Na
=> decreased Ca expulsion
=> increased intracellular Ca
=> decreased intracellular K & increased actin/myosin interaction=> increased contractility
Potassium and Digitalis interaction
K and Digitalis compete for binding site on Na/K–ATPase.
Potassium is a competitive inhibitor of Digitalis and is an effective treatment of Digitalis toxicity.
Potassium is useful in decreasing the automaticity of the heart by pumping more Na out which causes more Ca to also be pumped out=> decreased actin/myosin interaction.
Effect of Ca levels and digitalis
Ca enhances the effect of Digitalis and therefore should never be used in cases of Digitalis toxicity
Digitalis and HR
Digitalis will always reduce HR, but it only affects CO in the failing heart, but no effect in the healthy heart.
In failing heart, increased contractility=> increased CO=> decreased baroreceptor response=> decreased SNS tone and decreased HR
Digitalis and vascular effects
Normal Heart: causes contraction of smooth muscle => vasoconstriction (why there is no change in CO in normal patients despite decrease in HR)
Failing Heart: causes vasodilation due to reduced baroreceptor firing and decreased SNS output
Digitalis Pharmacokinetics:
Oral availability, Half-life, Renal elimination
Oral Avail: 75%
Half-life: 40 hours
Renal Elim: >80%
Adverse effects of Digitalis in GI tract
Anorexia, diarrhea, vomiting, abdominal pain
Earliest signs of digitalis intoxication
GI symptoms as well as copius salivation
How safe is Digitalis?
Has a narrow margin of safety– therapeutic dose is 50% of toxic dose. Toxicity is common. Most severe effect is cardiac toxicity leading to death.
Adverse effects of Digitalis
Most serious effects are cardiac: Bradycardia, Ectopic ventricular beats, AV block, Bigeminy (PVB’s, T-wave inversion, ST depression)
Digitalis drug interactions
Diuretics: loop and thiazide cause hypokalemia=> enhanced effects
Beta blockers: decrease SA and AV node conduction predisposing for AV block
Ca Channel antagonists: decrease contractility
Catecholamines: sensitize myocardium to digoxin
Name Phosphodiesterase inhibitors (bipyridines) and how they work.
Inamrinone & Milrinone
Inodilators: meaning they are inotropic and vasodilators
Work by inhibiting cAMP phosphodiesterase in cardiac and vascular muscle which usually breaks down cAMP.
Helps by improving diastole and contractility along with vasodilation.
Use of bipyridines
Not used often. Not shown to be safe or effective in long-term treatment of heart failure.
Name positive inotropic sympathomimetic agents
Dopamine
Dobutamine
Calcium Sensitizers
Dopamine use as inotropic agent
Used in severe refractory CHF
Low doses=> increased CO (pos inotropic effect) and increased renal perfusion
Lowers peripheral resistance
Enhances Na excretion
Dobutamine characteristics
Selective beta-1 agonist
Positive inotropic with less tachycardia
Classes of drugs used for CHF that don’t have a positive inotropic effect.
1) Diuretics
2) ACE inhibitors
3) Beta Blockers
4) Vasodilators
Name potassium sparing diuretics used in CHF
Amiloride: inhibits ENaK function in principle cells, can lead to hyperkalemia when combined withACE inhibitors or ANG II antagonists
Spironolactone: also inhibits aldosterone receptors
Explain B type natriuretic peptide
hBNP: produced by ventricular muscle, prepared for use in acute treatment of decompensated CHF.
Works to reduce pulmonary capillary wedge pressure and relieve CHF symptoms of fatigue and dyspnea
Monitor closely to prevent hypotension
What is pulmonary capillary wedge pressure?
Pressure measured in a pulmonary artery that is used to estimate the pressure in the left atrium. Elevations indicate failure of the left ventricle and backup of pressure into the atrium.
Three general effects of Angiotensin II
1) Vasoconstriction and increase rate of pressor response
2) Altered kidney function (increase Na absorption, aldosterone release and effects, renal vasoconstriction)
3) Cardiac and vascular remodeling (increased growth hormone production, increased ECM production, increased vascular tension)
Why/how are ACE inhibitors and ANG II antagonists helpful in CHF?
Both reduce RAAS.
This is helpful because it decreases the afterload on the heart from vasoconstriction by ANG II and it decreases the preload by inhibiting aldosterone release and increased fluid retention.
Beta blocker use in CHF
Dangerous because of neg inotropic effect
Useful to enhance diastolic function and ejection fraction. Also reduces cardiac remodeling.
Vasodilators used for CHF
Sodium Nitroprusside: IV administration for acutely decompensated CHF, dilates both arteries and veins, can cause hypotension
Nitroglycerin or Isosorbide Dinitrate: orally, dilates veins more than arteries, tolerance develops
Hydralazine: relaxes arteriolar smooth muscle=> reflex increase in HR, increase CO, Increase LV ejection fraction, tolerance can develop
Long term use of hydralazine and isosorbide dinitrate can reduce damaging remodeling of the heart
