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pharm 2 > Lecture 8/9 Heart Failure > Flashcards

Lecture 8/9 Heart Failure Flashcards

1
Q

Can heart failure be cured?

A

No, it can only be managed through medication or by eventual transplant

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2
Q

Name the 6 major markers used in lab results to diagnose heart failure.

A

BNP
Troponin T
Troponin I
CK-MB
C-reactive protein
TNF Alpha

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3
Q

Describe the pathogenesis of heart failure in order.

A
  1. Initial trigger or insult results in cardiac dysfunction (various causes such as genetic or metabolic)
  2. Initial cardiac dysfunction exhibits as decrease in cardiac output
  3. Results in decreased perfusion of vessels and tissues, leading to oxygen deprivation and increased oxygen demand for heart muscle
  4. This turns on adaptive mechanisms to compensate (RAAS system) with aid of sympathetic nervous system
  5. After a period, the compensatory mechanisms fail accompanied by baroreceptor dysfunction
  6. Further contributes towards heart failure
  7. Increased RAAS activity results in edema, vascular dysfunction, and cardiac tissue damage
  8. Finally, cardiac output drops drastically
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4
Q

Heart failure is accompanied by:

A

increased resistance and decreased stroke volume, as the failing heart no longer abides by the Frank-Starling law

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5
Q

Name the two types of heart failure:

A

HFrEF: heart failure with reduced ejection fraction AKA systolic heart failure

HFpEF: heart failure with preserved ejection fraction AKA diastolic heart failure

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6
Q

Describe HFrEF:

A

Heart failure with reduced ejection fraction is presented with signs of impaired systolic function. the LVEF <40% (left ventricle ejection fraction)

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7
Q

Describe HFpEF:

A

Heart failure with preserved ejection fraction is presented with signs of PRESERVED systolic function, but the diastolic function is impaired, effecting cardiac relaxation. the LVEF >50%. HFpEF can be determined with both noninvasive and invasive measurements

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8
Q

Describe the major structural changes in the heart in HFrEF:

A

The LV is dilated and there is a weakened pump. Blood will back up and overload the heart. The ventricles are stretched and pump out less blood than normal.

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9
Q

Describe the major structural changes in HFpEF:

A

The walls of the LV are thickened or stiff (can be due to scarring), and there is abnormal relaxation which prevents the LV from filling up all the way before it squeezes. The thickened ventricles contract normally but have less blood to pump out.

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10
Q

What are the two types of drugs used for heart failure?

A
  1. Acute measures (short term) for acute events
  2. Maintenance measures (long term)
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11
Q

What are positive inotropic agents?

A

drugs that increase the force of contraction of the heart

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12
Q

name the inotropic agents

A

Digoxin (only one WITHOUT vascular effects)
Dopamine
Dobutamine
Phosphodiesterase (PDE) inhibitors
Inamrinone
Sildenafil

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13
Q

Digoxin is part of the _____ family

A

Cardiac glycosides

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14
Q

What is the mechanism of action for digoxin?

A

They inhibit the PHOSPHORYLATED ALPHA SUBUNIT (and ONLY this subunit) of the plasma membrane residing Na+K+ATPase channel

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15
Q

What is the result of taking digoxin?

A

Na+ EFFLUX via the NaKATPase is prevented, leading to an increase in cytosolic Na+ ions. This increase leads to Ca+ retention in cells, causing an increase in cytoslic Ca+ as well as Ca+ release from the sarcoplasmic reticulum by SERCA2. This all leads to increased contraction of the myocyte

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16
Q

What happens if digoxin is taken chronically?

A

This results in decreased drug action. The resultant increase in extracellular K+ levels promotes dephosphorylation of the Na+K+ATPase alpha subunit, minimizing the drugs potency

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17
Q

General notes on Digoxin:

A

T1/2 is 36-48 hours
steady state achieved following 7 days after maintenance dose
MOSTLY EXCRETED VIA RENAL ROUTE
affinity for skeletal muscle deposition, so dosing should be based on lean mass

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18
Q

Adverse affects/contraindications of digoxin:

A

Very narrow therapeutic window (<1ng/mL)
need to be careful in patients with ionic or acid base imbalances, and those with renal failure
co administration with Ca2+ can result in MALIGNANT ARRHYTHMIA

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19
Q

What is the mechanism of action for dopamine?

A

dopamine acts via the Dopamine receptors (D1 and D2)

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20
Q

How does the dosage of dopamine impact its effect?

A

extremely low dose (<2ug/kg lean body mass/min): induces cAMP and VASORELAXATION. acts on D2 receptors in sympathetic neurons inhibiting NE release

moderate dose (2-5ug/kg/min): direct stimulation of cardiac B1 receptors thus increasing contractility and sympathetic neuronal NE release

higher doses (>10ug/kg/min): stimulate alpha adrenergic receptor in both arteries and veins resulting in vasoconstriction, recommended during circulatory collapse

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21
Q

adverse effects of dopamine are:

A

tachycardia
causes ischemic attacks in patients with coronary artery disease
systemic nonspecific adverse effects

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22
Q

how are dobutamine infusions given?

A

started at a dose of 2-3ug/kg/min and slowly titrated up based on requirement

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23
Q

what is the mechanism of action for dobutamine?

A

it is a nonspecific BETA RECEPTOR AGONIST. they stimulate the B1 receptor in cardiac tissue resulting in increased contractility (major effect). They also act on beta 2 receptors in vascular smooth muscle resulting in vasodilation and decreasing resistance (minor effect)

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24
Q

What are the adverse effects of dobutamine?

A

tolerance may develop following 1 week of treatment due to increased PDE activity. If so, PDE3 inhibitor will yield better pharmacologic results

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25
Q

What is the mechanism of action for the PDE inhibitors inamrinone and sildenafil?

A

they inhibit PDE enzymes which raise or upregulate the cellular cAMP levels

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26
Q

What are the effects of PDE inhibitors?

A

there is a positive inotropic effect (increased contractility) in cardiac tissue as well as decreased resistance in both arteries and veins. this reduces both preload and afterload

27
Q

Describe Inamrinone

A

inamrinone is a PDE 3 inhibitor and is approved for short term therapy in advanced CHF

28
Q

What are the adverse effects of inamrinone?

A

around 10% of patients develop thrombocytopenia

29
Q

describe sildenafil

A

Sildenafil is a PDE 5 inhibitor, which is mostly found in lung tissue. It is most effective for right ventricular systolic failure due to pulmonary artery hypertension

30
Q

what is the major role of diuretics in treating heart failure?

A

decrease the preload and edema

31
Q

how do diuretics work?

A

they decrease preload without a major change in cardiac output. they decrease ventricular filling pressure, and are preferred mostly to maintain a euvolemic state for patients suffering from hypervolemia

32
Q

which are the loop diuretics used in treating heart failure?

A

Furosemide
Bumetamide
Torsemide

33
Q

Describe the mechanism of action for loop diuretics

A

they inhibit the Na+K+2CL symporter on the apical membrane of the ascending limb of the loop of henle. This promotes Na+ and K+ excretion. They are suggested for hypervolemic patients with edema. They are known as high ceiling diuretics because of their ability to expel maximum Na+,Cl- and water

34
Q

what are the thiazide and thiazide like diuretics?

A

chlorothiazide
hydrochlorothiazide
chlorthalidone

35
Q

what is the mechanism of action for the thiazide and thiazide like diuretics?

A

they inhibit the Na+Cl- co-transporter in the apical membrane of the distal convoluted tubule. they are only recommended for combinatorial therapy

36
Q

what are the K+ sparing diuretics?

A

amiloride and triamterene (direct ENaC inhibitors)
spironolactone and eplerenone (MR antagonists)

37
Q

what is the mechanism of action for the direct ENaC inhibiting K+ sparing diuretics?

A

they are direct ENaC inhibitors. they target ENaC channels and prevent Na+ reabsorption in the collecting duct with minimal K+ and Mg2+ loss

38
Q

what is the mechanism of action for the MR antagonist K+ sparing diuretics?

A

they downregulate ENaC expression on the luminal surface due to MR antagonism. heart failure patients have almost 20% more aldosterone in their circulation, so administration of aldosterone antagonists will provide benefits

39
Q

what are the additional benefits exhibited by the MR antagonist k+ sparing diuretics?

A

protection against cardiac and renal fibrosis (beneficial for those with HFpEF)
prevents ischemia and inflammation
prevents endothelial and vascular smooth muscle constriction and damage

40
Q

what are the adverse effects of the MR antagonist K+ sparing diuretics?

A

10% of men develop gynecomastia due to non specific effects (mostly with spironolactone. this can be substituted with eplerenone if it occurs

41
Q

What is the major adverse effect from diuretics in general?

A

diuretic resistance. this occurs mostly because of a compensatory increase in Na+ reabsorption following Na+ loss from the body by RAAS activation (mostly seen with loop diuretics). some other factors that contribute are patient non-compliance and non adherence to sodium and fluid intake restrictions

42
Q

what is the newer mechanism for diuretic resistance?

A

the enzymes plasmin and prostasin present in the tubular lumen cleaves the gamma subunit of the ENaC and activates the channel, resulting in enhanced reabsorption of sodium (mostly for k+ sparing diuretics)

43
Q

how do NSAIDs contribute to diuretic resistance?

A

NSAIDs inhibit the prostaglandins which decreases renal perfusion and thus diuretic efficiency, as there will be a lesser amount of filtrate in the lumen

43
Q

what are the SGLT2 inhibitors used for heart failure?

A

empagliflozin and dapagliflozin

44
Q

What is the SGLT2?

A

the sodium glucose transporter 2 which is present in excess in the proximal tubule and is responsible for 90% of the filtered glucose and a considerable amount of Na+

45
Q

what is the mechanism of action for the SGLT2 inhibitors?

A

they inhibit glucose and sodium uptake through SGLT2 transporters, reducing hyperglycemia, hypernatremia, and hypervolemia, leading to a decrease in preload

46
Q

what are adverse effects of SGLT2 inhibitors?

A

UTI infections and could aggravate CKD

47
Q

What is the vasodilating drug used for heart failure?

A

Bidil (brand name)

48
Q

What is bidil?

A

bidil is a combination of both isosorbide dinitrate and hydralazine HCl. hydralazine is an arterial dilator and nitrate is a venous dilator, thus reducing both preload and afterload

49
Q

Describe how the isosorbide dinitrate in bidil works

A

it gets converted to nitric oxide via the CYP450 system and promotes venous dilation

50
Q

describe how the hydralazine HCl in bidil works

A

it causes a decrease in the release of calcium from intracellular pools by inhibiting inositol tri-phosphate 3 (IP3) decreasing vascular contraction

51
Q

what are the systemic positive effects of nitrates

A

reduces preload by relaxing vascular smooth muscle and decreases incidences of MI and heart failure

known to increase cGMP levels inside platelets resulting in the prevention of platelet aggregation

52
Q

what are the effects of Ang II in the RAAS system?

A

arterial vasoconstrictor, promotes Na+ and H2O retention

53
Q

what are the drugs that target the RAAS system for heart failure?

A

Captopril, ramipril, lisinopril (ACE inhibitors)
candesartan, losartan (AT1R blockers)

54
Q

what effects do drugs targeting the RAAS system have?

A

mortality reducing effect on heart failure patients with systolic dysfunction

prevent ventricular remodeling and LV dysfunction

AT1 receptor blockade provides both short and long term management of heart failure

AT1 receptors preferred due to less side effects

55
Q

what is a combinatorial therapy used to target the RAAS system?

A

AT1R blockers with MR antagonists

for example: candesartan and spironolactone together improves quality of life and cardiac ejection fraction. this combo should be avoided in the elderly and can induce hypotension, renal dysfunction and hyperkalemia

56
Q

what is entresto?

A

entresto is a combination drug made up of sacubitril and valsartan. it was approved by the FDA in 2015 for heart failure

sacubitril is a produg, converted to sacubitrilat which is a neprilysin inhibitor. neprilysin inhibits ANP and BNP and breaksdown ang2

57
Q

what is the mechanism of action for entresto?

A

promotes the simultaneous inhibition of neprilysin and AT1R

58
Q

what are the adverse effects of entresto?

A

hypotension, angioedema, hyperkalemia, reduced renal function

black box warning for fetal toxicity and should be avoided in pregnancy

should not be used with another ARB (angiotensin 2 receptor blocker)

59
Q

which drugs reduce cardiac muscle stress resulting in proper diastolic filling and improving oxygen demand?

A

beta blockers and ivabradine

60
Q

which drugs are beta blockers?

A

metoprolol (B1 selective)
carvedilol (nonselective b blocker)

beta blockers initiated at very lose dose and titrated upwards

61
Q

what is the mechanism of action for ivabradine?

A

directly inhibits of Na+ entry (inward funny current) through HCN channels in the SA node, decreasing cardiac rate and reducing myocardial oxygen demand

62
Q

who is recommended to use ivabradine?

A

patients with HFrEF with stable angina with a heart rate equal or greater than 70 as a combination therapy with ACE/ARB inhibitors or MR antagonists.

also especially useful for those intolerant to beta blockers

63
Q

what are the adverse effects and contraindications of ivabradine?

A

bradycardia and atrial fibrillation

contraindicated in those with decompensated heart failure or a prior history of bradycardia or atrial fibrillation

pharm 2 (11 decks)

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