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Pharma 2- Semmelweis > A-19+20. Drugs used for treatment of heart failure I: Drugs decreasing the load on the heart. Drugs of acute cardiac failure and chronic heart failure. Positive inotropic agents. > Flashcards

A-19+20. Drugs used for treatment of heart failure I: Drugs decreasing the load on the heart. Drugs of acute cardiac failure and chronic heart failure. Positive inotropic agents. Flashcards

1
Q

What is Heart Failure?

A

Heart failure is any decrease in cardiac output to a level which is insufficient to provide sufficient oxygenation and perfusion of peripheral organs

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2
Q

Cardiac output can decrease carotid sinus firing leading to increase sympathetic discharge while also decreasing renal blood flow that increases RAAS. What are the following compensatory steps of the heart caused by these two pathways?

A

The increase of sympathetic discharge leads to…
-Greater force
-Increased heart rate
-Increase in preload and afterload
-Increase in Renin (activation of RAAS)
The increase in RAAS leads to more angiotensin II which
-Increases preload and afterload
-Remodeling of the heart
-Aldosterone, which increase salt and water retention
-Increase in sympathetic discharge

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3
Q

Which drugs directly increase cardiac output? Are they always effective in HF?

A

Positive inotropic drugs: Dobutamine, digoxin, PDE inhibitors, Ca-sensitizers all are temporary solutions which eventually wear out the heart.
*Heart rate is increased for all these drugs cause of positive chonotropic effect except digoxin since it stimulates vagus

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4
Q

Beta blockers are used in heart failure to

Drugs include?

A

-Decrease sympathetic discharge
-Decreases risk of mortality (only if no atrial fibrillation is present)
Carvedilol, labetolol, metoprolol, bisoprolol, nevibolol

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5
Q

Venodilators are used in HF to

more detail later

A

Two cases of venodilator use
Case 1- increase in preload requires nitrates to decrease preload by dilating venules
Case 2- reduced cardiac output, hypotension can be treated with hydralazine dilating the arterioles and reduces the afterload
Combined Case 1+2
-Nitrates and hydralazine both decrease mortality
*Also nesiritide- recombinant BNP can be used to increase cGMP in SM to causes both arteriolar and venous dilation; Na+ loss via diuresis. Used in acute HF

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6
Q

ACE-I/ARBs are used in HF to

Name 4 drugs

A

Decrease angiotensin II and angiotensin subsequent effects
-Decrease afterload, preload, remodeling process
-Decrease mortality
Captopril, enalapril, losartan, valsartan

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7
Q

Diuretics are used in HF to

A

-Decreases salt and water retention
-Decreases preload (and afterload
They don’t decrease mortality except for aldosterone antagonist does

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8
Q

Ivabradine MOA

A

Inhibitor of funny channel current in the SA causing bradycardia.
Given to patients with coronary heart disease and chronic heart failure

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9
Q

Treatment strategy for HF by Stage (1-4)

A 
ACE or ARB (stage 1 through 4)
BB (stage 1 near to the end of stage 4)
Diuretics (stage 2 through 4)
Digoxin (stage 2 through 4)
Sympathomimetics and vasodilators (stage 3 through 4)
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10
Q

Drugs groups used in acute heart failure (3)?
When are they used?
Side-effect of long term use?

A

Sympathomimetics
PDE3 inhibitors
Ca2+-sensitizer
They are used in NYHA 4th stage and cardiogenic shock
All can lead to tachycardia leading to arrhythmia and heart exhaustion/death

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11
Q

B-1 agonists used in HF (3)

A

Dobutamine, Dopamine, Norepinephrine

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12
Q

Dobutamine selective for?
Administration? Half life?
Tolerance?
Indications?

A

Most selective for B-1
Parenteral admin and short half life
Tolerance develops in 72 hours (tachyphylaxis) via B-1 receptor downregulation
Indicated for acute decompensated HF, acute HF, post MI, and cardiogenic shock

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13
Q

Dopamine dose effect
Low dose?
Moderate dose?
High dose?

A

Low dose causes D receptor to increase renal blood flow and indicated in kidney shock
Moderate dose upregulates the D and B-1 receptor with same indication/side effects as dobutamine
High dose acts on alpha-1 receptors causing vasoconstriction

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14
Q

Norepinephrine
Receptor effect?
MOA? reflex?
Indication

A

Less reflex tachycardia due to less B-2 effect, highest effect at a-1
Strong vasoconstriction leading to reflex bradycardia
Indicated cardiogenic shock

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15
Q

Phosphodiesterase 3 inhibitors (inodilators) MOA

A

PDE3 inhibition causes increase cAMP leading to positive ino-/dromo-/chronotropy (as well as inactivation of myosin light chain kinase).
This leads to SM relaxation and arteriolar vasodilation which decreases afterload

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16
Q

Bipyridine PDE3 inhibitors drugs

A

Amrinone and Milrinone

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17
Q

Methylxanthine PDE3 inhibitors drugs

A

Aminoophylline and Theophylline

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18
Q

Amrinone indications

A

Acute HF (for refractory patients tolerant for dopamine/dobutamine and as bridging therapy for patient waiting for transplant)

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19
Q

Side effects of Amrinone

A

Hepatoxicity, Thrombocytopenia, Tachycardia/tachyarrhythmia, hypotension

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20
Q

Milrinone is similar to Amrinone except

A

20x more potent, only IV, same side effects except no thrombocytopenia so more often used
Used in pulmonary edema (vasodilatory effect) + acute heart failure

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21
Q

Aminophylline and Theophylline administered?

Indications

A

Aminophylline= parenteral
Theophylline= oral
Indications are acute HF, bridging therapy, pulmonary edema (maybe)

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22
Q

Mixed effect PDE3 inhibitor

A

Vesnarinone

23
Q

Vesnarinone MOA and effect

A

-Strong inhibitor of K+ channels, weak activator of Na_ channels- increasing IC Ca2+ elongation of action potential plateau phase
-TNFalpha and IL-6 formation inhibitor
-Weak PDE3 inhibitor
THis leads to inotropic and vasodilator effect
ONLY for acute treatment- increased mortality in chronic use

24
Q

Calcium sensitizer drugs

A

Levosimendan and Pimobendan

25
Q

Calcium sensitizer MOA

A

interact with Troponin C to increase contractility with increasing calcium level (this makes them non-arrhythmogenic)

26
Q

Calcium sensitizer disadvantage

A

Increases contractility so diastolic relaxation can be inhibited

27
Q

Calcium sensitizer indication

A

Acute heart failure (infusion in NYHA stage 4)

28
Q

Levosimendan MOA

A
  1. ) Activates ATP-sensitive K+ channel causing venodilation
  2. )Binds troponin C and stabilizes conformation necessary for the interaction of actin and myosin, yet binds in a calcium depend manner so it doesn’t effect relaxation
    * This means that increases affinity to troponin-C so in systole high Ca2+ causes high association. In diastole low Ca2+, causes low binding)
29
Q

Levosimendan kinetics

A

Parentereal admin

30
Q

Pimobendan MOA and kinetics and indication

Not used anymore

A

Increases affinity to troponin C to Ca2+ (increases contractility), also inhibits PDE
Kinetics: oral admin
Used in late stages of congestive HF

31
Q

Acute Heart Failure
Wet and warm (adequate peripheral perfusion) patient (typically elevated or normal systolic blood pressure)

Vascular type- fluid redistribution hypertension predominates
Drugs?

A
  1. ) Vasodilators

2. ) Diuretics

32
Q

Acute Heart Failure
Wet and warm (adequate peripheral perfusion) patient (typically elevated or normal systolic blood pressure)

Cardiac type-fluid accumulation, Congestion predominates
Drugs?

A
  1. ) Diuretic
  2. ) Vasodilator
  3. ) Ultrafiltration (consider if diuretic resistance)
33
Q

Acute Heart Failure
Wet and Cold (inadequate peripheral perfusion)
Systolic blood pressure is below 90 mmHg

A
  1. ) Inotropic agent
  2. ) Consider vasopressor in refractory cases
  3. ) Diuretic (when perfusion corrected)
  4. )Consider mechanical circulatory support if no response to drugs
34
Q

Acute Heart Failure
Wet and Cold (inadequate peripheral perfusion)
Systolic blood pressure is above 90 mmHg

A
  1. ) Vasodilator
  2. ) Diuretics
  3. ) Consider inotropic agent in refractory cases
35
Q

Acute Heart Failure
Dry and warm
Adequately perfused= compensated

A

adjust oral therapy

36
Q

Acute Heart Failure
Dry and cold
Hypoperfused, hypovolemic

A

Consider fluid challenge, consider iontropic agent if still hypoperfused

37
Q

Contraindication drugs acute heart failure

A

Acute B-blocker administration, ACE-inhibitors/ARBs, and Ca-antagonists

38
Q

Cardiac glycoside drugs

A

Digoxin and Digitoxin

39
Q

Digoxin and digitoxin MOA

A

1.)Bind and inhibit Na/K-ATPase to increase IC Na+ leading to Na+/Ca2+ exchanged slowed or reversed increasing IC Ca2+.
The disrupted calcium homeostasis and increased cytoplasmic calcium concentrations cause increased calcium uptake into the sarcoplasmic reticulum (SR) via the SERCA2 transporter. Raised calcium stores in the SR allow for greater calcium release on stimulation, so the myocyte can achieve faster and more powerful contraction by cross-bridge cycling.
(Ca2+ storage decreases in some HF due to SERCA dysfunction so glycosides restores SERCA function)
2.) Also stimulates vagus centrally via acetylcholine
at cardiac M2 receptors open K+ channels leading to hyperpolarization. This slows the sinus and AV nodes leading to bradycardia.

40
Q

Number of Na/K-ATPase that need to be inhibited for cardiac glycosides to have a therapeutic effect

A

20-30% ATPase inhibited

41
Q

Kinetics of Digoxin

A 
Oral
Faster onset
DOA (36-40 hours)
Lower protein binding
Not metabolized
Kidney eliminated
42
Q

Digitoxin

A 
Oral
Slower onset
DOA (5-7 days)
High protein binding
Metabolized and eliminated by liver
43
Q

Therapeutic index for both digitoxin and digoxin

A

Narrow

44
Q

Indications for digitoxin and digoxin

A

1.) CHF- NYHA stages III-IV (when ACE-I/diuretics fail); does not decrease mortality
2.) Atrial flutter and fibrillation- digoxin vagal stimulation decreases aberrant automaticity
(Used rarely in supraventricular tachycardia for AV node slowing, (mainly if associated with HF)

45
Q

Absolute contraindications for digitoxin and digoxin

A
  1. ) Hypertropic CMP
  2. ) WPW- digoxin increases AV node refractory period, which may stimulate conduction through the accessory pathway
  3. ) AV block- vagal effects can exacerbate heart block
  4. ) Diastolic HF- increases contractility from digoxin and can decrease diastolic relaxation
46
Q

Relative contraindications for digitoxin and digoxin

A
  1. )Sinus bradycardia and sick sinus syndrome
  2. ) Use with other negative chronotropes (verapamil, diltiazem, amiodarone) cause they can lead to severe bradycardia
  3. ) Combination of drugs that compete for elimination such as quinine and amiodarone
  4. ) Circumstances with increased digitalis sensitivity (hypokalemia). Such as when you take diuretics, be careful
  5. ) Renal failure. In this case use digitoxin instead so it is eliminated by the liver
47
Q

Toxicity symptoms of digoxin and digitoxin

A
  1. ) Hyperkalemia due to Na/K-ATPase inhibition
  2. ) Arrhytmias
    - PVCs most common
    - Bradycardia from vagal stimulation
    - Vagal stimulation plus excess IC Ca2+ can lead to ventricular bigeminy or AV block
    - When you have more than 20-30% Na/K-ATPase blocked then IC Ca2+ can get too high leading delayed afterdepolarization (DAD) which causes slight increase in membrane potential after normal cardiac AP causing extrasystole (PVC, ventricular tachycardia, and ventricular fibrillation)
  3. )Vision issues- color vision disturbances, blurred visio, photo-sensitivity, xanthopsia (yellow vision)
  4. ) Neuro issues- HA, anxiety, nightmare, hallucination, lethargy, disorientation
  5. ) GI issues- via ATPase inhibition in GI tract: nausea, vomiting, abdominal pain
48
Q

ECG signs of digoxin toxicity

A

Shortened QT, scooped ST depression, and T inversion

49
Q

Treatment for digoxin bradycardia and ventricular tachycardia

A

bradycardia- treat with atropine

ventricular tachycardia- lidocaine/phenytoin (type I/B antiarrhythmics)

50
Q

How to treat digoxin neural issues

A

Digiban/digibind/digoxin immune fab is a digitalis binding antibody; used mainly in suicide attempts related to psych symptoms

51
Q

Things that increase digoxin toxicity + interactions

A
  1. ) Hypokalemia
  2. ) Hypercalcemia (can increase risk for DAD meaning extrasystole and ventricular tachycardia)
  3. ) Hypomagnesemia
    - Magnesium needed for ATPase function so when magnesium drop it enhances digoxins effect (ex. loop diuretics waste Mg)
  4. ) Renal damage
  5. ) Beta blockers- both combined can decrease conduction of SA/AV nodes (co-use should be cautious)
  6. ) Antibiotics- digoxin is inactivated in GI tract by flora so antibiotics increase serum levels
52
Q

What is the hypokalemia and digoxin interaction cause

A

Mostly with K-wasting diuretics, sometimes via diarrhea/vomiting; glycosides bind competitively to ATPase’s K+ binding site, so less K+ increases digitalis bind
Always monitor K levels when you have diuretics with glycoside use together
ACE-I, ARB, and K sparing diuretics can also cause hyperkalemia and decrease digital binding/effect

53
Q

Renal Damage and digoxin interaction

A

Increase in half-life of digoxin since it is renally eliminated.
Monitor BUN/creatinine in renal patients on digoxin; often must switch to digitoxin instead (hepatic elimination)
-Amiodarone, verapamil, diltiazem, and quinidine all compete for renal elimination

Pharma 2- Semmelweis (43 decks)

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