Pharm II Block 1.4 Heart Failure Drugs

Created by dgballin21 

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Iontotropic Drugs:

Digoxin
Dobutamine
Dopamine
Milrinone (PDEi)

Other Drug Groups Used:

RAA blockers
Diuretics (Furosemide & Thiazides)
Beta Blockers (-olol)
Vasodilators (Nitrates, Hydrazaline)

Cardiac Failure Compensatory Mechanisms?

Cariac Mechanisms:
1) Frank Starling Law (increase volume return to heart = increased stretch = greater contractility)
2) Myocardial Hypertrophy

Neuroendocrine Mechanisms:
1) Sympathetic NS activation
2) RAA system

4 causes of myocardial hypertrophy

1) Increased preload
2) Increased afterload
3) Loss of myocytes (MI)
4) Depression of contractility (dilated cardiomyopathy)

Concentric vs. Eccentric Hypertrophy

*Concentric hypertrophy = diastolic heart failure = commonly from hypertension

*Eccentric hypertrophy = systolic heart failure = commonly from dilated cardiomyopathy

Cardiac Glycoside: Digoxin MOA?

*Inhibits the 3Na+/2k+ pump resulting in more intracellular Na+.

*More intracellular Na+ means the Ca++/3Na++ antiporter has reduced action.

*Overall result is increased intracellular Ca++ meaning greater contractile intensity.

Additional Mechanism of Digoxin

Digoxin facilitates Ca++ entry through the voltage gated Ca++ channels and the independent effect on SR results in increased release of Ca++ from intracellular storage sites.

In the failing heart, this reduces O2 consumption

Cardiac Glycosides on chronic heart failure MOA?

Two Main Effects: Positive inotropic & negative inotropic effect
*Positive inotropic effect increases stroke work & cardiac output which then leads to:
1) Elimination of stimuli evoking increased sympathetic outflow.
2) Lowering end diastolic fiber tension
3) Increased renal blood flow

Digoxin effects on CNS?

Direct stimulation of chemoreceptor trigger zone.

Reflex stimulatio nof the vomiting center

Direct stimulation of vagal nuclei

Digoxin Toxicity:
CV system?
GI system?
CNS?
Other systems?

CV System: Cardiac Arrhythmias

GI System: Nausea & vomiting (chemotactic trigger zone)

CNS: nightmares, confusion, disorientation, agitation, hallucinations "Digitalis Delirium"

Other Systems: Visual disturbances (blurred vision, green-yelllow halos around bright objects)

Dopamine MOA

Low Doses = activation of D1 R leading to vasodilation. increased renal perfusion

Intermediate Doses = also activate Beta 1 & beta 2 R and release of NE. Leading to positive ionotropic effect

High Doses = Activate alpha 1 R and D1 R leading to increase, htn, nausea & vomiting

Dopamine Therapeutic Uses:

Cardiac failure
Cardiogenic shock
Distributive shock (neurogenic / septic)

Dobutamine MOA?

Selective activation of beta 1 R (beta 2 R and alpha 1 R activation w/ high doses)

Causes a positive ionotropic effect on the heart. Peripheral vasodilation

Dobutamine Therapeutic Uses

Acute cardiac failure or cardiogenic shock, when LEFT VENTRICULAR FUNCTION IS SEVERELY DEPRESSED

Phosphodiesterase Inhibitor Drugs?

Milrinone
Inamrinone

PDEi MOA and effect in the myocardium & smooth muscle at the cellular level?

Inhibition of phosphodiesterase isozyme 3 resulting in increase in cAMP causing:

a) in myocardium: phosphorylation of PKA which increases free intracellular Ca++

b)in smooth muscle: inactivation of myosin light chain kinase which decreases the phosphorylation of myosin light chain.

PDEi Pharmacological Effects:
Inotropy?
HR?
Peripheral Vasculature?

Positive Inotropic Effect
Slight increased HR
Peripheral Vasodilation

PDEi Adverse Effects

*Dose related hypotension, syncope (Milrinone)
*Ventricular Arrhythmias
*Thrombocytopenia

PDEi Therapeutic Uses?

*Acute cardiac failure or cardiogenic shock in px who dont respond well to other therapies or are on beta blockers.

*Long term therapy is associated w/ increased mortality.

Combo Therapy for heart failure:
Stage A (1st line)
Stage B
Stage C
Stage D

Stage A: Risk factor reduction, ACEi (or ARB)

Stage B: ACEi (or ARB) & Beta Blocker

Stage C: ACEi (ARB) + Beta Blocker + Diuretics. (Digoxin, Aldosterone antagonist, Hydralazine / nitrates in certain px)

Stage D: All the above + continuous IV of inotropes, mechanical assist devices, heart transplant, hospice care

Vasodilators & Heart Failure Drug Classes and drugs and how they affect preload & afterload?

*Nitrovasodilators (Nitrates, Nitropruside)
-Strongly reduces preload & afterload b/c affects both arteries and veins.

*ACEi (Captopril) - Reduces preload & afterload

*Angiotensin R Antagonists (Losartan)
-Reduces both preload & afterload

*PDEi (Milrinone) - Inhibits afterload more than preload

*Direct Vasodilators (Hydrazaline) - Greatly decreases afterload more than preload.

Atrial Natriuretic Peptide in Acute Heart Failure:
Drug?
MOA?
Effect on arteries &/or veins?
Adverse Effect?
Therapeutic Uses

*Drug = Nesiritide (recombinant brain natriuretic peptide)

*MOA = Activation of guanylyl cyclase & increased synthesis of cGMP

*Vasodilates arterioles & venuoles, increases diuresis.

*Adverse Effects: Excessive hypotension, Renal failure

Therapeutic Uses: IV tx of px w/ acute, decompensated heart failure

Beta Blocker Therapeutic Use & Contraindication

Therapeutic Use: Chronic Systolic Heart Failure

Contraindication = Acute Heart Failure b/c of their negative inotropic effects

Beta Blocker MOA in chronic heart failure?

1) Prevent chronic overactivity of sympathetic NS (decreased HR, reduced myocardial remodeling)

2) Inhibition of Renin

3) Up regulation of beta 1 R

Drugs of Choice for all stages of Heart failure?

Diuretic & ACEi

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