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Other Drug Groups Used:
Diuretics (Furosemide & Thiazides)
Beta Blockers (-olol)
Vasodilators (Nitrates, Hydrazaline)
Cardiac Failure Compensatory Mechanisms?
1) Frank Starling Law (increase volume return to heart = increased stretch = greater contractility)
2) Myocardial Hypertrophy
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
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)
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:
Distributive shock (neurogenic / septic)
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
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:
Positive Inotropic Effect
Slight increased HR
PDEi Adverse Effects
*Dose related hypotension, syncope (Milrinone)
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 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:
Effect on arteries &/or veins?
*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
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