Pathology of afterload
Increasing left ventricular afterload include elevated BP & aortic valve disease
Increases the LV afterload because the LV must work harder to eject blood into the aorta. This is because the aortic valve won't open until the pressure generated in the left ventricle is higher than the elevated BP in the aorta
Increased BP w/in the right heart leading to the lungs. PH indicates a regionally applied increase in afterload dedicated to the right side of the heart.
Often increases afterload because the LV must overcome the pressure gradient caused by the calcified & stenotic aortic valve in addition to the BP in order to eject blood into the aorta. If the BP is 120/80, & the aortic valve stenosis creates a trans-valvular gradient of 30 mmHg, the LV has to generate a pressure of 110 mmHg in order to open the aortic valve & eject blood into the aorta.
Increases afterload because a percentage of the blood that is ejected forward regurgitates back through the diseased aortic valve. This leads to elevated systolic BP. The diastolic BP would fall, d/t regurgitation. This would result in an increased pulse pressure.
Decreases afterload. In ventricular systole under MR, regurgitant blood flows backwards/retrograde back & forth through a diseased & leaking mitral valve. The remaining blood loaded into the LV is then optimally ejected out through the aortic valve. With an extra pathway for blood flow through the mitral valve, the left ventricle doesn't have to work as hard to eject its blood, i.e. there is a decreased afterload
What is afterload largely dependent upon?
The tension or stress developed in the wall of the LV during ejection. The 'load' against which the heart MUST contract to eject blood.
What agents reduce afterload?
Vasodilators (alpha blockers, ACEi, ARBS, BBs, CCBs, nitrodilators, ganglionic blockers, PDE III inhibitors)
Alpha adrenoceptor antagonists
Act as competitive antagonists to the binding of NE that is released by sympathetic nerves synapsing on smooth muscle. These drugs are referred to as sympatholytics because they antagonize sympathetic activity. Some alpha-blockers are non-competitive (e.g., phenoxybenzamine), which greatly prolongs their action.
MOA of alpha blockers
Dilate both arteries and veins (prominent arterial)
Indications of alpha blockers
Alpha blocker drugs
Prazosin, terazosin, phenoxybenzamine
Produce vasodilation by inhibiting the formation of angiotensin II.
Actions of ACEi
Dilate arteries & veins by blocking angiotensin II formation & inhibiting bradykinin metabolism. This vasodilation reduces arterial pressure, preload & afterload on the heart.
Down regulate sympathetic adrenergic activity by blocking the facilitating effects of angiotensin II on sympathetic nerve release & reuptake of NE.
Promote renal excretion of Na & H2O (natriuretic & diuretic effects) by blocking the effects of angiotensin II in the kidney & by blocking angiotensin II stimulation of aldosterone secretion. This reduces blood volume, venous pressure & arterial pressure.
Inhibit cardiac & vascular remodeling associated w/ chronic HTN, heart failure, & MI.
Angiotensin receptor blockers (ARBs)
Similar effects to ACEis, used for HTN, heart failure, & post MI
Actions of ARBs
Dilate arteries & veins->reduces arterial pressure, preload, & afterload.
Down regulate sympathetic adrenergic activity by blocking the effects of angiotensin II on sympathetic nerve release & reuptake of NE.
Promote renal excretion of Na & H2O (natriuretic & diuretic effects) by blocking the effects of angiotensin II in the kidney & by blocking angiotensin II stimulation of aldosterone secretion.
Inhibit cardiac & vascular remodeling associated w/ chronic HTN, heart failure, and MI.
All end in SARTAN
Beta-adrenoceptor agonists (β-agonists)
Bind to β-receptors on cardiac & smooth muscle tissues. They also have important actions in other tissues, especially bronchial smooth muscle (relaxation), the liver (stimulate glycogenolysis) & kidneys (stimulated renin release).
Normally bind to NE released by sympathetic adrenergic nerves, & to circulating epinephrine. Therefore, β-agonists mimic the actions of sympathetic adrenergic stimulation acting through β-adrenoceptors. Overall, the effect of β-agonists is cardiac stimulation (increased HR, contractility, conduction velocity, relaxation) & systemic vasodilation.
Beta-adrenoceptor agonists (β-agonists) drugs
Epinephrine, NE, dopamine, dobutamine, isoproternol
Trimethaphan, used for hypertensive emergencies, block the sympathetic & parasympathetic ganglia.
Play an important 2nd messenger role in regulating cardiac muscle contraction
Increases contractility (inotropy), HR (chronotropy) & conduction velocity (dromotropy).
Indications for PDEIII inhibitors
Tx of heart failure. Arterial dilation reduces afterload on the failing ventricle & leads to an increase in SV & EF, as well as increases organ perfusion. Reducing the afterload leads to a 2˚ decrease in preload on the heart that helps to improve the mechanical efficiency of dilated hearts & to reduce ventricular wall stress & the 02 demands placed on the failing heart. The cardiostimulatory effects of these drugs increase inotropy, which further enhances SV & EF.
MOA of PDE3 inhibitors
Inhibition of the PDE isoenzyme 3 leads to an increase of intracellular concentrations of the 2nd messenger cyclic adenosine monophosphate (cAMP).