Flashcards in Heart Failure Pharmacology Deck (56):
Compensatory mechanisms in congestive heart failure
Decreased cardiac output leads to decreased carotid sinus firing and decreased renal blood flow.
Decreased carotid sinus firing causes increased sympathetic discharge which increases force, rate, and preload of contractions.
Decreased renal blood flow causes increased renin release, which causes ang II to increase. Which increases preload, afterload and causes cardiac remodeling.
Vasoactive peptides include what types of drugs?
Angiotensinogen is convertin to ANG I by renin.
Ang I is converted into ang II by ACE.
Angiotensin II binds ot Angiotensin receptors (AT1-4)
Where is angiotensinogen made?
Liver, secreted into blood stream
Where is renin made?
In JG cells in kidney, with low perfusion pressure it is secreted into blood stream. Also with beta activation, also with decreased nacl delivery.
Effects of ANG II
Increased sodium retention and therefore fluid retention.
Increased blood volume by thirst.
Increases secretion of aldosterone from adrenals
Increases secretion of ADH from pituitary.
Converted to renin in JG cells of the kidney. Higher levels of prorenin in circulation than renin.
Binds to prorenin receptor which activates kinases and TFs associated with fibrosis
Binds renin and prorenin. Activates kinases and TFs that are associated with fibrosis.
How is renin released?
When macula densa cells sense increased delivery of NaCl (meaning increased flow), they inhibit renin release from JG cells. This process is mediated by adenosine.
Decreased delivery of NaCl to JG cells (decreased flow) stimulates renin release. This process is mediated by prostaglandins
What factors inhibit renin release and stimulate renin release?
Are there sympathetic receptors in the kidney?
Yes, beta receptors on juxtaglomerular cells. Hypotension activates sympathetic system (increase preload, contractility, rate)
Direct feedback loop for renin?
AT1 receptor at JG cells. So if high AngII, renin inhibited.
Aliskerin mechanism of action
Renin inhibitor that directly inhibits renin. So it decreases BP. However, renin levels INCREASE, though renin activity does not.
What happens to renin levels with aliskerin?
Renin levels increase because of loss of negative feedback from ang II.
Is renin necessary for ang II creation?
No, there are alternative pathways that utilize cathepsin G.
Don't use in hyperkalemic patients because aldosterone decreases, which will cause a further increase of K in blood.
Watch out in patients with increased creatinine. Because decrease in ang II will cause decreased Pgc and decreased GFR.
Equation for GFR
GFR = Kf * [(Pgc-pi gc) - (Pbs-pi bs)]
ACE inhibitors mechanism of action
Competitive inhibitor of ace, which converts ang I to ang II. ACE also breaks down bradykinin, so when inhibited, cough.
ACE inhibitor effect on renin, angiotensin I, and ang II levels?
ANG II levels decrease, so renin and ang I levels increase.
5 clinical indications for ace inhibitors?
Congestive heart failure
Coronary artery disease
Why don't ace inhibitors cause reflex tachycardia?
Because baroreceptors are thought to reset.
Why are ACEI used for hypertension?
Because ACEIs inhibit AngII mediated vasoconstriction. Decreased BP without reflex tachycardia.
Why are ACEI used for DM?
Renoprotective because of decreased GFR, decrease risk of DM nephropathy, decrease proteinuria.
Why are ACEi used for CHF?
Prevents progression of heart failure by reducing vasoconstriction, which decreases afterload and increases CO. Also decreased aldosterone which causes less Na reabsorption so preload and edema decrease. Also causes venodilation which decreases preload. Finally, reduces ventricular remodeling.
Adverse effects of ACEIs
Hypotension, cough, hyperkalemia (due to decreased aldosterone), decreased GFR so avoid in patients with bilateral renal artery stenosis.
Can also cause angioedema (rare) -- rapid swelling in oropharynx, lips, tongue. Thought to be bradykinin mediated.
Captopril -- when used and unique side effect
Alteration in taste because it has a sulfhydryl group. Also unique because it has the shortest half life of all the ACEIs (3 hours). Can titrate in CHF patients with low BP, but must be dosed frequently.
A prodrug that is converted by hepatic esterases to the active drug enalaprilat. Only IV ace inhibitor
Active drug that is created by cleavage of enalapril
How are ACEIs metabolized or excreted?
ARB mechanism of action
Selective AT1 receptor antagonists (10,000 more than AT2)
Losartan and clinical indication
ARB that is used for hypertension, CHF, MI, and diabetic nephropathy.
Adverse effects of ARBs
Can cause hypertension, hyperkalemia, decreased GFR, and is teratogenic.
How are ARBs metabolized
Hepatically by CYP 3A4 and 2C9
How do beta blockers affect the RAAS?
Decrease plasma renin concentration and activity, because beta receptors on JG cells release renin.
How do ARBs affect plasma renin concentration, plasma renin activity, angiotensinogen levels, angiotensin I and angiotensin II
Renin increases because of lower BP, which increases ang I and ang II.
ANP and BNP
Atrial naturietic peptide. Released from atria when volume overloaded. BNP Secreted by left ventricle when volume overloaded. Can order BNP levels to determine fluid overload status.
How do ANP and BNP work?
Work by decreasing proximal tubule sodium reabsorption, which causes diuresis. Also causes vasodilation to decrease blood pressure
Effect of ANP and BNP on RAAS?
Decreases renin, aldosterone and ADH.
How do ANP and BNP cause vasodilation
By increasing cGMP in vascular smooth muscle. This decreases available calcium for contraction.
Synthetic recombinant human BNP. Decreases BP by promoting vasodilation (increases cGMP).
Clinical indications for nesiritide?
Short term treatment of acute CHF. Improves cardiac output by vasodilating (which decreases afterload), and decreases preload.
Endothelin produced by vascular endothelium. A potent vasoconstrictor.
How does ET-1 work?
Works by binding to ETb receptor and causing transient vasodilation (by releasing NO), but then binds to ETa and causes direct contraction of vascular smooth muscle.
Other major effect of ET-1?
Causes pulmonary vascular cells to proliferate, thereby causing pulmonary arterial hypertension.
An ET receptor antagonist. Indicated for pulmonary arterial hypertension.
Direct inhibitor of Na, K pump. Prevents Na from exiting cell, accumulates, so Na can't move in to exchange with Ca. Therefore Ca accumulates in the cell and increases contraction.
When to be careful with using digoxin?
With hyperkalemia, which increases digoxin's affinity for Na K pump.
Effect of digoxin on nervous system
Increases parasympathetic outflow at the baroreceptor level.
Electrical effects of digoxin
Early prolongation of AP, but then shortening of AP at therapeutic levels. This results from the increased K conductance due to Ca activated K currents. Also reduced resting membrane potentials because decreased intracellular K.
Toxic effects of digoxin
Calcium stores are overloaded. Delayed after depolarizations occur in ventricles right after action potentials. This causes ventricular bigeminy. At even higher concentrations, ventricles will just fire spontaneously.
Clinical indications for digoxin
Congestive heart failure -- will increase CO
Also used in afib and aflutter. Will control rate.
Adverse effects for digoxin
Yellow-green halos, blurred vision, nausea.
ST segment sags and looks like dali's mustache.
How to treat digoxin overdose
Digoxin immune fab (digibind). But before that, stop or reduce dose.
Phosphodiesterase 3 inhibitor. Causes ionotropy because it increases cAMP (increased PKA, increased SERCA), which increases cardiac contractility. Also vasodilates.
Milrinone effect on vascular system
Vasodilates because cAMP inhibits MLCK, which normally causes contraction.