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What key problems associated with heart failure need to be addressed with drugs? (8)
- increased preload
- increased afterload
- increased or decreased contractility
- myocardial ischemia
- arrhythmia
- chronic chamber remodeling
- chronic neirohormonal activation
- prothrombotic state
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What are indications for use of positive inotropic drugs? (5)
DCM, hert failure (cardiogenic shock, CHF), critical care patients (septic shock), general anesthesia, drug overdosages (chemotherapy, beta blockers)
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How, in general, do positive inotropic drugs work?
increase Ca2+ influx into cardiomyocytes
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What are examples of classes of inotropic drugs? (4)
beta-agonists (catecholamines), digitalis, PDE inhibitors, Ca2+ sensitizers
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Any increase of Ca2+ will increase ___________ but it will also increase ___________, so we must find a balance point.
contractility; arrhythmogenicity
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What is the mechanism of action of digitalis glycosides?
increased cytosolic Ca2+ by inhibition of Na+K+ATPase, thus activating the Na+/Ca2+ exchanger---> more Ca2+ comes in
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What is the mechanism of action of catecholamines as a positive inotrope?
stimulate beta receptors to increase Ca2+ entry
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What is the mechanism of action of PDE III inhibitors as positive inotropic drugs?
prevent degradation of cAMP, keeping Ca2+ channel open in SR
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What is the mechanism of action of Ca2+ sensitizers as positive inotropes?
sensitize contractile filaments to Ca2+ (DOES NOT increase Ca2+ content within the cell)
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What are examples of catecholamine drugs [sympathomimetics]? (5)
dobutamine, dopamine, norepinephrine, epinephrine, phenylephrine (not used)
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Dobutamine mainly affects _______ receptors; at the commonly used dose, it has __(2)__ affects; at higher doses, it causes __________ as well.
beta; + intropic and vasodilatory; vasoconstrictive (begins to activate alpha receptors as well at high doses)
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What is the drug of choice for cardiogenic shock?
Dobutamine (high dose--> vasoconstriction and + inotropy)
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Dopamine mainly affects ______ receptors; its affects include... (3)
beta AND alpha; increased HR, vasoconstriction, + inotropy
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NE affects _______ receptors; its effects include __(2)__, making it a good therapy for __________ patients.
beta1 and alpha1; vasoconstriction and+ inotropy; hypotensive
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What is the drug of choice for cardiac arrest?
epinephrine
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What are the affects of epinephrine? (3)
beta-2 stimulator/ + inotrope, increase HR, vasodilation
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Effects of beta-adrenergic drugs in general. (5)
+ inotropy, increased HR, increased propagation velocity, increased relaxation, increased excitement of normal and subsidiary pacemaker cells
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Effects of alpha-adrenergic drugs in general. (2)
mixed vasoconstriction, increased contractilty
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What are the effects of Pimobendan? (4)
+ inotrope, vasodilatory, Ca2+ sensitization, PDE III inhibition
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What makes pimobendan such a safe drug?
minimal impact on ventricular ectopy- does not increase arrythmias
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Does Pimobendan increase the amount of Ca2+ within the cells?
No- it increases Ca2+ binding by sensitizing the sarcomeres to Ca2+
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What are indications for Pimobendan? (3)
dogs with CHF, mitral valve disease and DCM, +/- extra-label in cats with cardiogenic shock
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What is the mechanism of action of digoxin as a + inotrope?
blocks Na+K+ATPase (normally pumps Na+ out and K+ in), causing Na+ to accumulate within the cell--> increased water content, causing cells to swell and burst--> to prevent this, cell activates the Na+Ca2+ exchanger--> increase in free Ca2+ and increased contractility
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What are the effects of digitalis glycosides (digoxin)? (5)
mild + inotrope, increase vagal tone/ decreased SNS tone, decreased HR (antiarrhythmic), blocks AV node, [side effect] pro-arrhythmic related to Ca2+ influx
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What is the major indication for digoxin?
control HR in afib (delays conduction of atrial impulses across AV node)
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What are contraindications of digoxin? (6)
ventricular ectopy, renal failure, brady-arrhythmias, diastolic heart failure, low K+, GI disease
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What are potential adverse effects of digoxin? (3)
anorexia, GI signs, arrhythmias
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When should you monitor serum conc of digoxin? (ie. when is the trough level)
8-12 hrs post pill
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What electrolyte conc can affect the potential toxicity of digoxin?
the higher the serum [K+], the less toxic digoxin is (DON'T GIVE IT TO A HYPOKALEMIC ANIMAL)
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How is digoxin metabolism/removed from body? How is the clinically significant?
renally; decrease dose in renal failure or when given concurrently with another drug excreted by renal mechanisms
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Increased preload leads to ________; this is called __________.
CHF; backward failure (congestion)
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Abnormal ______ activation increases venous pressure.
RAAS
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Increased venous and capillary pressure leads to __(2)__.
edema and cavity effusions
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How are diuretics useful in heart failure?
increase formation of urine, reduce absorption of Na+/Cl-/K+/Mg2+ and water--> decrease blood volume to prevent overload
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What is the main indication for diuretics?
CHF
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What are the types of diuretics, and what does each block? (3)
- loop diuretics: block Na+K+2Cl- symporter in LoH
- thiazides: block Na+Cl- co-transporter in LoH and distal tubule
- Aldosterone receptor blockers: work in collecting duct
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What are the most effective of all diuretics?
loop diuretics
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Describe the mechanism of action of Furosemide.
90% binds to albumin--> actively secreted in proximal tubule into tubular lumen--> carried to LoH--> inhibits Na+K+2Cl- symporter--> Cl-, Na+, K+, and water are lost in urine
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What are examples of each type of diuretic?
- Loop diuretic: Furosemide
- Thiazide: hydrochlorothiazide
- Aldosterone receptor blocker: Spironolactone
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What is the mechanism of action of thiazides, such as Hydrochlorothiazide?
inhibit Na+ and H2O reabsorption in distal tubules
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Compare the potency of loop diuretics to thiazides.
thiazides are less potent and longer-actin because there is only 6-12% of the Na+ left by the time the UF gets to the distal tubule (a lot has already been reabsorbed)
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What is the mechanism of action of spironolactone?
antagonizes effects of aldosterone distally, inhibiting RAAS (and remodeling associated with RAAS)
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What is the main use of spironolactone?
primarily used as a cardioprotective drug by inhibiting RAAS
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What are the high-ceiling and low-ceiling diuretics? When are each used?
- High-ceiling: loop diuretics- CHF
- Low-ceiling: thiazides- sequential nephron blockade/add on; K+ sparing diuretics (Spironolactone)- cardioprotection/add on
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What is sequential nephron blockade?
use multiple diuretics (loop diuretics and thiazide) to block several regions of the nephron for maximal effect of the diuretics
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What are strategies to overcome diuretic resistance?
increase dose (also increases side effects, so beware), switch to Torasemide, add SQ injections, sequential nephron blockade (ie. add thiazide)
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What are potential causes of diuretic resistance? (9)
severe heart failure and decreased CO (kidney not getting perfused), NSAIDs, excess diuresis (and now dehydrated), decreased renal blood flow, aldosterone-induced hypertrophy of epithelial cells in distal nephron, decreased GI absorption of drug, hypoalbuminemia (needed to bind in glomerulus), aldosterone escape, activation of RAAS and SNS (increased Na+ reabsorption in proximal and distal tubules)
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How does excessive diuresis cause diuretic resistance?
sometimes we initiate too much diuresis initially and dehydrate the animal--> delivery of blood to the kidneys is abnormal--> apparent resistance to diuretics
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What are the potential adverse effects of diuretics, and what process leads to each? (6)
- RAAS activation: progression of heart disease/ cardiac remodeling
- Loss of K+: increased digoxin toxicity
- Loss of K+, Mg2+, Ca2+, Cl-: muscle weakness, arrhythmias, alkalemia
- Volume depletion (low CO and renal perfusion): systemic hypotension, renal failure
- Interaction with other cardiac drugs: toxicity or decreased efficacy
- PU/PD
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What are causes of increased afterload? (5)
hypertrophic obstructive cardiomyopathy, semilunar valve stenosis, systemic hypertension, "relative" hypertension (advanced myocardial disease, leading to high sensitivity to afterload), pulmonary hypertension
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What drug classes do we use to combat increased afterload? (5)
beta blockers, calcium channel blockers, ACE inhibitors, specific pulmonary arterial vasodilators, nitrates
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Beta1 blockers affect the ___________; beta2 blockers affect __(2)__.
myocardium; peripheral vessels and lungs (bronchial walls)
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What are the effects of beta-blockers? (5)
decrease SA node discharge, decreased AV node discharge (neg chronotrope), decreased contractility (neg inotrope), decreased myocardial oxygen demand (anti-ischemic), pro-arrhythmic
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Substantial/persistent tachycardia leads to __________ with _________ because filling goes down and contraction is faster.
decreased CO; fibrillation
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What does excess beta stimulation lead to?
down-regulation and internalization of cardiac beta-receptors--> cardioprotective BUT if exercising or need a sympathetic push, the heart's response is decreased and exercise intolerance occurs
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What receptors are affected by:
Propranolol-
Atenolol/Metoprolol-
Esmolol-
Carvedilol-
- Propranolol- beta 1 and 2
- Atenolol/Metoprolol- beta 1 (cardioselective)
- Esmolol- beta 1 (ultra-short-acting)
- Carvedilol- beta 1 and 2, alpha, antioxidant, antiproliferative (cardioprotective)
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What are potential adverse effects of beta blockers, and what causes each? (4)
- Bradycardia (beta1): weakness, collapse
- Hypotension (beta 1 and 2): weakness, collapse
- Decreased systolic function (beta1): weakness, collapse, worsening of heart failure
- Bronchospasm (beta2): coughing, wheezing
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Why shouldn't you give beta blockers to patients with primary respiratory disease?
beta-2 blockers cause bronchoconstriction and can lead to respiratory distress
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What are indications for use of beta blockers? (6)
- hypertrophic obstructive cardiomyopathy
- pulmonic/aortic stenosis
- antiarrhythmic effects
- HR control in A fib
- cardioprotection in canine cardiomyopathy
- hyperthyroidism
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What are the beneficial mechanisms of beta blockers? (5)
neg inotrope, neg chronotrope, anti-ischemic, slows AV nodal conduction, decreased neurohormonal activation
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What drug is normally used in semi-lunar valve stenosis? Why?
Atenolol- decreased dynamic outflow tract obstruction, neg inotrope, control of HR during exercise
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What beta blocker is preferred in cats and in dogs to reduce the number of premature ventricular contraction (VPCs)?
- Cats- Atenolol (pure beta blocker)
- Dogs- Sotalol (K-channel antagonist, beta blocker)
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What are the downsides to using Sotalol to treat VPCs in dogs? (2)
negative inotropy (dogs w/ cardiomyopathy), pro-arrhythimic
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What patients should you NOT use beta blockers in? (2)
congestive heart failure ("wet" patients), patients with systolic dysfunction
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How do you dose beta-blockers?
start at a very low dose (1/10 of target dose) and uptitrate dose over several weeks
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What drug classes are used to manage impaired diastolic function, myocardial ischemia, and supraventricular tachycardia? (2)
beta blockers, Ca2+ channel blockers
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What is the mechanism of action of Ca2+-channel blockers?
decrease magnitude of Ca2+ (through L-type channels) and act by depressing the physiologic effects of calcium
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What are the 2 major effects of Ca2+-channel blockers?
peripheral vasodilation, negative inotropic effects in heart
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What are the physiologic effects of Ca2+ influx? (3)
depolarization of SA and AV nodes, myocardial contraction (inotropy), constriction of vascular smooth muscles
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What are the 2 groups of Ca2+-channel blockers and what are the effects of each?
- Dihydropyridines: vascular selectivity (vasodilation)
- Non-dihydropyridines: effects nodal tissues and myocardium (not so much on vessels)
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What specific drug is a commonly used dihydropyridine (Ca2+-channel blocker), and what is it commonly used for?
Amlodipine (Norvasc)- systemic arterial hypertension in dogs and cats
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What specific drug is a non-dihydropyridine (Ca2+-channel blocker), and what is it commonly used for?
Diltiazem; decreases HR (decreases AV node conduction), mild neg inotrope (neg effect)
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Most calcium-channel blockers have __________ metabolism.
hepatic
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What are indications for using calcium-channel blockers, and what causes each effect? (5)
- Atrial tachyarhythmia: decreases AV node conduction
- Re-entrant SVTs: AV node depression
- Feline HCM: increases lusitropy
- Systemic hypertension: peripheral vasodilation
- CHF: reduced afterload (dogs)
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What are potential adverse effects of calcium-channel blockers, and what is a clinical manifestation of each? (4)
- Bradycardia: weakness, collapse
- Hypotension: weakness, collapse
- Decreased systolic function: weakness, collapse, worsening heart failure
- Bitter taste and erratic absorption: inappetence, weight loss, salivation
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What is the drug of choice for arrhythmias in dogs?
Diltiazem
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What drugs are considered cardioprotective (antiremodeling drugs)? (3)
ACE inhibitors, beta blockers, spironolactone
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Cardioprotective drugs are mostly used in _______________; benefits are only seen after _____________.
occult canine cardiomyopathy (DCM); long-term therapy
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What are clinical indications to use cardioprotective drugs? (11)
[RAAS, excessive SNS traffic, excess vasopressin, cytokine cascade] clinical signs of these systems being activated: gallop sound, cyanosis, pale MMs, jugular distention, tachycardia, increased BNP, low Na+, cardiac cachexia (cytokine activation), CHF (preload elevation) (RAAS), dilation of cardiac chambers, ascites
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What are 2 examples of ACE inhibitors?
Enalapril, Benazepril
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What are indicators of a prothrombotic state? (3)
LA enlargement, dysfunction, "smoke" on echo
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What is the most common disease associated with a prothrombotic state?
cats with HCM--> feline arterial thromboembolism (FATE)--> saddle thrombus
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What drugs are used to manage a prothrombotic state? (2)
Plavix, +/- Aspirin
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What are the stages of heart failure?
- Stage A: "at risk", no current evidence of dz
- Stage B: heart dz present; B1 normal heart size, B2 remodeling and cardiomegaly
- Stage C: current or past CHF
- Stage D: refractory CHF (additional therapies or higher doses needed)
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What is the therapeutic plan for CHF in HOSPITAL?
- Furosemide
- Oxygen
- Nitroglycerine (topical)
- Sedation (butorphanol)
- Pimobendan (dogs)
- [Horses- oxygen and Furosemide only]
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What drug should you add to you therapeutic plan for CHF when you are dealing with cardiogenic shock?
Dobutamine for increased inotropy
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What is your therapeutic plan for CHF in HOME? (5)
- Pimobendan
- Ace-inhibitor
- Spironolactone
- Furosemide
- Exercise modulation
- [+/- digoxin, diltiazem, sildenafil, potassium]
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What dietary modifications are usually instituted with CHF? (3)
sodium restriction, omega-3 fatty acids, taurine (cats only)
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Describe the mechanism of action of Pimobendan.
PDEIII inhibitor--> cAMP is not degraded--> cAMP keeps Ca2+ channel open and activates PKA, which phosphorylates phospholamban--> increased cytosolic Ca2+ + increased uptake by SERCA--> increased inotropy and lusitropy; also sensitizes contractile filaments to Ca2+
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What are the effects of Dobutamine on HR, arrhythmogenicity, inotropy, AVN conduction, RBF, and SVR?
Increased HR, arrhythmogenicity, inotropy, AVN conduction, and RBF; decreased SVR (at commonly used dose)
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What is the effect of diuretics on preload, afterload, SVR, HR, and inotropy?
Decreases preload, afterload, SVR, and inotropy (loss of Ca2+ in urine); Increases HR
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Despite the fact that urine volume does increase considerably after administration of a diuretic, why might GFR deteriorate and BUN/Cre increase?
GFR deteriorates because CO decreases due to decreased plasma volume,leading to decreased renal perfusion; BUN/Cre increase initially due to contracted plasma volume (pre-renal azotemia)... renal failure can result due to decreased RBF if not monitored closely.
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Explain the cardioprotective effects of fish oil and how they achieve this.
Omega-3 fatty acids (EPA and DHA) prevent cardiac cachexia in dogs and reduce the number of ventricular ectopic beats in Boxers with RAAV; they work by antagonizing the cytokine cascade
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Explain why the administration of nitroglycerine or sodium nitroprusside will lead to a reduction of pulmonary edema in a cat with severe HCM.
NTG and nitroprusside are direct-acting vasodilators; nitrates work by activating guanylate cyclase--> increasing cGMP--> inhibiting Ca2+-MLCK interaction--> vasodilation; decrease pulmonary edema by decreasing venous return, thus decreasing RV pressure and lowering pulmonary hypertension
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What is "aldosterone escape", and what are the long term consequences?
the inability of ACE inhibitor therapy to reliably suppress aldosterone release; thought to be mediated byK+ dependent aldosterone secretion (unrelated to RAAS); consequences are that cardiac remodeling may take place and worsen heart failure
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What can we do to combat adolsterone escape?
add a mineralocorticoid antagonist in the txt of heart failure- Spironolactone (K+ sparing and cardioprotective)
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A dog with pulmonic valve stenosis is overdosed on atenolol. What effects might you expect on HR, heart function, and systemic BP?
bradycardia--> decreased CO--> weakness, collapse; decreased systolic function due to decreased inotropy; decreased systemic BP due to decreased CO
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A cat on a special homemade vegan diet has signs of L-CHF. Echo shows dilated LV and poor systolic function. How do you proceed?
furosemide, oxygen, nitroglycerine, sedation, and taurine supplementation
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