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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
- chronic chamber remodeling
- chronic neirohormonal activation
- prothrombotic state
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)
How, in general, do positive inotropic drugs work?
increase Ca2+ influx into cardiomyocytes
What are examples of classes of inotropic drugs? (4)
beta-agonists (catecholamines), digitalis, PDE inhibitors, Ca2+ sensitizers
Any increase of Ca2+ will increase ___________ but it will also increase ___________, so we must find a balance point.
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
What is the mechanism of action of catecholamines as a positive inotrope?
stimulate beta receptors to increase Ca2+ entry
What is the mechanism of action of PDE III inhibitors as positive inotropic drugs?
prevent degradation of cAMP, keeping Ca2+ channel open in SR
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)
What are examples of catecholamine drugs [sympathomimetics]? (5)
dobutamine, dopamine, norepinephrine, epinephrine, phenylephrine (not used)
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)
What is the drug of choice for cardiogenic shock?
Dobutamine (high dose--> vasoconstriction and + inotropy)
Dopamine mainly affects ______ receptors; its affects include... (3)
beta AND alpha; increased HR, vasoconstriction, + inotropy
NE affects _______ receptors; its effects include __(2)__, making it a good therapy for __________ patients.
beta1 and alpha1; vasoconstriction and+ inotropy; hypotensive
What is the drug of choice for cardiac arrest?
What are the affects of epinephrine? (3)
beta-2 stimulator/ + inotrope, increase HR, vasodilation
Effects of beta-adrenergic drugs in general. (5)
+ inotropy, increased HR, increased propagation velocity, increased relaxation, increased excitement of normal and subsidiary pacemaker cells
Effects of alpha-adrenergic drugs in general. (2)
mixed vasoconstriction, increased contractilty
What are the effects of Pimobendan? (4)
+ inotrope, vasodilatory, Ca2+ sensitization, PDE III inhibition
What makes pimobendan such a safe drug?
minimal impact on ventricular ectopy- does not increase arrythmias
Does Pimobendan increase the amount of Ca2+ within the cells?
No- it increases Ca2+ binding by sensitizing the sarcomeres to Ca2+
What are indications for Pimobendan? (3)
dogs with CHF, mitral valve disease and DCM, +/- extra-label in cats with cardiogenic shock
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
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
What is the major indication for digoxin?
control HR in afib (delays conduction of atrial impulses across AV node)
What are contraindications of digoxin? (6)
ventricular ectopy, renal failure, brady-arrhythmias, diastolic heart failure, low K+, GI disease
What are potential adverse effects of digoxin? (3)
anorexia, GI signs, arrhythmias
When should you monitor serum conc of digoxin? (ie. when is the trough level)
8-12 hrs post pill
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)
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
Increased preload leads to ________; this is called __________.
CHF; backward failure (congestion)
Abnormal ______ activation increases venous pressure.
Increased venous and capillary pressure leads to __(2)__.
edema and cavity effusions
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
What is the main indication for diuretics?
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
What are the most effective of all diuretics?
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
What are examples of each type of diuretic?
- Loop diuretic: Furosemide
- Thiazide: hydrochlorothiazide
- Aldosterone receptor blocker: Spironolactone
What is the mechanism of action of thiazides, such as Hydrochlorothiazide?
inhibit Na+ and H2O reabsorption in distal tubules
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)
What is the mechanism of action of spironolactone?
antagonizes effects of aldosterone distally, inhibiting RAAS (and remodeling associated with RAAS)
What is the main use of spironolactone?
primarily used as a cardioprotective drug by inhibiting RAAS
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
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
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)
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)
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
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
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
What drug classes do we use to combat increased afterload? (5)
beta blockers, calcium channel blockers, ACE inhibitors, specific pulmonary arterial vasodilators, nitrates
Beta1 blockers affect the ___________; beta2 blockers affect __(2)__.
myocardium; peripheral vessels and lungs (bronchial walls)
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
Substantial/persistent tachycardia leads to __________ with _________ because filling goes down and contraction is faster.
decreased CO; fibrillation
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
What receptors are affected by:
- 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)
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
Why shouldn't you give beta blockers to patients with primary respiratory disease?
beta-2 blockers cause bronchoconstriction and can lead to respiratory distress
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
What are the beneficial mechanisms of beta blockers? (5)
neg inotrope, neg chronotrope, anti-ischemic, slows AV nodal conduction, decreased neurohormonal activation
What drug is normally used in semi-lunar valve stenosis? Why?
Atenolol- decreased dynamic outflow tract obstruction, neg inotrope, control of HR during exercise
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)
What are the downsides to using Sotalol to treat VPCs in dogs? (2)
negative inotropy (dogs w/ cardiomyopathy), pro-arrhythimic
What patients should you NOT use beta blockers in? (2)
congestive heart failure ("wet" patients), patients with systolic dysfunction
How do you dose beta-blockers?
start at a very low dose (1/10 of target dose) and uptitrate dose over several weeks
What drug classes are used to manage impaired diastolic function, myocardial ischemia, and supraventricular tachycardia? (2)
beta blockers, Ca2+ channel blockers
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
What are the 2 major effects of Ca2+-channel blockers?
peripheral vasodilation, negative inotropic effects in heart
What are the physiologic effects of Ca2+ influx? (3)
depolarization of SA and AV nodes, myocardial contraction (inotropy), constriction of vascular smooth muscles
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)
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
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)
Most calcium-channel blockers have __________ metabolism.
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)
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
What is the drug of choice for arrhythmias in dogs?
What drugs are considered cardioprotective (antiremodeling drugs)? (3)
ACE inhibitors, beta blockers, spironolactone
Cardioprotective drugs are mostly used in _______________; benefits are only seen after _____________.
occult canine cardiomyopathy (DCM); long-term therapy
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
What are 2 examples of ACE inhibitors?
What are indicators of a prothrombotic state? (3)
LA enlargement, dysfunction, "smoke" on echo
What is the most common disease associated with a prothrombotic state?
cats with HCM--> feline arterial thromboembolism (FATE)--> saddle thrombus
What drugs are used to manage a prothrombotic state? (2)
Plavix, +/- Aspirin
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)
What is the therapeutic plan for CHF in HOSPITAL?
- Nitroglycerine (topical)
- Sedation (butorphanol)
- Pimobendan (dogs)
- [Horses- oxygen and Furosemide only]
What drug should you add to you therapeutic plan for CHF when you are dealing with cardiogenic shock?
Dobutamine for increased inotropy
What is your therapeutic plan for CHF in HOME? (5)
- Exercise modulation
- [+/- digoxin, diltiazem, sildenafil, potassium]
What dietary modifications are usually instituted with CHF? (3)
sodium restriction, omega-3 fatty acids, taurine (cats only)
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+
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)
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
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.
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
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
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
What can we do to combat adolsterone escape?
add a mineralocorticoid antagonist in the txt of heart failure- Spironolactone (K+ sparing and cardioprotective)
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
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