CVPR 03-28-14 10-11am Inotropic Agents in CHF slides - Port

Question 1

Dogma of Positive Inotropic Agents

Answer 1

Positive Inotropy = Increased effect [Ca2+]

Question 2

Positive Inotropic Agents

Answer 2

Cardiac glycosides, Beta receptor agonists, Phosphodiesterase inhibitors, Ca2+ sensitizing agents

Question 3

Adrenergic system in HF & Beta-adrenergic blockers

Answer 3

Pts w/HF have increased adrenergic drive as manifest by high concentrations of circulating catecholamines, esp. NE (norepinephrine)…for this reason, beta blockers are used

Question 4

Beta-adrenergic blockers – action

Answer 4

Competitively block endogenous catecholamines (e.g., NE) from interacting w/Beta-adrengeric receptors —> 1. Reduce metabolic demands associated with increased HR and myocardial contractility….. 2. Prevent the direct toxic effects that high amounts of catecholamines have on cardiomyocytes….. 3. Prevent norepi-induced beta-receptor down-regulation and/or desensitization, possibly allowing receptor density to return towards normal abundances so pt can regain sensitivity to endogenous catecholamines and/or therapeutic beta-agonists

Question 5

Negative inotropic potential of Beta-blockers

Answer 5

Previously, beta-blockers were contraindicated in HF b/c of their prominent negative inotropic potential; still true for 1st gen. beta-blockers like propranolol…However, newer generations (2nd & 3rd) w/out significant negative inotropic effects now exist, and have proven highly useful in treatment of HF (current “gold standard” therapy).

Question 6

Beta blockers approved in HF

Answer 6

Metoprolol & carvedilol, in both generic “standard” formulations and “branded” extended release formulations (once a day) of each drug (Toprol XL & Coreg CR, respectively)….both have been shown to dramatically improve the symptoms of HF

Question 7

Metoprolol vs. Carvedilol targets

Answer 7

Metoprolol is a Beta-1-AR selective agent…..Carvedilol is a relatively nonselective inhibitor of both B1- and B2-ARs, as well as alpha-1-AR (—> vasodilatory effects)

Question 8

Beta-blockers in HF- Effects

Answer 8

Increase CO, EF, and submaximal exercise tolerance…..Reduce pulmonary artery & LV end-diastolic pressure —> change in cardiac dimension (esp. reduction in left ventricular and diastolic volume)…..Prolonged survival in pts w/NHYA Class II-IV HF (though perhaps not Class IV w/very limited cardiac function —> unable to up-titrate dose of beta-blocker necessary to achieve effects)

Question 9

Caveats of Beta-blocker use in HF

Answer 9

HF pts have limited cardiac reserve, so dose of beta-blocker must be carefully “up-titrated” over several weeks to achieve target dose…..many pts are unable to ever reached target dose (likely b/c of necessity of intensive clinical management during the up-titration phase, as well as the fact that beta-blockers often make people feel worse 1st, before they feel better) = non-responders (measured by EF)

Question 10

Speed of effect of Beta-Blockers

Answer 10

Act rapidly at their target site (Beta-AR), but salutary effects often take months (3-12) to manifest, due to the fact that beta-blocker-mediated improvements are secondary to cardiac (reverse) remodeling (reducing cardiac ventricular dimension —> smaller, less dilated heart that is more metabolically & mechanically efficient)

Question 11

Current medical therapy of HF includes…

Answer 11

…diuretics, ACE-I/ARBs + newer gen. beta-blockers = thus, complex

Question 12

Genetic polymorphisms in adrenergic receptors

Answer 12

Contribute to progression & therapeutic effectiveness of individual beta-blocking agens; EX: gain of function B1-AR variant & loss of function a2c-AR variant are more prevalent in HF pts

Question 13

Digitalis

Answer 13

From plant Digitalis purpurea; Generally refers to extracted compounds, digoxin & digitoxin (members of cardiac glycosides class)

Question 14

Cardiac glycosides –Indications for use in HF

Answer 14

1. Treatment of chronic HF in presence of atrial fibrillation, 2. Treatment of chronic HF with confirmed S3 gallop

Question 15

Benefits of cardiac glycosides (digitalis)

Answer 15

Use in CHF w/ normal sinus rhythm is controversial; BUT, use in pts w/Class II-III HF limited to systolic dysfunction derive benefits from cardiac glycosides above & beyond that afforded by ACE-Is & diuretics— benefits include reduced probability of worsening HF, maintenance of exercise capacity, and pt perception of better quality of life

Question 16

Chemistry of cardiac glycosides

Answer 16

Cardiac glycosides are a combination of an aglycone and 1 to 4 carbohydrate molecules. The aglycone is a 3-, 14-dihydrocyclopentanoperhydrophenanthrene with a 17-lactone ring. The nucleus of the aglycone closely resembles the structure of steroid molecules. The carbohydrate moieties are attached to the aglycone at the C3 position.

Question 17

Difference between digoxin & digitoxin

Answer 17

Digoxin differs from digitoxin by the presence of a hydroxyl at C12. —> Digoxin has shorter half-life & is renally excreted, while Digitoxin is eliminated via the liver.

Question 18

Digitals & morbidity

Answer 18

Digitalis has been shown to have NO EFFECT on overall mortality [thus, today¸…..There was some reduction in deaths due to worsening HF, but also a increase in incidence of sudden death due to arrhythmias…..Statistically significant increased risk of death in women but not men… Also, there is a modest decrease in hospitalization, providing at least economic reasons for use of cardiac glycosides

Question 19

Mechanism of Action of Cardiac Glycosides:

Answer 19

Positive inotropes = ultimately act by increasing effective intracellular Ca2+ ….. Digitalis binds selectively & saturably to the -subunit of the heterodimeric Na+/K+/ATPase —> decreases rate of extrusion of intracellular Na+ —> decreases trans-sarcolemmal (SL) sodium gradient —> decrease in the rate of efflux of intracellular Ca2+ as well as an increase in the rate of influx of extracellular Ca2+ facilitated by the bi-directional Na+/Ca++ exchanger (3Na+ to 1Ca2+)

Question 20

Cardiac glycosides & [Ca2+]

Answer 20

Ultimate positive inotropic mechanism is to increase the effective [Ca2+] —> enhanced physical interaction of actin & myosin (cross-bridge formation).

Question 21

Negative effects of Cardiac glycosides

Answer 21

Increase intravascular Ca2+ as well as intracellular; Increase sympathetic tone by activation of CNS descending pathways; Decrease NE reuptake

Question 22

Positive effects of Cardiac glycosides

Answer 22

Increase parasympathetic (vagal) tone; Increase renal blood flow thereby decrease circulating volume & decreasing RAAS; Positive inotropic effect decreases sympathetic tone by resolving the symptoms of HF (decrease adrenergic & RAAS system drive)

Question 23

Contraction Initiation Overview

Answer 23

In relaxed state, actin & myosin are sterically hindered from interacting by tropomyosin …. Contraction is initiated by AP traveling down sarcolemma causing cellular depolarization due to fast inward Na+ current, (INa), followed by the slow inward Ca2+ current. (Isi)—> The influx of Ca2+ induces a further release of Ca2+ from the SR, increasing [Ca2+]i —> increased binding of Ca2+ to troponin-C —> weakens interaction of troponin-I w/ actin so that tropomyosin can move laterally & permit myosin to act as an ATPase in the presence of actin.

Question 24

Relaxation of Contraction Overview

Answer 24

Relaxation occurs when intracellular Ca2+ levels decline due to 1. active reuptake by SR Ca++/ATPase, 2. exchange for Na+ by SL Na+/Ca++ exchanger, and 3. active pumping out of cell by SL Ca++/ATPase.

Question 25

Myocardial Effects of Cardiac glycosides

Answer 25

Modestly increase myocardial contractility, i.e. positive inotropic agents…..The salutary effects of digitalis in treatment of HF are due primarily to this

Question 26

PV Loops & Digitalis

Answer 26

Improve ejection fraction (move curve to the left, towards normal)

Question 27

Starling curve & Digitalis

Answer 27

Move up & to the left…. Remove excess fluid & increase CO

Question 28

Manifestations of Positive Inotropic effects of Cardiac glycosides

Answer 28

Increased CO, Increased rates of pressure development, contraction, and relaxation, Increased myocardial EF (i.e., % of ventricular emptying), Increased SV, and Decreases in systemic vascular resistance (SVR), right atrial pressure (RAP), and in left ventricular end systolic and diastolic volumes (LVESV, LVEDV).

Question 29

Cardiac glycosides positive inotropic effect ---> Decreased ventricular volumes -->

Answer 29

Ultimately result in decreased transmural wall pressure (P = T x (1/R1 + 1R2); Law of Laplace) and thus reduce myocardial work.

Question 30

Myocardial oxygen consumption (MVO2) & Cardiac glycosides

Answer 30

Beneficial changes in MVO2 from cardiac glycosides depend on initial degree of pathophysiology, but are often limited, at least in comparison to several newer positive inotropes [phosphodiesterase (PDE) inhibitors]

Question 31

P-V loop with cardiac glycosides

Answer 31

Cardiac glycosides tend to bring failing heart back towards normal physiology….. PV loop produced by failing heart is far to the right of PV loop produced by the normal heart, indicating both end systolic & diastolic volumes are much greater in the failing heart…. Treatment w/cardiac glycosides tends to normalize these values, shifting the pressure volume loop to the left.

Question 32

Frank- Starling curve with cardiac glycosides

Answer 32

Cardiac glycosides tend to bring failing heart back towards normal physiology….. Both end systolic & diastolic volumes are much greater in the failing heart…. Treatment w/cardiac glycosides tends to normalize these values, shifting the Frank-Starling curve "up and to the left"

Question 33

Vascular and Central Effects of Cardiac Glycosides

Answer 33

Mechanism that increases inotropy (increased intracellular Ca2+) also increases vascular tone…..Also, indirect effects of digitalis mediate increased sympathetic tone by activation of central (CNS) descending pathways ---> increased amount of NE released as well as sometimes decreased NE reuptake and/or increased post-synaptic sensitivity to NE ---> NOT BENEFICIAL for treatment of CHF…..Take home message: over time, the beneficial positive inotropic effects of cardiac glycosides decreases overall sympathetic tone by resolving the symptoms of CHF….Lastly, cardiac glycosides increase parasympathetic tone (vagal tone).

Question 34

Renal Effects of Cardiac glycosides

Answer 34

Cardiac glycosides are both diuretics & natriuretics…..The increase in CO leads to increased renal blood flow (RBF), glomerular filtration rate (GFR) and eventually, to a decrease in circulating blood volume….. The resolution of the symptoms of CHF (including reduced sympathetic tone) act to resolve imbalances in the renin-angiotensin system and to decrease aldosterone levels, which in turn further reduces Na+/water retention.

Question 35

Electrophysiological Effects of Cardiac glycosides - complexity

Answer 35

The effects of digitalis on the myocardial conduction system are complex, non-uniform, and far from intuitive….. Plus, they are both time- and concentration-dependent, and vary with the pathophysiology of the heart & with differences in electrolyte balance.

Question 36

Electrophysiological Effects of Digitalis – overview

Answer 36

SA node = decreases conduction velocity….. AV node = decreases conduction velocity, increase refractory period ….. Purkinje fibers = increases excitability….. Ventricular muscle = decrease refractory period…… i.e., Calm down nodes, rev up Purkinje fibers & ventricular muscle

Question 37

Electrophysiological Effects of Digitalis on Purkinje fibers

Answer 37

Resting potential is increased (less negative), which leads to decreased phase 0 (Vmax); Rate of phase-4 depolarization is increased (---> delayed afterdepolarization, premature ventricular contraction)

Question 38

"Delayed after depolarization"

Answer 38

High serum concentrations of digitalis can lead to Ca2+ overload in SR ---> amplifies the normal oscillatory release & reuptake of calcium by the SR; If amplitude of Ca2+ oscillation is large enough to depolarize the cell beyond threshold, it can lead to a coincident transient inward current resulting in an after-depolarization and, often, an after-contraction = key mechanism by which premature ventricular contractions (PVC's) & other forms of ectopy are produced secondary to digitalis toxicity.

Question 39

Important effects of Cardiac glycosides on the AV node

Answer 39

Decrease in conduction velocity and Increase in effective refractory period (ERP) in the AV node…..As with SA node, these effects are modified by the sympathetic & parasympathetic nervous systems (for the most part, vagal influence dominates)….. The increase in the effective refractory period (ERP) of the AV node is the rationale for the use of cardiac glycosides in the treatment of supraventricular tachycardia, atrial flutter, and atrial fibrillation.

Question 40

Important effects of Cardiac glycosides on the Purkinje fibers & specialized atrial conduction fibers

Answer 40

The excitability of Purkinje fibers & specialized atrial conduction fibers is enhanced due to increased rate of rise of phase-4 depolarization…..The increase in automaticity can be proarrhythmic and, at high doses, can cause PVC's, ventricular tachycardia (VT) and ventricular fibrillation and (VF)….. The enhanced conduction velocity in accessory pathways in combo w/ the decrease in effective refractory period are the main reasons why cardiac glycosides are contraindicated in WPW (Wolff-Parkinson-White Syndrome, a condition were there is aberrant A-V conduction bypassing the AV node).

Question 41

Important effects of Cardiac glycosides on ventricular muscle

Answer 41

In ventricular muscle, effective refractory period is generally decreased and automaticity is increased….. Especially true at toxic levels.

Question 42

Electrocardiographic effects of digitalis

Answer 42

1. Increased PR interval, 2. Decreased QT interval, 3. Inversion in T wave polarity…..At toxic, as well as nontoxic doses, there may be marked ST segment depression

Question 43

Pharmacokinetics of digoxin vs. digitalis

Answer 43

Marked differences in terms of dose, bioavailability, half-life, and route of elimination.

Question 44

Steady state of digoxin vs. digitalis

Answer 44

Steady state is not rapidly achieved for either drug ---> B/c of this, a loading or "digitalizing" dose is sometimes given

Question 45

Route of administration of Cardiac glycosides

Answer 45

Parenteral (IV) if necessary (NOT IM, only IV), but generally not the case given that the onset of CHF is slow in progression, so rapidity of onset of max therapeutic effect is usually not an issue….. HOWEVER, when onset of HF is rapid due to MI or other precipitating factors &therapy needs to be instituted immediately, digitalis is of limited usefulness (ability of digitalis to treat HF secondary to acute MI is inversely related to the degree of insult) ---> So, more potent & rapidly acting positive inotropes such as the alpha-adrenergic agonists are usually indicated.

Question 46

Historical Considerations of which cardiac glycosides to use:

Answer 46

1. Half-life (shorter t1/2 of digoxin means steady state can be achieved more quickly & toxic concentrations diminish more rapidly than w/digitoxin)….. 2. Route of elimination (digoxin has limited use in pts w/compromised renal function; Conversely, digitoxin must not be used w/severely limited hepatic function)

Question 47

Agents that slow of AV nodal conduction

Answer 47

Digitalis, Beta blockers, Ca2+ channel blockers ---> often used in conjunction, thus may have many cardiac side effects (arrhythmias, etc.)

Question 48

Preparations of Cardiac glycosides Available for Clinical Use:

Answer 48

Digoxin (Lanoxin) is available in parenteral & PO forms --- tablets or capsules (Lanoxicaps) or as an IV preparation…… Digitoxin (Crystodigin, Purodigin) is available in tablets…. While parenteral Digoxin must not be given IM (only IV), Deslanoside (precursor glycoside) is more soluble & may be given IM.

Question 49

Digitalis Toxicity: causes

Answer 49

Very low therapeutic index & many of its toxic side effects are quite common….One of the more frequent causes of digitalis toxicity is the concurrent administration of non-potassium sparing diuretics: Low serum [K+] increases intracellular [Na+]I & thus intracellular [Ca++]I ---> can contribute to Ca2+ overload…..Digitalis overdose can be fatal & treatment is probably best when administered by a cardiologist in an ICU setting.

Question 50

Non-cardiac symptoms of Digitalis toxicity:

Answer 50

Most common are: anorexia, n/v, H/A, fatigue, etc; Additionally, mental confusion, hallucinations, and in particular, visual disturbances (yellow halo around lights) can occur.

Question 51

Cardiac Symptoms of Digitalis Toxicity:

Answer 51

Several types of ventricular arrhythmias including multifocal PVC's, VT and VF…… AV-block arrhythmia (I, II, or III) - Other drugs that decrease conduction velocity can exacerbate the degree of AV block & ultimately produce cardiac standstill….. Arrhythmias induced by digitalis are most effectively treated w/either phenytoin or lidocaine.

Question 52

1st step in treatment of digitalis toxicity

Answer 52

Discontinue its administration & determine plasma concentration of digitalis & serum potassium

Question 53

Treatment of digitalis toxicity in hypokalemic pt:

Answer 53

VERY SLOW carefully controlled infusion of K+ may be all that is necessary…. Potassium displaces digitalis from myocardial binding sites and, although the actual serum concentration of the glycoside may increase, the effective concentration of the drug at its receptor site is decreased…..If serum [K+] is already high, a further increase may produce complete heart block.

Question 54

Treatment of life-threatening digitalis concentrations (overdose)

Answer 54

Decrease effective cardiac glycoside concentrations by administering digitalis-specific Fab (antibody) fragments (Digibind)…. Fab-digitalis complex is pharmacologically inactive & readily eliminated in urine…..Use of this mode of therapy is predicated upon adequate renal function….. Repeated administration of Fab fragments is potentially antigenic…..Less desirable modes of reversal therapy are the administration of activated charcoal or cholestyramine and hemoperfusion through charcoal or XAD-resin.

Question 55

Drug interactions w/Digoxin

Answer 55

Digoxin is a great example of a pharmacological agent subject to pharmacodynamic changes associated with drug/drug interaction…Underlying reason is its low therapeutic index…Drugs such as antibiotics, Ca2+ channel blockers and antiarrhythmic agents interact with digoxin….Mechanisms of interaction include changes in bioavailability, metabolism, and clearance.

Question 56

Drug Interactions of Digoxin with Quinidine (antiarrhythmic)

Answer 56

Quinidine can increase plasma concentration of digoxin 2- to 4-fold

Question 57

Drug interactions of Digoxin with Non-K+ sparing diuretics

Answer 57

Non-potassium-sparing diuretics may increase digitalis toxicity

Question 58

Drug interactions of Digoxin with - adrenergic agonists

Answer 58

Beta- adrenergic agonists can increase automaticity and thus increase the frequency of ectopy with digoxin treatment

Question 59

Drug interactions of Digoxin with Calcium channel blockers

Answer 59

Calcium entry blockers, which also slow AV conduction, may contribute to or exacerbate existing heart block with digoxin treatment

Question 60

Positive Inotropic Agents other than Cardiac Glycosides - Classes

Answer 60

1. Sympathomimetics w/ -adrenergic agonist activity, with or without -adrenergic Effects….. 2. Phosphodiesterase (PDE) inhibitors

Question 61

Positive Inotropic Agents other than Cardiac Glycosides – properties/when to use

Answer 61

Both classes (sympathomimetic beta-agonists & PDE-I’s), but especially the beta-agonists, are significantly more potent inotropes than cardiac glycosides…. Can be used for patients that fail to respond to digitalis due to severe HF ….. If these inotropic agents are insufficient, no options other than mechanical circulatory support or therapeutic cardiac transplant exist.

Question 62

Examples of Beta-Agonist Inotropic agents

Answer 62

Epinephrine & Norepinephrine (endogenous); Dopamine; Isoproterenol & Dobutamine (synthetic)

Question 63

Shortcomings of Beta-Agonist Inotropic agents

Answer 63

Many are not orally active (epi, NE, dopamine, dobutamine), Very short half-lives, Potently proarrhythmic, Increase significantly myocardial oxygen consumption (MVO2), Administration for more than a few days leads to a marked diminution of efficacy (due to intrxn of agonists w/ -adrenergic receptors causing marked decrease in receptor density & efficiency of coupling of the receptor to its signal transduction pathway = “homologous desensitization”).

Question 64

Issues w/Positive inotropic agents

Answer 64

1. Tachyphylaxis (desensitized & down-regulated)….. 2. Substantially increase MVO2 (increase squeeze but also oxygen needs of the heart ---> could make ischemic condition worse)….. 3. Increase risk of sudden death (arrhythmias)….. 4. Generally not orally active….. 5. Very short plasma half-life

Question 65

Orally active Beta-Agonist Inotropic agents

Answer 65

Prenalterol, pirbuterol, ibopamine, butopamine, & albuterol

Question 66

B2-receptor stimulation --->

Answer 66

Positive inotropic, Bronchodilation, Vasodilation

Question 67

B1-receptors stimulation --->

Answer 67

Positive inotropic, Vasoconstriction

Question 68

Alpha-adrenergic agonists - action

Answer 68

Also produce positive inotropy, by a different mechanism than that of -agonists….. Stimulate phospholipase-C (PL-C) ---> increase turnover of membrane phosphatidylinositides (just like Ang II) ---> Phosphoinositol bisphosophate (PIP2) is broken down to inositol triphosphate (IP3), which stimulates release of intracellular Ca2+ stores, and diacylglycerol (DAG), which stimulates protein kinase-C (PK-C) ---> PK-C, in turn, modulates numerous signal transduction pathways by phosphorylation of target substrates

Question 69

Mechanism of action of Beta-adrenergic agonist

Answer 69

Increased contractility caused by inotropes is a direct consequence of increased [Ca2+]i. Beta-agonists binds beta-adrenergic receptor ---> a conformational change in the receptor is transduced as a signal via a stimulatory guanine nucleotide regulatory protein (Gs) to adenylylcyclase (AC) ---> enzymatically converts ATP to cAMP ---> cAMP (2nd messenger) activates protein kinase-A (PK-A) ---> two particularly important phosphorylation targets of PKA are: a) voltage sensitive calcium channels (VSCC's) in sarcolemmal membrane….. b) phospholamban in SR ---> Both regulate intracellular Ca2+ ---> The influx of Ca++ through L-type calcium channels triggers a much larger release of Ca2+ through Ryanodine receptors (RyRs) [“calcium induced calcium release”] ---> inotropic action

Question 70

Action of voltage sensitive calcium channels (VSCC's)

Answer 70

Regulate intracellular Ca2+ by increasing the slow inward calcium current (Isi)

Question 71

Action of phospholamban

Answer 71

Regulate intracellular Ca2+ by regulating uptake of Ca2+ from cytosol into SR

Question 72

Epinephrine (adrenaline) – what it is & what receptors it effects

Answer 72

Naturally occurring catecholamine w/full agonist potency….. high affinity for both alpha and beta adrenergic receptors…..In heart, positive inotropy is modulated by both Beta1 Beta2 receptors, whereas positive chronotropy is modulated primarily by Beta- receptors

Question 73

Epinephrine (adrenaline) – how & when to give

Answer 73

Drug given IV & used only in acute, critical care settings…... Main indication is during post-cardiopulmonary bypass setting when difficulty in removing the pt from the bypass pump is encountered (epi often used in conjunction w/ IV calcium chloride)

Question 74

Beta1 vs. Beta2 Receptors in failing vs. non-failing heart

Answer 74

Non-failing human ventricular myocardium has ~7% Beta1 % Beta2 receptors….. In HF, there is selective down-regulation of Beta1 receptors, presumably due to high level of endogenous catecholamines (NE); thus, in the failing heart, Beta2 receptors become increasingly important & just treating HF w/a Beta1 selective agonist (as in the past) would ignore a large potential reservoir of effective stimulatory pathway

Question 75

Norepinephrine (Levophed) – receptors/actions

Answer 75

Less potent at Beta2 receptors than Beta2 receptors (~0-fold) (differing frome epinephrine) …. Still a strong positive inotrope, but does not cause peripheral vasodilatation (via Beta2 receptors in the vasculature) characteristic of low dose epinephrine & isoproterenol….. Additionally, NE is a potent Alpha1 agonist & thus a potent vasoconstrictor & mitogen……By the same receptor-mediated pathway, NE decreases the rate of myocardial relaxation and increases myocardial oxygen demand; Indirectly, NE causes release of Ang II (another very potent vasoconstrictor)

Question 76

Dopamine – what & receptors/actions

Answer 76

Both a direct & indirect agonist (release of synaptic NE & blockade of reuptake)…..Modest Beta1 & alpha-adrenergic activities……Unique in this class b/c of its stimulatory actions at dopaminergic receptors ---> markedly enhance splanchnic & renal circulation (---> greater than expected diuresis)

Question 77

Dopamine – when to use

Answer 77

Often used in ICU in combination w/sodium nitroprusside (combo termed a pharmacological "balloon pump")

Question 78

Dosing of Dopamine

Answer 78

Dose of dopamine given correlates closely with its effect…. At lower doses, dopamine is vasodilatory (renal)…. At higher doses, via release of NE, can be potent vasoconstrictor ---> significant increases in afterload

Question 79

Dobutamine – what & receptor/actions

Answer 79

Relatively potent -agonist….. Beta1 selective….. Causes less Beta-receptor down-regulation than other beta agonists of equal efficacy ---> fewer tendencies for tachyphylaxis (sudden decrease in response to a drug)

Question 80

Dobutamine – when to use

Answer 80

IV dobutamine is sometimes used in treatment of severe CHF to reverse a decompensated condition. Typically, given for no more than a few days.

Question 81

Other beta-adrenergic drugs

Answer 81

Differences in agonist potency & receptor subtype selectivity…..Some (isoproterenol) may be useful in short-term therapy of CHF, but mostly limited to treating other disorders

Question 82

Dopamine vs. dobutamine

Answer 82

Dopamine has more of a hemodynamic effect than dobutamine

Question 83

Xanthine derivatives – examples & effect on heart

Answer 83

EX: caffeine & theophylline ---> engender positive inotropic effects

Question 84

PDE Inhibitors - Mechanism of Action

Answer 84

1. Prevent breakdown of cAMP by phosphodiesterase….. 2. Increase affinity of troponin-C for Ca2+…... 3. Increase Ca2+ reuptake by SR (persistent PK-A mediated phosphorylation of phospholamban) ….. 4. Inhibit competitively adenosine receptors (negatively coupled to adenylylcyclase)…..Relative contributions of each of these mechanisms are not fully understood.

Question 85

PDE Inhibitor Classes (3)

Answer 85

1. Bipyridines (amrinone & milrinone) ….. 2. Imidazolones (enoximone & peroximone)….. 3. Benzimidazoles (sulmazole & pimobendane)

Question 86

Advantages of PDE Inhibitors over Beta-agonists

Answer 86

Milrinone & enoximone appear to have few advantages over Beta-agonists other than lack of tachyphylaxis…… One advantage is that for comparable degrees of inotropic stimulation, PDE inhibitors appear to shift MVO2 in direction opposite that of Beta agonists (i.e., appear to affect positively the balance btwn work & oxygen consumption)

Question 87

Side effects of PDE inhibitors

Answer 87

Especially amrinone & milrinone…. Most important: excess mortality (sudden death to arrhythmias; somewhat due to too high of dose used in trials)

Question 88

Role of PDE-I’s

Answer 88

NOT considered first-line therapy in the treatment of mild, chronic CHF, BUT may have role in treating moderate to severe CHF, and possibly useful in pressure overload HF or with PPH ….. Recently, PDE-I’s are being used in combo w/certain beta-blocking agents ---> stimulate inotropy (preserve cAMP levels) while simultaneously blocking deleterious effects of endogenous NE at beta-ARs

Question 89

New direction in HF therapeutics

Answer 89

Cytokine inhibitors (TNF-alpha) = cytokines high in failing heart;….. Peptide antagonists (ET-1; Only in PPH so far)….. New diuretics (BNP; Natrecor) = increase renal function, urinating out salt ….. Metabolic modifiers = shift heart’s use of lipid vs. glucose for ATP….. Cardiac resyncronization therapy (electrical, BV pacing) = training heart to appropriately contract (but $$$)….. Pharmacogenomics/personalized medicine (beta blockers, ACE-I, others… give drug only to those who’d benefit)

Question 90

Metabolic syndrome

Answer 90

A disorder of energy utilization & storage, which increases the risk of developing cardiovascular disease such as HF and diabetes, diagnosed by a co-occurrence of 3 out of 5 of the following medical conditions: abdominal (central) obesity, elevated BP, elevated fasting plasma glucose, high serum triglycerides, and low HDL levels.