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

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Flashcards in CVPR 03-28-14 10-11am Inotropic Agents in CHF slides - Port Deck (90):
1

Dogma of Positive Inotropic Agents

Positive Inotropy = Increased effect [Ca2+]

2

Positive Inotropic Agents

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

3

Adrenergic system in HF & Beta-adrenergic blockers

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

4

Beta-adrenergic blockers – action

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

5

Negative inotropic potential of Beta-blockers

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).

6

Beta blockers approved in HF

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

7

Metoprolol vs. Carvedilol targets

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)

8

Beta-blockers in HF- Effects

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)

9

Caveats of Beta-blocker use in HF

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)

10

Speed of effect of Beta-Blockers

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)

11

Current medical therapy of HF includes…

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

12

Genetic polymorphisms in adrenergic receptors

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

13

Digitalis

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

14

Cardiac glycosides –Indications for use in HF

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

15

Benefits of cardiac glycosides (digitalis)

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

16

Chemistry of cardiac glycosides

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.

17

Difference between digoxin & digitoxin

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.

18

Digitals & morbidity

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

19

Mechanism of Action of Cardiac Glycosides:

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+)

20

Cardiac glycosides & [Ca2+]

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

21

Negative effects of Cardiac glycosides

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

22

Positive effects of Cardiac glycosides

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)

23

Contraction Initiation Overview

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.

24

Relaxation of Contraction Overview

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.

25

Myocardial Effects of Cardiac glycosides

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

26

PV Loops & Digitalis

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

27

Starling curve & Digitalis

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

28

Manifestations of Positive Inotropic effects of Cardiac glycosides

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).

29

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

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

30

Myocardial oxygen consumption (MVO2) & Cardiac glycosides

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]

31

P-V loop with cardiac glycosides

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.

32

Frank- Starling curve with cardiac glycosides

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"

33

Vascular and Central Effects of Cardiac Glycosides

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).

34

Renal Effects of Cardiac glycosides

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.

35

Electrophysiological Effects of Cardiac glycosides - complexity

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.

36

Electrophysiological Effects of Digitalis – overview

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

37

Electrophysiological Effects of Digitalis on Purkinje fibers

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)

38

"Delayed after depolarization"

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.

39

Important effects of Cardiac glycosides on the AV node

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.

40

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

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).

41

Important effects of Cardiac glycosides on ventricular muscle

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

42

Electrocardiographic effects of digitalis

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

43

Pharmacokinetics of digoxin vs. digitalis

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

44

Steady state of digoxin vs. digitalis

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

45

Route of administration of Cardiac glycosides

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.

46

Historical Considerations of which cardiac glycosides to use:

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)

47

Agents that slow of AV nodal conduction

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

48

Preparations of Cardiac glycosides Available for Clinical Use:

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.

49

Digitalis Toxicity: causes

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.

50

Non-cardiac symptoms of Digitalis toxicity:

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.

51

Cardiac Symptoms of Digitalis Toxicity:

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.

52

1st step in treatment of digitalis toxicity

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

53

Treatment of digitalis toxicity in hypokalemic pt:

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.

54

Treatment of life-threatening digitalis concentrations (overdose)

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.

55

Drug interactions w/Digoxin

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.

56

Drug Interactions of Digoxin with Quinidine (antiarrhythmic)

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

57

Drug interactions of Digoxin with Non-K+ sparing diuretics

Non-potassium-sparing diuretics may increase digitalis toxicity

58

Drug interactions of Digoxin with - adrenergic agonists

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

59

Drug interactions of Digoxin with Calcium channel blockers

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

60

Positive Inotropic Agents other than Cardiac Glycosides - Classes

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

61

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

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.

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Examples of Beta-Agonist Inotropic agents

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

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Shortcomings of Beta-Agonist Inotropic agents

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”).

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Issues w/Positive inotropic agents

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

65

Orally active Beta-Agonist Inotropic agents

Prenalterol, pirbuterol, ibopamine, butopamine, & albuterol

66

B2-receptor stimulation --->

Positive inotropic, Bronchodilation, Vasodilation

67

B1-receptors stimulation --->

Positive inotropic, Vasoconstriction

68

Alpha-adrenergic agonists - action

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

69

Mechanism of action of Beta-adrenergic agonist

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

70

Action of voltage sensitive calcium channels (VSCC's)

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

71

Action of phospholamban

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

72

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

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

73

Epinephrine (adrenaline) – how & when to give

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)

74

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

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

75

Norepinephrine (Levophed) – receptors/actions

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)

76

Dopamine – what & receptors/actions

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)

77

Dopamine – when to use

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

78

Dosing of Dopamine

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

79

Dobutamine – what & receptor/actions

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)

80

Dobutamine – when to use

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

81

Other beta-adrenergic drugs

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

82

Dopamine vs. dobutamine

Dopamine has more of a hemodynamic effect than dobutamine

83

Xanthine derivatives – examples & effect on heart

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

84

PDE Inhibitors - Mechanism of Action

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.

85

PDE Inhibitor Classes (3)

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

86

Advantages of PDE Inhibitors over Beta-agonists

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)

87

Side effects of PDE inhibitors

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

88

Role of PDE-I’s

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

89

New direction in HF therapeutics

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)

90

Metabolic syndrome

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.

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