CVPR 03-28-14 10-11am Adrenergic & Angiotensin Block in CHF in CHF slides - Port

Question 1

Physiological vs. pathological hypertrophy

Answer 1

Physiological = good (athletic, etc.); shorter & fatter (concentric hypertrophy) ….Pathological = bad (HF); longer and skinnier (eccentric hypertrophy)

Question 2

Gender & Age – HF

Answer 2

Women protected pre-menopausally; then, after menopause, females catch up to men

Question 3

Primary causes of HF

Answer 3

CAD > HTN > Valve disease > specific cardiomyopthay > idiopathic > myocarditis

Question 4

NYHA Class I HF – Treatment

Answer 4

Asymptomatic HF; Vasodilators/ACE-I/ARBs

Question 5

NYHA Class II HF - Treatment

Answer 5

Symptomatic HF; Vasodilators/ACE-I/ARBs; Diuretics (lower dose); Beta-blockers, Digoxin

Question 6

NYHA Class III HF – Treatment

Answer 6

Severe HF; Vasodilators/ACE-I/ARBs; Diuretics (higher dose); Beta-blockers, Digoxin; Aldosterone antagonists

Question 7

NYHA Class IV HF - Treatment

Answer 7

Refractory HF; Vasodilators/ACE-I/ARBs; Diuretics (even higher dose); Beta-blockers, Digoxin; Aldosterone antagonists; CRT/Assist devices/transplant

Question 8

Trajectory of heart disease & objective of treatment

Answer 8

Progressive & irreversal (w/out transplant); Treatment is to prolong survival & improve quality of life, not cure

Question 9

Sympathetic vs. Parasympathetic in HF

Answer 9

Normally, Parasympathetic & ACh predominate; In HF, Sympathetic & NE increases to increase HR/Contractility to compensate for low flow, oxygenation & ATP

Question 10

Targets of HF Treatment – the Heart

Answer 10

Inotropes (Cardiac glycosides, Catecholamines); Beta-blockers; ACE-I/ARB

Question 11

Targets of HF Treatment – the Blood vessels

Answer 11

Vasodilators; ACE-I/ARBs

Question 12

Targets of HF Treatment – the Kidney

Answer 12

Diuretics (loop, aldosterone antagonists); Vasodilators; Ace-I/ARBs

Question 13

Vasodilators

Answer 13

Perhaps most important drug category for HF; Nitrates, ACE-I’s, ARBs

Question 14

Nitrate

Answer 14

EX: Hydralazine + ISDN; Reduced mortality from HF; ACE-I’s have been shown to be more effective than Nitrates, though an combo drug of Hydralazine/ISDN (BiDil) is especially effective in African Americans

Question 15

Angiotensin II actions (why we block in HF w/ACE-I’s)

Answer 15

Vasoconstriction, Activation of Sympathetic NS, elevate aldosterone, vasopressin, endothelin (all vasoconstrictors), platelet aggregation, collagen deposition, hypertrophy, superoxide production, cytokine elevation, etc.

Question 16

K+ & ACE-I’s

Answer 16

ACE-I’s can potentially raise serum [K+]…caution when using w/K+-sparing diuretics

Question 17

ACE-I’s & Mortality

Answer 17

ACE-I’s have unequivocably proven to decrease Class II-III HF mortality

Question 18

Differences btwn ACE-I’s

Answer 18

No major differences except half-life & potency; usually determine based on what insurance pays for [same for ARBs]; Some pt rxn differences (side effects like cough, efficacy); some ACE-I’s are prodrugs (PO enalapril > IV enalaprilat)

Question 19

ACE-I’s vs. ARBs

Answer 19

Seemingly equivalent; often use ARBs when pt can’t tolerate ACE-I’s (cough, usually); In some pt’s, potential additive effects of ACE-I’s & ARBs in combo

Question 20

Beta-blocking agents

Answer 20

Produce bronchoconstriction & vasodilation

Question 21

Beta-blocking agents – Generations

Answer 21

Gen 1: Nonselective; Propranolol…… Gen 2: Selective of B1-AR or B2-AR; Metoprolol (B1 selective)….. Gen 3: Selective or non-selective of Beta-AR; Carvedilol (also an alpha-AR blocker, anti-oxidant, etc.)

Question 22

Receptor agonists/antagonist levels

Answer 22

Neutral receptor agonists (just sit on receptor & do nothing/prevent bad things;Carvedilol, Metoprolol)…. Full agonist (sit on receptor & completely activate receptor; Norepi/Iso)….Negative agonist or Antagonist (sit on receptor and completely inactivate receptor activity)

Question 23

Beta blocker - action

Answer 23

Prevent Norepi from doing bad things (increased contractively, hypertrophy, apoptosis, etc.); 1st stops Epi from doing bad things, but take a while to improve LV volumes/remodeling (many pts don’t achieve target level of beta-blocker in body via up-titration – genetic differences, can’t main adequate HR/BP as you up-titrate, can’t stand feeling worse before feeling better)

Question 24

Beta-blockers available

Answer 24

Metoprolol (standard)/Toprol-XL (extended release; once a day) and Carvedilol (standard)/CorReg (extended release; once a day) – neither intrinsically better; just depends on patient

Question 25

Genetic polymorphisms in Beta-adrenergic receptors

Answer 25

Can determine whether they will respond to beta-blockers, and likelihood of progression to HF

Question 26

Prognosis of Congestive Heart Failure (CHF)

Answer 26

Poor prognosis, esp. for males over 55; In advanced HF, about half die in one year; More generally, half die in 5 years and 90% in 10 years from 1st Dx

Question 27

Treating HF, a progressive disease

Answer 27

HF is a progressive disease requiring incremental & escalating treatment; As symptoms increase, the therapy or combo of therapy used becomes more complex

Question 28

1st step to treat HF

Answer 28

Elimination of contributing factors must be attempted, including reduction of HTN, reduction of Na+ intake, weigh loss, smoking cessation, etc.

Question 29

Major Criteria for Dx of HF

Answer 29

Paroxysmal nocturnal dyspnea or orthopnea, neck vein distension, rales; Cardiomegaly; Acute pulmonary edema; S3 gallop, Increased venous pressure, Hepatojugular distension

Question 30

Minor Criteria for Dx of HF

Answer 30

Ankle edema, night cough, dyspnea on exertion, hepatomegaly, pleural effusion, tachycardia

Question 31

Vasodilators in CHF treatment – action

Answer 31

Act to decrease systemic vascular resistance (SVR), LV chamber size, and myocardial oxygen consumption (MVO2)….May increase or decrease sympathetic outflow, though tend to increase it by their vasodilatory effect [reflex response to reduced BP]…..May act preferentially at arteries to reduce afterload, at veins to reduce preload, or nonselectively at both (depending on agent)

Question 32

Venodilators – examples

Answer 32

Nitroglycerin, Isosorbide dinitrate (ISDN)

Question 33

Arterial dilators – examples

Answer 33

Hydralazine, minoxidil, and nifedipine (a Ca2+ channel blocker)

Question 34

Special treatment of HF in African Americans

Answer 34

Though ACE-Is are usually more effective than the combo of hydralazine & ISDN, in African Americans this combination is particularly effective; A new combination of these two drugs is called BiDil

Question 35

Actions of ACE (Angiotensin Converting Enzyme)

Answer 35

Not only converts inactive angiotensin I to active angiotensin II (potent vasoconstrictor), but also causes the degradation of bradykinin (potent vasodilator)

Question 36

Location of ACE (angiotensin converting enzyme)

Answer 36

Throughout vasculature + in many tissue, including the myocardium (“tissue RAS”)

Question 37

Actions of Angiotensin II

Answer 37

Not only a potent vasoconstrictor, but also mitogenic (working through GPCRs) ---> cardiac myocyte hypertrophy, fibroblast hyperplasia, myocardial remodeling, myocardial hypertrophy (often found secondary to MI or HF)

Question 38

Receptor of Angiotensin II

Answer 38

Ang II works through angiotensin AT1 receptors, which are similar to alpha1-adrenergic receptors and endothelin (ET1) receptors in that they are coupled to Gq G proteins ---> activate phospholipase C (PLC) ---> second messengers IP3 and DAG (inositol triphosphate and diacylglyceral)

Question 39

Action of IP3 (inositol triphosphate)

Answer 39

Increases intracellular Ca2+ through activation of IP3 receptors

Question 40

Action of DAG (diacylglyceral)

Answer 40

Stimulates protein kinase C (PKC) ---> targets numerous intracellular proteins like ion channels & activates transcription factors leading to induction of gene expression & hypertrophic phenotype

Question 41

Genetic polymorphisms in the RAS system

Answer 41

Several functional genetic polymorphisms found, including through in ACE and AT1 receptors…several seem to be important markers for HTN & heart disease

Question 42

Combination arterial-venous dilators – examples

Answer 42

Most important: ACE-inhibitors such as captopril, enalapril, lisinopril

Question 43

Enalapril vs. Captopril vs. Lisinopril characteristics

Answer 43

All are ACE-I/Combination A-V dilator….. Enalapril, a prodrug, has a slower onset & longer duration of action than Captopril, permitting a 1-2x per day dosing…..Lisinopril’s action persists for 24hr, permitting once a day dosing….Besides potency, dosing considerations, and route of elimination considerations (in context of compromised renal/hepatic function), all seem to have the same therapeutic effects

Question 44

Enalapril metabolism

Answer 44

Enalapril is a prodrug metabolized in the liver to enalaprilat (a separate prep that is available IV)

Question 45

ACE-I’s and K+

Answer 45

ACE inhibitors may increase serum [K+]….Angiotensin II increases aldosterone, which tends to save Na+ at the expense of K+; since ACE-inhibitors decrease levels of AngII, there is less aldosterone stimulation, leading to less Na+ retention & thus increase in K+….thus, caution must be used when ACE-Is are administered along w/K-sparing diuretics

Question 46

ACE-I’s and HF

Answer 46

Significantly reduce morbidity & mortality and improved NYHA classifications--- Enalapril has been shown to do so in severe CHF, as well as in asymptomatic HF w/compromised LV function--- Captopril has been shown to do so in LV dysfunction post MI, when therapy initiated 3-16 days after event --- however, Enalapril was shown to NOT be effective in reducing mortality post MI when used acutely (w/in 24hrs)

Question 47

ACE-I’s and HF w/LV compromise

Answer 47

ACE-I’s have unequivocally demonstrated positive effect on morbidity & mortality in pts w/HF when there is some evidence of compromised LV function (the assumption being that even mild, asymptomatic LV dysfunction will eventually progress to symptomatic HF)

Question 48

Most recognized side effect of ACE-I’s

Answer 48

COUGH – both individual pt & individual agent dependent; though to be a result of preservation of bradykinin concentrations secondary to inhibition of ACE

Question 49

Angiotensin II Receptor Blockers (ARBs) - action

Answer 49

Block both AT1 & AT2; Completely bypass the converting enzyme and simply block the biological receptor for Angiotensin II…. Direct pharmacological mechanism of action….Useful especially in patients who are intolerant of ACE-I’s

Question 50

ARBs for HF – examples

Answer 50

Candesartan, irbesartan, losartan, valsaran (all are approved for treatment of HTN)

Question 51

ACE-I’s vs. ARBs

Answer 51

No definitive answer to which is superior in all cases or indications; In some pts, a combination might work best