CVPR 03-28-14 10-11am Adrenergic & Angiotensin Block in CHF in CHF slides - Port Flashcards
Physiological vs. pathological hypertrophy
Physiological = good (athletic, etc.); shorter & fatter (concentric hypertrophy) ….Pathological = bad (HF); longer and skinnier (eccentric hypertrophy)
Gender & Age – HF
Women protected pre-menopausally; then, after menopause, females catch up to men
Primary causes of HF
CAD > HTN > Valve disease > specific cardiomyopthay > idiopathic > myocarditis
NYHA Class I HF – Treatment
Asymptomatic HF; Vasodilators/ACE-I/ARBs
NYHA Class II HF - Treatment
Symptomatic HF; Vasodilators/ACE-I/ARBs; Diuretics (lower dose); Beta-blockers, Digoxin
NYHA Class III HF – Treatment
Severe HF; Vasodilators/ACE-I/ARBs; Diuretics (higher dose); Beta-blockers, Digoxin; Aldosterone antagonists
NYHA Class IV HF - Treatment
Refractory HF; Vasodilators/ACE-I/ARBs; Diuretics (even higher dose); Beta-blockers, Digoxin; Aldosterone antagonists; CRT/Assist devices/transplant
Trajectory of heart disease & objective of treatment
Progressive & irreversal (w/out transplant); Treatment is to prolong survival & improve quality of life, not cure
Sympathetic vs. Parasympathetic in HF
Normally, Parasympathetic & ACh predominate; In HF, Sympathetic & NE increases to increase HR/Contractility to compensate for low flow, oxygenation & ATP
Targets of HF Treatment – the Heart
Inotropes (Cardiac glycosides, Catecholamines); Beta-blockers; ACE-I/ARB
Targets of HF Treatment – the Blood vessels
Vasodilators; ACE-I/ARBs
Targets of HF Treatment – the Kidney
Diuretics (loop, aldosterone antagonists); Vasodilators; Ace-I/ARBs
Vasodilators
Perhaps most important drug category for HF; Nitrates, ACE-I’s, ARBs
Nitrate
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
Angiotensin II actions (why we block in HF w/ACE-I’s)
Vasoconstriction, Activation of Sympathetic NS, elevate aldosterone, vasopressin, endothelin (all vasoconstrictors), platelet aggregation, collagen deposition, hypertrophy, superoxide production, cytokine elevation, etc.
K+ & ACE-I’s
ACE-I’s can potentially raise serum [K+]…caution when using w/K+-sparing diuretics
ACE-I’s & Mortality
ACE-I’s have unequivocably proven to decrease Class II-III HF mortality
Differences btwn ACE-I’s
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)
ACE-I’s vs. ARBs
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
Beta-blocking agents
Produce bronchoconstriction & vasodilation
Beta-blocking agents – Generations
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.)
Receptor agonists/antagonist levels
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)
Beta blocker - action
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)
Beta-blockers available
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
Genetic polymorphisms in Beta-adrenergic receptors
Can determine whether they will respond to beta-blockers, and likelihood of progression to HF
Prognosis of Congestive Heart Failure (CHF)
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
Treating HF, a progressive disease
HF is a progressive disease requiring incremental & escalating treatment; As symptoms increase, the therapy or combo of therapy used becomes more complex
1st step to treat HF
Elimination of contributing factors must be attempted, including reduction of HTN, reduction of Na+ intake, weigh loss, smoking cessation, etc.
Major Criteria for Dx of HF
Paroxysmal nocturnal dyspnea or orthopnea, neck vein distension, rales; Cardiomegaly; Acute pulmonary edema; S3 gallop, Increased venous pressure, Hepatojugular distension
Minor Criteria for Dx of HF
Ankle edema, night cough, dyspnea on exertion, hepatomegaly, pleural effusion, tachycardia
Vasodilators in CHF treatment – action
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)
Venodilators – examples
Nitroglycerin, Isosorbide dinitrate (ISDN)
Arterial dilators – examples
Hydralazine, minoxidil, and nifedipine (a Ca2+ channel blocker)
Special treatment of HF in African Americans
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
Actions of ACE (Angiotensin Converting Enzyme)
Not only converts inactive angiotensin I to active angiotensin II (potent vasoconstrictor), but also causes the degradation of bradykinin (potent vasodilator)
Location of ACE (angiotensin converting enzyme)
Throughout vasculature + in many tissue, including the myocardium (“tissue RAS”)
Actions of Angiotensin II
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)
Receptor of Angiotensin II
Ang II works through angiotensin AT1 receptors, which are similar to alpha1-adrenergic receptors and endothelin (ET1) receptors in that they are coupled to Gq G proteins —> activate phospholipase C (PLC) —> second messengers IP3 and DAG (inositol triphosphate and diacylglyceral)
Action of IP3 (inositol triphosphate)
Increases intracellular Ca2+ through activation of IP3 receptors
Action of DAG (diacylglyceral)
Stimulates protein kinase C (PKC) —> targets numerous intracellular proteins like ion channels & activates transcription factors leading to induction of gene expression & hypertrophic phenotype
Genetic polymorphisms in the RAS system
Several functional genetic polymorphisms found, including through in ACE and AT1 receptors…several seem to be important markers for HTN & heart disease
Combination arterial-venous dilators – examples
Most important: ACE-inhibitors such as captopril, enalapril, lisinopril
Enalapril vs. Captopril vs. Lisinopril characteristics
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
Enalapril metabolism
Enalapril is a prodrug metabolized in the liver to enalaprilat (a separate prep that is available IV)
ACE-I’s and K+
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
ACE-I’s and HF
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)
ACE-I’s and HF w/LV compromise
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)
Most recognized side effect of ACE-I’s
COUGH – both individual pt & individual agent dependent; though to be a result of preservation of bradykinin concentrations secondary to inhibition of ACE
Angiotensin II Receptor Blockers (ARBs) - action
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
ARBs for HF – examples
Candesartan, irbesartan, losartan, valsaran (all are approved for treatment of HTN)
ACE-I’s vs. ARBs
No definitive answer to which is superior in all cases or indications; In some pts, a combination might work best
