7/31/2019 Drugs Used in HF II
1/40
Drugs Used in Heart FailureWawaimuli Arozal, MD, D.Pharm
1. Introduction
2. Cardiac Contractility
3. Pathophysiology of heart failure4. Pathophsiology of cardiac performance
5. Basic pharmacology of drugs used in
heart failure
7/31/2019 Drugs Used in HF II
2/40
Introduction
Heart failure (HF): is a complex clinical syndrome thatcan result from any functional or structural cardiacdisorder that impairs the ventricles ability to fill with oreject blood cardiac output is inadequate to provide the
oxygen needed a systemic response attempting tocompensate for the inadequacy
Diagnosis based on careful history and physicalexamination and supported by ancillary tests such aschest radiograph, electrocardiogram, and
echocardiography 2 mechanisms of reduced cardiac output and HF:
systolic dysfunction and diastolic dysfunction
7/31/2019 Drugs Used in HF II
3/40
Introduction
Systolic dysfunction : defined by a left-ventricularejection fraction of < 50%
Most common causes : ischemic heart disease,idiopathic dilated cardiomyopathy, hypertension,
and valvular heart disease Diastolic dysfunction: defined as dysfunction of
left-ventricular filling with preserved systolicfunction.
Causes: hypertension, ischemic heart disease,hypertrophic cardiomyopathy, and restrictivecardiomyopathy
7/31/2019 Drugs Used in HF II
4/40
Introduction
Modified Framingham Criteria for the Diagnosis ofCHF :
Major Criteria : Neck-vein distention, orthopnea or
paroxysmal nocturnal dyspnea, cardiomegaly onchest radiograph, S3 gallop, Central venouspressure >12 mmHg, LV dysfunction on echo,weight loss >4.5 kg, acute pulmonary edema
Minor criteria: bilateral ankle edema, night cough,dyspnea on exertion, hepatomegaly, pleuraleffusion, tachycardia (>120 beats/min)
7/31/2019 Drugs Used in HF II
5/40
Introduction
New York Heart Association Classificationon CHF :
I (none) No symptoms from ordinary
activitiesII (mild) comfortable at rest or during mild
exertion
III (moderate) symptomatic with any activityIV (severe) symptomatic at rest, confined to
bed or chair
7/31/2019 Drugs Used in HF II
6/40
Cardiac contractility
Contraction results from the interaction ofactivator calcium (during systole) with theactin-troponin-tropomyosin system, there
by releasing the actin-myosin interaction.The calcium released from sarcoplasmicreticulum (SR) ; see figure
7/31/2019 Drugs Used in HF II
7/40
7/31/2019 Drugs Used in HF II
8/40
Pathophysiology of heart failure
7/31/2019 Drugs Used in HF II
9/40
Pathophysiology of heart failure
7/31/2019 Drugs Used in HF II
10/40
Pathophysiology of heart failure
Intrinsic compensatory mechanism
1. myocardial hypertrophy ischemicchanges, impairment of diastolic filling,and alteration ventricular geometry
2. Remodeling proliferation of connectivetissue
7/31/2019 Drugs Used in HF II
11/40
7/31/2019 Drugs Used in HF II
12/40
Heart Failure
Cardiac output
Symphatetic nervoussystem activation
Vasoconstriction
Cardiac
remodeling
Elevatedcardiac filling
pressures
Na+ and waterretention
Renin
Angiotensin I
Angiotensin II
Aldosterone
X
X
X
X
X X
X
X
X
X
X
X
ARBs Diuretics
Inotropic agents, digoxin
DigoxinB-blockers
Renininhibitors
ACE-I
Vasodilators
Spironolactons
7/31/2019 Drugs Used in HF II
13/40
7/31/2019 Drugs Used in HF II
14/40
7/31/2019 Drugs Used in HF II
15/40
Pathophsiology of cardiac
performance
Determinants of cardiac output
Cardiac Output
Strokevolume
Preload Contractility Afterload
Heart rate
7/31/2019 Drugs Used in HF II
16/40
Pathophsiology of cardiac
performance
Preload : the volume that enters the left ventricle(LV)
Afterload : the impedance of the flow from LV;resistance against which the heart must pump
bloodCardiac contractility : muscular pumping of the
heart = ejection fractionHeart rate: major determinant of cardiac output
(CO); increase in heart rate through sympatheticactivation of B-adrenoreceptors is the firstcompensatory mechanism to maintain CO
7/31/2019 Drugs Used in HF II
17/40
7/31/2019 Drugs Used in HF II
18/40
Basic pharmacology of drugs used in heart failure
I. Digitalis
prototype: digoxinMechanism of action: inhibit membrane-bound alpha subunits of Na-K ATPase
(sodium pump) promotes Na-Ca exchange increases theintracellular Ca concentration contractile proteins resulting anincrease in the force of myocardial contraction
Baroreceptor function: improvement in baroreceptor function that results indecreased activation of the sympathetic nervous system (decreasessinoatrial and atrioventricular conduction)
Vagomimetic effect : increase vagal tonesCirculating neurohormones: decrease the serum NE concentration and plasma
renin activityPharmacokinetics : bioavailability 60-80 %; 6-8 hours tissue distribution phase.
In some patients, oral digoxin is partial inactivated by colonic bacteria.Excreted unchanged in the urine. Half life 36-48 hours in normalpatients (3.5-5 days in CRF). Oral daily maintenance results in Asteady state blood concentration in approximately 7 days
7/31/2019 Drugs Used in HF II
19/40
Mechanisms of Action of Digitalis
Inhibition of Na/K-ATPase
Na+ int
Ca++-induced
Ca++ release
Sarcoplasmicreticulum
MembraneDepolarization
Ca++ channelopening
Ca intracell
Na+/Ca++exchanger
CONTRACTILITY
7/31/2019 Drugs Used in HF II
20/40
Electrophysiologic effects of Digitalis
Lowers resting potential (phase 4 become lessnegative
Increases the slope of phase 4 otomaticity Produces Delayed after depolarization Shortening of potential action duration arrhythtmogenic
7/31/2019 Drugs Used in HF II
21/40
Direct effects on the heart Increases automaticity in the atrium, ventricle and
Purkinje fibrearrhythmogenic
Delays conductivity (AV node, Purkinje)
dromotropic (-)
Shortens refractory periods in the atrium andventriclearrythmogenik
Prolongs refractory period in AV node
chronotropic (-)
Atrium AV node Ventricle/Purkinje
Automaticity
Conductivity --
Refractory
period
-- /
7/31/2019 Drugs Used in HF II
22/40
Indirect effects
Vagal effect: In SA and AV nodes Vagal tone
Incereses sensitivity of heart to acetylcholine
Negative chronotropic
Sympathetic effects: Decreases sympathetic tone
Decreases sensitivity of heart to NE
Decreases sympathetic flow
Negative chronotropic effect
At high/toxic dose : sympathetic flow arrhythitmogenic
7/31/2019 Drugs Used in HF II
23/40
Pharmacodynamic effects
1. Direct effects: Positive Inotropism
Improved contractility Improve cardiac output Decrease pulmonary congestion
Improved dyspnoe2. Indirect effects Sympathetic tone
Decrease heart rate Decrease peripheral resistance afterload
Improved renal circulation SRA activity Peripheral resistance Aldosterone salt /water retention edema IMPROVE CARDIAC PERFORMANCE
7/31/2019 Drugs Used in HF II
24/40
Digitalis in Atrial Flutter / Fibrillation
Digitalis prolongs refractory period in AVnode
some impulses from atrium are retained inAV node and not transmitted to ventricle
In other words:
Digitalis prevent the transmission of fibrillationfrom atrium to ventricle
(Not directly eliminate AF)
(Although spontaneous conversion to sinus rhythm frequently occur)
7/31/2019 Drugs Used in HF II
25/40
Digoxin
Indication:
1. Patients with HF and impaired systolicfunction who are in sinus rhythm andcontinue to have signs and symptomsdespite standard therapy that includesACE-inhibitors and beta-blockers
2. Patients with atrial fibrillation with orwithout HF
7/31/2019 Drugs Used in HF II
26/40
Digoxin
Drug Interactions : Quinidine, verapamil, andamiodarone may significantly increase theconcentration of digoxin dose of digoxin
should reduce; tiazid, furosemid causinghypokalemia increase toxicity
Dose/serum concentration: low dose digoxinresulting in serum concentration less than 1
ng/ml beneficial clinical effect; > 1ng/mlincrease mortality; Usual dose 0.125 mg daily 0.8 ng/ml
7/31/2019 Drugs Used in HF II
27/40
Digoxin
Intoxication- Arrhythmias- Gastrointestinal abnormalities- CNS abnormalitiesIntoxication not only related to dose but also to the concurrent
medication (diuretics) or condition (renal insufficiency, ischemia)Special consideration in the use of digoxin :-Woman-Elderly-Coronary artery disease; myocardial ischemia cause inhibition of
sodium pump myocardial tissue moore sensitive to thearrhythmogenic effects of digoxin should be used very low dose
Precautions:Should not be used in patients with SA or 2nd/3rd AV block; WPW
syndrome, hypertrophic or restrictive cardiomyopathy
7/31/2019 Drugs Used in HF II
28/40
INTOXICATION
Digitalis has a low margin of savety
risk ofintoxication with increasing dose Potassium depletion due to diuretics facilitates
intoxication Symptoms of intoxication sometimes resembles
cardiac worsening.
CAUSES OF INTOXICATION To high doses Hypokalemia/hyperkalemia Hyperkalsemia Hypomagnesemia Myocardial ischemia
7/31/2019 Drugs Used in HF II
29/40
Symptoms of Intoxication GI symptoms (nausea, vomiting, abdominal pain) Neurologic symptoms (dizzy, restlessness,
confusion) Visual dysturbances (blurred, yellow vision) Cardiac: arrhythmia, AV-block
Treatment Stop digitalis and diuretic Electrolyte correction Management of arrhythmia: lidocain, phenitoin Antidigoxin-Antibody
INTOXICATION
7/31/2019 Drugs Used in HF II
30/40
Interaction
Quinidin Verapamil Increases plasma digoxin
Diltiazem
Amiodarone
Phenobarbital
Phenytoin Enzyme inducers metabolism
Fenilbutazon Decrease plasma digoxin
Rifampisin Amphoterisin hypokalemia digitalis toxicity
7/31/2019 Drugs Used in HF II
31/40
Other positive inotropic drugs
I. Inamrinone and milrinone (inhibitor of phosphodiesteraseisoenzyme 3 (PDE-3)
Increase cAMPIncrease myocardial contractility byincreasing inward Ca flux in heart and vasodilating effect
Toxicity : nausea, vomiting, arrhythmias, trombcytopenia,bone marrow toxicity
Only for acute HF or severe exacerbation of CHF
II. Beta adrenoceptor stimulants (dopamine and
dobutamine)Increase cardiac output together with a decrease inventricular filling pressure
Side effect : tachycardia
7/31/2019 Drugs Used in HF II
32/40
Diuretics
Mainstay of HF management No effect on cardiac contractility Major mechanism: reduce venous pressure and ventricular preload Reduction on salt and water retention and edema and its symptoms Loop diuretics : furosemide
Thiazide diuretics : combination with loop diuretics Aldosterone antagonist (AA): spironolactone and eplerenon ; HF
increase circulating plasma aldosterone myocardial and vascularfibrosis and baroreceptor dysfunction. AA decreased morbidity andmortality in patients with CHF who also receiving ACE inhibitors orother standard therapy
7/31/2019 Drugs Used in HF II
33/40
DIURETICS(First line drug for CHF)
(See also diuretics and antihyperensive agents) Furosemide:
Strong diuretic with rapid onset
For acute CHF (and also for chronic)
Mechanism of action: reduceing preload Thiazide: HCT, indapamid
For chronic CHF
Aldosteron Antagonist : spironolaktone
Reduces the risk of furosemide-inducedhypokalemia
To be used for longterm treatment
Prevent myocardial fibrosis
7/31/2019 Drugs Used in HF II
34/40
ACE inhibitors and AT-1 Blockers
ACE inhibitors : captopril, enalapril lisinopril ramipiril
Reduced peripheral resistance reduced afterload
Reduce salt and water retention (by reducingaldosterone secretion) reduce preload
Reduce tissue angiotensin level reduces sympatheticactivity
Reduce longterm remodeling of the heart and vessel
At-1 blockers : losartan, candesartan, valsartan similar
to ACE Inhibitors. Considered with patient intolerant ofACE-I
7/31/2019 Drugs Used in HF II
35/40
ARBs are comparable to ACE inhibitors inreducing all-cause mortality and HF related-hospitalization in patients with NYHA classes II
and III HF ARBs more expensive than ACE-I, but not cause
cough reasonable in patients who are unableto tolerate ACE-inhibitor therapy
Some studies reported that adding an ARB toACE-I provides benefit (reduced hospitalization)compared with ACE-I alone, but the combinationmay cause increase adverse effects (worseningof renal function, hypotension, and
hyperkalemia) combination may be reservedfor patients who remain symptomatic on therapywith ACE-I under strict monitoring
7/31/2019 Drugs Used in HF II
36/40
ACE-I side effects:- elevated bradykinin angioedema, drycough
- elevated serum K+ level low potassium dietor dose adjustment
- hypotensionDirect renin inhibitor (aliskiren) :- Developed for the treatment of hypertension- Appears to exert beneficial effects on myocardial remodeling, by decreasing
LV mass in hypertensive patients- In ALOFT trial (2008) aliskiren (150 mg/day) add on therapy to beta blocker
and ACE-I or ARBs was not associated with a significant increase inhypotension and hyperkalemia
- Not yet studied to analyze the efficacy for CHF
Beta adrenoceptor antagonists in
7/31/2019 Drugs Used in HF II
37/40
Beta-adrenoceptor antagonists in
CHF
-AR antagonist
Blockade of
-adrenoceptor
Prevention of cardiacremodelling
Beneficial effects inchronic heart failure
Anti-arrhythmicaction
EnergyconservationAntioxidantaction
Reduction insymphateticactivity
B t
d t t i t
7/31/2019 Drugs Used in HF II
38/40
Mechanism of action in HF :1. Decreasing the frequency of arrhytmias2. Affecting LV geometry, decreasing LV
chamber size, increasing LV ejection fraction
3. Inhibition of symphatetic nervous systemactivation prevent or delay progression ofmyocardial contractile dysfunction by inhibitingproliferative cell signaling in the myocardium,
reducing cathecholamine inducedcardiacmyocyte toxicity, and decreasingmyocyte apoptosis and fibrosis
Beta-adrenoceptor antagonistsin CHF
7/31/2019 Drugs Used in HF II
39/40
Data from > 15000 patients with mild-moderate CHFproved that B blockers improve disease-associatedsymptoms, hospitalization, and mortality
Recommendation : use in patients with LV ejection
7/31/2019 Drugs Used in HF II
40/40
Non pharmacologic management1. Dietary sodium restriction
Restricting sodium intake to 2 g or less (~0.25 tsp) perday can aid in the control of fluid status and thesymptoms of heart failure
2. Exercise
Moderate exercise (i.e. at 60% of maximum exercise
capacity on a stationary bicycle for 2 or 3 hours perweek) improves quality of life, decrease moratlity, anddecrease hospitality in patient with stable chronic heartfailure (for NYHA class I-III)
3. Smoking cessation, restricting alcohol
4. Patients with renal dysfunction should restrict fluid intaketo 1.5 2.0 L per day
5. Weight monitoring