6 cvs lecture 5 - drugs for heart failure
TRANSCRIPT
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
1/55
Congestive Cardiac Failure
Dr. E. McIntosh
October 2011
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
2/55
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
3/55
Introduction to Heart Failure
Heart unable to provide adequate perfusion
of peripheral organs to meet their metabolic
requirements
Characterized by:
1. Reduction in cardiac output
2. Increased TPR
Progressing to congestive heart failure (CHF) isaccompanied by peripheral and pulmonary
edema.
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
4/55
Acute Vs Chronic HF
In a patient with acute heart failure, theshort-term aim is stabilization by providingsymptomatic treatment through intravenousinterventions.
Management ofchronic heart failure ismultifaceted, with the long-term aims of: relieving symptoms
improving hemodynamics
improving quality of life and decrease mortality.
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
5/55
Cardiac Vs Noncardiac targets
Conventional belief that the primary
defect in HF is in the heart
Reality is that HF involves many otherprocesses and organs
Research has shown that therapy
directed at noncardiac targets are morevaluable than cardiac targets
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
6/55
Compensation in HF
Heart failure is usually accompanied by anincrease in:
1. Sympathetic nervous system (SNS)
2. Chronic up-regulation of the renin-angiotensin-aldosterone system (RAAS)and effects ofaldosterone on heart,vessels, and kidneys.
CHF should be viewed as a complex,interrelated sequence of events involvinghemodynamic, and neurohormonal events.
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
7/55
Compensation contd..
In a failing heart, the loss of contractile function leadsto a decline in CO and a decrease in arterial BP.
Baroreceptors sense the hemodynamic changes andinitiate countermeasures to maintain support of the
circulatory system. Activation of the SNS serves as a compensatory
mechanism in response to the earlier
This helps maintain adequate cardiac output by:
1. Increasing myocardial contractility and heart rate (1-adrenergic receptors)
2. Increasing vasomotor tone (1-adrenergic receptors)to maintain systemic blood pressure
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
8/55
Consequences of hyperadrenergic
state
Over the long term, this hyperadrenergic stateleads to irreversible myocyte damage, cell death, andfibrosis.
In addition, the augmentation in peripheral vasomotortone increases LV afterload
This places an added stress upon the left ventricleand an increase in myocardial O2 demand(ventricular remodeling).
The frequency and severity of cardiac arrhythmiasare enhanced in the failing heart
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
9/55
Figure p.203 kat
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
10/55
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
11/55
Therapeutic Overview
Problem
Reduced force of contraction
Decreased cardiac output
Increased total peripheral resistance Inadequate organ perfusion
Development of edema
Decreased exercise tolerance
Ischemic heart disease
Sudden death
Ventricular remodeling and decreased function
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
12/55
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
13/55
Goals and drug therapy
Goals
Alleviation of symptoms, improve quality of life
Arrest ventricular remodeling
Prevent sudden death
Nondrug therapy Reduce cardiac work; rest, weight loss, low Na+ diet
Drug therapy
Chronic heart failure ACE-I, -blockers, ARB, aldosterone antagonists, digoxin, diuretics
Acute heart failure Intravenous diuretics, inotropic agents, PDE inhibitors, vasodilator
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
14/55
Drugs for CCF
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
15/55
Drugs for CCF
Diuretics :
These are useful in reducing the
symptoms of volume overload by decreasing the extra cellular volume
decreasing the venous return
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
16/55
Drugs for CCF
Diuretics :
Loop diuretics like furosemide and
bumetanide are the most effective andcommonly used.
Thiazides are effective in mild cases
only.
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
17/55
Drugs for CCF
Diuretics :Adverse effects :
Loop diuretics and thiazides cause
hypokalemia. Potassium sparing diuretics help in
reducing the hypokalemia due to these
diuretics.
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
18/55
Drugs for CCF
Potassium Sparing Diuretics :Spironolactone :
Aldosterone inhibition minimizepotassium loss, prevent sodium andwater retention, endothelial
dysfunction and myocardial fibrosis.
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
19/55
Drugs for CCF
Spironolactone : Aldosterone antagonist
Spironolactone can be added to loop
diuretics to modestly enhance thediuresis; more importantly, improvesurvival.
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
20/55
Renin angiotensin system
Baroreceptor mediated activation of the SNSleads to an increase in renin release and
formation of angiotensin II
Angiotensin II acts through AT1 and AT2
receptors (most of its actions occur throughAT1 receptors)
This causes vasoconstriction and stimulates
aldosterone production
RAS remains the most important target of
chronic CHF therapy
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
21/55
Effects of AT-II
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
22/55
MOA
ACE-Inhibitors and ARBs Blockade of ACE
Decreased AT-II
Decreased aldosterone
Decreased fluid retention
Vasodilation
Reduced preload and afterload
Slows cardiac remodeling
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
23/55
Advantages
Improves symptoms significantly
Improves exercise tolerance
Slows progression of the disease Prolong survival in established cases
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
24/55
ADR
What are the ADR of ACEIs?
Cough (why?)
Hyperkalemia (possible Druginteractions?)
Contraindicated in pregnant women (1sttrimester)
Rare: angioedema
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
25/55
Other Vasodilators:
Mechanism 2:
Direct smooth muscle relaxants
Nitrates Venous dilators
Reduce preload
Eg: sodium nitropruside
Nit t i CCF
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
26/55
Nitrates in CCF
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
27/55
Inotropes
Increase force of contraction
All increase intracellular cardiac Ca++
concentration Eg:
Digitalis (cardiac glycoside)
Dobutamine (-adrenergic agonist) Amrinone (PDE inhibitor)
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
28/55
Cardiac glycosides
Digitalis
Sourced from foxglove plant
1785, Dr. William Witheringsmonograph on digitalis
Has a profound effect on the cardiac
contractility
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
29/55
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
30/55
Pck
Two drugs (digoxin, digitoxin)
Well absorbed orally
10% of population have bacteria in the gut,which inactivate digoxin, needing an
increased dose in such
Beware of using antibiotics in such patients
Digoxin has a very narrow ther. Margin
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
31/55
Pck
Taken orally
Enters CNS (so what?)
Renal clearance proportional toCreatinine Clearance
To be used with extreme caution in
patients suffering from renalimpairment
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
32/55
MOA
Regulation of cytosolic Ca metabolism:
Reversibly combine with sodium-potassiumATPase of the cardiac cell membrane
Results in inhibition of pump activity This leads to in intracellular Na conc.
This favors Ca ions in the cell
Ca levels result in increased systolic force ofcontraction
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
33/55
Digoxin MOA
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
34/55
Na/K ATPase inhibition
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
35/55
Additional MOA
Force of contraction resembles that of thenormal heart
Improved circulation leads to reduced
sympathetic activity This reduces PVR
All this leads to reduction in HR
Vagal tone is enhanced
Finally myocardial O2 demand is reduced
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
36/55
Electrophysiological effects on the
heart
Direct Indirect (increased vagal tone)
SA Node No effect at therapeutic dose No effect at therapeutic dose
Atrial muscle High dose increases rate ofspontaneous depolarization High dose decreases rate ofspontaneous depolarization
AV node Increased refractory period Decreased conduction velocity
Decreased conduction velocity Increased refractory period
His-Purkinje
system
Increased refractory period Increased refractory period
Decreased conduction velocity Decreased conduction velocity
High dose increases triggered
activity
None
Toxic doses enhance pacemaker
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
37/55
Uses
Severe LV systolic dysfunction
Only after initiation of diuretics andvasodialtor therapy
Management of patients with chronic atrialfibrillation
Cannot arrest the progression of pathologicalchanges causing heart failure, and does not
prolong life in patients with CHF
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
38/55
ADR
Digitalis toxicity is one among most
commonest encountered (why?)
Therapeutic concentration- 0.5-1.5 ng/ml
Often the first step is discontinuation of Rx
Digoxin levels must be monitored closely
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
39/55
Signs of digoxin toxicity
CNS: Malaise, confusion, depression,vertigo, vision (abnormalities in colorvision)
GI: Anorexia, nausea, intestinalcramping, diarrhea
Cardiovascular: Palpitations, syncope,
arrhythmias, bradycardia, AV nodeblock, tachycardia
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
40/55
Factors increasing the possibility of
digoxin toxicity
Pharmacological and toxic effects are greaterin hypokalemic patients.
K+-depleting diuretics are a majorcontributing factor to digoxin toxicity.
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
41/55
Management
Arrhythmias may be converted to normalsinus rhythm by K+. when the plasma K+conc. is low or within the normal range.
When the plasma K+ conc. is high,
antiarrhythmic drugs, such as lidocaine,procainamide, or propranolol, can be used.
Severe toxicity treated with Digibind, an anti-
digoxin antibody.
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
42/55
A 96-year-old AAF was admitted from a nursing home withcomplaints of abdominal pain, N/V, dizziness, confusion anddouble vision for 5 days. She was discharged from thehospital just 4 days ago. Digoxin was started during thatprevious hospitalization for control of tachycardia in atrial
fibrillation. One day prior to discharge, digoxin level was 1.8mg/mL and digoxin dose was decreased to 125 mcg PO Q48 hr.PMHHypertension, atrial fibrillation, coronary artery disease,stroke, congestive heart failure.MedicationsMetoprolol, Digoxin, ASA, lisinopril, Lasix, Coumadin,Nexium
What could it be???
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
43/55
Dopamine
Dopamine acts at a variety ofreceptors (dose dependant)
Dopamine receptors at low dose
Beta 2 at intermediate dose
Alpha 1 at high dose
Rapid elimination- can only be
administered as a continuous infusion Treatment for acute, severe heart
failure (LVF) esp. with low BP
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
44/55
Dobutamine
Stimulates beta-adrenergic receptors andproduces a positive inotropic response
Unlike the vasoconstriction seen with high
doses of dopamine, dobutamine producesa mild vasodilatation
Used in acute heart failure with normal or
high BP
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
45/55
MOA
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
46/55
PDE inhibitors
Amrinone and Milrinone (bipyridines) Acts by inhibiting the enzyme Phosphodiesterase
Thus lead to increase of intracellularconcentrations of cAMP
cAMP is responsible for the conversion ofinactive protein kinase to active form
Protein kinases are responsible forphosphorylation of Ca channels
Thus causing increased Ca entry into the cell.
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
47/55
MOA
Increase myocardial contractility by
increasing the Ca influx during AP
Also have vasodilating effect Selective for PDE isoenzyme-3 (found
in cardiac and smooth muscle)
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
48/55
Current status
Both are orally active
Only available in parenteral forms
Limited efficacy Clinical trials- increased mortality (oral)
Still new drugs are under trial
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
49/55
ADR
Amrinone: nausea, vomiting,
arrhythmias, thrombocytopenia and liver
enzyme changes
Withdrawn in some countries
Milrinone: arrhythmias, less likely to
cause other ADR
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
50/55
(BNP)-Niseritide
Brain (B-type) natriuretic peptide (BNP) issecreted constitutively by ventricularmyocytes in response to stretch
BNP binds to receptors in the vasculature,kidney, and other organs, producing potentvasodilation with rapid onset and offset ofaction by increasing levels of cGMP
Niseritide is recombinant human BNP
approved for treatment of acutedecompensated CHF.
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
51/55
BNP contd..
It reduces systemic and pulmonary
vascular resistances, causing an
indirect increase in cardiac output and
diuresis.
Effective in HF because cause
reduction in preload and afterload
ADR- hypotension
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
52/55
Beta blockers
Overwhelming evidence to support the use of-blockers in CHF, however
Mechanism involved remain unclear
Part of their beneficial effects may derive fromslowing of heart rate and decreasemyocardial O2consumption.
This would lessen the frequency of ischemic
events and potential for development of alethal arrhythmia.
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
53/55
Beta blockers
Suggested mechanisms also include reducedremodeling
-Blockers may be beneficial throughresensitization of the down-regulatedreceptor, improving myocardial contractility.
Recent studies with bisoprolol, carvedilol andmetoprolol showed a reduction in mortality inpatients with these drugs
CI in unstable cases
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
54/55
Management of Chronic HF
(combination of drugs) Limit physical activity Reduce weight
Reduce water intake
Control HT
Na restriction
Diuretics
ACE-Is
Digitalis (ther. margin, DI with quinidine) Beta blockers
Vasodilators
-
7/29/2019 6 CVS Lecture 5 - Drugs for Heart Failure
55/55
Management of acute HF
Diuretics
Vasodilators
Inotropic drugs Life support
Treating cause (surgery to correct
valvular disorders)