Cardiovascular Pharmacology - Inotropic Agents and Other Drugs
Used in Heart Failure
Edward JN Ishac, Ph.D.
Professor, Pharmacology and Toxicology
Smith 742, 828-2127, e-mail: eishac@vcu.edu
OBJECTIVES
1. Identify the pharmacologic basis of the following in treating heart failure
a. Converting enzyme inhibitors and angiotensin receptor blockers
b. Diuretics (Loop , Thiazide, and K-Sparing diuretics)
c. Vasodilators
d. Cardiac glycosides (Digoxin)
e. Inotropics other than digitalis (dobutamine, xanthines)
f. Beta Blockers
g. Beta natriuretic peptide (Nesiritide)
HEART FAILURE: cardiac output inadequate for body demand of oxygen (demand-supply)
Prevalence:
- heart failure is a common disease
- approximately 6 million Americans have symptomatic heart failure
- carries a mortality of 20 - 25% per year
Causes:
- coronary artery disease (main cause, 60-70%)
- primary cardiomyopathy
- hypertension (main cause for Afro-Americans)
- toxic injury by chemicals
- congenital or genetic abnormalities
- drug: adriamycin
Compensated heart failure:
- resting cardiac function meets demand
- cardiac output may not be sufficient
during stress or exercise
Congestive heart failure (CHF, decompensated):
- resting cardiac function inadequate
- ↑venous pressure  edema esp. lungs
- shortness of breath (dyspnea)
- ‘neurohumoral storm’
↓ Cardiac function → Neuro-humoral activation
→ ↑Sympathetic NS & RAA system
→ Tissue remodeling (hypertrophy, ↓ CO)
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Hemodynamic changes in congestive heart failure
i.
ii.
iii.
iv.
v.
 sympathetic tone
(tachycardia)
 parasympathetic tone
activation of renin-angiotensin
system
 blood volume
 vasopressin release
Consequences:
-  force of contraction
-  CO,  TPR,  stroke volume
-  venous pressure,  tissue perfusion
- cardiac hypertrophy
- Na+ & water retention
- edema (especially standing)
Figure 1.
Treatment Options:
Dietary, Lifestyle:
- exercise as tolerated
- salt restriction
Pharmacotherapy:
a. Positive inotropic agents: - cardiac glycosides (ie. digoxin)
- catecholamines (ie. dobutamine)
- phosphodiesterase inhibitors (ie. Milrinone)
b. Beta-blockers (ie. Metoprolol caution with use)
c. Diuretics (ie. Thiazides, Loop diuretics and K-sparing diuretics)
d. Angiotension converting enzyme (ACE) inhibitors (ie. lisinopril) or Receptor-blockers
e. Vasodilators (non-inotropic, ie. hydralazine, isosorbide dinitrate)
f. Beta type natriuretic peptide (Nesiritide)
Dr. Ishac
CHF & Cardiac Glycosides
Heart Physiology
Electrical components:
- Action potential (AP) generation (spontaneous)
- AP conduction (via specialized conductive system)
Excitation - contraction coupling:
- key role of IC Ca++
Figure 2a & 2b. Cellular ion movements
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DIGITALIS GLYCOSIDES
I.
INTRODUCTION AND HISTORY
The steroidal glycosides of digitalis have the unique ability to increase not only the
contractility of the failing heart, but also its mechanical efficiency by means of a decrease
in heart size which decreases O2 consumption.
Plant extracts containing cardiac glycosides (white and purple foxglove; Digitalis lanata
and D. purpurea) have been used in various parts of the world since the ancient Egyptians
(3000 years ago). The modern use of digitalis in medicine stems from the classical
observations of William Withering in 1785. Withering used digitalis with success in
treating "dropsy", but was unaware of the action of digitalis on the heart. Only within the
past 50 years have the actions of digitalis on the heart and their cellular mechanisms
become well understood.
Chemistry:
Digoxin (USA), Digitoxin (Europe)
i. steroid nucleus:
- lipophilic, essential for activity
ii. unsaturated five-membered lactone ring:
- hydrophilic, essential for activity
- opening the ring  loss of activity
- saturation  loss of activity
iii. series of sugars linked to C 3 of the steroid nucleus
- non-essential, hydrophilic
Figure 3. Structure of Digoxin
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PHARMACOLOGIC ACTIONS OF DIGITALIS
Congestive Heart failure: use decreasing for acute and chronic treatment
Arrhythmias: In atrial tachycardia, atrial flutter and atrial fibrillation, the depressant
action of digitalis on the A-V node conduction (via increasing vagal activity) protects the
ventricles from excessive atrial impulses.
A. Effect at the Cellular Level
Ion movements into and out of cell
Cardiac glycosides (CG): potent, highly selective inhibitors of Na+/K+ ATPase (Na+ pump)
Na+/K+ ATPase:
- membrane bound transporter (3 Na+ / 2 K+)
- found all over the body, /-subunits
- extracytoplasmic binding site for CG
- phosphorylation of cytoplasmic -subunit  stabilize CG binding
-  [K+]EC  dephosphorylates -subunit   CG binding
(ie. ACEI, ARBs, K-sparing diuretics)
-  [K+]EC   CG intoxication (ie. Thiazide, loop diuretics)
Inhibition of (Na+, K+-ATPase)
See Figure 2b
  exchange Na+ - K+ (3:2)
  [Na+]IC (10  10.5 mM)
  Na+ - Ca++ exchange (deploarized, 3:1)
  [Ca++]IC
  SR uptake Ca++ ( stores)
  contractile force
Therapeutic consequence of CG:
- moderate but persistent positive ionotropic effect,  sensitivity of the baroreceptor reflex
  CO   sympathetic activity
  HR and vascular tone
  pre- and afterload
  heart size
  oxygen demand
  CO   renal blood flow
 improved GFR
  renin-angiotensin activity level
  Na+ excretion   body Na+
  volume + vascular reactivity
 pre- and afterload
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B. Cardiac Effects
1.
Increase in contractile force of myocardium (inotropic effect)
2.
Increase in vagal activity - cardiac slowing (chronotropic effect)
3.
Major effects on electrophysiologic parameters
a.
decreased A-V conductivity due to decreased conduction velocity
and an increase in the refractory period
b.
EKG changes
1.
T wave becomes inverted
2.
ST segment becomes depressed
3.
PR interval becomes prolonged
4.
Heart size is decreased due to more complete ventricular emptying
Table 1. Summary of the cardiovascular effects of CHF and the results of digitalis administration
Figure 4. Use of the Frank-Starling mechanism as a compensation for congestive heart failure.
Curves depict ventricular function in normal subjects and in those with congestive heart failure
(CHF) and heart failure after treatment with digitalis. The points N through D represent in
sequence: initial reduction of contractility due to congestive heart failure (N to A); use of FrankStarling compensation to maintain cardiac output (A to B); increase in contractility when digitalis
is administered (B to C); and reduction in the use of Frank-Starling compensation, which digitalis
allows (C to D). Of note is the fact that points N, B and D all lie on the same line in the vertical
axis and thus all represent the same cardiac output, but each is on a different end-diastolic pressure
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III. PHARMACOKINETIC CHARACTERISTICS:
1.
Digoxin (USA; Lanoxin, Lanoxicaps)
a.
Absorption - from GI tract is good, but is incomplete and can be variable due to gut
bacteria (10% of population resistant, Eubact. lentum)
b.
Fate - 15% liver metabolism, 85% excreted unchanged in the urine.
2.
a.
b.
Digitoxin (Europe; Crystodigin)
Absorption - from GI tract nearly complete.
Fate - undergoes metabolism to other active glycosides, including digoxin. Most
digitoxin is eventually converted to inactive metabolites. Only 5-10% of digitoxin is
excreted unchanged.
3.
Ouabain - no longer in clinical use in the USA
Agent
Route
Biovail.%
Bound%
Peak effect
Digoxin
Digitoxin
oral, iv
oral, iv
45-85
>90
25
90
6 hr
12 hr
VI.
TOXICITY:
Narrow therapeutic window (50%):
T1/2
35 hr (kidney)
6-7 day (liver)
 oscillatory afterdepolarization
 ventricular tachycardia
Cardiac Glycoside (CG) Toxicity: ventricular tachycardia, delirium, fatigue, weakness, dizziness,
nausea, vomiting, vision/light disturbances (halo effect, mainly yellow and green, [van Gogh])
Figure 5a & 5b: Therapeutic index and toxicity of cardiac glycosides
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CHF & Cardiac Glycosides
Important interactions:
a.
Hypokalemia
 CG binding, ↑effect (Thiazides & Loop diuretics)
b.
Hyperkalemia
 ↓CG binding, ↓effect (ACEIs/ARBs & K-sparing diuretics)
b.
Quinidine
 displaces CG from plasma binding (↑effect)
c.
Ca++-blockers
 enhance effect, ie. increase toxicity (eg. verapamil)
d.
Catecholamines
 enhance toxicity (synergist effect)
e.
Amiodarone:
  serum concentration of cardiac glycosides (↓clearance)
f.
Cholestyramine
 decrease CG absorption, ↓effect
g.
Thyroid dysfunction  Hyperthyroidism ↓[CG)], Hypothyroidism ↑[CG)]
h.
Antibiotics
  CG bioavailability (eg. erythromycin)
i.
Alteration in renal function can affect digoxin concentration
Treatment of Toxicity:
a.
discontinue cardiac glycoside or alter dose
b.
discontinue K+ depleting diuretics or add K-sparing
c.
administer K+   arrhythmias (esp. with diuretics)
d.
use of antiarrhythmic agent eg. lidocaine, phenytoin
e.
use of antidigoxin antibodies eg. digoxin immune FAB (expensive)
CATECHOLAMINES:
Usually used (iv) in acute decompensated HF, sometimes used long-term.
Can induce angina and arrhythmias  discontinue or reduce dose
Dobutamine (Dobutrex); Dopamine (second line agent)
Stimulation of cardiac beta-1 receptors by dobutamine results in an increase in
contractile force, but relatively little increase in heart rate. Dobutamine does not
activate renal dopamine receptors.  cAMP   Ca++ influx   CO.
Figure 6: Actions of dobutamine and phosphodiesterase inhibitors.
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CARDIOACTIVE BIPYRIDINES: PHOSPHODIESTERASE INHIBITORS:
Inamrinone (previously Amrinone), Milrinone
Inhibition of specific phosphodiesterase III. PDE inhibition leads to increased cyclic AMP content
of cardiac muscle and an increase in intracellular calcium via phosphorylation of Ca-channel.
- used in acute and chronic HF
-  cAMP   Ca++ influx   CO (as per catecholamines)
- can decrease preload and afterload
- higher mortality reported with chronic use
- bronchodilation, benefit in asthma individual
OTHER AGENTS USED IN HEART FAILURE:
-discussed in detail in other sections of cardiovascular course (Hypertension)
a. Converting enzyme inhibitors / Angiotensin II receptor blockers (ARBs)
Frontline agents. Increasing use (e.g. Lisinopril, Enalapril) and Angiotensin II receptor
blockers (e.g. Losartan, Valsartan) - decrease preload and afterload, increase survival,
tissue remodeling
Renin Inhibitor: Aliskiren, newest agent, actions similar to ACEIs, no cough
Actions of Angiotensin-Converting Enzyme (ACE) Inhibitors/ARBs
- decrease activity of sympathetic NS
-  TPR, CO unchanged, HR unchanged
- no reflex  HR, probably due to resetting () of baroreceptor reflex sensitivity
-  aldosterone production   Na/water retention
-  bradykinin level (inhibit metabolism, only ACEIs)
- improves intrarenal hemodynamics
- less effective in elderly and Afro-Americans
Adverse effects: hyperkalemia, dry cough (ACEI only), loss of taste (Zn loss), angioedema (<1%,
less with ARBs), glossitis (<5%), tetrogenic (CI: pregnancy & renal artery stenosis)
ARBs recommended if can not tolerate ACE inhibitors
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b. Diuretics: Frontline agents: decrease preload and increase fluid excretion
1. Loop diuretics (Furosemide)
- Inhibit Na-K-2Cl ion cotransporter, ↓Na+, H2O reabsorption: ascending loop of henle,
hypokalemia, hypomagnesemia, hypocalcemia ototoxicity, most potent
2. Thiazides (Hydrochlorothiazide, Metolazone)
- Inhibit Na-Cl cotransporter, ↓Na+, water reabsorption in distal convoluted tube,
hypokalemia, hypercalcemia, ↑uric acid→gout, DM-2, photosensitivity
3. K+-sparing (Spironolactone, Eplerenone)
- aldosterone antagonism at collecting tube, hyperkalemia, least potent, adjunct, decreases
mortality, tissue remodeling, gynecomastia
c. Vasodilators: Good adjuncts, can decrease preload and afterload
Adverse effects: reflex tachycardia, headache, nausea, sweating, flushing
1. Not Ca-channel blockers
2. Hydralazine: direct vasodilation, mainly afterload
Bidil: combination of Isosorbide dinitrate and Hydralazine (FDA approved 2005 for use in
Afro-Americans). Adverse effect: Lupus reaction
3. Nitrates: NO/cGMP; decrease preload and afterload
- Nitroprusside, acute use (prolonged use can cause cyanide toxicity)
d. Beta blockers: (e.g., Metoprolol, Carvedilol and Bisoprolol; EBM, FDA approved)
Good agents (not all) in CHF Classes II-III, decrease mortality. Increasing use
Beneficial effects include: reduction of tachycardia and other adverse effects of high
catecholamine levels, alpha-1 blocking action with carvedilol, peripheral vasodilator effects,
blockade of renin secretion and scavenging of O2 free radicals
CI: decompensated HF, mental depression, bronchospasm, severe bradycardia
Adverse effects:
- effects enhanced in elderly
-  myocardial reserve (blockade of cardiac 1-ARs)
- fatigue, dizziness
- asthma (blockade of bronchial beta2-ARs)
- peripheral vascular insufficiency
- diabetes (blockade of hepatic beta2-ARs)
- CNS: nightmares, mental depression, insomnia
- withdrawal syndrome (supersensitivity, rebound HT)
- may worsen Raynand’s syndrome
e. Beta-type natriuretic peptide [Nesiritide (Natrecor)]
Increasing use for severe CHF (Class IV), iv. Administration (T1/2 – 18 mins)
Binds to a receptor on the surface of the vascular smooth muscle cell and increases cGMP,
leading to smooth muscle relaxation and vasodilation. Arterial and venous dilation decrease
preload and afterload.
Dilation of afferent renal arterioles increases GFR and sodium reabsorption, leading to
diuresis. The SNS and RAA systems are also suppressed.
Main adverse effect: - hypotension
Dr. Ishac
CHF & Cardiac Glycosides
GUIDELINES: PHARMACOTHERAPY OF HEART FAILURE (2004)
NYHA Heart Failure Classification
Pharmacotherapy
Class I (no limitations on activity)
ACE Inhibitor/AT-1 - RB
Class II
(slight, mild limitation of activity,
comfortable at rest)
Bi-Ventricle
Class III
pacing
(marked limitation of Bidil
activity, only
comfortable at rest)
Bi-Ventricle
Class IV
pacing
Bidil
(complete rest,
confined to bed or
chair)
Digoxin*, Furosemide,
ACE Inhibitor/AT-1 - RB,
Beta blocker
Digoxin*, Furosemide,
Thiazide, ACE Inhibitor/
AT-1 - RB, Beta blocker/
K+-sparing
Digoxin*, Furosemide (IV),
Thiazide, ACE Inhibitor/AT-1 Receptor blocker, K+-sparing/Inotropic Therapy/
Beta-Natruretic Peptide
*Recommended Digoxin not to be used in females for routine CHF, higher mortality.
Recommended Pharmacotherapy of CHF requires 4 or more agents Classes II-IV
AT-1 – RB: Angiotensin II Type 1 Receptor blockers recommended if cannot tolerate ACEI
Bidil: Isosorbide dinitrate & hydralazine (ISDN), effective for Afro-Americans
PHARMACOTHERAPY SUMMARY:
•
Improved survival
– ACE inhibitors/ARBs, Beta-blockers, K-sparing
•
Increased mortality
– Phosphodiesterase III inhibitors (chronic)
•
Neutral on survival
– Digoxin, Loop diuretics, Thiazides
•
Quality of life
– Digoxin, Loop diuretics, Thiazides, Beta-blockers
•
Reduction of edema
– Loop diuretics, Thiazides
•
Tissue Remodeling
– ACE inhibitors/ARBs, K-sparing
•
Prevention of ischemia
– Beta-blockers, Anticoagulant therapy
•
Hemodynamic improvement: All agents
– ACEI, ARBs, Digoxin, Diuretics, Beta-blockers, K-sparing
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ACC/AHA vs NYHA Classification
ACC/AHA (2001)
NYHA (2004)
A
Asymptomatic with no heart
damage but have risk factors
for heart failure.
No equivalent
B
Asymptomatic but have
signs of structural heart
damage
I
(Mild)
C
Have symptoms and
structural heart damage
II
(Mild)
D
Endstage disease with
advanced structural heart
disease and marked
symptoms at rest and
require specialized
interventions.
IV
Unable to carry out any physical activity
(Severe) without discomfort. Cardiac insufficiency at
rest.
No limitation of physical activity. Ordinary
physical activity does not cause undue fatigue,
palpitation, or dyspnea.
Slight limitation of physical activity.
Comfortable at rest, but ordinary physical
activity results in fatigue, palpitation, or
dyspnea.
III
Marked limitation of physical activity.
(Mod.) Comfortable at rest, but less than ordinary
activity causes fatigue, palpitation, or dyspnea.
LEARNING RESOURCES
Recommended Reading:
Basic and Clinical Pharmacology, B.G. Katzung (ed.), 10th ed., 2009, Ch. 13, pp. 209-224.