Download Pharmacology Objectives 9

Pharmacology
Lecture 9 Drugs Used in the Treatment of Heart Failure
1) List drugs used in the treatment of acute and chronic heart failure.
Acute Heart Failure – Diuretics (hydrochlorothiazide, furosemide), Digoxin, and
vasodilators including ACE inhibitors (captopril) or hydralazine + isosorbide
dinitrate.
Chronic Heart Failure – Diuretics (if signs and symptoms are present), Digoxin,
ACE inhibitor (captopril), β-blocker (metoprolol), and Spironolactone.
2) For each drug listed above describe its pharmacodynamic actions and relate
these actions to the beneficial action(s) when used in therapy of heart failure. See
Table.
3) For each drug listed in 1 describe the serious adverse reactions and
contraindications for use. See Table.
4) Indicate which of the drugs listed in 1 reduce morbidity (need for
hospitalization) and which confer a survival benefit.
Drug
Pharmacodynamic
actions
Benefits in Heart
Failure
Adverse reactions
Contraindications
Hydrochlorothiazide
inhibits Na+/Clsymport in distal
convoluted tubule
inhibit Na+/K+/2Clsymporter of the
loop of Henle
inhibits membrane
Na+/K+-ATPase
↓pulmonary and
peripheral edema
Fluid & electrolyte
imbalance
Hypokalemia
↓pulmonary and
peripheral edema
Fluid & electrolyte
imbalance
Reduces morbidity
Slows HR and
increases cardiac
output
Inhibits ACE - ↓
angiotensin II, ↑
bradykinin
Interferes with
proliferative
actions of
angiotensin and
aldosterone
↓TPR, ↓preload,
and ↑cardiac
contractility
Cardiac arrhythmia
Fatigue, anorexia,
nausea and
vomiting, altered
yellow-green vision
and confusion
HTN w/1st dose,
Cough, renal
insufficiency,
hyperkalemia
Anurea,
electrolyte
depletion
Hypokalemia
ventricular
fibrillation
Pregnancy
Hypotension
Reduces morbidity
and confers survival
benefit (25%)
Hypotension,
SLE-like symptoms
β blockers,
other
vasodilators
Depression, worsen
CHF and occlusive
peripheral vascular
disease,
bronchospasm
Hyperkalemia
Asthma,
COPD, CHF,
A-V block
Reduces morbidity
(39%) and confers
survival benefit
(43%)
Reduces morbidity
(40%) and confers
survival benefit
(30%)
Furosemide
Digoxin
Captopril
Hydralazine +
isosorbide dinitrate
Metoprolol
Cardioselective β1
receptor blockade
Spironolactone
antagonist of
aldosterone
receptors in the
distal tubule and
collecting duct
↓sympathetic
activation =
↑ejection fraction,
contractility, and
performance
↓Na+, ↑K+,
↑parasympathetic,
↓sympathetic,
↑vascular
compliance
NSAIDs,
extra K+,
ACE-I, and
K+ sparing
diuretics
Reduce morbidity/
confer survival
benefit
Reduces morbidity
Reduces morbidity
Reduces morbidity
(30%)
5) Describe the chemistry of Digoxin. Digoxin is a glycoside (sugars with non-sugar
entitiy) where the activity resides in a steroid with the attached sugars affecting
solubility, potency, and toxicity.
6) List the pharmacodynamic actions of digoxin, including actions on cardiac
mechanical function and cardiac electrophysiology. Digoxin increases the force of
myocardial contraction, a positive inotropic action seen in normal and failing hearts.
Digoxin influences cardiac electrical activity by changing excitability, automaticity,
conduction velocity and refractory periods.
7) Describe the biochemical mechanisms of the cellular action of digoxin. At
therapeutic concentrations digoxin inhibits membrane Na+/K+-ATPase activity
resulting in increased intracellular Na+ with augmented exchange for extracellular
Ca2+ and decreased intracellular K+. This increase in intracellular Ca2+ enhances
myocardial contractility.
8) Describe the overall benefits of digoxin when used in the management of mild to
moderate congestive heart failure associated with sinus rhythm. Digoxin confers
the added benefits of reduced hospitalization and slowed progression to persons with
mild to moderate heart failure receiving diuretics and ACE inhibitors. It does not
reduce mortality and should therefore only be used to reduce symptoms in patients
who do not experience relief with optimal medical treatment including β blockers and
ACE inhibitors.
9) Describe the cardiovascular actions of digoxin when it is used to treat atrial
fibrillation with a rapid ventricular response. Digoxin slows ventricular rate with
associated increase in cardiac output. This is accomplished by vagal stimulation,
baroreceptor sensitization and sympathetic withdrawal. These actions combine to
prolong the effective refractory period of the A-V node and slow conduction through
the node.
10) Characterize the pharmacokinetics of digoxin in terms of absorption, excretion
and half-life. The oral bioavailability is 50-80%. Elimination is accomplished by the
kidney and dosing should be adjusted according to kidney function tests, i.e.
creatinine clearance. The half-life with normal kidney function is 30-36 hours.
11) List the clinical indications for the use of digoxin and describe the benefits of its
use in the treatment of chronic heat failure. Therapeutic indications for digoxin use
are atrial fibrillation and congestive heart failure. In congestive heart failure the role
of digoxin has been controversial, but presently it is thought that in patients with
impaired ventricular systolic function and normal sinus rhythm, digoxin improves
symptoms and exercise tolerance.
12) Describe the utility and limitations of estimations of the plasma digoxin
concentration. Plasma digoxin concentration is not extremely useful because there
isn’t a clear value for toxic blood concentration. This is because other factors such as
serum K+ concentration, when low, will result in digoxin toxicity at serum digoxin
levels that would otherwise be “therapeutic”.
13) Describe the interaction between verapamil and digoxin. Verapamil, a calcium
channel blocker, will increase plasma digoxin levels by blocking digoxin uptake into
cells. Co-administration with digoxin requires a 50% reduction of digoxin dose.
Giving digoxin with verapamil or β blockers, both of which act on the A-V node, may
result in a high degree heart block.
14) List the risk factors for digoxin intoxication. Digoxin has a small therapeutic index,
is used in high doses to treat fatal disease, has a long half-life, and its therapeutic
endpoint is indistinct. Risk factors include the use of K+-wasting diuretics and renal
insufficiency (impaired elimination).
15) List the signs and symptoms of digoxin intoxication. The manifestations of digoxin
intoxication may be cardiac (arrhythmias of any type) or extracardiac, which include
fatigue (probably due to K+ loss), anorexia, nausea and vomiting, altered yellowgreen vision and confusion.
16) Describe the management of digoxin intoxication. Treatment of digoxin
intoxication requires hospitalization with cardiac monitoring. Potentiating factors
should be identified and corrected (renal insufficiency or low serum K+ and Mg2+).
When the serum K+ is low intravenous K+ will displace digoxin from its receptor, the
Na+/K+-ATPase. There is a digoxin antibody available for treatment of severe
intoxications and lidocaine can be used to treat digoxin induced arrhythmias.