Kursk state medical university

Department of clinical pharmacology

Clinical pharmacology of
cardiotonic drugs

Professor, doctor of medicine

Mal G.S.

Kursk 2007
 Introduction
• The function of the heart is to pump adequate blood
to all organs in the body to furnish oxygen and
substrates and to remove metabolites.
• Heart failure occurs when ventricular contraction is
compromised and the heart cannot meet demand.
• Several classes of drug are used to increase the force
of contraction and reduce blood volume.
 Congestive heart failure
•Congestive heart failure CHF is a complex
clinical syndrome characterized by impaired
ventricular performance, exercise intolerance, a
high incidence of ventricular arrhythmias, and
shortened life expectancy
•The signs and symptoms of heart failure include
tachycardia, decreased exercise tolerance and
shortness of breath, peripheral and pulmonary
edema, and cardiomegaly.
•Virtually all forms of heart disease can lead to
heart failure, with coronary artery disease,
hypertension, and diabetes mellitus being the
most common in the U.S.
 Pathogenesis of congestive heart failure

To understand and develop appropriate strategies for

pharmacologic therapy, the mechanisms underlying heart
failure must be understood. A number of large-scale
clinical trials over the past decade have shown that drug
therapies aimed at pathogenic mechanisms can play
important roles in long-term therapy of heart failure.
A number of compensatory mechanisms come into play
during the development of chronic heart failure in the
body's attempt to maintain perfusion pressure and
increase cardiac output:
•Augmented sympathetic activity
•Sodium and water retention
•Myocardial hypertrophy
•Ventricular dilatation
 Ventricular dysfunction
• May arise from conditions relating to systole
or diastole.
• Hypertension, valvular disease, or congenital
abnormalities produce diastolic dysfunction.
Chronic systolic dysfunction is produced by
ischaemic caridiomyopathic disease.
• Increased venous pressure results in oedema
 Systolic dysfunction or systolic CHF
•Due to inadequate force generation to eject blood normally
•This is a well-recognized syndrome with the following clinical symptoms:
•Breathlessness and fatigue
•Reduced left ventricular contractile function
•Cardiac output is depressed at rest and increases minimally with exertion
•Elevated heart rate at rest
•Large, dilated, and poorly contracting heart
•End-diastolic ventricular pressures and volumes are increased
•End-systolic volume is increased
•Diminished stroke volume (ejection fraction <45%), even though heart is
dilated
•Because of elevated diastolic left ventricular pressure, pulmonary capillary
pressure is increased which can lead to pulmonary edema
•Pulmonary edema causes the lungs to stiffen and breathing becomes more
difficult, resulting in dyspnea, orthopnea, and tachypnea
•Elevated right ventricular diastolic pressure and increases in systemic venous
pressure leads to peripheral venous congestion and edema
•Due to decreased cardiac output there is inadequate blood flow to vital organs
•Cerebral blood flow may be decreased enough to impair CNS function
•Reduced perfusion of liver and kidneys can impair hepatic and renal function
and reduce the clearance of many drugs
 Diastolic dysfunction or diastolic heart
failure
•Due to inadequate ventricular relaxation which prevents adequate
filling
•Patients show some clinical signs of CHF due to low cardiac output,
but lack specific characteristics of systolic dysfunction (e.g. ejection
fraction may be normal)
•Patients do not usually respond well to positive inotropic drugs
•There is no uniformly agreed upon therapy for CHF secondary to
diastolic dysfunction
•Agents used for systolic CHF (e.g. - vasodilators or positive
inotropes) may have no benefit or exacerbate diastolic
dysfunction
•Acute pulmonary edema due to dysfunction resulting from acute
myocardial infarction may be alleviated by treatment with
nitroprusside, nitroglycerin, or nifedipine
•In theory, angiotensin-converting enzyme inhibitors may prevent
chronic diastolic heart failure in patients with systemic
hypertension because of the ability of ACE inhibitors to reduce
preload and afterload, and minimize myocardial and vascular
smooth muscle hypertrophy
 Homeostatic Response
Maintance of arterial pressure puts extra strain
on the heart by increasing TPR.
– Sympathetic tone is increased
– Renin-angiotensin- vassopressin system is
activated.
– Blood volume is increased
 Energetic efficiency
• Greater wall tension is required to develop the
necessary intraventricular pressure.
• The heart hypertrophies
• Muscle relaxation is inhibited in the
hypertrophied heart.
• Cardiac output is reduced.
 Cardiac Contraction
• Only 10% of the total cell volume of a
myocardial cell is cytoplasm.
• Na channels open for 1-2 msec.
• Calcium channel open and concentration rises
from 50mM to 500mM.
• Contractile protein activation occurs.
• Potassium channels open and K+ efflux
restores RMP. Ca++ channels close.
 DETERMINANTS OF CARDIAC OUTPUT
Left heart
Right heart 1. Preload:
1. Preload: volume of blood
volume of blood returning to
returning to
LA→LV
RA→RU

2. Contractility: 2. Contractility:
RV myocardium LV myocardium

3. Afterload: 3. Afterload:
diastolic pressure in diastolic pressure in
PA and pulmonary AO and systemic
vascular resistance vascular resistance
 CAUSES OF HEART FAILURE
1.PULMONARY EMBOLISM.
2.INFECTION.
3.ANEMIA.
4.THYROTOXICOSIS AND PREGNANCY
5.ARRHYTHMIAS
6.RHEYMATIC AND OTHER FORMS OF
MYOCARDITIS.
7.INFECTIVE ENDOCARDITIS.
8.PHYSICAL DIETARY, FLUID, ENVIRONMENTAL
AND EMOTIONAL EXCESSES.
9.SYSTEMIC HYPERTENSION.
10.MYOCARDIAL INFARCTION.
 Neurohormonal Activation in CHF
•Plasma norepinephrine
•Angiotensin II, plasma renin activity
•Aldosterone
•Endothelin
•Arginine vasopressin
•Atrial, brain, C-natriuretic peptides
(AND, BNP, CNP)
•Inflammatory cytokines (? Role in
cardiac cachexia, skeletal muscle
catabolism and thus poor exercise
performance, negative inotropism,
myocardial cell apoptosis ??)
Tumor necrosis factor (TNF) alpha
Interleukin (IL) 6
 Clinical Manifestation of heart failure
•Dyspnea
•Orthopnea
•Paroxysmal (nocturnal)dyspnea cheyne –
stokes repiration
•Fatique, weakness, and reduced exercise
capacity
•Cerebral symptoms
Physical findings
•Pulmonary rales
•Cardiac edema
•Hydrothorax and ascitis
•Congestive hepatomedaly
•Jaundice
•Cardiac cachexia
 Drugs commonly used in chronic heart failure
•Loop diuretics (e.g. frusemide)
•ACE inhibitors (e.g. captopril, enalapril)
•Digoxin, especially for heart failure
associated with established rapid atrial
fibrillation. It is also indicated in patients
who remain symptomatic despite treatment with
loop diuretics and ACE inhibitors.
•Other vasodilators: organic nitrates (e.g.
isosorbide mononitrate) reduce pre-load, and
hydralazine reduces after-load. Used in
combination, these prolong life, but less
effectively than ACE inhibitors. They are used
when ACE inhibitors are contraindicated or not
tolerated.
 Possible interventions
• Enhanced Na+ influx.
• Increased Ca+ loading of the SR.
• Inhibition of Ca+ extrusion.
• Inhibition of K+ channels.
Treatment
Clinical Management of CHF
Objectives:
increase cardiac contractility
decrease preload (left ventricular filling pressure)
decrease afterload (systemic vascular resistance)
normalize heart rate and rhythym
Approaches:
1. Reduce workload of heart
limit activity level
reduce weight
control hypertension
2. Restrict sodium (low salt diet)
3. Give diuretics (removal of retained salt and water)
4. Give angiotensin-converting enzyme inhibitors
(decreases afterload and retained salt and water)
5. Give digitalis (positive inotropic effect on depressed heart)
6. Give vasodilators (decreases preload & afterload)
 Therapeutics
• Diuretics
• Vasodilators
– Nitrates isosorbided mono/dinitrate
• ACE inhibitors
– captopril, enalopril
• Angiotensin II receptor antagonists
– losartan
• Postive inotrophic drugs:
– Cardiac glycosides
– Sympathomemetics
– Phosphodiesterase inhibitors
• Angiotensin-converting Enzyme (ACE) Inhibitors
• Biosynthesis of Angiotensin
• -Renin is produced by juxtaglomerular cells (near afferent arterioles of
glomeruli) of the kidney
• -decreased ECF volume and decreased blood pressure leads to
increased renin secretion
• many conditions including CHF will stimulate renin secretion (eg.
hypotension, hemorrhage, dehydration, diuretics, Na+ depletion etc)
• -renin converts circulating angiotensinogen leads to angiotensin I
• Angiotensin converting enzyme (ACE) (found in endothelial cells)
converts angiotensin I to angiotensin II
• -also inactivates bradykinin
• Angiotensin II is one of most potent vasoconstrictors known
• -leads to increased systolic and diastolic blood pressure
• -acts directly on adrenal cortex leads to increased secretion of
aldosterone
• also increases release of norepinephrine from post-ganglionic
sympathetic neurons
• -decreased BP leads to contraction of mesangial cells leads to
decreased glomerular filtration rate
• -also increases release of antidiuretic hormone from pituitary gla
• ACE Inhibitors - Examples
• Mechanism:
• decreased angiotensin II leads to decreased peripheral
resistance leads to decreased afterload
• decreased aldosterone secretion leads to decreased salt
& water retention leads to decreased preload
• decreased degradation of bradykinin leads to increased
kinin activity ie. leads to increased vasodilation
• decreased sympathetic activity by decreased
angiotensin-mediated norepinephrine release
• Clinical effect:
• decreased blood pressure
• no effect on CO & HR
• no reflex sympathetic activation
• ie. no reflex tachycardia (unlike vasodilators), therefore
safe for use in persons with ischemic heart disease
 Clinical uses of ACE inhibitors
Hypertension
Cardiac failure
Following myocardial infarction (especially when
there is ventricular dysfunction, even when this is
mild)
Diabetic nephropathy
Progressive renal insufficiency
Clinical uses of angiotensin II subtype 1 (AT1) receptor
antagonists
 Experience with AT1 antagonists is more limited than
with ACEI, and it cannot be assumed that they will
prove to be therapeutically equivalent for all
indications. Many clinicians therefore currently
reserve them for patients with hypertension in whom an
ACEI is indicated, but who are unable to tolerate this
because of dry cough. (This side-effect is not caused
by AT1 antagonists.)
 Enalapril (1)
SIDE EFFECTS
Nausea, appetite loss, or diarrhea are sometimes
observed with this medication. In some patients, these
effects are severe enough to preclude the use of enalapril.
In some patients, blood pressure can drop too low as the
peripheral blood vessels are dilated. This manifests as
listlessness and lethargy.  Often the dose of enalapril can
be modified should this side effect occur.
Enalapril may lead to elevations in potassium blood
levels. 
Enalapril probably should not be used in patients with
impaired kidney function.
This medication should not be used in pregnancy or
lactation
 Enalapril (2)
INTERACTIONS WITH OTHER DRUGS

Enalapril is commonly used in combination with diuretics, especially

furosemide .  In this situation, monitoring kidney parameters is
especially important as both these medications serve to decrease
blood supply to the kidney as they support the heart.  Should a heart
failure crisis occur while a patient is on these two medications, it will
become necessary to rely on the diuretic to resovle the crisis. High
doses of diuretic are typically needed. This can easily lead to kidney
failure though there is no alternative when the heart is failing.

Blood potassium levels can become dangerously high when enalapril

is used with other medications that elevate blood potassium level.
Such drugs might include:  potassium supplements (Polycitra, or
Urocit-K) or spironolactone (a potassium sparing diuretic.)
Enalapril is less effective in the presence of aspirin or other NSAIDs.
 Diuretics

Most pateints with heart failure require treatment with

diuretics to relieve symptoms of fluid retention (edema
and congestion), but their is no evidence that diuretics
slow the progression of the disease or decrease mortality.
•Loop diuretics (furosemide, bumetanide, torsemide) are
the most effective diuretics
•Thiazide diuretics act on the distal loop and are less
effective than loop diuretics
•Concurrent use of two diuretics with different sites of
action may be needed in patients who do not respond well
to a single oral diuretic
•The most common adverse effect of diuretic therapy is
potassium depletion which can be prevented by use of
supplemental potassium, an ACE inhibitor, or a
potassium-sparing diuretic (spironolactone or amiloride)
• Diuretics
• Mechanism:
• decreased salt & water retention leads to
decreased ventricular preload
• Clinical Effect:
• decreased signs & symptoms of heart failure (ie.
edema)
• decreased cardiac size leads to improved
cardiac function
• Administration:
• start with a thazide diuretic and switch to a more
powerful agent as required
• check serum electrolytes to prevent K+ loss
 ACE inhibitors and Angiotensin II Receptor
Antagonists
Angiotensin-converting enzyme (ACE) inhibitors (enalapril, lisinopril,
captopril) are first-line therapy in all patients with heart failure.
•ACE inhibitors improve symptoms, slow progression of the disease,
reduce mortality, and decrease the incidence of hospitalization
•The most common adverse effects of ACE inhibitors are directly
related to lowering angiotensin II concentrations (hypotension and
renal insufficiency) and increasing concentrations of kinins (cough
and angioneurotic edema)
•Decreasing the dose of concurrent diuretic can minimize the effects
of lowering angiotensin II
•The effects caused by increased kinins can be relieved by
substituting the ACE inhibitor with an angiotensin II receptor
antagonist
•Clinical trials have yet to firmly establish that angiotensin receptor
antagonists (losartan, candesartan, valsartan) are as effective as ACE
inhibitors in treating heart failure, but it appears that therapeutic
efficacy may be comparable
 Inotropic Drugs
•Digitalis (cardiac glycosides)
•Digitalis has been used clinically for over 200 years to
treat heart failure and edema (dropsy), but its present use
in treating CHF is controversial
•The cardiac glycosides inhibit the Na+-K+ -ATPase pump,
which causes an increase in intracellular Na+, slowing the
rate of the Na+,Ca++-exchanger, and thereby causing an
increase in intracellular Ca++
•Although widely used, digitalis is associated with an
appreciable risk of toxicity and many patients do not
derive any benefit
•The recent Digitalis Investigation Group (DIG) clinical trial
indicated digoxin did not reduce overall mortality in
patients with heart failure (who were receiving diuretics
and ACE inhibitors), but did reduce the rate of
hospitalization
 Digitalis Glycosides
• Extracted for the foxglove plant
• Increase Na+ concentration in the cytoplasm.
• Inhibition of the Na+, K+-ATPase pump
• Inhibits Na influx which is coupled to Ca ++
efflux and thereby increases Ca++ loading in
the SR.
• Digitalis
• Digitalis is derived from the foxglove plant. It has been used to
treat heart disease since the 1700s. Digoxin (Lanoxin) is the
most commonly prescribed digitalis preparation. It is referred to
as an inotropic drug and has the following benefits:
• It increases the strength of the heart's contraction.
• Reduces heart size.
• Reduces certain arrhythmias.
• It improves symptoms and reduces hospitalization slightly.
• Unfortunately, digitalis does not reduce mortality rates.
Controversy has been on-going for more than 100 years over
whether the benefits of digitalis outweigh its risks and adverse
effects.
Candidates. Digitalis may be useful for the following patients:
• Patients with left-side (systolic) dysfunction who do not respond
to other agents (diuretics, ACE inhibitors).
• Heart failure patients with atrial fibrillation
Drugs Used in Congestive Heart Failure
1. Positive Inotropic Drugs
(Cardiac Glycosides)
Digitalis
extract of foxglove plant (Digitalis purpurea)
contain lactone ring (lipophilic) and steroid nucleus (hydrophilic)
essential for activity and determines pharmacokinetic properties
well absorbed orally (75%) and widely distributed (including CNS)
excreted unchanged in kidneys, clearance is slowed in renal disease

Mechanism
inhibits Na+/K+ ATPase (sodium pump) leads to increased intracellular
Na2+ leads to decreased Ca2+ expulsion from Na+-Ca2+ exchanger
leads to increased free intracellular Ca2+ leads to increased interaction of
actin and myosin filaments leads to increased contractility (positive
inotropic
 Cardiac glycosides
•Act by inhibiting Na+/K+ pump, thus
increasing [Na+]. This results in reduced
Na+/Ca2+ exchange, causing secondary rise
in Ca2+ accumulation by sarcoplasmic
reticulum.
•Main effect is increased force of
contraction.
•Additional important effects are:
increase of ectopic pacemaker activity
impairment of AV conduction increased
vagal activity, causing bradycardia.
•Effects are increased by hypokalemia.
• Administration & Dosage of digitalis
• General:
•
T1/2 is long (40 hrs)
Therapeutic plasma concentration: 0.5-2 ng/ml
Toxic plasma concentration: >2 ng/ml
• digitalis must be present in the body in certain
"saturating" amount before any effect on congestive
failure is noted
• this is achieved by giving a large initial dose in a process
called "digitalization"
• after intial dosages, digitalis is given in "maintenance"
amounts sufficient to replace that which is excreted
• to avoid exceeding therapeutic range during
digitalization:
- the loading dose should be adjusted according to the
health of the patient
- slow digitalization (over 1 week) is the safest technique
- plasma digoxin levels should be monitored
• Clinical effects
• In a failing heart increased HR, increased ventricular volume & pressure,
& decreased stroke volume leads to increased sympathetic activity and
blood volume. Digitalis corrects this through the following effects:
•
i) Mechanical effects:
• increased stroke volume and increased CO
• decreased heart rate and decreased vascular tone
(decreased sympathetic stimulation)
• decreased end-diastolic fibre tension
(due to increased stroke volume & decreased filling pressure)
• increased renal blood flow
(leads to increased glomerular filtration & decreased aldosterone-driven
Na+ resorption which results in edema fluid excretion)
•
ii) Electrical effects:
• parasympathomimetic effect
• prolonged refractoriness of AV node
• Net effect: slows ventricular rate and can cause arrhythmias
• Digitalis may be harmful in the following patients:
• Patients with right-side heart failure.
• Patients who stop taking digoxin after using it in combination with
ACE inhibitors are at risk for worsening heart failure.
• Factors that increase the risk of toxicity include the following:
• Advanced age.
• Low blood potassium levels (which can be caused by diuretics).
• Hypothyroidism.
• Anemia.
• Valvular heart disease.
• Impaired kidney function.
• Digitalis interacts with many other drugs, including quinidine,
amiodarone, verapamil, flecainide, amiloride, and propafenone.
 Clinical uses of digoxin
•Digoxin is the cardiac glycoside in widest clinical
use.
•Uses include:
slowing ventricular rate in rapid atrial
fibrillation
treatment of heart failure in patients who remain
symptomatic despite optimal use of diuretics (Ch.
20) and angiotensin-converting enzyme inhibitors
(Ch. 15).
•Adverse effects include nausea, vomiting, cardiac
arrhythmias, confusion.
•Administration is oral or, in urgent situations,
intravenous.
•Elimination is mainly by renal excretion; elimination
half-time is approximately 36 hours in patients with
normal renal function, considerably longer in elderly
patients and those with overt renal failure in whom
reduced doses are needed.
 Clinical uses of digoxin
•A loading dose is used in urgent situations.
•The therapeutic range of plasma
concentrations, below which digoxin is
unlikely to be effective and above which the
risk of toxicity increases substantially, is
fairly well defined. Determination of plasma
digoxin
concentration is useful when lack of efficacy
or toxicity is suspected.
•Clinically important interactions occur with
drugs that reduce plasma K* (e.g. loop
diuretics) or which simultaneously reduce
digoxin excretion and tissue binding (e.g.
amiodarone, verapamil).
 CARDIAC GLUCOSIDES: ROUTES OF ADMINISTRATION
Peak
Preparation Onset of Disappearanc
effect Dose (mg)
i.v. action (min) e (days)
(min)

Quabain 5 30-120 3 0.25-0.5

Digoxin 15 120 7 0.5-1.0

Initial Daily
Preparation Onset of Peak Disappearanc dose maintenance
per os action (hr) effect (hr) e (weeks)
(mg) dose (mg)

Digoxin 1-3 6-12 1 0.5-1.0 0.25

Digitoxin 2-4 6-12 3 0.2-0.4

 ORAL DOSAGE

SEVERE CASE MODERATE CASE MAINTENANCE

PREPARATION
DOSE
Until Until
Unitial digitaliz Initial digitaliz
ation ation

0.5mg 6 0.5mg 0.25 - 0.15

Digoxin... 1.5 mg 0.5 mg
hourly t.d.s. mg

0.1 - 0.2
Digitoxin... 0.6 mg 0.2 mg — 0.2 mg 0.2 mg —
mg

Canatoside 3mg 1 mg — 1 mg 1 mg — 0.5 -1 mg

 Digoxin (1)

•Digoxin is the most widely used preparation of digitalis

(half-life = 1-2 days), although digitoxin (half-life = 7 days) is
also used in situations where long half-life may be an
advantage
•Digitalis is a drug of choice for heart failure associated with
atrial fibrillation, although other antiarrhythmic drugs are
available and should be considered
•Patients who respond favorably to digoxin therapy generally
have more chronic and severe heart failure, greater left
ventricular dilatation, a very reduced ejection fraction, and a
third heart sound
•Digitalis' effect on A-V nodal conduction requires an intact
vagus nerve
•Improvement with digitalis depends upon the "cardiac
reserve"; badly damaged hearts will not respond well to
digitalis therapy
 Digoxin (2)
•Toxic effects of digitalis are also more likely if the heart is
severely damaged
•After digitalis has restored cardiac function, its use is typically
continued to prevent further recurrence of failure, even though
there is no evidence of prolongation of life with continued
therapy
•It is possible that digitalis may be effective in decreasing the
rate of progression of cardiac damage in some patients,
particularly those where a progressive increase in end-diastolic
pressure and volume is likely to occur
•There is recent evidence that digitalis may act directly to blunt
baroreceptor response and thereby exert some of its beneficial
effects through reduction of sympathetic tone
 Side effects
• Effective range = 1.0 - 2.5 ng/ml
• Toxic range = 1.5 - and up
• Gastrointestinal (relate to vagal effects)
– Anorexia, abdominal pain, vomiting, diarrhoea
• Cardiac - any arrhythmia ever described
– Premature ventricular depolarizations
– Nodal rhythms
– AV dissociation
 Cardiac glycosides
Alternative Names:
Digoxin; Digitoxin; Lanoxin; Purgoxin; Allocar;
Corramedan;
Cystodigin
Unwanted effects
body as a whole
- weakness
-headache
-apathy
-depression
-hallucinations *
eyes, ears, nose, and throat
-blurred vision
-halos around objects (yellow, green, white) *
skin
-rash
-hives
stevens-johnson syndrome
 Cardiac glycosides
gastrointestinal
-loss of appetite *
-vomiting or nausea
-abdominal pain (lower stomach)
-diarrhea

heart and blood vessels

-irregular heartbeat (or slow)
-low blood pressure

nervous system
-drowsiness
-confusion
-depression *
-headache
-fainting
-lethargy
-disorientation
* Usually only seen with chronic overdose cases
• Interactions:
•
Serious cardiac arrhythmias may develop if:
• hypokalemia develops (due to diuretic therapy or
diarrhea)
• given quinidine therapy (prevents digoxin clearance)
• Toxicity
• in 10% of individuals enteric bacteria inactivate digoxin
• antibiotic therapy can leads to sudden increased in
bioavailability
• narrow therapeutic index \ even minor variations in
bioavailability leads to serious digitalis toxicity
• Cardiac toxicity:
• digitalis leads to decreased duration of action potential leads to
decreased refractory period leads to ectopic beats leads to
ventricular tachycardia leads to ventricular fibrillation
• sodium pump is necessary for maintenance of normal resting
potential
• digitalis inhibition of Na+ pump leads to decreased resting
membrane potential (i.e. made less negative) leads to AV block
• also Na+ pump inhibition leads to oscillatory afterdepolarizations
(caused by overload of intracellular Ca2+) leads to premature
ventricular depolarization, and ventricular tachycardia
• GI toxicity:
• anorexia, nausea, vomiting and diarrhea
• CNS toxicity:
• sensitization of baroreceptors
• vagal stimulation
 THERAPY OF DIGITALIS TOXICITY
Indication Comments
Discontinue drug All suspected patients, Observe in monitored setting. Hypokaliemia: best of
hypo/hyperkaliemia corrected intravenously slowly over 4-8 hours.
Hyperkaliemia: immediate treatment necessary with glucose,
insulin, bicarbonate, potassium-binding resins and dialysis,
if necessary: poor prognostic sign.
Lidocaine Hemodynamically Central nervous system toxicity is common, and suppression
Phenytoin significant ventricular of rhythm may lead to asystole.
arrhythmias
Other Refractory ventricular Selection necessary.
antiarrhythmics arrhythmias
Atropine Hemodynamically Effect is short-lasting.
significant bradycardia
and heart block
Temporary Severe bradycardia External or right ventricular transvenous pacemaker. Clinical
pacemaker and advanced heart decision necessary; must weigh benefit/risk ratio.
block
Cardioversion Ventricular May precipitate asystole. Begin with low energy and
tachycardia/ increase if necessary.
ventricular fibrillation
Digitalis-specific Severe life-treatening Rapid onset of action may precipitate hypokaliemia,
antibodies toxicity congestive heart failure.
Activated charcoal Massive acute Decreases absorbtion digitalis preparation via entero-hepatic
 Treatment of Toxicity
• Stop giving the drug (for a time)
• Antiarrhythmics (lidocaine, procainamide, propranolol,
phenytoin) IF the arrhythmias appear to be life-threatening in
their own right (multi-focal pvcs, high rate ventricular
tachycardia) or if the arrhythmias severely compromise
cardiac output.
• Potassium (if hypokalemic)
• Cholestyramine, activated charcoal etc. to bind digoxin in GI
tract and shorten half-life
• Digoxin Antibodies (therapeutic monitoring becomes
irrelevant).
Contraindications and Precautions of
Digoxin

Known hypersensitivity to cardiac glycosides.

Caution in preterm infants, especially extreme
immaturity.
Caution in infants with renal impairment.
Caution in infants with acute myocarditis,
bradyarrhythmias (especially heart block).
Ventricular dysrhythmias.
Pre-existing hypokalaemia may precipitate
adverse reactions.
 Beta-Blockers and Heart Failure

A number of studies beginning in the 1970s have shown that

beta-blockers can improve symptoms and ventricular function
in patients with moderate to severe heart failure, and may slow
the progression of heart failure in some patients

•Though beta-blockers were widely considered to be

contraindicated for patients with heart failure only a decade
ago, they are now considered first-line therapy for patients with
mild to moderate heart failure
•The adverse effects of beta-blockers in patients with heart
failure include worsening of symptoms, hypotension, and
bradycardia
•These symptoms can be minimized by initiating therapy with
low doses and gradually increasing dosage until tolerable
therapeutic doses are reached
•Beta-blockers are contraindicated in patients with asthma or
severe bradycardia
 Beta-Adrenergic Agonists
•Beta1-adrenergic agonists (dopamine, dobutamine, prenalterol,
xamoterol) have been used to treat acute and chronic heart failure, but
have limited usefulness in chronic CHF because of their arrhythmogenic
effects, short duration of action, the development of tolerance, and
necessity of parenteral administration
•Dopamine (i.v.) is used in ьacute heart failure (cardiogenic shock) to
increase blood pressure and increase cardiac output
•It has a short half-life (1 min)
•At high doses dopamine has potent peripheral vasoconstrictor effects
(alpha-receptor stimulation), in addition to its inotropic effects
•Low dose dopamine has a renal artery dilating effect and may improve
sodium and water excretion in patients refractory to loop diuretics
•When systolic pressure is greater than 90 mm Hg, nitroprusside can be
added to reduce ventricular filling pressure and reduce afterload
•i.v. furosemide should also be administered to reduce edema
•Levodopa and ibopamine, analogs of dopamine that can be
administered orally, have been shown to improve symptoms in some
patients, but can exhibit arrhythmogenic side-effects and tachyphylaxis
 Agents that are currently used to treat CHF

•Carvedilol, a nonselective beta-blocker with alpha1-

adrenergic antagonist (vasodilator) activity, but longer
acting than labetolol; this agent also possesses
significant antioxidant properties which may be beneficial
(FDA-approved)
•Metoprolol, a relatively selective beta1-adrenergic
antagonist (not FDA-approved for CHF)
•Bisoporol, a beta1-selective adrenergic antagonist (not
FDA-approved for CHF)
•Bisopolol beta-blockers agents that have been
investigated for use in treating CHF include:
•Labetolol, a nonselective beta-blocker with alpha1-
adrenergic antagonist (vasodilator) activity
•Bucindolol, a non-selective beta-blocker with vasodilator
 MYOCARDIAL FUNCTION: HEART FAILURE.
SOME VASODILATOR DRUGS.
VENOUS:
NITRATES (ISOSORBIDE DINITRATE) 10-40 mg 4 to 6 hourly
orally or 2-7 mg per hour intravenously.

ARTERIAL:
HIDRALAZINE (APRESOLINE) 25-50 mg 3 or 4 times daily.

VENOUS AND ARTERIAL:

SODIUM NITROPRUSSIDE (NIPRIDE) 10-400 mg/min
intravenously.
PRAZOSIN (HYPOVASE) 0,5-5 mg 4 times daily orally.
CAPTOPRIL (CAPOTEN) 25-150 mg 3 times daily orally.
 Types of vasodilator drugs
 ACE inhibitors (e.g. captopril, enalapril):
prevent conversion of angiotensin I to
angiotensin II; therefore most effective when
renin release is increased.
 Nitrates (e.g. glyceryl trinitrate,
nitroprusside): act like endogenous NO,
causing increased cGMP formation.
 Calcium antagonists (diltiazem, nifedipine and
many other dihydropyridines): act by blocking
Ca2+ entry in response to depolarisation;
dilate both resistance and capacitance
vessels.
 Drugs that interfere with sympathetic
transmission (e.g. α1-adrenoceptor
antagonists).
 Types of vasodilator drugs
K+ channel activators (e.g. diazoxide,
cromokaiim, pinacidil): open membrane K+
channels, thus causing hyperpolarisation;
thought to affect insulin-secreting cells and
neurons, as well as smooth muscle, so produce
various side-effects.
Angiotensin II subtype-1 (AT1) receptor
antagonists (e.g. losartan).
Other agents include: p2-adrenoceptor
agonists; adenosine; methylxanthines. (e.g.
theophylline); various diuretics and numerous
agents that stimulate endothelial NO production
(Ch. 11).
 Clinical uses of calcium antagonists

Calcium antagonists are used for:

•supraventricular
tachyarrhythmias; verapamil is
used as described in the clinical
box on class IV drugs;
•hypertension;
•reducing the frequency of attacks
of angina.
 Calcium antagonists
Block Ca2+ entry by preventing opening of voltage-
gated L-type and, recently, T-type Ca2+ channels.
Three main L-type antagonists, typified by
verapamil, diltiazem and dihydropyridines (e.g.
nifedipine).
Mainly affect heart and smooth muscle, inhibiting
the Ca2+ entry caused by depolarisation in these
tissues.
Selectivity between heart and smooth muscle varies:
verapamil is relatively cardioselective; nifedipine
is relatively smooth-muscle selective and diltiazem
is intermediate.
Vasodilator effect (mainly dihydropyridines) is
mainly on resistance vessels, causing reduced
after-load. Calcium antagonists also dilate
coronary vessels, which is important in variant
angina.
 Calcium antagonists
Effects on heart (verapamil, diltiazem):
antidysrhythmic action (mainly atrial
tachycardias) because of impaired AV
conduction, and reduced contractility.
Clinical uses include: antidysrhythmic therapy
(mainly verapamil, especially atrial
tachycardias), angina (by reducing cardiac
work) and hypertension.
Unwanted effects include headache, constipation
(verapamil), and ankle oedema
(dihydropyridines). There is a risk of causing
cardiac failure or heart block, especially with
verapamil and diltiazem.
 Calcium channel blockers
Though most clinical trials have indicated that calcium
channel blockers are detrimental in patients with heart
failure, specific calcium channel blockers may be
beneficial
•Amlodipine, a long-acting dihydropyridine, has been
shown to reduce mortality in patients with CHF due to
nonischemic cardiomyopathy
•Mibefradil, a T-type channel blocker, was in clinical trials
for use in treating patients with heart failure (Mortality
Assessment in Congestive Heart Failure; MACH-1) based
on favorable results in animal studies where it was
beneficial as a ACE inhibitor in improving survival. This
drug has been withdrawn from the market due to possible
risks associated with drug interactions.
•Other calcium channel blockers have not proven to be
beneficial in heart failure
• Vasodilators
• Mechanism:
• decreased preload (through venodilation)
• decreased afterload (through arteriolar dilation)
• or both
• Clinical Considerations:
• -either selective arteriolar dilators, venous dilators and/or
combined venous and arteriolar dilators
• -patient's signs determine the choice
• eg. dyspnea due to high filling pressures and pulmonary
congestion therefore use venous dilator
• eg. fatigue due to low left ventricular output, therefore
use arteriolar dilator to increase forward cardiac output
• -in severe CHF use both
 Dobutamine

•Dobutamine is a somewhat selective beta1-adrenergic agonist that

lacks vasoconstrictor activity and causes minimal changes in heart
rate
•It is frequently added to nitroprusside when blood pressure is
adequate to increase cardiac output
•It is administered as an i.v. infusion to treat acute severe heart
failure
•It has a short half-life (2.4 min) and is only used on a short-term
basis, although long-term beneficial effects on cardiac function
have been noted
•After 72 hours of therapy, tolerance can develop to dobutamine
necessitating switch to other inotropic support (e.g. milrinone)
•Dobutamine can enhance AV conduction and worsen atrial
tachycardia
•Prenalterol and xamoterol are partial beta1-adrenergic agonists that
may simultaneously stimulate beta1-receptors and block the
receptors from stimulation by endogenous catecholamines, thereby
protecting against beta1-receptor down-regulation
 Cyclic Nucleotide Phosphodiesterase (PDE-III,
cGMP-inhibitable PDE) Inhibitors (1)

•Several agents increase myocardial and vascular smooth

muscle cAMP concentrations through inhibition of cyclic
nucleotide phosphodiesterase (PDE-III, cGI PDE) activity
•These agents should therefore simultaneously increase
cardiac contractility and reduce afterload and preload
•A number of clinical trials have indicated that PDE inhibitors
can increase mortality in patients with heart failure, but there
are suggestions that PDE inhibitors might be very useful in
combination with beta-blockers
•The bipyridines, amrinone and milrinone, are potent PDE-III
inhibitors that are approved for short-term support (by
parenteral administration) of patients with advanced heart
failure
 Cyclic Nucleotide Phosphodiesterase (PDE-III,
cGMP-inhibitable PDE) Inhibitors (2)

•Duration of action is several hours in patients with CHF

•Milrinone is the drug of choice of currently available PDE-III
inhibitors because of its greatly selectivity for PDE-III, shorter
half-life (30-60 min), and fewer side effects (amrinone is
associated with thrombocytopenia in 10% of patients)
•Clinical trials with oral formulations of milrinone were shown
to have increased adverse effects (hypotension, syncope,
arrhythmias), increased mortality, and no long-term
hemodynamic benefit
•The imidazolone derivatives, enoximone and piroximone, are
other PDE III inhibitors shown to have beneficial short-term
effects on left ventricular function
•- The benzimidazole derivatives, sulmazole and pimobendan,
are PDE III inhibitors that may also act by sensitizing
myocardial contractile proteins to Ca2+ ("Ca2+-sensitizers")
 Other Agents with Therapaeutic Potential

Because there are a large number of neurohumoral

factors that are elevated in heart failure, and because of
the effectiveness of ACE inhibitors and beta-blockers in
slowing the progression of the disease, there are
considerable efforts to identify additional neurohumoral
antagonists that could be useful in the treatment of heart
failure.
•Endothelin-1 Antagonists
•The vasoconstrictor peptide, endothelin-1, is known
to be elevated in heart failure and is a predictor of
mortality in patients with heart failure. Animal models
of heart failure indicate endothelin receptor
antagonists such as bosentan may have long-term
benefits in reversing myocardial remodeling and
improving survival. Short-term, small-scale trials in
humans indicate possible beneficial effects on
systemic and pulmonary hemodynamics
 Heart failure Drugs (1)
UNDESIRABLE
DRUG MECHANISM /ACTIONS INDICATIONS
EFFECTS
Bipyridine derivatives
Amrinone Inhibits Added to d igoxin Gl intolerance,
(Inocor) phosphodiesterase (the therapy when hepatotoxicity, fever.
enzyme that breaks heart failure Reversible
down cAMP). cAMP persists despite thrombocytopenia
increases calcium digoxin. (20%). Not
uptake. Increases arrhythmogenic
contractility, stroke
volume, ejection
fraction, and sinus rate.
Decreases peripheral
resistance.
Milrinone Twenty times more Very few side effects.
(Primacor) potent than amrinone. Headache and worsening
Same actions. of angina have been
reported.
 Heart failure Drugs 2
UNDESIRABLE
DRUG MECHANISM /ACTIONS INDICATIONS
EFFECTS
Other agents
Dobutamine Beta 1 receptor-preferring To increase cardiac Tachycardia, hypotension,
(Dobutrex) adrenergic agonist At output in chronic nausea, headache,
moderate dose, increases heart failure. May palpitations, anginal
contractility without be used with symptoms, dyspnea,
increasing heart rate or afterload reducing ventricular arrhythmias.
blood pressure. Minimal agents. Also used
effect on blood vessels. for treatment of
shock.
Prazosin Selective antagonist at ul Heart failure (recent Orthostatic hypotension,
(Minipress) adrenergic receptors. studies show poor syncope, fluid retention.
Dilates arteries and veins. efficacy! Also used
for hypertension
and Raynaud's
phenomenon.
Terazosin Heart failure. Lightheadedness, fatigue,
headache,Gl distress, nasal
congestion, tachycardia,
edema.
ARMACOLOGIC AGENTS USED TO INCREAS CARDIAC OUTP

DRUG DOSE ACTION COMMENT

Effective in hypotension
Parasympatholyti
ATROPIN 0,01 mg/kg c
secondary to bradycardia
minimum dose 0,1 mg
0,01mg/kg α - and β- Used primarily for
EPINEPHRINE 0,02-0,2 adrenergic emergency resuscitation.
stimulation Avoid intracardiac route
mg/kc/min
Increases heart rate and
0,05-0,5 β - adrenergic contractility decreases afterload.
ISOPROTERENOL Maintain adequate preload
mg/kc/min stimulation
arrhythmias at high doses
Potent vasoconstriction may
0,02-0,10 α - adrenergic compromise organ perfusion
NOREPINEPHRINE in excess doses or in the
mg/kc/min stimulation
presence of hypovolemia
2-5 mg/kc/min
(low dose) α - and β- Splanchnic and renal
vasodilatation at low doses.
5-15 mg/kc/min adrenergic Increasing p - adrenergic
DOPAMINE
(moderate dose) receptor effect at moderate doses and
15-30 mg/kc/min stimulation a effect at high doses
(high dose)
 Strategies for Treating Cardiovascular Disease
Pharmacologic strategies. Prototype drug listed,
Therapeutic goals
alternative drugs listed in following tables
Digoxin increases calcium influx into myocardial cells.
Amrinone inhibits cAMP degradation (cAMP is a
Heart failure.
biochemical messenger that stimulates the heart).
Improve myocardial contractility
Dobutamine increases cAMP production by binding B1
adrenergic receptors.

Reduce preload. Preload is the

volume of blood that fills the Nitroslycerin reduces venous tone (it also dilates
ventricle during diastole. Elevated coronary arteries, enhancing blood delivery to the
preload causes over filling of the heart).
heart which increases the workload

Reduce afterload. Afterload refers

to the pressure that must be Diuretics and Captopril decrease blood volume by
overcome in order for the heart to increasing the volume of water excreted in the urine.
pump freshly oxygenated blood into Hydralasine relaxes arterioles
the arterial system
 Strategies for Treating Cardiovascular Disease
Pharmacologic strategies. Prototype drug listed,
Therapeutic goals
alternative drugs listed in following tables
Hypertension. Reduce Diuretics and Captopril decrease blood volume by
volume overload increasing the volume of water excreted in the urine
Reduce sympathetic Clonidine is an agonist a A2 receptors. Clonidine inhibits
outflow from the further release sympathetic agonist, nor epinephrine and
brain inhibits sympathetic outflow from the brain.
Block adrenergic in Atenolol is a B1 adrenergic receptor antagonist that reduces
the hear hear rate and myocardial work.
Prasosin blocks A1 adrenergic receptor, causing
vasodilation. Nifedipine blocks calcium entry into smooth
Dilate blood vessels
muscle cells of arterial walls, preventing contraction.
Hydralasine relaxes arterioles.
Nitroglycerin reduces preload by venodilation. Atenolol
Angina Reduce work decreases myocardial work (B1 antagonist). Nifedipine
of heart decreases blood pressure through vasodilation, by blocking
calcium entry.
 Mode of Drugs Adverse effects Special features
action Postural Impotence Other
hypotension

Reduction of Thiazide Urinary frequency, Reduce stroke in clinical

blood diuretics gout glucose trials, inexpensive
Volume/indirect
vasodilatation
- ++ intolerance,
hypokalemia,
hyponatraemia,
thrombocytopenia
Block of β- Propranolol Fatigue, cold Reduce stroke in clinical
adrenoceptors Atenolol peripheries trials, inexpensive, additional
Metoprolol
- ± benefit after Ml.
Contraindications: asthma,
heart failure, heart block,
peripheral vascular disease
ACE inhibition Captopril First dose Additional benefit in insulin-
Enalapril hypotension, dry dependent diabetics with
Lisinopril cough, reversible proteinuria, following Ml, and
Trandolapril
Ramipril
- ± renal failure in
patients with
in patients with heart failure-
cause regression of left
bilateral renal artery ventricular hypertrophy
stenosis
Arteriolar Ca2+ Flushing, headache,
vasodilatation antagonists, ankle oedema
e.g. nifedipine,
amlodipine
- ±
nicardipine
α-adrenoceptors Prazosin First dose Longer-acting drugs (e.g.
Terazosin hypotension terazosin, doxazosin) better
Doxazosin
+ ± tolerated than prazosin.
Improve plasma lipids. Useful
addition to other drugs when
two drugs needed