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CHAPTER

Cardiovascular Pharmacology
Roman M. Sniecinski, Susan Wright, and Jerrold H. Levy

In this chapter the pharmacology of cardiovascular drugs

that are used in the intensive care unit (ICU) is reviewed.
Specific indications for particular drugs are discussed in
other relevant chapters. Guidelines for the reintroduction
of medications following routine cardiac surgery are
provided in Chapter 17.

INOTROPES AND VASOPRESSORS

Inotropes and vasopressors are some of the most widely
used drugs in the ICU, and they can be broadly classified
on the basis of their effects on circulation. Inotropic
drugs with vasodilatory effects (e.g., isoproterenol, milrinone, levosimendan) are termed inodilators; inotropic
drugs with vasoconstrictive effects (e.g., norepinephrine)
are termed inoconstrictors. Some drugs are inodilators
at lower doses and inoconstrictors at higher doses
(e.g., dopamine, epinephrine). Other drugs are pure vasoconstrictors or vasodilators. Vasoactive drugs can also
be classified on the basis of their mechanism of action,
for example, as sympathomimetics, phosphodiesterase
inhibitors, or calcium sensitizers.
The effect of a drug on a vascular bed depends on the
activity of the drug at various receptors and the relevant
receptor population in that vascular bed. However, the
overall effects of a drug on blood pressure, cardiac output,
and regional blood flow depend on a complex interplay of
factors, of which the direct pharmacologic properties of
the drug is but one. Other relevant factors include:

Baroreceptor-mediated responses.
The underlying hemodynamic state (circulating
volume, vascular tone, ventricular function).
Indirect actions of the drug.
Receptor sensitivity.

Pharmacokinetic variability.
The integrity of vascular endothelium.

For these reasons it is often difficult to predict the

precise effect of a particular agent on an individual patient.
These concepts are discussed in greater detail in the
following material.
Infusions of vasoactive drugs are prescribed in different ways in different institutions. Three common
methods are micrograms per kilogram per minute
(g/kg/min), micrograms per minute (g/min), and
milligrams per hour (mg/hr). In this book g/kg/min
is used. A conversion among the methods is provided in
Appendix 1.

Sympathomimetics
All sympathomimetics are derived from -phenylethylamine. The presence of hydroxyl groups on the 3- and
4-carbons in the benzene ring designates a compound as
a catecholamine, which may be endogenous or synthetic
(Fig. 3-1). The noncatecholamine sympathomimetics
include a diverse range of drugs, such as the asthma
medication albuterol and the central nervous system
stimulant amphetamine. Two commonly used vasoactive
noncatecholamine sympathomimetics are ephedrine and
phenylephrine.

Mechanism of Action
Sympathomimetics bind to and stimulate adrenergic receptors that are located on cell membranes. In 1948, Alquist
described two adrenergic receptor subtypes, alpha ()
and beta (), based on their relative responsiveness to
norepinephrine, epinephrine, and isoproterenol.1 In the
1970s this classification was refined to include 1, 2,
1, and 2 receptor subtypes. Subsequently, further divisions of each receptor subtype have been discovered, but
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6
5

CH2CH2NH2

-phenylethylamine

HO
OH
Catecholamines

Endogenous
Epinephrine
Norepinephrine
Dopamine

Synthetic
Isoproterenol
Dobutamine

Non-catecholamines

Indirect-acting
Ephedrine

Direct-acting
Phenylephrine

Figure 3.1: Classification of sympathomimetics. All sympathomimetics have a benzene ring and an ethylamine
group in position 1. Catecholamines have hydroxyl substitutions in positions 3 and 4 of the benzene ring.
Noncatecholamine sympathomimetics may also have substitutions in the benzene ring (e.g., phenylephrine has a
single hydroxyl substitution in position 4).

clinically useful drugs to exploit these expanded classifications have not been developed.
Adrenergic receptors are part of a family of receptors
known as G protein coupled receptors. Receptor stimulation by an agonist (see Chapter 4) facilitates the
binding of the nucleotide guanosine triphosphate to a
G protein, which activates it. The activated G protein then
stimulates or inhibits one of a number of second messenger systems. Two second messenger systems mediate the
actions of adrenergic receptors:

34

Inositol triphosphate/diacylglycerol (IP3/DAG). This

second messenger system regulates the release of calcium
from intracellular stores. An activated G protein stimulates the enzyme phospholipase C, which causes the
hydrolysis of a membrane-bound phospholipid into IP3
and DAG. IP3 diffuses into the cytoplasm and triggers
the release of calcium from the endoplasmic reticulum.
The IP3/DAG system mediates the actions of 1
receptors. (It also mediates the actions of angiotensin
II and vasopressin type-1 receptors.)
Cyclic adenosine monophosphate (cAMP). Activation
of stimulatory or inhibitory G proteins regulates the activity of the membrane-bound enzyme adenylate cyclase,
which catalyzes the conversion of adenosine triphosphate
into cAMP. Then cAMP activates protein kinases, which
cause the phosphorylation of various intracellular
enzymes, modulating their function. The cAMP system
regulates the intracellular calcium concentration through
protein-kinase-mediated phosphorylation of transmembrane calcium channels; cAMP is metabolized into an
inactive form by phosphodiesterase, of which there are
several types. The cAMP second-messenger system mediates the actions of 1 and 2 receptors via a stimulatory G

protein and 2 receptors via an inhibitory G protein.

(An analogous second-messenger system based on
cyclic guanosine monophosphate (cGMP) mediates the
actions of the natriuretic peptides and nitric oxide.)

Receptor Effects
The direct cardiovascular effects of the adrenergic receptor
subtypes are summarized in Table 3-1.
a Receptors. 1 Receptors are widely distributed in vascular smooth muscle, particularly in the arterioles of
skeletal muscle and the gastrointestinal tract. They are
also present on the radial muscle of the eye, the smooth
muscle of the uterus, and the sphincters of the bladder
and gastrointestinal tract. Stimulation of 1 receptors
causes vasoconstriction, pupillary dilatation (mydriasis),
and sphincter contraction.
Peripheral 2 receptors are located on sympathetic
nerve terminals. Stimulation of these receptors inhibits
norepinephrine release and therefore causes vasodilation.
Stimulation of central 2 receptors causes sedation, analgesia, and reduced sympathetic outflow. The last effect
contributes to vasodilation.
b Receptors. 1 Receptors are present on the heart; their
stimulation results in increased heart rate (chronotropy),
increased conduction (dromotropy), reduced refractoriness within the atrioventricular (AV) node, and increased
contractility (inotropy). The 1 receptors are also found
on the juxtaglomerular cells of the kidney; their stimulation leads to increased renin release.
2 Receptors are found on the heart and throughout the
vasculature, particularly the arterioles of skeletal muscle,

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Chapter 3

Table 3-1

Cardiovascular Pharmacology

Effects of Adrenergic Receptor Subtypes on the Cardiovascular System

Receptor

Location

Action

Systemic arterioles, mainly:

Abdominal viscera
Coronary
Skin
Skeletal muscle
Veins
Pulmonary arterioles

Vasoconstriction

Pre- and postsynaptic sympathetic

nerve terminals
Central nervous system

Vasodilation

Heart

Increased contractility
Increased conduction velocity and reduced refractoriness
(particularly within pacemaker cells)
Increased automaticity

Veins
Pulmonary arterioles, mainly:
Systemic arterioles
Abdominal viscera
Coronary
Skeletal muscle

Vasodilation

the coronary circulation, and the liver. Their stimulation

leads to vasodilation and enhanced diastolic relaxation
(lusitropy). Outside of the cardiovascular system, 2
receptor activation causes bronchodilation, uterine and
bladder relaxation, and decreased gastrointestinal motility.

a result, their duration of effect tends to be longer than

that of the catecholamines. Patients taking antidepressants that act by MAO inhibition may experience
prolonged and exaggerated hemodynamic responses to
noncatecholamine sympathomimetics.

Metabolic Effects
Adrenergic receptor stimulation causes important metabolic effects, including inhibition of insulin release, stimulation of glycogenolysis and lipolysis, increased oxygen
consumption and carbon dioxide production, hypokalemia
due to increased potassium uptake into cells, and lactic
acidosis. These effects are most marked in the case of
drugs with potent 2 receptor activity, such as epinephrine, isoproterenol, and albuterol.

Individual Sympathomimetics
Epinephrine. Epinephrine is a potent catecholamine with
actions at both and receptors. At lower doses (0.01 to
0.03 g/kg/min) effects predominate, resulting
in an increase in contractility and heart rate. Despite
2 receptor-mediated vasodilation, a fall in blood pressure
is uncommon. As the dose increases, receptor-mediated
vasoconstriction predominates, such that at higher doses
(>0.05 to 0.1 g/kg/min) vasoconstriction occurs in
most vascular beds. In the acutely failing heart, epinephrine has the advantage of providing increased cardiac
output while maintaining coronary perfusion pressure.
Epinephrine can cause sinus tachycardia, atrial and
ventricular arrhythmias, and marked metabolic disturbance, particularly hypokalemia, hyperglycemia, and
lactic acidosis.

Indirect Effects
Some sympathomimetics, notably dopamine and ephedrine,
exert part of their effect by stimulating the release of
stored norepinephrine from sympathetic nerve terminals.
In conditions such as heart failure and shock, endogenous
norepinephrine stores become depleted, and indirect acting
agents become less effective.
Metabolism
Catecholamines have a very short duration of action
(1 to 2 minutes) because of their rapid inactivation by
the enzymes monoamine oxidase (MAO) and catecholO-methyltransferase (COMT). Metabolism of noncatecholamine sympathomimetics is mostly via MAO, and as

Norepinephrine. Norepinephrine causes potent stimulation at and 1 receptors, but unlike epinephrine, it has
minimal effect at 2 receptors. Blood pressure is reliably
increased but the effect on cardiac output is variable.
Although 1 receptor stimulation has a direct inotropic
effect, in the setting of hypovolemia or impaired ventricular function, increased left ventricular afterload due to

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1 receptor stimulation can cause cardiac output to fall.

Similarly, the effect on heart rate is variable: direct 1
stimulation has a chronotropic effect but increased blood
pressure can cause baroreceptor-mediated bradycardia.
Norepinephrine is useful following cardiac surgery to
counter the vasodilatory effects of cardiopulmonary bypass
and sedation. However, doses above 0.05 to 0.1 g/
kg/min should be avoided in patients with impaired ventricular function unless cardiac output is being measured.
Norepinephrine is commonly combined with an inodilator such as dobutamine or milrinone. Norepinephrine is
typically commenced at a dose of 0.01 to 0.05 g/kg/
min and titrated to blood pressure. There is no maximum dose, but infusions greater than 0.1 to 0.2 g/kg/
min are rarely needed in cardiac surgery patients except
in the presence of vasoplegic syndrome (Chapter 2) or
septic shock, in which case doses as high as 0.5 to 1 g/
kg/min may be required. Troublesome metabolic effects,
particularly lactic acidosis, are much less common with
norepinephrine than with epinephrine.2

Dopamine. Dopamine is a precursor to norepinephrine

and is itself an important neurotransmitter in the peripheral and central nervous systems. Dopamine stimulates
and receptors and type 1 and 2 dopamine (DA)
receptors. DA-1 receptors are found in the renal, mesenteric, and cerebral circulations,3 and their stimulation
results in vasodilation. DA-1 receptors are also found in
the renal tubule, where they mediate natriuresis. DA-2
receptors are analogous to 2 receptors in that they are
found presynaptically and inhibit the release of norepinephrine. Dopamine also has an indirect mechanism of
action.
At low doses (<3 g/kg/min), dopaminergic effects
predominate. At higher doses, initially receptor effects
predominate; then receptor effects predominate. The
widely accepted dose range is 3 to 10 g/kg/min for
effects and more than 10 g/kg/min for effects.
However, these dose ranges must be viewed with skepticism. There is huge individual variability in the pharmacokinetics of dopamine such that dramatically different
plasma concentrations may occur in different patients
who are receiving the same dose.4 Furthermore, the clinical effects of a given plasma concentration are dependent on the functional activity of the adrenergic receptors.
Receptors are desensitized in a variety of clinical
settings, including after cardiac surgery and with heart
failure.5-7 Because of its indirect action, dopamine has
reduced effectiveness in patients with heart failure or
shock. Despite these caveats, it is generally true that as
the dose of dopamine increases, there is a progressive
increase in blood pressure and heart rate.
Dopamine at a dose of 1 to 3 g/kg/min has been
termed renal-dose dopamine and has traditionally been
used to provide selective renal vasodilation in patients at
risk for renal dysfunction. However, it is now clear that
although low-dose dopamine may increase blood flow to
36

the renal cortex, blood flow to the renal medulla may

actually decrease.8 Given the relatively hypoxic environment of the renal medulla under normal circumstances
(Chapter 1), this effect is potentially harmful. Furthermore,
the increase in urine output that occurs with low-dose
dopamine is due primarily to a direct tubular natriuretic effect rather than to renal vasodilation. In a wellconducted, large, randomized trial, low-dose dopamine
did not reduce the incidence of acute renal failure in
patients with early renal dysfunction.9 Dopamine has a
number of other potentially detrimental effects, including
inhibition of hypoxic ventilatory drive, impairment of
ventilation-perfusion matching in the lung, and suppression of the secretion of some anterior pituitary hormones,
such as prolactin, growth hormone, and thyrotropin.8

Isoproterenol. Isoproterenol is a potent receptor agonist that has virtually no effect at receptors. The principal actions of isoproterenol are increased contractility,
increased heart rate, and vasodilation. Cardiac output
is reliably increased and blood pressure typically falls.
In patients with coronary artery disease, isoproterenol
can precipitate myocardial ischemia. The main indication for isoproterenol is the treatment of symptomatic
bradycardia or heart block, but its use is limited by the
development of arrhythmias, hypotension, and metabolic
disturbances. The usual dose is 0.01 to 0.05 g/kg/min.
Dobutamine. Dobutamine is a synthetic catecholamine
with relative specificity for 1 receptors. Although heart
rate is increased, tachycardia is less pronounced than
with isoproterenol. Modest 2 receptor-mediated vasodilation may occur. Cardiac output is reliably increased,
but the effect on blood pressure is unpredictable; it may
increase, remain stable, or occasionally fall.
Dobutamine is useful for treating low cardiac output
following cardiac surgery,10 and it may be used in combination with norepinephrine for treating septic shock.11
The dose range is 1 to 10 g/kg/min. At higher doses
tachyarrhythmias become common. Metabolic side effects
are minimal.
Ephedrine. Ephedrine is a synthetic noncatecholamine
sympathomimetic that has effects at both and receptors. It is not metabolized by COMT and therefore
has a longer duration of action than the catecholamines.
For the most part, ephedrine acts indirectly; thus, its
efficacy is reduced in patients with shock or heart failure
and after prolonged administration. Ephedrine is not
suitable for continuous infusion but may be administered
as an intravenous bolus of 5 to 20 mg to treat acute
hypotension.
Phenylephrine. Phenylephrine is a noncatecholamine,
direct-acting receptor agonist that does not possess any
significant receptor activity. Bolus doses of 50 to 100 g
are commonly used during induction of anesthesia in

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Chapter 3

patients with aortic stenosis to counteract the vasodilation

produced by anesthetic drugs. In this situation phenylephrine has the advantage of increasing coronary perfusion
pressure without increasing heart rate. Cardiac output may
fall due to increased afterload and baroreceptor-mediated
reflex bradycardia. Phenylephrine has a slightly longer
duration of action than norepinephrine. The drug may be
administered as a continuous infusion at a dose of 0.1
to 1 g/kg/min.

Phosphodiesterase Type III Inhibitors

The phosphodiesterases (PDEs) are a family of enzymes
that catalyze the breakdown of cyclic nucleotides, including cAMP and cGMP. There are multiple subtypes of
PDE that have varying tissue distributions and actions.12
Caffeine and theophylline are nonspecific PDE inhibitors
that are used as bronchodilators. Papaverine is a vasodilator and nonspecific PDE inhibitor that is used by cardiac
surgeons during coronary artery bypass graft (CABG)
surgery to prevent spasm of the internal mammary artery.
Drugs that selectively inhibit PDE subtype III function as inodilators. The commercially available PDE-III
inhibitors all have a similar pharmacologic profile: they
increase contractility and cause pulmonary and systemic
(arteriolar and venous) vasodilation. As such, PDE-III
inhibitors are useful for treating low cardiac output, particularly in the presence of pulmonary edema or pulmonary hypertension. They are potent vasodilators of
coronary grafts13 and cause less tachycardia and atrial
fibrillation than dobutamine.10 The inotropic effect is
independent of the 1 receptor, which is advantageous
in patients with 1 receptor desensitization (see earlier
discussion). Also, by combining a PDE-III inhibitor with
a 1 receptor agonist, a dual mechanism of action is
exploited. Arteriolar and venous dilation can cause modest
hypotension. This can be treated with either fluid or
low-dose norepinephrine, depending on the status of the
patients intravascular volume. In patients with cardiogenic shock, the combination of a PDE-III and norepinephrine provides support for both cardiac output
and blood pressure, but without the troublesome tachycardia and metabolic disturbance that can occur with
epinephrine.
PDE-III inhibitors are available as intravenous formulations for short-term use. Unlike the sympathomimetics, they have durations of action measured in hours, so
their effects cannot be readily judged. Oral formulations
of PDE-III inhibitors for the treatment of chronic heart
failure have been studied but have resulted in higher
mortality rates.14
Milrinone. Milrinone is a bipyridine derivative with an
elimination half-time of about 2.5 hr. It is administered as
a loading dose of 50 g/kg over 30 min, followed by an
infusion of 0.25 to 0.75 g/kg/min. In patients at risk for
hypotension, the loading dose should be reduced or given
very slowly. Milrinone is eliminated via the kidneys, and the

Cardiovascular Pharmacology

rate of infusion should be adjusted in patients with severe

renal dysfunction so as to avoid excessive vasodilation.

Amrinone. Amrinone was the first selective PDE-III

inhibitor introduced into clinical practice. Like milrinone,
it is a bipyridine derivative and is eliminated by the kidneys.
Amrinone can cause thrombocytopenia, and for this reason
is no longer widely used.
Enoximone. Enoximone is an imidazolone derivative,
and is metabolized primarily by the liver. It is therefore
less affected by renal function than the bipyridines. The
elimination half-time of enoximone is about 4 hours.
Enoximone is administered as a loading dose of 0.5 to
1 mg/kg over 30 minutes, followed by an infusion of
5 to 20 g/kg/min.
Miscellaneous Vasoactive Drugs
Calcium. An intravenous bolus dose of calcium chloride of
5 mg/kg (or 0.035 mmol/kg) increases blood pressure but
has little effect on myocardial contractility.15 The duration
of effect following a bolus dose is 5 to 10 minutes. The
pressor effect is much more pronounced in the presence of
hypocalcemia. Calcium chloride does not improve outcome
after cardiac arrest16 and is no longer included in routine
resuscitation protocols. However, calcium is useful in the
management of hyperkalemia because it reduces potassiuminduced arrhythmias, and in the treatment of hypocalcemia.
Vasopressin. Vasopressin (V; antidiuretic hormone) is
a peptide hormone released from the posterior pituitary
in response to an increase in serum osmolarity or hypovolemia (Chapters 1 and 32). Stimulation of V1 receptors
within vascular smooth muscle results in vasoconstriction
(via the IP3/DAG second-messenger system), whereas
stimulation of V2 receptors in the kidney results in water
retention (via the cAMP second-messenger system). An
additional action of vasopressin is to increase the release
of the von Willebrand factor from the vascular endothelium, which increases platelet aggregation. The elimination half-time of vasopressin is 10 to 30 minutes.
Exogenously administered vasopressin is used to treat
catecholamine-resistant vasodilatory shock. In early shock,
endogenous stores of vasopressin are released from the
posterior pituitary, but as shock progresses, these stores
become depleted. In patients with advanced vasodilatory
shock, vasopressin infusion at 4 units/hr combined with
norepinephrine has been shown to be superior to norepinephrine alone in terms of hemodynamics and markers of splanchnic perfusion.17 However, higher doses of
vasopressin, sufficient to replace rather than augment
norepinephrine, can cause a marked reduction in cardiac
output and may worsen splanchnic perfusion.18 In animal
models, vasopressin is associated with relatively less vasoconstriction within the coronary, cerebral, and pulmonary
circulations than is associated with catecholamines.19,20
Despite an antidiuretic effect, in patients with vasodilatory
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shock urine output may actually improve with vasopressin,21 presumably due to an improvement in renal
blood flow. As with all vasoconstrictors, precipitous
reductions in cardiac output can occur with vasopressin,
particularly in the settings of hypovolemia and impaired
ventricular function. Current recommendations are that
vasopressin, in a dose of 0.01 to 0.04 units/min, should
be considered in patients with vasodilatory shock who
have adequate volume resuscitation and are refractory to
high doses of catecholamines.22

Levosimendan. Levosimendan is an inotropic drug that

acts by stabilizing the interaction between calcium and
tropo-nin, so-called calcium sensitization. In addition,
levosimendan functions as a vasodilator, partly through
PDE-III inhibition and partly by opening adenosine
triphosphate gated potassium channels. Because the effect
of levosimendan is not mediated by 1 receptors or
increased cAMP, it does not increase myocardial oxygen
consumption and is not arrhythmogenic. Levosimendan
may be a particularly useful inotropic agent in patients
who are receiving blockers. In the treatment of heart
failure, levosimendan is more effective than dobutamine
in improving cardiac output and, in one study, was associated with better mortality compared to dobutamine.23
Levosimendan has an elimination half-time of 1 hour,
but it has pharmacologically active metabolites with
elimination half-times of up to 80 hours. The drug is
usually administered as a continuous infusion of 0.1 to
0.2 g/kg/min for 24 hours, which may be preceded by
a loading dose of 12 to 24 g/kg. Following a 24-hour
infusion, a positive inotropic effect is sustained for
several days. Side effects are typically modest and include
mild tachycardia and hypotension. So far, levosimendan
has been used primarily in patients with decompensated
heart failure, but there is some limited experience in its
use in patients after cardiac surgery.24
b Blockers
Blockers antagonize the effect of endogenous and
exogenous sympathomimetics at adrenergic receptors,
thereby reducing heart rate and myocardial contractility.
Blockers can be broadly classified as nonselective
(blockade of both 1 and 2 receptors) or as 1-receptorselective. Some blockers also have peripheral vasodilatory activity mediated by either 1 receptor blockade
(e.g., carvedilol, labetalol) or 2 receptor stimulation
(e.g., celiprolol).
Blockers tend to be either lipid-soluble (e.g., metoprolol) or water-soluble (e.g., atenolol). Lipid-soluble
agents typically undergo extensive hepatic metabolism
and have a low oral bioavailability. Some lipid-soluble
blockers are metabolized by the cytochrome P-450
(CYP) 2D6 enzyme system, so their metabolism is susceptible to inhibition by other drugs (see Table 4-3). In
contrast, water-soluble agents have high oral bioavailability and tend to be eliminated unchanged by the kidney.
38

In patients with hepatic impairment, a water-soluble

blocker is appropriate, whereas in patients with renal
impairment, a lipid-soluble blocker may be more
appropriate.
Blockers have antihypertensive, antiarrhythmic,
and antiischemic actions, and they inhibit ventricular
remodeling. Treatment with blockers is associated with
reduced mortality rates in patients with coronary artery
disease25-28 and chronic heart failure (see Chapter 19) and
in high-risk patients undergoing noncardiac surgery.29
In patients undergoing CABG surgery, preoperative
treatment with blockers is associated with reduced perioperative mortality rates.30 Acute cessation of chronic
blocker treatment can precipitate myocardial ischemia.31
In the cardiothoracic ICU, blockers are used in the
following circumstances:

As routine treatment following CABG surgery

For postoperative hypertension
For the treatment and prevention of arrhythmias
In cases of acute coronary syndromes
In cases of dynamic left and right ventricular outflow
tract obstruction.

The adverse effects of blockers include bradycardia

and AV block (particularly when used with digoxin,
verapamil, or diltiazem); hypotension; acute ventricular
decompensation; bronchospasm; and central nervous
system effects such as headache and sleep disturbance.
Central effects are potentially worse with lipid-soluble
blockers. Peripheral vascular effects are potentially
worse with nonselective agents.
In patients with ventricular dysfunction, introduction
of a blocker may initially worsen the symptoms of heart
failure. Ventricular remodeling and improved ejection
fraction develop slowly over several months. Thus, blockers should be avoided in patients who have only recently
discontinued inotropic support or who are fluidoverloaded. Introduction of blockers for the treatment
of heart failure is generally not appropriate in the ICU.
Characteristics of commonly used blockers are listed in
Table 3-2.

Esmolol. Esmolol is an intravenously administered, cardioselective blocker that undergoes very rapid metabolism by plasma esterases. A single bolus dose has a peak
effect within 2 to 6 minutes and a duration of effect of
less than 20 minutes. The drug may be given as repeated
bolus doses of 25 mg or as an intravenous infusion (25 to
300 g/kg/min). Esmolol is useful for heart rate control
of atrial fibrillation or as an adjuvant for suppressing
life-threatening ventricular arrhythmias. Esmolol may be
used as a test blocker in patients who are at risk for
bronchospasm or ventricular decompensation. Esmolol
is usually ineffective in treating acute hypertension.
Labetalol. Labetalol is an 1 blocker and a nonselective
blocker that is formulated for intravenous and oral use.

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Table 3-2

Cardiovascular Pharmacology

Characteristics of Selected b Blockers

Drug

Main Route
of Elimination

Peripheral
Vasodilation

Standard Daily Dose

Intravenous
Bolus Dose

Nonselective (b1 and b2 Receptor Antagonists)

Nadolol

Kidney

40-160 mg once daily

Pindolol

Liver and kidney

5-15 mg twice daily

Propranolol

Liver

40-160 mg twice daily

1-3 mg

Sotalol

Kidney

40-160 mg twice daily

25-100 mg

Timolol

Liver

5-20 mg twice daily

Selective (b1 Receptor Antagonists)

Acebutolol

Liver and kidney

200-600 mg once or twice daily

Atenolol

Kidney

25-100 mg once daily

Bisoprolol

Kidney and liver

2.5-20 mg once daily

Celiprolol

Kidney

200-600 mg once daily

Esmolol

Plasma esterases

Intravenous only

25-50 mg

Metoprolol

Moderate

23.75-190 mg ER once daily

2.5-5 mg

2.5-5 mg

Combined b and a1 Receptor Antagonists

Labetalol

Liver

200-800 mg twice daily

Carvedilol

Liver

3.125-50 mg twice daily

5-20 mg

ER = extended release.

Labetalol is a useful drug for the treatment of postoperative

hypertension. Intravenously, labetalol may be administered as repeated bolus doses of 5 to 10 mg. Labetalol
undergoes significant hepatic metabolism and has low
oral bioavailability; thus, the oral dose is much higher
than the intravenous dose.

Metoprolol. Metoprolol is a selective blocker that is

available in intravenous and oral formulations. Intravenous
metoprolol is useful in the cardiothoracic ICU for treating hypertension and for acute heart rate control in
patients with rapid atrial fibrillation (repeat bolus doses
of 2.5 mg every few minutes). Orally, metoprolol is used
in the dose range of 25 to 200 mg day, typically as a
sustained-release formulation. The starting dose for
patients with heart failure is 25 mg daily; the dose is
gradually increased every 2 weeks.
Carvedilol. As with labetalol, carvedilol has both
1 receptor and nonselective blocking properties.
In addition, carvedilol has unique antiproliferative and

antioxidant properties.32 Carvedilol is widely used in

treating chronic heart failure and patients with impaired
left ventricular function following myocardial infarction.
The starting dose for patients with heart failure is
3.125 to 6.25 mg twice daily; the dose is increased every
2 weeks. The target maintenance dose is at least 25 mg
twice daily.32

Nitrates
The organic nitrates (nitroglycerin, isosorbide dinitrate,
isosorbide mononitrate) cause vasodilation in veins and
pulmonary and systemic arterioles. Nitrates reduce preload and afterload, decrease myocardial work, and cause
coronary vasodilation within large conductive arteries.
The organic nitrates and sodium nitroprusside function
as nitric oxide donors, which cause vasodilation via the
cGMP second-messenger system.
Nitroglycerin. Nitroglycerin is a very short-acting
organic nitrate that is available in several formulations.
As a sublingual spray or tablet, nitroglycerin is used in
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treating acute angina. As a transdermal patch or topical

ointment, nitroglycerin is used in the prevention of angina
and the treatment of congestive cardiac failure. In the
ICU, nitroglycerin is typically administered as a continuous intravenous infusion for the:

Prevention of spasm in coronary artery bypass conduits.

Treatment of decompensated heart failure.
Treatment of acute myocardial ischemia.
Treatment of systemic and pulmonary hypertension.

The dose range is 0.25 to 5 g/kg/min, and the

clinical effect dissipates within a few minutes after the
infusion is stopped. At lower doses (<2 g/kg/min)
the main effect is dilation of veins, coronary arteries, and
pulmonary arterioles. Thus, low-dose nitroglycerin is useful
in the treatment of myocardial ischemia, pulmonary hypertension, and congestive cardiac failure. By selectively
dilating large coronary arteries, nitroglycerin, unlike sodium
nitroprusside, does not cause coronary steal. At higher
doses, systemic vasodilation becomes more prominent,33
which can result in hypotension and cause paradoxical
worsening of myocardial ischemia. However, in patients
with severe hypertension, nitroglycerin is often ineffective in controlling blood pressure.
The production of nitric oxide by the organic nitrates
requires the presence of thio- compounds within the vascular endothelium. Infusing nitroglycerin for longer than
8 hours can cause depletion of these compounds, leading
to reduced clinical effect.
Other than hypotension, the side effects of nitroglycerin are minimal. Reflex tachycardia can occur but is
usually slight. There may be a dose-dependent fall in
arterial oxygen saturation due to inhibition of hypoxic
pulmonary vasoconstriction. The nitrite metabolites of
nitroglycerin can lead to methemoglobinemia but it is
not usually clinically significant.

Long-acting Organic Nitrates. Isosorbide dinitrate and

its major active metabolite, isosorbide mononitrate, are
orally administered organic nitrates that are available as
extended-release preparations for the prevention of angina.
As with nitroglycerin, tolerance rapidly develops, and a
daily drug-free interval is recommended. With once-daily
dosing (in the morning) of isosorbide dinitrate or isosorbide mononitrate, a 12-hour duration of effect is achieved.
Nicorandil is a newer long-acting nitrate-like drug that
also has potassium-channel-activating properties. It functions as a balanced venous and arteriolar vasodilator,
reducing preload and afterload and improving angina.
Nicorandil does not appear to be associated with significant
tolerance.
Sodium Nitroprusside. Sodium nitroprusside is a potent
dilator of veins and systemic and pulmonary arterioles.
It has a rapid onset of action and a very short duration
of effect (1 to 2 min). Severe hypotension can occur and
the drug must be carefully titrated. The main indication
40

for nitroprusside is the rapid control of hypertension.

Nitroprusside can also be used to increase cardiac output
in patients with heart failure and for treating pulmonary
hypertension; however, there is a substantial risk of systemic hypotension, and other drugs may be more suitable.
The starting dose of nitroprusside is 0.2 to 0.5 g/
kg/min; it can be increased to a maximum of 10 g/
kg/min. The maximum dose should not be used for more
than a few minutes. In fact, if doses higher than 2 g/
kg/min are used for any length of time, cyanide toxicity
can occur. The metabolism of nitroprusside results in the
formation of cyanide, which then reacts with cytochrome
C, inhibiting aerobic metabolism and causing lactic acidosis.
Cyanide also combines with hemoglobin to form methemoglobin and with sulfur to form thiocyanate. Thiocyanate
accumulation can occur following prolonged treatment
in patients with renal failure; it manifests as drowsiness,
disorientation, delirium, and seizures. Nitroprusside can
also cause hypoxemia in patients with acute or chronic lung
disease because it inhibits hypoxic pulmonary vasoconstriction. Because nitroprusside causes nonselective dilation of coronary arterioles, it has the potential to cause
coronary steal, in which vasodilation within nonischemic myocardium diverts blood away from ischemic
myocardium. Reflex tachycardia is common.

Calcium Channel Blockers

Calcium channel blockers reduce the intracellular calcium
concentration within vascular smooth muscle and myocytes,
causing, to a variable degree, inhibition of cardiac conduction, reduced myocardial contractility, and arteriolar
vasodilation. All agents are available orally. In addition,
diltiazem, verapamil, nifedipine, and nicardipine are available as intravenous formulations. Some calcium antagonists undergo hepatic metabolism by the CYP3A enzyme
system, and therefore their metabolism may be enhanced
or inhibited by other drugs (see Table 4-3). Calcium
channel blockers are widely used in treating angina, hypertension, and cardiac arrhythmias. In the ICU, calcium
channel blockers are indicated for treatment of postoperative hypertension, for preventing spasm within coronary
artery bypass grafts, and for treating cardiac arrhythmias.
The dihydropyridine calcium channel blockers (nifedipine, amlodipine, isradipine, felodipine) are specific arteriolar vasodilators (including potent coronary vasodilation)
and have minimal effects on myocardial contractility and
cardiac conduction. Intravenous nicardipine is useful in
the ICU for the rapid control of hypertension. Its main
disadvantage is its relatively long half-time (about 40 min),
making the drug less readily able to be titrated than
nitroglycerin or nitroprusside. Long-acting dihydropyridine calcium channel blockers are used primarily for treating hypertension and angina but are also used after CABG
surgery to prevent spasm within arterial bypass grafts.
The main side effects of chronically administered dihydropyridine calcium channel blockers are headache and
dependent (ankle) edema; reflex tachycardia can occur

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Chapter 3

but is usually modest with the long-acting agents. Shortacting formulations such as the original capsule form of
nifedipine cause rapid reflex adrenergic activation and
are associated with increased mortality rates in patients
with myocardial infarction.34 For this reason, short-acting
formulations are no longer used.
Two other types of calcium channel blockers are
in clinical use: verapamil, a phenylalkylamine; and diltiazem, a benzothiapine. Besides causing vasodilation,
these drugs have effects on myocardial contractility and

Table 3-3

Cardiovascular Pharmacology

cardiac conduction. Diltiazem is discussed later under

the heading Antiarrhythmic Drugs. The characteristics
of selected calcium channel blockers are provided in
Table 3-3.

Miscellaneous Vasodilators
Hydralazine. Hydralazine is an arteriolar vasodilator that
is available for the acute control of hypertension. The
intravenous dose is 2.5 to 10 mg, with an onset of action
within 15 minutes and a duration of action of 2 to 4 hours.

Characteristics of Selected Calcium Channel Blockers

Effect
Vasodilation

Cardiac
Conduction

Myocardial
Depression

Clinical Uses

Usual Dose

Side Effects

Verapamil

++

+++

+++

Angina
Hypertension
AV nodal reentry
tachycardia

Oral: 80-160 mg
8 hourly, up to
240 mg 12-24
hourly (CR)
IV bolus: 5-10 mg
IV infusion:
1 mg/min up to
10 mg

Hypotension,
bradycardia,
conduction block,
dependent edema;
increased
digoxin levels.

Diltiazem

++

Angina
Hypertension
Rate control for
atrial fibrillation
and flutter

Oral: 60-120 mg
8 hourly, up to
360 mg/day (CR)
IV bolus: 10-20 mg
IV infusion:
5-15 mg/hr

Hypotension and
bradycardia.

Dihydropyridines
Amlodipine

+++

Hypertension
Angina (including
patients with
heart failure)

5-10 mg daily

Hypotension
Headache
Dependent
(ankle edema)

Felodipine

+++

Hypertension
Angina

5-10 mg daily

Reflex tachycardia
(minimal with
these longacting agents)

Isradipine

+++

Hypertension

2.5-10 mg
12 hourly

Nicardipine

+++

Hypertension
(including acute
postoperative
hypertension)
Angina

Oral: 20-40 mg
8 hourly
IV infusion:
2.5-5 mg/hr
titrated to a
maximum of
15 mg/hr

Nisoldipine

+++

Hypertension

20-40 mg daily

CR, controlled release; IV, intravenous.

41

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Reflex tachycardia is common but may be prevented by

coadministration of a blocker. Hydralazine is available
for oral use but is rarely given by this route because of
problems involving reflex tachycardia, sodium and water
retention, metabolic variability, and immunologic reactions.

Fenoldopam. Fenoldopam is a specific DA-1 receptor

agonist that causes natriuresis and vasodilation within
mesenteric, renal, coronary, and cerebral circulations. For
the treatment of hypertension, doses of 0.1 to 1.6 g/
kg/min have been studied.35 The initial dose should
be low (0.1 to 0.2 g/kg/min) and slowly increased, as
this results in less reflex tachycardia than starting at
higher doses. The clinical effect dissipates within a few
minutes of stopping an infusion. Fenoldopam has an
efficacy similar to that of nitroprusside in the treatment
of hypertension following cardiac surgery,36,37 but it is
significantly more expensive. Fenoldopam has been
investigated as a renal protective agent in cardiac surgery
patients. The results of these trials have been conflicting38,39
and, on balance, current evidence does not support the
use of fenoldopam for this purpose.
Nesiritide. Nesiritide is a synthetic analog of brain (B-type)
natriuretic peptide (see Chapter 1). It acts via the
cGMP second-messenger system, causing vasodilation of
veins, coronary arteries and, to a lesser extent, systemic
arterioles.40 It also has a mild natriuretic effect. In the
treatment of decompensated heart failure, nesiritide is
more effective than nitroglycerin in reducing pulmonary
capillary wedge pressure and improving dyspnea.41 Side
effects are few and include mild hypotension. Nesiritide is
administered as a loading dose of 2 g/kg followed by an
infusion of 0.01 g/kg/min. Currently, there is only limited experience with nesiritide in cardiac surgery patients.42
Angiotensin-Converting Enzyme Inhibitors
and Angiotensin Receptor Blockers
Angiotensin-converting Enzyme Inhibitors. Angiotensinconverting enzyme (ACE) inhibitors block the angiotensinconverting enzyme and therefore inhibit the conversion
of angiotensin I into angiotensin II and reduce the
synthesis of aldosterone. ACE inhibitors cause arteriolar
dilatation and potassium-sparing diuresis, and facilitate
ventricular remodeling. ACE inhibitors also inhibit the
degradation of other substances including bradykinin,
substance P, and the enkephalins. This inhibition contributes to their hypotensive action and is responsible for
the side effects of cough and angioedema.
ACE inhibitors are indicated for a range of cardiovascular disorders, including hypertension, coronary artery
disease,43,44 and asymptomatic45 and symptomatic left
ventricular dysfunction.46,47 ACE inhibitors also improve
survival rates in patients with risk factors for, but without
documented evidence of, coronary artery disease.44
Side effects of ACE inhibitors include hypotension
(particularly with the first dose), renal impairment,
42

and hyperkalemia. These problems are more common in

elderly patients with severely impaired ventricular function and those with renal artery stenosis. Serum creatinine may increase by 10% to 15% with commencement
of ACE inhibitor therapy, but with continued treatment it usually remains stable or returns to baseline.
An abrupt rise in creatinine may indicate the presence
of renal artery stenosis in which case the drug should
be discontinued. Chronic cough occurs in 5% to 10% of
patients.
ACE inhibitors are useful in treating postoperative
hypertension, particularly in patients receiving ACE
inhibitors preoperatively. However, this class of drug
must be used very carefully in the ICU, especially in patients
with preexisting renal dysfunction or perioperative hemodynamic instability. The initial dose of ACE inhibitor
should be low (e.g., enalapril 1 to 2 mg/day) and only
slowly increased. In patients with impaired ventricular
function or renal impairment, reintroduction of ACE
inhibitor therapy should be delayed for 1 to 2 days after
surgery.48 The doses of various ACE inhibitors are listed
in Table 3-4.

Angiotensin Receptor Blockers. The angiotensin

receptor blockers (ARBs; see Table 3-4) have an action,
therapeutic application, and side-effect profile similar to
those of the ACE inhibitors, except that ARBs are not
associated with angioedema and cough and are used
primarily for treating hypertension. ARBs may be combined with an ACE inhibitor in patients with resistant
hypertension or chronic heart failure, and they may have
a specific role in the treatment of diastolic heart failure
(Chapter 19).
Antiarrhythmic Drugs
The ideal antiarrhythmic drug for use in the ICU would
have minimal myocardial depression, have a rapid onset of
action when given intravenously, have a low incidence of
proarrhythmia, and be effective against common postoperative arrhythmiasparticularly atrial fibrillation and
life-threatening ventricular tachycardia/fibrillation.
The agent that most closely suits these ideals is amiodarone, and this agent is discussed in detail subsequently.
Other drugs commonly used in the cardiothoracic ICU
include diltiazem, digoxin, blockers, adenosine, and
the electrolytes potassium and magnesium.
Antiarrhythmic drugs may be classified on the basis
of their electrophysiologic properties using the system
proposed by Vaughan Williams and Brahma Singh
(Table 3-5). Digoxin, adenosine, and magnesium do
not fit into this classification system. The electrophysiologic basis of cardiac action potentials is described in
Chapter 1, and the treatment of specific arrhythmias, in
Chapter 21.
Class I. Class I agents (known as membrane-stabilizing
drugs) block fast sodium channels responsible for phase 0

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Table 3-4

Cardiovascular Pharmacology

Dosages of Selected ACE Inhibitors and Angiotensin Receptor Blockers

Drug

Initial Dose (mg)

Maintenance Dose

ACE Inhibitors
Captopril

6.25 mg three times daily

25-50 mg three times daily

Enalapril

2.5 mg daily

10-20 mg daily or twice daily

Lisinopril

2.5 or 5 mg daily

10-40 mg daily

Quinapril

2.5 or 5 mg daily

10-40 mg daily

Perindopril

2 mg daily

4-8 mg daily

Ramipril

1.25 or 2.5 mg daily

2.5-10 mg daily

Cilazapril

0.5 mg daily

1-5 mg daily

Fosinopril

10 mg daily

20-40 mg daily

Angiotensin Receptor-Blocking Drugs

Losartan

25 or 50 mg once daily

50-100 mg daily

Candesartan

8 or 16 mg once daily

8-32 mg daily

Telmisartan

20 or 40 mg daily

80-120 mg daily

of the action potential (see Fig. 1.1). Class I agents are

further subdivided on the basis of their effect on the
duration of the action potential: class IA agents prolong
the action potential (class III activity); class IB agents
shorten the action potential; class IC agents have no
effect on the duration of action potential. Class I drugs
act by reducing automaticity, inhibiting retrograde conduction within reentry circuits, and prolonging the
refractory period (class IA only). However, the blockade
of fast sodium channels reduces the speed of conduction
of the action potential, which can precipitate reentry
arrhythmias. Class IA agents can also cause torsades de
pointes ventricular tachycardia (see subsequent material).
Thus, proarrhythmia is a significant problem with class
IC agents. The class I drugs encainide and flecainide have
been shown to increase mortality rates in patients after
myocardial infarction.49

Class II. Class II agents are the blockers. Blockers

function as antiarrhythmic drugs by blunting sympathetic tone and reducing the excitability of myocardial
cells. Within pacemaker cells, blockers reduce the slope
of phase 4 of the action potential, thus decreasing the
rate of firing of the sinoatrial node and increasing the
conduction time (PR interval) and refractoriness of
the AV node.

Class III. Class III drugs block potassium channels

responsible for phase 3 (repolarization) of the action
potential. Thus, class III drugs prolong the action potential and increase the QT interval. Prolongation of the
action potential increases myocyte refractoriness, which can
interrupt reentry circuits. However, it also predisposes to
early after-depolarizations (Chapter 21), which can precipitate torsades de pointes ventricular tachycardia. All
class III (and class IA) drugs have the potential to cause
torsades de pointes and should be avoided in patients
with QT prolongation.
Class IV. The class IV agents are the calcium channel
blockers. Diltiazem and verapamil reduce the slope of phase
4 of the action potential within pacemaker tissue, causing a
decrease in heart rate and an increase in the PR interval.
Amiodarone (Class III). is a class III antiarrhythmic drug
that also has class I, II, and IV activity. Acutely, amiodarone
functions mainly as a b blocker. It is available in both oral
and intravenous preparations. Amiodarone has proven efficacy for prophylaxis and pharmacologic cardioversion of
a wide range of arrhythmias, including atrial fibrillation and
life-threatening ventricular arrhythmias (see Chapter 21).
Compared to other class III agents, amiodarone has a
low incidence of proarrhythmia, with a rate of torsades
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Table 3-5

Electrophysiologic Effects of Antiarrhythmic Drugs at Therapeutic Dosages

ECG
AV Node

Classification

44

Primary Effects
on Action
Potential

SA Node
Heart Rate

Refractory
Period

Conduction
(PR interval)

QRS
Duration

QT
Interval

Class IA
Procainamide

Inhibits phase 0 and

prolongs plateau in
myocytes
Variable inhibition of
pacemaker tissue,
depending on agent

Class IB
Lidocaine
Mexiletine

Inhibits phase 0 and

shorten plateau in
diseased myocytes
Minimal effect on
normal myocytes and
pacemaker tissue

Class IC
Propafenone

Inhibit phase 0 in
myocytes
Variable inhibition of
pacemaker tissue,
depending on agent

Class II
blockers

Reduce slope of phase 4

in pacemaker cells
Reduce excitability in
myocytes

Class III
Amiodarone
Sotalol
Dofetilide
Ibutilide

Prolong the plateau

in myocytes
Amiodarone and
sotalol also have
important inhibitory
effects on pacemaker
cells

Class IV
Calcium channel
blockers

Reduce slope of phase 4

in pacemaker cells

Digoxin

Reduces slope of phase 4

in pacemaker cells
(parasympathomimetic effect)

Adenosine

Reduces slope of phase 4

in pacemaker cells

Magnesium

Mechanism not well

understood; similar
to calcium channel
blockers?

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Table 3-6

Cardiovascular Pharmacology

Dosing Schedules for Amiodarone

Indication

Dosing Regime

Acute suppression of life-threatening arrhythmias in the ICU

Option 1
5 mg/kg IV over 30 min, followed by infusion of 1 mg/min
Option 2
150-300 mg over 10-30 min, followed by infusion of 2 mg/min
for 4 hr, followed by infusion of 1 mg/min

Intravenous prophylaxis of atrial and ventricular arrhythmias

in critically unwell patients

2 mg/min for 4 hours followed by 1 mg/min

Oral postoperative prophylaxis of atrial fibrillation

400 mg three times daily for 2 days, followed by 200 mg

three times daily for 1 week, then stop

Oral loading dose with amiodarone

400 mg twice daily for 7 days, followed by

400 mg daily for 6 weeks

Maintenance oral dose

200 mg daily

de pointes ventricular tachycardia of less than 1%.

Furthermore, amiodarone causes less hypotension than
many other intravenously administered agents and can
therefore be used with relative safety in patients who are
inotrope-dependent or who have impaired ventricular
function. Rapid intravenous administration can cause
transient (but marked) hypotension; this effect is due
primarily to the Tween 80 solvent. When given as a slow
intravenous bolus (e.g., 300 mg over 15 to 30 min) or
as a continuous infusion, amiodarone is remarkably well
tolerated.
Amiodarone is highly lipid soluble with a very large
steady-state volume of distribution. It is rapidly concentrated within myocardial tissue but only slowly distributed to fat. The use of the term loading dose with
respect to amiodarone is confusing. To fully load the
steady-state volume of distribution requires more than
10 g of amiodarone; an amount of drug that must be
given over days to weeks to avoid plasma levels that are
toxic. In the acute setting, the term loading dose
refers to the initial volume of distribution (see Chapter
4, Pharmacokinetic Considerations, and Fig. 4-1). Once
the initial volume of distribution has been loaded, a
reduced dose of drug is administered, either orally or by
continuous infusion, to maintain plasma levels as the
drug is redistributed to peripheral compartments. Once
a steady state has been achieved, a much lower maintenance dose is required. Dose regimes for intravenous and
oral amiodarone are provided in Table 3-6.
Acutely, amiodarone is associated with relatively few
side effects. One concern is a possible relationship between
amiodarone and acute respiratory distress syndrome
(ARDS). This association has been observed in critically
unwell patients50 and following cardiac51 and thoracic52
surgery. However, these studies are retrospective and
observational, and the association has not been confirmed

by all investigators.53 Given the clear benefits of amiodarone in cardiac surgery patients and the lack of a definitive association between it and ARDS, it is reasonable to
continue to use the drug for the treatment and prevention
of perioperative arrhythmias.
In contrast to acute treatment, chronic treatment with
amiodarone is associated with a number of side effects
(Table 3-7). Pulmonary fibrosis is a rare but potentially
fatal complication that usually, but not always, resolves
after discontinuation of the drug. The high iodine
content of amiodarone causes thyroid dysfunction
(hypo- and hyperthyroidism) in up to 10% of patients in
long-term treatment. Mild hypothyroidism may be

Table 3-7

Side Effects of Chronic Amiodarone Therapy

Atropine-resistant bradycardia or heart block

Pulmonary fibrosis
Hypo- and hyperthyroidism
Elevated hepatic transaminases
Corneal deposits causing peripheral visual halos
Photodermatitis and photosensitivity
Gray-blue skin discoloration
Tremor and ataxia
Parasthesia
Proximal myopathy

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managed with thyroxine without the need to discontinue

treatment.
Amiodarone interacts with many hepatically metabolized drugs and also displaces some protein-bound drugs,
notably warfarin and digoxin. Amiodarone inhibits a
number of subtypes of the CYP enzyme system, including 2C9 (responsible for warfarin metabolism), 2D6, and
3A. Substrate drugs for CYP2D6 and CYP3A are listed
in Table 4-3. The maintenance dose of warfarin may need
to be greatly reduced in patients receiving amiodarone.
Amiodarone should be avoided in patients with documented hypersensitivity to iodine and in patients with
prolonged QT intervals or histories of torsades de
pointes ventricular tachycardia.

Sotalol (Class III). This is a nonselective blocker with

important class III activity.54 Higher doses are required for
the class III effect than for b blockade. Sotalol is effective
against a wide range of arrhythmias, including atrial fibrillation and recurrent ventricular tachycardia (Chapter 21).
However, in patients with impaired ventricular function,
sotalol can cause considerable hypotension, particularly
when given intravenously. Proarrhythmia is a greater concern with sotalol than with amiodarone, with an incidence
of torsades de pointes of about 2%. Sotalol should be
avoided in a patient who has a corrected QT (QTc) interval greater than 0.45 seconds and should be discontinued
if the QTc exceeds 0.55 seconds during treatment.
The intravenous dose is 1 mg/kg (not exceeding
100 mg) over 10 to 20 min. The oral dose is 80 mg
twice daily, increasing to 160 mg twice daily as tolerated.
Sotalol is eliminated mostly unchanged by the kidneys,
and the dose should be reduced in cases of renal failure.
Sotalol should be avoided in patients with asthma, severe
renal impairment, marked bradycardia and heart block,
and uncorrected hypokalemia or hypomagnesemia. Only
the oral formulation is available in the United States.
Ibutilide (Class III). This is a class III antiarrhythmic drug
available for intravenous use.55 It is structurally similar to
sotalol but, unlike sotalol, does not usually cause hypotension in patients with impaired ventricular function. Ibutilide
may be used for the pharmacologic cardioversion of atrial
fibrillation, atrial flutter, and ventricular tachycardia. The
use of ibutilide is limited by its relatively high incidence of
torsades de pointes ventricular tachycardia. The dose (for
patients >60 kg) is 1 mg over 10 minutes; if unsuccessful,
the dose may be repeated 10 minutes later.55,56
Ibutilide should be avoided in a patient with a QTc
greater than 0.45 seconds and in a patient with hypokalemia
or hypomagnesemia.55 The drug should be administered
under continuous ECG monitoring, and the infusion
should be stopped when the patient reverts to sinus rhythm
or if the QTc exceeds 0.55 seconds. ECG monitoring
should continue for 4 hours following treatment.

46

Dofetilide (Class III). This is an orally administered

class III antiarrhythmic agent that is indicated for the

pharmacologic cardioversion of atrial fibrillation and flutter.

Dofetilide can be safely used in a patient with impaired
ventricular function57 but is associated with a high incidence of torsades de pointes ventricular tachycardia. The
drug should be avoided in a patient with a QTc greater
than 0.45 seconds. The dose is 250 to 500 g twice
daily, but this must be decreased in a patient with renal
failure. Dofetilide is contraindicated in a patient with a
creatinine clearance less than 20 ml/min.56

Diltiazem (Class IV). This is indicated for rate control of

atrial fibrillation and for the pharmacologic cardioversion
of AV nodal reentry tachycardia. Intravenously, diltiazem
may be administered as repeated bolus doses of 10 to
20 mg or as a continuous infusion of 5 to 15 mg/hr. Orally,
diltiazem may be commenced at 30 to 60 mg every
6 hours, increasing up to a maximum of 360 mg per day.
Alternatively, a slow-release formulation may be used at
a dose of 180 to 360 mg daily. Diltiazem has a very low
rate of proarrhythmia but can cause marked bradycardia
and heart block, particularly when administered with a
blocker or digoxin. Diltiazem has less effect on cardiac
contractility than verapamil but must be used cautiously
in patients with impaired ventricular function. Diltiazem
is both a substrate and an inhibitor of the CYP3A
enzyme system (see Table 4-3) and is therefore involved
in important drug interactions.
Lidocaine (Class IB). This is an intravenously administered local anesthetic drug that has been used for many
years for the treatment of ventricular tachycardia. In
patients with myocardial infarction, lidocaine suppresses
ventricular extrasystoles but does not reduce the likelihood of developing ventricular fibrillation; therefore,
lidocaine is not indicated for suppression of ectopy.
For the treatment of intractable ventricular tachycardia,
lidocaine is usually less effective than amiodarone (see
Chapter 21).
Because of high first-pass metabolism, lidocaine must
be administered intravenously. (Mexiletine is an orally
administered drug with pharmacologic properties virtually identical to those of lidocaine.) The elimination halftime of lidocaine is about 4 hours, but the duration of
effect following an intravenous bolus dose is only a few
minutes because of redistribution. Lidocaine is usually given
as a bolus dose of 1 mg/kg over 1 to 2 minutes, which
may be supplemented with one or two further doses of
0.5 mg/kg separated by 15 minutes. Following this,
lidocaine may be administered as an intravenous infusion
at 1 to 4 mg/min, ensuring that the total dose does not
exceed 300 mg in the first hour. Serum levels should be
obtained after 12 to 24 hours, aiming for a concentration
of 6 to 21 mol/l, (1.5 to 5 g/ml). High serum levels
produce neurologic symptoms, which include paresthesia, dysphoria, and agitation. The infusion rate should
be reduced in patients with low cardiac output (because
of a reduced rate of redistribution) and in patients who
develop neurologic symptoms. Although lidocaine has

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Chapter 3

no sedative properties itself, it augments the sedative

effect of other hypnotic drugs.

Digoxin. This is a cardiac glycoside that is useful for rate

control in patients with atrial fibrillation and as a supplementary treatment for heart failure. At therapeutic doses,
digoxin has a parasympathomimetic effect, which causes
increased refractoriness of the AV node and a slowing
of the ventricular response rate in atrial fibrillation.
However, at toxic doses digoxin has a sympathomimetic
effect and causes delayed after-depolarizations; both of
these effects cause arrhythmias. Many different arrhythmias are seen with digoxin toxicity. Common types include
junctional tachycardia, bigeminy, and second-degree
AV block. Cardiac toxicity is exacerbated by hypokalemia,
hypercalcemia, and hypomagnesemia. Noncardiac signs
of toxicity include nausea, vomiting, diarrhea, delirium,
agitation, and visual disturbances. Serum levels of digoxin
are increased in patients taking amiodarone and, to a lesser
extent, diltiazem. The maintenance dose of digoxin should
be halved in patients receiving amiodarone.
Digoxin may be given as a loading dose of 10 to 15 g/
kg in three divided doses 4 hours apart. A typical adult
loading-dose regime involves 500 g, then two doses of
250 g 4 and 8 hours later. The maintenance dose is
0.125 to 0.25 mg daily. Digoxin has an oral bioavailability of 75%, so the intravenous dose should be slightly less
than the oral dose. If rapid heart-rate control is required
the loading dose should be given intravenously. Digoxin
is excreted largely unchanged by the kidneys, and the
maintenance dose should be reduced in patients with
renal impairment. A digoxin level should be obtained
24 to 48 hours following a loading dose (taken 6 hours
after the daily maintenance dose). The therapeutic range
is 0.6 to 2 nmol/l (or 0.5 to 1.5 ng/ml), and toxicity
occurs with levels above 2.6 nmol/l (2 ng/ml).
Adenosine. This is an endogenous nucleoside that causes
brief but profound inhibition of the sinoatrial and AV
nodes. Adenosine is effective for the acute conversion of
supraventricular AV nodal reentry tachycardia and can be
used to slow down atrial flutter to confirm the diagnosis.
The drug is most effective if given as a rapid intravenous
bolus into a central vein. The initial dose is 6 mg which,
if ineffective, may be increased to 12 then 18 mg.
Adenosine can cause transient heart block (or even asystole), vasodilation, hypotension, chest pain, dyspnea, and
bronchospasm. Following an intravenous bolus dose,
adenosine is very rapidly cleared from plasma, resulting
in a duration of effect of only a few seconds.
Propafenone. This is a class IC agent with weak -blocking
properties that is used in the treatment of supraventricular and ventricular arrhythmias. Propafenone is associated
with proarrhythmia, causing ventricular tachycardia (not
torsades de pointes) in up to 5% of patients. Propafenone
can also cause marked hypotension in patients with
impaired ventricular function. For these reasons,

Cardiovascular Pharmacology

propafenone is not commonly used in the ICU.

Intravenously, propafenone is administered as a bolus
dose of 1 to 2 mg/kg for pharmacologic cardioversion of
atrial fibrillation or AV nodal reentry tachycardia. Orally,
propafenone is used as second-line therapy for the maintenance of sinus rhythm in patients with paroxysmal
atrial fibrillation. The dose is 150 to 300 mg three times
daily, up to 900 mg daily.

Magnesium sulfate. This is a safe and efficacious antiarrhythmic agent that has a broad application in the
cardiothoracic ICU (Chapter 21). It is useful in preventing and treating postoperative atrial and ventricular
arrhythmias and is specifically indicated for torsades de
pointes ventricular tachycardia (including that which is
drug induced) and multifocal atrial tachycardia.
The dose of magnesium sulfate is 0.05 to 0.1 mmol/
kg (or 15 to 30 mg/kg) intravenously over 10 minutes,
which may be repeated after 30 minutes. Magnesium is
reasonably well tolerated, even in patients with impaired
ventricular function. However, rapid intravenous administration can cause hypotension and bradycardia. Magnesium
is a useful pulmonary vasodilator. Extracardiac side effects
include muscle weakness and prolongation of the effect
of neuromuscular blocking drugs. Elimination is reduced
in renal failure.
Diuretics
Diuretic drugs cause sodium loss (natriuresis) and water
loss (diuresis) by the kidney and, as such, are important in
the management of hypertension and edematous states.
Diuretic drugs are classified by their mechanism of action
within the kidney as loop diuretics, thiazide diuretics,
or potassium-sparing diuretics. Doses of commonly
encountered diuretics are listed in Table 3-8.
Loop Diuretics. Loop diuretics (furosemide and
bumetanide) are the most potent of the diuretics and are
widely used in the treatment of pulmonary and systemic
edema. Loop diuretics bind reversibly to a chloride channel receptor site in the ascending limb of the loop of
Henle, inhibiting the reabsorption of filtered sodium
and chloride. This reduces the hypertonicity of the
renal medulla, inhibiting water reabsorption by the collecting ducts. In addition, loop diuretics increase the
excretion of potassium, hydrogen ions, magnesium, and
calcium.
Both furosemide and bumetanide are available in oral
and intravenous preparations. Following an intravenous
dose of either agent, diuresis is very rapid, beginning
15 minutes after administration and lasting up to 2 hours.
Following an oral dose, diuresis begins in 30 to 60 minutes and lasts 2 to 4 hours. The oral bioavailability of
furosemide is 60% and is 100% for bumetanide. Loop
diuretics are effective in renal failure, but higher doses
are required. However, the elimination of furosemide and,
to a lesser extent, bumetanide is impaired in renal failure,
increasing the risk of side effects.

47

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Table 3-8

Dosages of Selected Diuretics

Maximum
Daily Dose

Dosing Frequency

1000 mg

Up to 6 hourly

Infusion

10-40 mg (80-160 in
renal failure)
5-40 mg/hr

Oral and IV bolus

0.5-1 mg

4 mg

12-24 hourly

Hydrochlorothiazide

Oral

25 mg

100 mg

12-24 hourly

Chlorothiazide

Oral and IV

250-500 mg

2000 mg

12-24 hourly

Metolazone

Oral

2.5 mg

20 mg

Daily

Amiloride

Oral

2.5 mg

20 mg

12-24 hourly

Spironolactone

Oral

25 mg

100 mg

12-24 hourly

Eplerenone

Oral

25 mg

100 mg

Daily

Diuretic

Route of Administration

Initial Dose

Oral and IV bolus

Loop
Furosemide

Bumetanide
Thiazide

Potassium-sparing

The main adverse effect of loop diuretics is an excessive

clinical effect: hypovolemia, hypokalemia, hypochloremic
metabolic alkalosis, and hypomagnesemia. Other side
effects include deafness, hyperuricemia (and gout), and
allergic skin rashes. The effect of loop diuretics on serum
sodium concentration is difficult to predict. The urinary
sodium concentration in a patient on a furosemide infusion is typically less than 100 mmol/l; thus, acutely,
hypernatremia can occur. However, if urinary losses are
replaced with a low-sodium solution (e.g., intravenous
5% dextrose or oral water), hyponatremia will develop.
Chronic furosemide use typically results in hyponatremia.
Furosemide and, to a lesser extent, bumetanide can cause
deafness. This risk is greatest in patients with renal
impairment who are receiving high doses of furosemide,
by either infusion or rapidly administered intravenous
bolus doses. The role of loop diuretics in the treatment
of systemic edema and renal failure is debatable and is
discussed in Chapters 32 and 33, respectively.

Thiazide Diuretics. Thiazides diuretics (e.g., chlorothiazide, hydrochlorothiazide, metolazone) inhibit sodium
and chloride reabsorption in the distal nephron. Thiazide
diuretics promote potassium and magnesium excretion but,
unlike loop diuretics, inhibit calcium excretion. Thiazide
diuretics are less potent than loop diuretics and
are ineffective when the glomerular filtration rate falls
below about 30 ml/min.58 Thiazide diuretics are used
in the treatment of hypertension and mild heart failure.
48

All thiazide diuretics are administered orally except

chlorothiazide, which is also available for intravenous use.
Thiazide diuretics are formulated with other agents such
as ACE inhibitors for the treatment of hypertension.
In the cardiothoracic ICU, thiazides, particularly metolazone, are occasionally useful as cotreatment in patients
who are refractory to loop diuretics. Metolazone has a
long duration of action (12 to 24 hours) and is slightly
more efficacious than other thiazide diuretics because
it has an additional diuretic effect in the proximal
nephron. Adverse effects of thiazides include excessive
clinical effects (hypovolemia, hyponatremia, hypokalemia,
hypochloremic metabolic alkalosis), hyperuricemia,
hyperlipidemia, hyperglycemia, photosensitivity, and
allergic skin rashes.

Potassium-sparing Diuretics. Aldosterone antagonists

(spironolactone, eplerenone) inhibit the action of aldosterone in the collecting duct; as such, these agents cause
modest diuresis and natriuresis but inhibit potassium and
hydrogen ion secretion. Aldosterone antagonists are most
useful in conditions associated with increased aldosterone secretion, notably congestive cardiac failure and
hepatic cirrhosis. Spironolactone and eplerenone have
been shown to reduce mortality rates in patients with
severe heart failure.59,60 Both agents are administered
orally and are suitable for once-daily dosing.
The side effects of aldosterone antagonists include hyperkalemia, hyperchloremic metabolic acidosis, gynecomastia,

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Chapter 3

acute renal failure, and kidney stones. Hyperkalemia,

with the potential for cardiac arrest, is the most feared
complication of aldosterone antagonists. Toxicity is greatest in patients with renal impairment and those receiving
ACE inhibitors or nonsteroidal antiinflammatory drugs.
Following the initiation of treatment with an aldosterone
antagonist, potassium supplements should be stopped
and serum potassium and creatinine carefully monitored.
Amiloride is a potassium-sparing diuretic that blocks
sodium reabsorption in the collecting duct. It is useful as
an adjuvant to furosemide in patients with hypokalemia.
It too should be avoided in cases of renal failure.

Antiplatelet Drugs
A number of antiplatelet drugs are encountered in the
cardiothoracic ICU, all of which, to varying degrees, can
increase bleeding. All antiplatelet drugs cause prolongation of the bleeding time but do not cause any abnormalities in routine tests of coagulation. Antiplatelet drugs
vary with respect to their duration of effect (5 to 7 days
for aspirin and clopidogrel; 4 to 12 hours for glycoprotein IIb/IIIa receptor antagonists), and their impact on
postsurgical bleeding (minor for aspirin; intermediate for
clopidogrel; high for glycoprotein IIb/IIIa receptor
blockers). Recommendations for antiplatelet drugs in acute
coronary syndromes are summarized in Table 18.12.
Other drugs relating to bleeding and coagulation are
discussed in Chapter 30.
Aspirin. Aspirin is a nonsteroidal antiinflammatory drug
that irreversibly inhibits the enzyme cyclooxygenase, an
essential component in the synthesis of prostaglandins and
thromboxanes. Aspirin has antiinflammatory, analgesic,
antipyretic, and antiplatelet effects. The antiplatelet action
of aspirin occurs as a consequence of the inhibition of the
synthesis of platelet thromboxane A2, which is essential
for platelet aggregation. A single dose of aspirin inhibits
aggregation for the lifespan of the platelet (5 to 7 days).
Low-dose aspirin (83 mg/day) is indicated in a wide
range of thromboembolic conditions, including acute
coronary syndromes, stable or unstable angina, ischemic
neurologic events, and the implantation of bioprosthetic
valves and following coronary artery bypass graft surgery. However, aspirin is a relatively weak antiplatelet
agent, inhibiting only thromboxane-induced aggregation. Platelet aggregation can still be induced by other
stimuli, notably thrombin. Low-dose aspirin is relatively
safe and does not appear to increase postoperative bleeding, even in patients undergoing repeat sternotomy.61
Thus, in most cardiac surgical units, aspirin is continued
throughout the perioperative period.
Thienopyridines: Ticlopidine and Clopidogrel.
Ticlopidine and clopidogrel are structurally related
thienopyridine compounds that irreversibly inhibit
adenosine-diphosphate-induced platelet aggregation.
Clopidogrel has a more rapid action and a better safety

Cardiovascular Pharmacology

profile than ticlopidine. Maximal inhibition of platelet

aggregation occurs 3 to 5 days after taking a standard dose
of clopridogrel (75 mg) but within 6 hours of taking
a 300 mg loading dose.62 Platelet function takes 5 to
7 days to return to normal after the drug is withheld.
Clopidogrel improves survival in patients with unstable
angina and non-ST segment myocardial infarction63 and
reduces myocardial infarction and other adverse outcomes
in patients undergoing percutaneous coronary intervention (PCI).64 The optimal duration of treatment has not
been determined, but the major benefit occurs in the first
30 days.63 Clopidogrel is also used by some surgeons following off-pump CABG surgery to improve graft patency.
Patients receiving both clopidogrel and aspirin prior to
CABG surgery are more likely than those treated with
aspirin alone to have major bleeding that requires transfusion or reoperation.62 Thus, if possible, clopidogrel should
be stopped at least 5 days prior to surgery.65

Glycoprotein IIB/IIIA Receptor Blockers. Glycoprotein

IIb/IIIa receptor blockers (tirofiban, lamifiban, epifibatide,
abciximab) inhibit platelet aggregation by preventing the
binding of fibrinogen and the von Willebrand factor (and
other adhesive molecules) to glycoprotein IIb/IIIa receptors on the surface of activated platelets. Glycoprotein
IIb/IIIa receptor blockers are used in the treatment of
acute coronary syndromes, particularly if PCI is undertaken
(Chapter 18). All currently available agents are administered as an intravenous bolus followed by an infusion for
1 to 3 days. Inhibition of platelet aggregation occurs
within 30 minutes of a bolus dose and persists for up to
12 hours following discontinuation of the infusion.
The main adverse effect of glycoprotein IIa/IIIb receptor blockers is bleeding, particularly in patients undergoing surgery. There is no reversal for these agents, and any
transfused platelets are inactivated. The best strategy is
to delay surgery for 8 to 12 hours following discontinuation of the infusion. Contraindications to glycoprotein
IIb/IIIa receptor blockers are similar to those for fibrinolytic agents and include coagulopathy, platelet disorders,
cerebrovascular disease, major surgery, and severe hypertension. Platelet count and hemoglobin should be checked
prior to treatment every 6 hours after commencement of
therapy, then daily.
Lipid-lowering Drugs
Statins. Hydroxy-methylglutaryl-coenzyme A (HMG
CoA) reductase inhibitors (commonly referred to as
statins) form the mainstay of lipid-lowering treatment.
Available compounds include simvastatin, atorvastatin,
pravastatin, and fluvastatin. These compounds are structural analogs of HMG CoA reductase, the enzyme that
controls the rate-limiting step in cholesterol synthesis.
All statins have high first-pass extraction by the liver with
most of the absorbed dose being excreted in the bile.
Statins are indicated primarily in the treatment of dyslipidemia, particularly in patients with coronary artery
49

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disease and after CABG surgery.66 There is also evidence

that statins have antiinflammatory effects that provide an
additional benefit over and above their lipid-lowering
effect.67,68 Statins inhibit the development of inflammatory coronary artery disease following heart transplantation69 and appear to have a protective effect in patients
who develop septic shock.70-72
The main adverse effects of statins are hepatotoxicity
and myopathy. Intermittent elevations in aminotransferases
occur in some patients taking statins, but severe hepatotoxicity is rare. If aminotransferase levels increase to more
than three times the upper limit of normal, the drug should
be stopped. Increases in serum creatine kinase without
muscle pain occur in up to 10% of patients. If muscle
pain does occur, creatine kinase should be measured; if
levels are elevated, the drug should be stopped immediately because rhabdomyolysis can develop.

Other Lipid-lowering Drugs. Nicotinic acid is a watersoluble vitamin (B3) that decreases serum cholesterol
and triglycerides by decreasing the synthesis of very-lowdensity lipoproteins. Nicotinic acid is indicated in the
treatment of elevated plasma triglyceride levels. Many
patients experience unpleasant flushing with nicotinic
acid, which can be ameliorated by aspirin or ibuprofen.
Deranged liver function tests may occur, but hepatic toxicity is rare. Acipimox is a nicotinic-acid-like lipid-lowering drug but has fewer side effects.
The fibric acid derivatives (gemfibrozil, fenofibrate,
bezafibrate) are lipid-lowering agents that act by a number
of mechanisms, including reduced secretion of very-lowdensity lipoproteins by the liver. Side effects include skin
rash, gastrointestinal symptoms, myopathy, arrhythmias,
hypokalemia, and deranged liver-function tests. There is
an increased risk for myopathy when administered with
statins; with this combination, creatine kinase and liver
function should be monitored every 3 to 6 months.
Etzetimibe inhibits the gastrointestinal absorption of
cholesterol from dietary and biliary sources. It has a rapid
onset of action, a long duration of effect, and very few
side effects.

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