Académique Documents
Professionnel Documents
Culture Documents
4/16/07
11:31 AM
Page 33
CHAPTER
Cardiovascular Pharmacology
Roman M. Sniecinski, Susan Wright, and Jerrold H. Levy
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.
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
33
H7572-Ch03
4/16/07
Section I
11:31 AM
Page 34
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
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,
H7572-Ch03
4/16/07
11:31 AM
Page 35
Chapter 3
Table 3-1
Cardiovascular Pharmacology
Receptor
Location
Action
Vasoconstriction
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
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
35
H7572-Ch03
4/16/07
Section I
11:31 AM
Page 36
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
H7572-Ch03
4/16/07
11:31 AM
Page 37
Chapter 3
Cardiovascular Pharmacology
H7572-Ch03
4/16/07
Section I
11:31 AM
Page 38
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
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.
H7572-Ch03
4/16/07
11:31 AM
Page 39
Chapter 3
Table 3-2
Cardiovascular Pharmacology
Drug
Main Route
of Elimination
Peripheral
Vasodilation
Intravenous
Bolus Dose
Kidney
Pindolol
Propranolol
Liver
1-3 mg
Sotalol
Kidney
25-100 mg
Timolol
Liver
Atenolol
Kidney
Bisoprolol
Celiprolol
Kidney
Esmolol
Plasma esterases
Intravenous only
25-50 mg
Metoprolol
Moderate
2.5-5 mg
2.5-5 mg
Liver
Carvedilol
Liver
5-20 mg
ER = extended release.
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
39
H7572-Ch03
4/16/07
Section I
11:31 AM
Page 40
H7572-Ch03
4/16/07
11:31 AM
Page 41
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
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.
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
41
H7572-Ch03
4/16/07
Section I
11:31 AM
Page 42
H7572-Ch03
4/16/07
11:31 AM
Page 43
Chapter 3
Table 3-4
Cardiovascular Pharmacology
Drug
Maintenance Dose
ACE Inhibitors
Captopril
Enalapril
2.5 mg 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
2.5-10 mg daily
Cilazapril
0.5 mg daily
1-5 mg daily
Fosinopril
10 mg daily
20-40 mg daily
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
H7572-Ch03
4/16/07
Section I
11:31 AM
Page 44
Table 3-5
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
Class IB
Lidocaine
Mexiletine
Class IC
Propafenone
Inhibit phase 0 in
myocytes
Variable inhibition of
pacemaker tissue,
depending on agent
Class II
blockers
Class III
Amiodarone
Sotalol
Dofetilide
Ibutilide
Class IV
Calcium channel
blockers
Digoxin
Adenosine
Magnesium
H7572-Ch03
4/16/07
11:31 AM
Page 45
Chapter 3
Table 3-6
Cardiovascular Pharmacology
Indication
Dosing Regime
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
200 mg daily
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
45
H7572-Ch03
4/16/07
Section I
11:31 AM
Page 46
46
H7572-Ch03
4/16/07
11:31 AM
Page 47
Chapter 3
Cardiovascular Pharmacology
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
H7572-Ch03
4/16/07
Section I
11:31 AM
Page 48
Table 3-8
Maximum
Daily Dose
Dosing Frequency
1000 mg
Up to 6 hourly
Infusion
10-40 mg (80-160 in
renal failure)
5-40 mg/hr
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
Loop
Furosemide
Bumetanide
Thiazide
Potassium-sparing
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
H7572-Ch03
4/16/07
11:31 AM
Page 49
Chapter 3
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
H7572-Ch03
4/16/07
Section I
11:31 AM
Page 50
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.
REFERENCES
1. Alquist RP: A study of adrenotropic receptors. Am J Physiol
53:506, 1948.
2. Totaro RJ, Raper RF: Epinephrine-induced lactic acidosis following
cardiopulmonary bypass. Crit Care Med 25:1693-1699, 1997.
3. Goldberg LI, Rajfer SI: Dopamine receptors: applications in
clinical cardiology. Circulation 72:245-248, 1985.
4. MacGregor DA, Smith TE, Prielipp RC, et al: Pharmacokinetics
of dopamine in healthy male subjects. Anesthesiology 92:338-346,
2000.
5. Schwinn DA, Leone BJ, Spahn DR, et al: Desensitization of
myocardial beta-adrenergic receptors during cardiopulmonary
bypass: evidence for early uncoupling and late downregulation.
Circulation 84:2559-2567, 1991.
50
H7572-Ch03
4/16/07
11:31 AM
Page 51
Chapter 3
25. Dargie HJ: Effect of carvedilol on outcome after myocardial
infarction in patients with left-ventricular dysfunction: the
CAPRICORN randomised trial. Lancet 357:1385-1390, 2001.
26. Anonymous: Timolol-induced reduction in mortality and
reinfarction in patients surviving acute myocardial infarction.
N Engl J Med 304:801-807, 1981.
27. Olsson G, Wikstrand J, Warnold I, et al: Metoprolol-induced
reduction in postinfarction mortality: pooled results from five
double-blind randomized trials. Eur Heart J 13:28-32, 1992.
28. Bunch TJ, Muhlestein JB, Bair TL, et al: Effect of beta-blocker
therapy on mortality rates and future myocardial infarction
rates in patients with coronary artery disease but no history of
myocardial infarction or congestive heart failure. Am J Cardiol
95:827-831, 2005.
29. Mangano DT, Layug EL, Wallace A, et al: Effect of atenolol on
mortality and cardiovascular morbidity after noncardiac surgery.
Multicenter Study of Perioperative Ischemia Research Group.
N Engl J Med 335:1713-1720, 1996.
30. Ferguson TB Jr, Coombs LP, Peterson ED, Society of Thoracic
Surgeons National Adult Cardiac Surgery D: Preoperative
beta-blocker use and mortality and morbidity following CABG
surgery in North America. JAMA 287:2221-2227, 2002.
31. Psaty BM, Koepsell TD, Wagner EH, et al: The relative risk of
incident coronary heart disease associated with recently stopping
the use of beta-blockers. JAMA 263:1653-1657, 1999.
32. Keating GM, Jarvis B: Carvedilol: a review of its use in chronic
heart failure. Drugs 63:1697-1741, 2003.
33. Gerson JI, Allen FB, Seltzer JL: Arterial and venous dilation by
nitroprusside and nitroglycerinis there a difference? Anesth
Analges 61:256-260, 1982.
34. Psaty BM, Heckbert SR, Koepsell TD, et al: The risk of myocardial infarction associated with antihypertensive drug therapies.
JAMA 274:620-625, 1995.
35. Murphy MB, Murray C, Shorten GD: Fenoldopam: a selective
peripheral dopamine-receptor agonist for the treatment of severe
hypertension. N Engl J Med 345:1548-1557, 2001.
36. Hill AJ, Feneck RO, Walesby RK: A comparison of fenoldopam
and nitroprusside in the control of hypertension following coronary artery surgery. J Cardiothorac Vasc Anesth 7:279-284, 1993.
37. Tanaka KA, Szlam F, Katori N, et al: In vitro effects of antihypertensive drugs on thromboxane agonist (U46619)-induced
vasoconstriction in human internal mammary artery. Br J Anaesth
93:257-262, 2004.
38. Caimmi P-P, Pagani L, Micalizzi E, et al: Fenoldopam for renal
protection in patients undergoing cardiopulmonary bypass.
J Cardiothorac Vasc Anesth 17:491-494, 2003.
39. Bove T, Landoni G, Calabro MG, et al: Renoprotective action
of fenoldopam in high-risk patients undergoing cardiac surgery:
a prospective, double-blind, randomized clinical trial. Circulation
111:3230-3235, 2005.
40. Keating GM, Goa KL: Nesiritide: a review of its use in acute
decompensated heart failure. Drugs 63:47-70, 2003.
41. Publication Committee for the VMAC Investigators: Intravenous
nesiritide vs nitroglycerin for treatment of decompensated
congestive heart failure: a randomized controlled trial. JAMA
287:1531-1540, 2002.
42. Moazami N, Damiano RJ, Bailey MS, et al: Nesiritide (BNP) in
the management of postoperative cardiac patients. Ann Thorac
Surg 75:1974-1976, 2003.
43. Kober L, Torp-Pedersen C, Carlsen JE, et al: A clinical trial
of the angiotensin-converting-enzyme inhibitor trandolapril in
patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group.
N Engl J Med 333:1670-1676, 1995.
44. Yusuf S, Sleight P, Pogue J, et al: Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events
in high-risk patients. The Heart Outcomes Prevention Evaluation
Study Investigators. N Engl J Med 342:145-153, 2000.
Cardiovascular Pharmacology
51
H7572-Ch03
4/16/07
Section I
11:31 AM
Page 52
52