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Chapter 8
Cardiovascular Pharmacology
Roger L. Royster, MD • John F. Butterworth IV, MD •
Leanne Groban, MD • Thomas F. Slaughter, MD •
David A. Zvara, MD
Anti-ischemic Drug therApy
Anti-ischemic drug therapy during anesthesia is indicated whenever evidence of
myocardial ischemia exists. The treatment of ischemia during anesthesia is compli-
cated by the ongoing stress of surgery, blood loss, concurrent organ ischemia, and the
patient’s inability to interact with the anesthesiologist. Nonetheless, the fundamental
principles of treatment remain the same as in the unanesthetized state. All events
of myocardial ischemia involve an alteration in the oxygen supply/demand balance
(Table 8-1). The 2007 American College of Cardiology/American Heart Association
(ACC/AHA) Guidelines on the Management and Treatment of Patients with Unstable
Angina and Non–ST-Segment Elevation Myocardial Infarction provide an excellent
framework for the treatment of patients with ongoing myocardial ischemia.^1
Nitroglycerin
Nitroglycerin (NTG) is clinically indicated as initial therapy in nearly all types
of myocardial ischemia. Chronic exertional angina, de novo angina, unstable
angina, Prinzmetal’s angina (vasospasm), and silent ischemia respond to NTG
Anti-Ischemic Drug Therapy Nitroglycerin β-Adrenergic Blockers Calcium Channel Blockers
Drug Therapy for Systemic Hypertension Medical Treatment for Hypertension Management of Severe Hypertension
Pharmacotherapy for Acute and Chronic Heart Failure Heart Failure Classification Pathophysiologic Role of the Renin- Angiotensin System in Heart Failure β-Adrenergic Receptor Antagonists Adjunctive Drugs Future Therapy Management of Acute Exacerbations of Chronic Heart Failure Low-Output Syndrome
Pharmacologic Treatment of Diastolic Heart Failure Current Clinical Practice
Pharmacotherapy for Cardiac Arrhythmias Class I Antiarrhythmic Drugs: Sodium Channel Blockers Class II: β-Adrenergic Receptor Antagonists Class III: Agents That Block Potassium Channels and Prolong Repolarization Class IV: Calcium Channel Antagonists Other Antiarrhythmic Agents
Summary Anti-Ischemic Drug Therapy Drug Therapy for Systemic Hypertension Pharmacotherapy for Acute and Chronic Heart Failure Pharmacotherapy for Cardiac Arrhythmias
References
CARDIOVASCULAR PHARMACOLOGY
administration. During intravenous therapy with NTG, if blood pressure (BP) drops
and ischemia is not relieved, the addition of phenylephrine will allow coronary
perfusion pressure (CPP) to be maintained while allowing higher doses of NTG to
be used for ischemia relief. If reflex increases in heart rate (HR) and contractility
occur, combination therapy with β-adrenergic blockers may be indicated to blunt
this undesired increase in HR. Combination therapy with nitrates and calcium chan-
nel blockers may be an effective anti-ischemic regimen in selected patients; however,
excessive hypotension and reflex tachycardia may be a problem, especially when a
dihydropyridine calcium antagonist is used.
Mechanism of Action
NTG enhances myocardial oxygen delivery and reduces myocardial oxygen demand.
NTG is a smooth muscle relaxant that causes vasculature dilation. 2 Nitrate-mediated
vasodilation occurs with or without intact vascular endothelium. Nitrites, organic
nitrites, nitroso compounds, and other nitrogen oxide–containing substances
(e.g., nitroprusside) enter the smooth muscle cell and are converted to reactive nitric
oxide (NO) or S -nitrosothiols, which stimulate guanylate cyclase metabolism to pro-
duce cyclic guanosine monophosphate (cGMP) (Fig. 8-1). A cGMP-dependent pro-
tein kinase is stimulated with resultant protein phosphorylation in the smooth muscle.
This leads to a dephosphorylation of the myosin light chain and smooth muscle
relaxation. Vasodilation is also associated with a reduction of intracellular calcium.
Sulfhydryl (SH) groups are required for formation of NO and the stimulation of gua-
nylate cyclase. When excessive amounts of SH groups are metabolized by prolonged
exposure to NTG, vascular tolerance occurs. The addition of N -acetylcysteine, an
SH donor, reverses NTG tolerance. The mechanism by which NTG compounds are
uniquely better venodilators, especially at lower serum concentrations, is unknown
but may be related to increased uptake of NTG by veins compared with arteries.^3
Physiologic Effects
Two important physiologic effects of NTG are systemic and regional venous dilation.
Venodilation can markedly reduce venous pressure, venous return to the heart, and
cardiac filling pressures. Prominent venodilation occurs at lower doses and does not
increase further as the NTG dose increases. Venodilation results primarily in pooling
O 2 Supply O2 Demand
Heart rate* Heart rate* O 2 content Contractility Hemoglobin, percent oxygen saturation, Pao 2
Wall tension
Coronary blood flow Afterload CPP = DBP − LVEDP* Preload (LVEDP)* Coronary vascular resistance
CPP = coronary perfusion pressure; DBP = diastolic blood pressure; LVEDP = left ventricular end‑diastolic pressure. *Affects both supply and demand. Modified from Royster RL: Intraoperative administration of inotropes in cardiac surgery patients. J Cardiothorac Anesth 6(Suppl 5):17, 1990.
Table 8‑ 1 Myocardial Ischemia: Factors Governing O 2 Supply
and Demand
CARDIOVASCULAR PHARMACOLOGY
Coronary arteriographic studies in humans demonstrate that coronary collateral ves-
sels increase in size after NTG administration. This effect may be especially impor-
tant when epicardial vessels have subtotal or total occlusive disease. Improvement in
collateral flow may also be protective in situations in which coronary artery steal may
occur with other potent coronary vasodilator agents. The improvement in blood flow
to the subendocardium, the most vulnerable area to the development of ischemia, is
secondary to both improvement in collateral flow and reductions in left ventricular
end-diastolic pressure (LVEDP), which reduce subendocardial resistance to blood
flow. With the maintenance of an adequate CPP (e.g., with administration of phenyl-
ephrine), NTG can maximize subendocardial blood flow. The ratio of endocardial to
epicardial blood in transmural segments is enhanced with NTG. Inhibition of platelet
aggregation also occurs with NTG; however, the clinical significance of this action is
unknown.
Intravenous Nitroglycerin
Nitroglycerin has been available since the early 1980s as an injectable drug with
a stable shelf half-life in a 400-μg/mL solution of D 5 W. Blood levels are achieved
instantaneously, and arterial dilating doses with resulting hypotension may quickly
occur. If the volume status of the patient is unknown, initial doses of 5 to 10 μg/min
are recommended. The dose necessary for relieving myocardial ischemia may vary
from patient to patient, but relief is usually achieved with 75 to 150 μg/min. In a
clinical study of 20 patients with rest angina, a mean dose of 72 μg/min reduced or
abolished ischemic episodes in 85% of patients. However, doses as high as 500 to
600 μg/min may be necessary for ischemic relief in some patients. Arterial dilation
becomes clinically apparent at doses around 150 μg/min. Drug offset after discon-
tinuation of an infusion is rapid (2 to 5 minutes). The dosage of NTG available is less
when the drug is administered in plastic bags and polyvinylchloride tubing because
of NTG absorption by the bag and tubing, although this is not a significant clinical
problem because the drug is titrated to effect.
Summary
Nitroglycerin remains a first-line agent for the treatment of myocardial ischemia.
Special care must be taken in patients with signs of hypovolemia or hypotension,
because the vasodilating effects of the drug may worsen the clinical condition.
Recommendations from the ACC/AHA on intraoperative use of NTG are given in
Box 8-2.
BOX 8-1 EffectsofNitroglycerinandOrganicNitrates
ontheCoronaryCirculation
- Epicardial coronary artery dilation: small arteries dilate proportionately more than larger
arteries
- Increased coronary collateral vessel diameter and enhanced collateral flow
- Improved subendocardial blood flow
- Dilation of coronary atherosclerotic stenoses
- Initial short-lived increase in coronary blood flow, later reduction in coronary blood
flow as MṾo 2 decreases
- Reversal and prevention of coronary vasospasm and vasoconstriction
Modified frgom Abrams J: Hemodynamic effects of nitroglycerin and long-acting nitrates. Am Heart J 110(part 2):216, 1985.
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CARDIOVASCULAR PHYSIOLOGY, PHARMACOLOGY, AND MOLECULAR BIOLOGY
β-Adrenergic Blockers
β-Adrenergic blockers have multiple favorable effects in treating the ischemic heart
during anesthesia (Box 8-3). They reduce oxygen consumption by decreasing HR, BP,
and myocardial contractility. HR reduction increases diastolic CBF. Increased collateral
blood flow and redistribution of blood to ischemic areas may occur with β-blockers.
More free fatty acids may be available for substrate consumption by the myocardium.
Microcirculatory oxygen delivery improves, and oxygen dissociates more easily from
hemoglobin after β-adrenergic blockade. Platelet aggregation is inhibited. β-Blockers
should be started early in ischemic patients in the absence of contraindications. Many
patients at high risk of perioperative cardiac morbidity should be started on β-blocker
therapy before surgery and continued on this therapy for up to 30 days after surgery.
Perioperative administration of β-adrenergic blockers reduces both mortality and
morbidity when given to patients at high risk for coronary artery disease who must
undergo noncardiac surgery.^4 These data suggest that intermediate- and high-risk
patients presenting for noncardiac surgery should receive perioperative β-adrenergic block-
ade to reduce postoperative cardiac mortality and morbidity. Recommendations on the
perioperative use of β-adrenergic blockade for noncardiac surgery are given in Box 8-4.
Physiologic Effects
anti-ischemic effects
β-Blockade on the ischemic heart may result in a favorable shift in the oxygen demand/
supply ratio.^5 The reductions in the force of contraction and HR reduce myocardial oxy-
gen consumption and result in autoregulatory decreases in myocardial blood flow. Several
studies have shown that blood flow to ischemic regions is maintained with propranolol.
antihypertensive effects
Both β 1 - and β 2 -receptor blockers inhibit myocardial contractility and reduce HR; both
effects should reduce BP. No acute decrease in BP occurs during acute administration
of propranolol. However, chronic BP reduction has been attributed to a chronic reduc-
tion in cardiac output (CO). Reductions in high levels of plasma renin have been sug-
gested as effective therapy in controlling essential hypertension.
electrophysiologic effects
Generalized slowing of cardiac depolarization results from reducing the rate of dia-
stolic depolarization (phase 4). Action potential duration and the QT interval may
BOX 8-2 RecommendationsforIntraoperativeNitroglycerin
*Conditions for which there is evidence for and/or general agreement that a procedure be performed or a treatment is of benefit. �Conditions for which there is a divergence of evidence and/or opinion about the treatment. �Conditions for which there is evidence and/or general agreement that the procedure is not necessary.
- Class I* High-risk patients previously on nitroglycerin who have active signs of myocardial
ischemia without hypotension.
- Class II� As a prophylactic agent for high-risk patients to prevent myocardial ischemia
and cardiac morbidity, particularly in those who have required nitrate therapy to control
angina. The recommendation for prophylactic use of nitroglycerin must take into account
the anesthetic plan and patient hemodynamics and must recognize that vasodilation and
hypovolemia can readily occur during anesthesia and surgery.
- Class III� Patients with signs of hypovolemia or hypotension.
II
CARDIOVASCULAR PHYSIOLOGY, PHARMACOLOGY, AND MOLECULAR BIOLOGY
excreted renally. Protein binding is less than 10%. Metoprolol’s serum half-life
is 3 to 4 hours.
As with any cardioselective β-blocker, higher serum levels may result in greater
incidence of β 2 -blocking effects. Metoprolol is administered intravenously in 1- to 2-mg
doses, titrated to effect. The potency of metoprolol is approximately one half that of
propranolol. Maximum β-blocker effect is achieved with 0.2 mg/kg given intravenously.
esmolol
Esmolol’s chemical structure is similar to that of metoprolol and propranolol, except
it has a methylester group in the para position of the phenyl ring, making it suscepti-
ble to rapid hydrolysis by red blood cell esterases (9-minute half-life). Esmolol is not
metabolized by plasma cholinesterase. Hydrolysis results in an acid metabolite and
methanol with clinically insignificant levels. Ninety percent of the drug is eliminated in
the form of the acid metabolite, normally within 24 hours. A loading dose of 500 μg/kg
given intravenously, followed by a 50- to 300- μg/kg/min infusion, will reach steady-
state concentrations within 5 minutes. Without the loading dose, steady-state con-
centrations are reached in 30 minutes.
Esmolol is cardioselective, blocking primarily β 1 -receptors. It lacks ISA and mem-
brane-stabilizing effects and is mildly lipid soluble. Esmolol produced significant reduc-
tions in BP, HR, and cardiac index after a loading dose of 500 μg/kg and an infusion of
300 μg/kg/min in patients with coronary artery disease, and the effects were completely
reversed 30 minutes after discontinuation of the infusion. Initial therapy during anesthe-
sia may require significant reductions in both the loading and infusion doses.
Hypotension is a common side effect of intravenous esmolol. The incidence of hypo-
tension was higher with esmolol (36%) than with propranolol (6%) at equal therapeutic
endpoints. The cardioselective drugs may cause more hypotension because of β 1 -induced
myocardial depression and the failure to block β 2 peripheral vasodilation. Esmolol appears
safe in patients with bronchospastic disease. In another comparative study with proprano-
lol, esmolol and placebo did not change airway resistance whereas 50% of patients treated
with propranolol developed clinically significant bronchospasm.
labetalol
Labetalol provides selective α 1 -receptor blockade and nonselective β 1 - and β 2 -blockade.
The potency of β-adrenergic blockade is 5- to 10-fold greater than α 1 -adrenergic block-
ade. Labetalol has partial β 2 -agonist effects that promote vasodilation. Labetalol is moder-
ately lipid soluble and is completely absorbed after oral administration. First-pass hepatic
metabolism is significant with production of inactive metabolites. Renal excretion of the
unchanged drug is minimal. Elimination half-life is approximately 6 hours.
In contrast to other β-blockers, clinically, labetalol should be considered a
peripheral vasodilator that does not cause a reflex tachycardia. BP and systolic vascu-
lar resistance decrease after an intravenous dose. Stroke volume (SV) and CO remain
unchanged, with HR decreasing slightly. The reduction in BP is dose related, and
acutely hypertensive patients usually respond within 3 to 5 minutes after a bolus dose
of 100 to 250 μg/kg. However, the more critically ill or anesthetized patients should
have their BP titrated beginning with 5- to 10-mg intravenous increments. Reduction
in BP may last as long as 6 hours after intravenous dosing.
Summary
β-Adrenergic blockers are first-line agents in the treatment of myocardial ischemia.
These agents effectively reduce myocardial work and oxygen demand. There is grow-
ing evidence that β-adrenergic-blocking agents may play a significant role in reduc-
ing perioperative cardiac morbidity and mortality in noncardiac surgery.^6
CARDIOVASCULAR PHARMACOLOGY
Calcium Channel Blockers
Calcium channel blockers reduce myocardial oxygen demands by depression
of contractility, HR, and/or decreased arterial BP. 7 Myocardial oxygen supply
may be improved by dilation of coronary and collateral vessels. Calcium channel
blockers are used primarily for symptom control in patients with stable angina
pectoris. In an acute ischemic situation, calcium channel blockers (verapamil
and diltiazem) may be used for rate control in situations when β-blockers can-
not be used. The most important effects of calcium channel blockers, however,
may be the treatment of variant angina. These drugs can attenuate ergonovine-
induced coronary vasoconstriction in patients with variant angina, suggesting
protection via coronary dilation. Most episodes of silent myocardial ischemia,
which may account for 70% of all transient ischemic episodes, are not related
to increases in myocardial oxygen demands (HR and BP) but, rather, intermit-
tent obstruction of coronary flow likely caused by coronary vasoconstriction or
spasm. All calcium channel blockers are effective at reversing coronary spasm,
reducing ischemic episodes, and reducing NTG consumption in patients with
variant or Prinzmetal’s angina. Combinations of NTG and calcium channel
blockers, which also effectively relieve and possibly prevent coronary spasm,
are at present rational therapy for variant angina. β-Blockers may aggravate
anginal episodes in some patients with vasospastic angina and should be used
with caution. Preservation of CBF with calcium channel blockers is a significant
difference from the predominant β-blocker anti-ischemic effects of reducing
myocardial oxygen consumption.
Calcium channel blockers have proven effective in controlled trials of stable
angina. However, rapid-acting dihydropyridines such as nifedipine may cause a
reflex tachycardia, especially during initial therapy, and exacerbate anginal symptoms.
Such proischemic effects probably explain why the short-acting dihydropyridine
Drug Selectivity
Partial Agonist Activity Usual Dose for Angina
Propranolol None No 20 to 80 mg twice daily Metoprolol β 1 No 50 to 200 mg twice daily Atenolol β 1 No 50 to 200 mg/d Nadolol None No 40 to 80 mg/d Timolol None No 10 mg twice daily Acebutolol β 1 Yes 200 to 600 mg twice daily Betaxolol β 1 No 10 to 20 mg/d Bisoprolol β 1 No 10 mg/d Esmolol (intravenous)
β 1 No 50 to 300 μg/kg/min
Labetalol* None Yes 200 to 600 mg twice daily Pindolol None Yes 2.5 to 7.5 mg 3 times daily
*Labetalol is a combined α‑ and β‑blocker. Adapted from Gibbons RJ, Chatterjee K, Daley J, et al: ACC/AHA/ACP‑ASIM Guidelines for the Management of Patients with Chronic Stable Angina: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Chronic Stable Angina). J Am Coll Cardiol 33:2092, 1999.
Table 8‑ 2 Properties of β-Blockers in Clinical Use
CARDIOVASCULAR PHARMACOLOGY
moderate vasodilation without significant change in HR, CO, or SV. Verapamil can
significantly depress myocardial function in patients with preexisting ventricular
dysfunction.
Diltiazem is a less potent vasodilator and has fewer negative inotropic effects
compared with verapamil. Studies in patients reveal reductions in SVR and BP, with
increases in CO, pulmonary artery wedge pressure, and ejection fraction. Diltia-
zem attenuates baroreflex increases in HR secondary to NTG and decreases in HR
secondary to phenylephrine. Regional blood flow to the brain and kidney increases,
whereas skeletal muscle flow does not change. In contrast to verapamil, diltiazem is
not as likely to aggravate congestive heart failure, although it should be used carefully
in these patients.
Coronary Blood Flow
Coronary artery dilation occurs with the calcium channel blockers with increases in
total CBF. Nifedipine is the most potent coronary vasodilator, especially in epicardial
vessels, which are prone to coronary vasospasm. Diltiazem is effective in blocking
coronary artery vasoconstriction caused by a variety of agents, including α-agonists,
serotonin, prostaglandin, and acetylcholine.
Electrophysiologic Effects
Calcium channel blockers exert their primary electrophysiologic effects on tis-
sue of the conducting system that is dependent on calcium for generation of
the action potential, primarily at the sinoatrial (SA) and atrioventricular (AV)
nodes. They do not alter the effective refractory period of atrial, ventricular,
or His-Purkinje tissue. Diltiazem and verapamil exert these electrophysiologic
effects in vivo and in vitro, whereas the electrophysiologic depression of the
dihydropyridines (nifedipine) is completely attenuated by reflex sympathetic
activation. Nifedipine actually can enhance SA and AV node conduction, where-
as verapamil and diltiazem slow conduction velocity and prolong refractoriness
of nodal tissue.
Amlodipine Diltiazem Nifedipine Verapamil
Heart rate ↑/0 ↓ ↑/0 ↓ Sinoatrial node conduction
Atrioventricular node conduction
Myocardial contractility
Neurohormonal activation
Vascular dilatation
Coronary flow ↑ ↑ ↑ ↑
From Eisenberg MJ, Brox A, Bestawros AN. Calcium channel blockers: An update. Am J Med 116:35, 2004.
Table 8‑ 3 Calcium Channel Blocker Vasodilator Potency
and Inotropic, Chronotropic, and Dromotropic
Effects on the Heart
II
CARDIOVASCULAR PHYSIOLOGY, PHARMACOLOGY, AND MOLECULAR BIOLOGY
Pharmacology
nifedipine
Nifedipine was the first dihydropyridine derivative to be used clinically. Other
dihydropyridines available for clinical use include nicardipine, isradipine, amlodi-
pine, felodipine, and nimodipine. In contrast to the other calcium channel blockers,
nimodipine is highly lipid soluble and penetrates the blood-brain barrier. It is indi-
cated for vascular spasm after intracerebral bleeding.
Nifedipine’s oral bioavailability is approximately 70%, with peak plasma levels
occurring within 30 to 45 minutes. Protein binding is 95%, and elimination half-life
is approximately 5 hours. Nifedipine is available for oral administration in capsular
form. The compound degenerates in the presence of light and moisture, preventing
commercially available intravenous preparations. Puncture of the capsule and sub-
lingual administration provide an onset of effects in 2 to 3 minutes.
nicardipine
Nicardipine is a dihydropyridine agent with a longer half-life than nifedipine and
with vascular selectivity for coronary and cerebrovascular beds. Nicardipine may
be the most potent overall relaxant of vascular smooth muscle among the dihy-
dropyridines. Peak plasma levels are reached 1 hour after oral administration,
with bioavailability of 35%. Plasma half-life is 8 to 9 hours. Although the drug
undergoes extensive hepatic metabolism with less than 1% of the drug excreted
renally, greater renal elimination occurs in some patients. Plasma levels may
increase in patients with renal failure; reduction of the dose is recommended in
these patients.
Verapamil
Verapamil’s structure is similar to that of papaverine. Verapamil exhibits significant
first-pass hepatic metabolism, with a bioavailability of only 10% to 20%. One hepatic
metabolite, norverapamil, is active and has a potency approximately 20% of that of
verapamil. Peak plasma levels are reached within 30 minutes. Bioavailability mark-
edly increases in hepatic insufficiency, mandating reduced doses. Intravenous ve-
rapamil achieves hemodynamic and dromotropic effects within minutes, peaking at
15 minutes and lasting up to 6 hours. Accumulation of the drug occurs with pro-
longed half-life during long-term oral administration.
Diltiazem
After oral dosing, the bioavailability of diltiazem is greater than that of verapamil,
varying between 25% and 50%. Peak plasma concentration is achieved between
30 and 60 minutes, and elimination half-life is 2 to 6 hours. Protein binding is
approximately 80%. As with verapamil, hepatic clearance is flow dependent and
major hepatic metabolism occurs with metabolites having 40% of the clinical activ-
ity of diltiazem. Hepatic disease may require decreased dosing, whereas renal failure
does not affect dosing.
Significant Adverse Effects
Most significant adverse hemodynamic effects can be predicted from the calcium
channel blockers’ primary effects of vasodilation and negative inotropy, chronot-
ropy, and dromotropy. Hypotension, heart failure, bradycardia and asystole, and AV
nodal block have occurred with calcium channel blockers. These side effects are more
likely to occur with combination therapy with β-blockers or digoxin, in the presence
of hypokalemia.
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CARDIOVASCULAR PHYSIOLOGY, PHARMACOLOGY, AND MOLECULAR BIOLOGY
BP Classification
Systolic BP
(mm Hg)
Diastolic BP
(mm Hg)
LifestyleModification
m
anagement*
i
nitial Drug
t
herapy
Without CompellingIndication
With CompellingIndication
Normal
and
Encourage
Prehypertension
120 to 139
or
80 to 89
Yes
No antihypertensive drug
indicated
Drug(s) for the compelling
indications
†
Stage 1
hypertension
140 to 159
or
90 to 99
Yes
Thiazide
‑type diuretics for
most; may consider ACEinhibitor, ARB,
β
‑blocker,
CCB, or combination
Drug(s) for the compelling
indications Other antihypertensive drugs
(diuretics, ACE inhibitor, ARB, β‑
blocker, CCB) as needed
Stage 2
hypertension
≥^160
or
Yes
Two
‑drug combination for most (usually thiazide
‑type
diuretic and ACE inhibitoror ARB or
β
‑blocker or CCB)
Drug(s) for the compelling
indications Other antihypertensive drugs
(diuretics, ACE inhibitor, ARB, β‑
blocker, CCB) as needed
ACE = angiotensin
‑converting enzyme; ARB = angiotensin
‑receptor blocker; BP = blood pressure; CCB = calcium channel blocker.
*Treatment determined by highest BP category.†Treat patients with chronic kidney disease or diabetes to BP goal or < 130/80 mm Hg. ‡Initial combination therapy should be used cautiously in those at risk for orthostatic
hypotension.
Adapted with permission from Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC
‑7 Report. JAMA 289:2560, 2003.
Table 8
‑^4
Classification and Management of Blood Pressure for Adults Aged 18 Years or Older
CARDIOVASCULAR PHARMACOLOGY
Drug (Trade Name)
Usual Dose Range (mg/d)
Usual Daily Frequency
Thiazide Diuretics
Chlorothiazide (Diuril) 125 to 500 1 to 2 Chlorthalidone (generic) 12.5 to 25 1 Hydrochlorothiazide (Microzide, HydroDIURIL†)
12.5 to 50 1
Polythiazide (Renese) 2 to 4 1 Indapamide (Lozol†) 1.25 to 2.5 1 Metolazone (Mykrox) 0.5 to 1.0 1 Metolazone (Zaroxolyn) 2.5 to 5 1
Loop Diuretics
Bumetanide (Bumex†^ ) 0.5 to 2 2 Furosemide (Lasix†) 20 to 80 2 Torsemide (Demadex†) 2.5 to 10 1
Potassium-Sparing Diuretics
Amiloride (Midamor†) 5 to 10 1 to 2 Triamterene (Dyrenium) 50 to 100 1 to 2
Aldosterone Receptor Blockers
Eplerenone (Inspra) 50 to 100 1 Spironolactone (Aldactone†)
25 to 50 1
β-Blockers
Atenolol (Tenormin†) 25 to 100 1 Betaxolol (Kerlone†) 5 to 20 1 Bisoprolol (Zebeta†) 2.5 to 10 1 Metoprolol (Lopressor†^ ) 50 to 100 1 to 2 Metoprolol extended release (Toprol XL)
50 to 100 1
Nadolol (Corgard†) 40 to 120 1 Propranolol (Inderal†^ ) 40 to 160 2 Propranolol long‑acting (Inderal LA†)
60 to 180 1
Timolol (Blocadren†) 20 to 40 2
β-Blockers with Intrinsic Sympathomimetic Activity
Acebutolol (Sectral†) 200 to 800 2 Penbutolol (Levatol) 10 to 40 1 Pindolol (generic) 10 to 40 2
Combined α-Blockers and β-Blockers
Carvedilol (Coreg) 12.5 to 50 2 Labetalol (Normodyne, Trandate†^ ) 200 to 800 2
Angiotensin-Converting Enzyme Inhibitors
Benazepril (Lotensin†) 10 to 40 1 Captopril (Capoten†) 25 to 100 2 Enalapril (Vasotec†) 5 to 40 1 to 2 Fosinopril (Monopril) 10 to 40 1 Lisinopril (Prinivil, Zestril†) 10 to 40 1 Moexipril (Univasc) 7.5 to 30 1 Perindopril (Aceon) 4 to 8 1 Quinapril (Accupril) 10 to 40 1
Table 8‑ 5 Oral Antihypertensive Drugs
Table continued on following page
CARDIOVASCULAR PHARMACOLOGY
Combination Type Fixed-Dose Combination (mg) * Trade Name
ACEIs and CCB Amlodipine‑benazepril hydrochloride (2.5/10, 5/10, 5/20, 10/20)
Lotrel
Enalapril‑felodipine (5/5) Lexxel Trandolapril‑verapamil (2/180, 1/240, 2/240, 4/240)
Tarka
ACEIs and diuretics
Benazepril‑hydrochlorothiazide (5/6.25, 10/12.5, 20/12.5, 20/25)
Lotensin HCT
Captopril‑hydrochlorothiazide (25/15, 25/25, 50/15, 50/25)
Capozide
Enalapril‑hydrochlorothiazide (5/12.5, 10/25)
Vaseretic
Fosinopril‑hydrochlorothiazide (10/12.5, 20/12.5)
Monopril/HCT
Lisinopril‑hydrochlorothiazide (10/12.5, 20/12.5, 20/25)
Prinzide, Zestoretic Moexipril‑hydrochlorothiazide (7.5/12.5, 15/25)
Uniretic
Quinapril‑hydrochlorothiazide (10/12.5, 20/12.5, 20/25)
Accuretic
ARBs and diuretics
Candesartan‑hydrochlorothiazide (16/12.5, 32/12.5)
Atacand HCT
Eprosartan‑hydrochlorothiazide (600/12.5, 600/25)
Teveten‑HCT
Irbesartan‑hydrochlorothiazide (150/12.5, 300/12.5)
Avalide
Losartan‑hydrochlorothiazide (50/12.5, 100/25)
Hyzaar
Olmesartan medoxomil‑ hydrochlorothiazide (20/12.5, 40/12.5, 40/25)
Benicar HCT
Telmisartan‑ hydrochlorothiazide (40/12.5, 80/12.5)
Micardis‑HCT
Valsartan‑ hydrochlorothiazide (80/12.5, 160/12.5, 160/25)
Diovan‑HCT
BBs and diuretics
Atenolol‑chlorthalidone (50/25, 100/25)
Tenoretic
Bisoprolol‑hydrochlorothiazide (2.5/6.25, 5/6.25, 10/6.25)
Ziac
Metoprolol‑hydrochlorothiazide (50/25, 100/25)
Lopressor HCT
Nadolol‑bendroflumethiazide (40/5, 80/5)
Corzide
Propranolol LA‑ hydrochlorothiazide (40/25, 80/25)
Inderide LA
Timolol‑hydrochlorothiazide (10/25)
Timolide
Centrally acting drug and diuretic
Methyldopa‑ hydrochlorothiazide (250/15, 250/25, 500/30, 500/50)
Aldoril
Reserpine‑chlorthalidone (0.125/25, 0.25/50)
Demi‑Regroton, Regroton
Table 8‑ 6 Combination Drugs for Hypertension
Table continued on following page
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CARDIOVASCULAR PHYSIOLOGY, PHARMACOLOGY, AND MOLECULAR BIOLOGY
necessitates immediate therapeutic intervention, most often in an intensive care setting,
with intravenous antihypertensive therapy and invasive arterial BP monitoring. In the most
extreme cases of malignant hypertension, severe elevations in BP may be associated with reti-
nal hemorrhages, papilledema, and evidence of encephalopathy, which may include head-
ache, vomiting, seizure, and/or coma. Progressive renal failure and cardiac decompensation
are additional clinical features characteristic of the most severe hypertensive emergencies.
The favored parenteral drug for rapid treatment of hypertensive emergencies remains
sodium nitroprusside (Table 8-7). An NO donor, sodium nitroprusside induces arterial
and venous dilation, providing rapid and predictable reductions in systemic BP. Prolonged
administration of large doses may be associated with cyanide or thiocyanate toxicity; how-
ever, this is rarely a concern in the setting of acute hypertensive emergencies. Although
less potent and predictable than sodium nitroprusside, NTG, another NO donor, may be
preferable in the setting of myocardial ischemia or after coronary artery bypass grafting
(CABG). NTG preferentially dilates venous capacitance beds as opposed to arterioles; how-
ever, rapid onset of tolerance limits the efficacy of sustained infusions to maintain BP con-
trol. Nicardipine, a parenteral dihydropyridine calcium channel blocker, and fenoldopam,
a selective dopamine-1 (D 1 )-receptor antagonist, have been utilized increasingly in select
patient populations after CABG and in the setting of renal insufficiency, respectively.^11
Several drugs remain available for intermittent parenteral administration in the set-
ting of hypertensive emergencies or urgencies. Hydralazine, labetalol, and esmolol provide
additional therapeutic options for intermittent parenteral injection for hypertensive control.
phArmAcOtherApy FOr Acute AnD chrOnic
heArt FAiLure
Chronic heart failure is one major cardiovascular disorder that continues to increase
in incidence and prevalence, both in the United States and worldwide. It affects nearly
5 million persons in the United States, and roughly 550,000 new cases are diagnosed each
year.^12 Currently, 1% of those 50 to 59 years of age and 10% of individuals older than
Combination Type Fixed-Dose Combination (mg) * Trade Name
Reserpine‑chlorothiazide (0.125/250, 0.25/500)
Diupres
Reserpine‑ hydrochlorothiazide (0.125/25, 0.125/50)
Hydropres
Diuretic and diuretic
Amiloride‑ hydrochlorothiazide (5/50)
Moduretic
Spironolactone‑ hydrochlorothiazide (25/25, 50/50)
Aldactazide
Triamterene‑hydrochlorothiazide (37.5/25, 75/50)
Dyazide, Maxzide
BB = β‑blocker; ACEI = angiotensin‑converting enzyme inhibitor; ARB = angiotensin‑receptor blocker; CCB = calcium channel blocker. *Some drug combinations are available in multiple fixed doses. Each drug dose is reported in milligrams. Adapted with permission from Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pres‑ sure: The JNC‑7 Report. JAMA 289:2560, 2003.
Table 8‑ 6 Combination Drugs for Hypertension (Continued)
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CARDIOVASCULAR PHYSIOLOGY, PHARMACOLOGY, AND MOLECULAR BIOLOGY
Drug
Dose
Onsetof Action
Durationof Action
Adverse Effects
†^
Special Indications
Vasodilators Sodium
nitroprusside
0.25 to 10
μ
g/
kg/min as IVinfusion
Immediate
1 to 2 min
Nausea, vomiting,
muscle twitching,sweating, thiocyanateand cyanide intoxication
Most hypertensive
emergencies; cautionwith high intracranialpressure or azotemia
Nicardipine
hydrochloride
5 to 15 mg/hr IV
5 to 10 min
15 to 30 min,
may exceed4 hr
Tachycardia, headache,
flushing, local phlebitis
Most hypertensive
emergencies exceptacute heart failure;caution with coronaryischemia
Fenoldopam
mesylate
0.1 to 0.
μ
g/kg/
min IV infusion
<5 min
30 min
Tachycardia, headache,
nausea, flushing
Most hypertensive
emergencies;caution with glaucoma
Nitroglycerin
5 to 100
μ
g/min
as IV infusion
2 to 5 min
5 to 10 min
Headache, vomiting,
methemoglobinemia,tolerance withprolonged use
Coronary ischemia
Enalaprilat
1.25 to 5 mg
every 6 hr IV
15 to 30 min
6 to 12 hr
Precipitous fall in
pressure in high
renin states, variableresponse
Acute left ventricular
failure; avoid inacute myocardialinfarction
Table 8
‑^7
Parenteral Drugs for Treatment of Hypertensive Emergencies
CARDIOVASCULAR PHARMACOLOGY
Reproduced with permission from Chobanian AV, Bakris GL, Black HR, et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure. Hypertension 42:1206, 2003.
