CHAPTER 9 Adrenoceptor Agonists & Sympathomimetic Drugs 147

SUMMARY Sympathomimetic Drugs

Clinical Pharmacokinetics,
Subclass Mechanism of Action Effects Applications Toxicities, Interactions

`1 AGONISTS
• Midodrine Activates phospholipase C, Vascular smooth muscle con- Orthostatic hypoten- Oral • prodrug converted to
resulting in increased intracellu- traction increasing blood sion active drug with a 1-h peak
lar calcium and vasoconstriction pressure (BP) effect • Toxicity: Supine hyperten-
sion, piloerection (goose bumps),
and urinary retention

• Phenylephrine: Can be used IV for short-term maintenance of BP in acute hypotension and intranasally to produce local vasoconstriction as a decongestant

`2 AGONISTS
• Clonidine Inhibits adenylyl cyclase and Vasoconstriction is masked Hypertension Oral • transdermal • peak effect
interacts with other intracellular by central sympatholytic 1–3 h • half-life of oral drug
pathways effect, which lowers BP ~12 h • produces dry mouth and
sedation

• a-Methyldopa, guanfacine, and guanabenz: Also used as central sympatholytics

• Dexmedetomidine: Prominent sedative effects and used in anesthesia
• Tizanidine: Used as a muscle relaxant
• Apraclonidine and brimonidine: Used in glaucoma to reduce intraocular pressure

a1 AGONISTS
1
• Dobutamine Activates adenylyl cyclase, Positive inotropic effect Cardiogenic shock, IV • requires dose titration to
increasing myocardial acute heart failure desired effect
contractility

B2 AGONISTS
• Albuterol Activates adenylyl cyclase Bronchial smooth muscle Asthma Inhalation • duration 4–6 h
dilation • Toxicity: Tremor, tachycardia

• See other b2 agonists in Chapter 20

DOPAMINE
D1 Agonists
• Fenoldopam Activates adenylyl cyclase Vascular smooth muscle Hypertension Requires dose titration to
relaxation desired effect

D2 Agonists
• Bromocriptine Inhibits adenylyl cyclase and Mimics dopamine actions in Parkinson’s disease, Oral • Toxicity: Nausea, headache,
interacts with other intracellular the central nervous system prolactinemia orthostatic hypotension
pathways

• See other D2 agonists in Chapters 28 and 37

1
Dobutamine has other actions in addition to b1-agonist effect. See text for details.
148 SECTION II Autonomic Drugs

P R E P A R A T I O N S A V A I L A B L E 1

Amphetamine, racemic mixture (generic) Isoproterenol (generic, Isuprel)

(attention deficit hyperactivity disorder [ADHD], narcolepsy) (bradycardia)
Oral: 5, 10 mg tablets Parenteral: 1:5000 (0.2 mg/mL), 1:50,000 (0.02 mg/mL) for injection
Oral (Adderall): 1:1:1:1 mixtures of amphetamine sulfate, amphet- Metaraminol (Aramine)
amine aspartate, dextroamphetamine sulfate, and dextroamphet- (hypotension)
amine saccharate, formulated to contain a total of 5, 7.5, 10, 12.5, Parenteral: 10 mg/mL for injection
15, 20, or 30 mg in tablets; or 10, 20, or 30 mg in capsules
Methamphetamine (Desoxyn)
Apraclonidine (Iopidine) (ADHD)
(glaucoma) Oral: 5 mg tablets
Topical: 0.5, 1% ophthalmic solutions
Methylphenidate (generic, Ritalin, Ritalin-SR)
Armodafinil (Nuvigil) (ADHD, narcolepsy)
(narcolepsy) Oral: 5, 10, 20 mg tablets
Oral: 50, 150, 250 mg tablets Oral sustained release: 10, 18, 20, 27, 36, 54 mg tablets; 20, 30,
Brimonidine (Alphagan) 40 mg capsules
(glaucoma) Midodrine (ProAmatine)
Topical: 0.15, 0.2% ophthalmic solution (hypotension)
Dexmedetomidine (Precedex) Oral: 2.5, 5, 10 mg tablets
(sedation) Modafinil (Provigil)
Parenteral: 100 mcg/mL (narcolepsy)
Dexmethylphenidate (Focalin) Oral: 100, 200 mg tablets
(ADHD) Naphazoline (generic, Privine)
Oral: 2.5, 5, 10 mg tablets (decongestant)
Oral sustained release: 5, 10, 15, 20, 30 mg capsules Nasal: 0.05% drops and spray
Dextroamphetamine (generic, Dexedrine) Ophthalmic: 0.012, 0.02, 0.03, 0.1% drops
(ADHD, narcolepsy) Norepinephrine (generic, Levophed)
Oral: 5, 10 mg tablets (hypotension)
Oral sustained release: 5, 10, 15 mg capsules Parenteral: 1 mg/mL for injection
Oral mixtures with amphetamine: see Amphetamine (Adderall)
Oxymetazoline (generic, Afrin, Neo-Synephrine 12 Hour, Visine LR)
Dobutamine (generic, Dobutrex) (decongestant)
(hypotension) Nasal: 0.05% spray
Parenteral: 12.5 mg/mL in 20 mL vials for injection Ophthalmic: 0.025% drops
Dopamine (generic, Intropin) Phenylephrine (generic, Neo-Synephrine)
(hypotension) (hypotension, decongestant)
Parenteral: 40, 80, 160 mg/mL for injection; 80, 160, 320 mg/100 Oral: 10 mg chewable tablets
mL in 5% D/W for injection Parenteral: 10 mg/mL for injection
Ephedrine (generic) Nasal: 0.125, 0.16, 0.25, 0.5, 1% drops and spray
(hypotension, asthma) Ophthalmic: 0.12, 2.5, 10% solution
Oral: 25 mg capsules Pseudoephedrine (generic, Sudafed)
Parenteral: 50 mg/mL for injection (decongestant)
Epinephrine (generic, Adrenalin Chloride, others) Oral: 30, 60 mg tablets; 30, 60 mg capsules; 15, 30 mg/5 mL syrups;
(anaphylaxis, hypotension, asthma) 7.5 mg/0.8 mL drops
Parenteral: 1:1000 (1 mg/mL), 1:2000 (0.5 mg/mL), 1:10,000 (0.1 Oral extended release: 120, 240 mg tablets, capsules
mg/mL), 1:100,000 (0.01 mg/mL) for injection Tetrahydrozoline (generic, Visine)
Parenteral autoinjector (EpiPen): 1:1000 (1 mg/mL), 1:2000 (0.5 mg/ (decongestant)
mL) Nasal: 0.05, 0.1% drops
Ophthalmic: 0.1, 0.5, 1, 2% drops Ophthalmic: 0.05% drops
Nasal: 0.1% drops and spray
Tizanidine (Zanaflex)
Aerosol for bronchospasm (Primatene Mist, Bronkaid Mist): 0.22
(muscle relaxant)
mg/spray
Oral: 2, 4, 6 mg capsules; 2, 4 mg tablets
Solution for nebulizer aerosol: 1:100
Xylometazoline (generic, Otrivin)
Fenoldopam (Corlopam)
(decongestant)
(hypertension)
Nasal: 0.05, 0.1% drops
Parenteral: 10 mg/mL for IV infusion
Hydroxyamphetamine (Paremyd)
(mydriatic)
Ophthalmic: 1% drops (includes 0.25% tropicamide)

1
Primary clinical indications are given in parentheses. α2 agonists used in hypertension are listed in Chapter 11. β2 Agonists used in asthma are listed in
Chapter 20. Norepinephrine transporter inhibitors are listed in Chapter 30. The primary clinical indications are given in parentheses.
 CHAPTER 10 Adrenoceptor Antagonist Drugs 165

stimulates the heart via glucagon receptors, which are not blocked rather than abrupt cessation of dosage when these drugs are dis-
by β antagonists), but neither of these methods is without hazard. continued, especially drugs with short half-lives, such as propra-
A very small dose of a β antagonist (eg, 10 mg of propranolol) may nolol and metoprolol.
provoke severe cardiac failure in a susceptible individual. Beta The incidence of hypoglycemic episodes exacerbated by
blockers may interact with the calcium antagonist verapamil; β-blocking agents in diabetics is unknown. Nevertheless, it is
severe hypotension, bradycardia, heart failure, and cardiac con- inadvisable to use β antagonists in insulin-dependent diabetic
duction abnormalities have all been described. These adverse patients who are subject to frequent hypoglycemic reactions if
effects may even arise in susceptible patients taking a topical (oph- alternative therapies are available. Beta1-selective antagonists offer
thalmic) β blocker and oral verapamil. some advantage in these patients, since the rate of recovery from
Patients with ischemic heart disease or renovascular hyperten- hypoglycemia may be faster compared with that in diabetics
sion may be at increased risk if β blockade is suddenly interrupted. receiving nonselective β-adrenoceptor antagonists. There is con-
The mechanism of this effect might involve up-regulation of the siderable potential benefit from these drugs in diabetics after a
number of β receptors. Until better evidence is available regarding myocardial infarction, so the balance of risk versus benefit must be
the magnitude of the risk, prudence dictates the gradual tapering evaluated in individual patients.

SUMMARY Sympathetic Antagonists

Pharmacokinetics,
Subclass Mechanism of Action Effects Clinical Applications Toxicities, Interactions

ALPHA-ADRENOCEPTOR ANTAGONISTS
• Phenoxybenzamine Irreversibly blocks α1 and α2• Lowers blood pressure (BP) • Pheochromocytoma • high Irreversible blocker • duration
indirect baroreflex activation heart rate (HR) rises due to catecholamine states > 1 day • Toxicity: Orthostatic
baroreflex activation hypotension • tachycardia
• myocardial ischemia
• Phentolamine Reversibly blocks α1 and α2 Blocks α-mediated vasocon- Pheochromocytoma Half-life ~45 min after
striction, lowers BP, increases IV injection
HR (baroreflex)

• Prazosin Block α1, but not α2 Lower BP Hypertension • benign pro- Larger depressor effect with first
• Doxazosin static hyperplasia dose may cause orthostatic
hypotension
• Terazosin

• Tamsulosin Tamsulosin is slightly selective α1A Blockade may relax pros- Benign prostatic hyperpla- Orthostatic hypotension may be
for α1A tatic smooth muscles more sia less common with this subtype
than vascular smooth muscle

• Yohimbine Blocks α2• elicits increased cen- Raises BP and HR Male erectile dysfunction • May cause anxiety • excess pres-
tral sympathetic activity • hypotension sor effect if norepinephrine
increased norepinephrine transporter is blocked
release

• Labetalol (see β > α1 block Lowers BP with limited HR Hypertension Oral, parenteral • Toxicity: Less
carvedilol section below) increase tachycardia than other α1 agents

BETA-ADRENOCEPTOR ANTAGONISTS
• Propranolol Block β1 and β2 Lower HR and BP • reduce Hypertension • angina pec- Oral, parenteral • Toxicity:
• Nadolol renin toris • arrhythmias • Bradycardia • worsened asthma •
migraine • hyperthyroidism fatigue • vivid dreams • cold
• Timolol hands

• Metoprolol Block β1 > β2 Lower HR and BP • reduce Angina pectoris • hyperten- Toxicity: Bradycardia • fatigue •
• Atenolol renin • may be safer in sion • arrhythmias vivid dreams • cold hands
asthma
• Alprenolol
• Betaxolol
• Nebivolol

(continued )
166 SECTION II Autonomic Drugs

Pharmacokinetics,
Subclass Mechanism of Action Effects Clinical Applications Toxicities, Interactions
1
• Butoxamine Blocks β2 > β1 Increases peripheral resis- No clinical indication Toxicity: Asthma provocation
tance

• Pindolol β1, β2, with intrinsic sympath- Lowers BP • modestly lower Hypertension • arrhythmias Oral • Toxicity: Fatigue • vivid
• Acebutolol omimetic (partial agonist) HR • migraine • may avoid dreams • cold hands
effect worsening of bradycardia
• Carteolol
1
• Bopindolol
• Oxprenolol1
• Celiprolol1
• Penbutolol

• Carvedilol β > α1 block Heart failure Oral, long half-life • Toxicity:

• Medroxalol
1 Fatigue
• Bucindolol1
(see labetalol above)

• Esmolol β1 > β2 Very brief cardiac β blockade Rapid control of BP and Parenteral only • half-life ~ 10
arrhythmias, thyrotoxicosis min • Toxicity: Bradycardia •
and myocardial ischemia hypotension
intraoperatively

TYROSINE HYDROXYLASE INHIBITOR

• Metyrosine Blocks tyrosine hydroxylase • Lowers BP • in central ner- Pheochromocytoma Toxicity: Extrapyramidal symp-
reduces synthesis of dopamine, vous system may elicit toms • orthostatic hypotension
norepinephrine, and extrapyramidal effects (due • crystalluria
epinephrine to low dopamine)
1
Not available in the USA.

P R E P A R A T I O N S A V A I L A B L E *

ALPHA BLOCKERS BETA BLOCKERS

Alfuzosin (Uroxatral) Acebutolol (generic, Sectral)
Oral: 10 mg tablets (extended release) Oral: 200, 400 mg capsules
Doxazosin (generic, Cardura) Atenolol (generic, Tenormin)
Oral: 1, 2, 4, 8 mg tablets; 4, 8 mg extended-release tablets Oral: 25, 50, 100 mg tablets
Phenoxybenzamine (Dibenzyline) Parenteral: 0.5 mg/mL for IV injection
Oral: 10 mg capsules Betaxolol
Phentolamine (generic) Oral (Kerlone): 10, 20 mg tablets
Parenteral: 5 mg/vial for injection Ophthalmic (generic, Betoptic): 0.25%, 0.5% drops
Prazosin (generic, Minipress) Bisoprolol (generic, Zebeta)
Oral: 1, 2, 5 mg capsules Oral: 5, 10 mg tablets
Silodosin (Rapaflow) Carteolol
Oral: 4, 8 mg capsules Oral (Cartrol): 2.5, 5 mg tablets
Ophthalmic (generic, Ocupress): 1% drops
Tamsulosin (Flomax)
Oral: 0.4 mg capsule Carvedilol (Coreg)
Oral: 3.125, 6.25, 12.5, 25 mg tablets; 10, 20, 40, 80 mg extended-
Terazosin (generic, Hytrin) release capsules
Oral: 1, 2, 5, 10 mg tablets, capsules
Esmolol (Brevibloc)
Tolazoline (Priscoline) Parenteral: 10 mg/mL for IV injection; 250 mg/mL for IV infusion
Parenteral: 25 mg/mL for injection

∗
In the USA
 CHAPTER 10 Adrenoceptor Antagonist Drugs 167

Labetalol (generic, Normodyne, Trandate) Pindolol (generic, Visken)

Oral: 100, 200, 300 mg tablets Oral: 5, 10 mg tablets
Parenteral: 5 mg/mL for injection Propranolol (generic, Inderal)
Levobunolol (Betagan Liquifilm, others) Oral: 10, 20, 40, 60, 80, 90 mg tablets; 4, 8, 80 mg/mL solutions
Ophthalmic: 0.25, 0.5% drops Oral sustained release: 60, 80, 120, 160 mg capsules
Metipranolol (Optipranolol) Parenteral: 1 mg/mL for injection
Ophthalmic: 0.3% drops Sotalol (generic, Betapace)
Metoprolol (generic, Lopressor, Toprol) Oral: 80, 120, 160, 240 mg tablets
Oral: 50, 100 mg tablets Timolol
Oral sustained release: 25, 50, 100, 200 mg tablets Oral (generic, Blocadren): 5, 10, 20 mg tablets
Parenteral: 1 mg/mL for injection Ophthalmic (generic, Timoptic): 0.25, 0.5% drops, gel
Nadolol (generic, Corgard)
Oral: 20, 40, 80, 120, 160 mg tablets
Nebivolol (Bystolic) TYROSINE HYDROXYLASE INHIBITOR
Oral: 2.5, 5, 10 mg tablets Metyrosine (Demser)
Penbutolol (Levatol) Oral: 250 mg capsules
Oral: 20 mg tablets

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Ambrosio G et al: β-Blockade with nebivolol for prevention of acute ischaemic
Lanfear et al: β2-Adrenergic receptor genotype and survival among patients receiv-
events in elderly patients with heart failure. Heart 2011;97:209.
ing β-blocker therapy after an acute coronary syndrome. JAMA
Bell CM et al. Association between tamsulosin and serious ophthalmic adverse 2005;294:1526.
events in older men following cataract surgery. JAMA 2009;301:1991.
Lepor H et al: The efficacy of terazosin, finasteride, or both in benign prostate
Blakely RD, DeFelice LJ: All aglow about presynaptic receptor regulation of neu- hyperplasia. N Engl J Med 1996;335:533.
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Maggio PM, Taheri PA: Perioperative issues: Myocardial ischemia and protection–
Blaufarb I, Pfeifer TM, Frishman WH: Beta-blockers: Drug interactions of clinical beta-blockade. Surg Clin North Am 2005;85:1091.
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Marquis RE, Whitson JT: Management of glaucoma: Focus on pharmacological
Boyer TD: Primary prophylaxis for variceal bleeding: Are we there yet? therapy. Drugs Aging 2005;22:1.
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McVary KT: Alfuzosin for symptomatic benign prostatic hyperplasia: Long-term
Berruezo A, Brugada J: Beta blockers: Is the reduction of sudden death related to experience. J Urol 2006;175:35.
pure electrophysiologic effects? Cardiovasc Drug Ther 2008;22:163.
Nickerson M: The pharmacology of adrenergic blockade. Pharmacol Rev
Brantigan CO, Brantigan TA, Joseph N: Effect of beta blockade and beta stimula- 1949;1:27.
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Nickel JC, Sander S, Moon TD: A meta-analysis of the vascular-related safety
Bristow M: Antiadrenergic therapy of chronic heart failure: Surprises and new profile and efficacy of alpha-adrenergic blockers for symptoms related to
opportunities. Circulation 2003;107:1100. benign prostatic hyperplasia. Int J Clin Pract 2008;62:1547.
Cheng J, Kamiya K, Kodama I: Carvedilol: Molecular and cellular basis for its Perez DM: Structure-function of alpha1-adrenergic receptors. Biochem Pharmacol
multifaceted therapeutic potential. Cardiovasc Drug Rev 2001;19:152. 2007;73:1051.
Cleland JG: Beta-blockers for heart failure: Why, which, when, and where. Med Pojoga L et al: Beta-2 adrenergic receptor diplotype defines a subset of salt-sensitive
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Eisenhofer G et al: Current progress and future challenges in the biochemical Roehrborn CG, Schwinn DA: Alpha1-adrenergic receptors and their inhibitors in
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Ellison KE, Gandhi G: Optimising the use of beta-adrenoceptor antagonists in Schwinn DA, Roehrborn CG. Alpha1-adrenoceptor subtypes and lower urinary
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Fitzgerald JD: Do partial agonist beta-blockers have improved clinical utility? Tank J et al: Yohimbine attenuates baroreflex-mediated bradycardia in humans.
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Freemantle N et al: Beta blockade after myocardial infarction: Systematic review Wespes E: Intracavernous injection as an option for aging men with erectile dys-
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172 SECTION III Cardiovascular-Renal Drugs

Vasomotor center
Methyldopa
Clonidine
Guanabenz
Guanfacine

Sympathetic nerve terminals

Guanethidine
Guanadrel
Reserpine

Sympathetic ganglia
β-Receptors of heart Trimethaphan
Propranolol and
other β-blockers

Angiotensin α-Receptors of vessels Vascular smooth muscle

receptors of vessels Prazosin and Hydralazine Verapamil and other
Losartan and other α1-blockers Minoxidil calcium channel
other angiotensin Nitroprusside blockers
receptor blockers Diazoxide Fenoldopam

β-Receptors of juxtaglomerular
Kidney tubules cells that release renin
Thiazides, etc Propranolol and
other β-blockers

Angiotensin-
converting
enzyme
Renin
Angiotensin II Angiotensin I Angiotensinogen

Aliskiren
Captopril and
other ACE inhibitors

FIGURE 11–3 Sites of action of the major classes of antihypertensive drugs.

2. Sympathoplegic agents, which lower blood pressure by reduc- increased efficacy and, in some cases, decreased toxicity. (See Box:
ing peripheral vascular resistance, inhibiting cardiac function, Resistant Hypertension & Polypharmacy.)
and increasing venous pooling in capacitance vessels. (The lat-
ter two effects reduce cardiac output.) These agents are further
subdivided according to their putative sites of action in the DRUGS THAT ALTER SODIUM &
sympathetic reflex arc (see below).
3. Direct vasodilators, which reduce pressure by relaxing vascu-
WATER BALANCE
lar smooth muscle, thus dilating resistance vessels and—to Dietary sodium restriction has been known for many years to decrease
varying degrees—increasing capacitance as well. blood pressure in hypertensive patients. With the advent of diuretics,
4. Agents that block production or action of angiotensin and sodium restriction was thought to be less important. However, there
thereby reduce peripheral vascular resistance and (potentially) is now general agreement that dietary control of blood pressure is a
blood volume.
relatively nontoxic therapeutic measure and may even be preventive.
The fact that these drug groups act by different mechanisms Even modest dietary sodium restriction lowers blood pressure (though
permits the combination of drugs from two or more groups with to varying extents) in many hypertensive persons.
 CHAPTER 11 Antihypertensive Agents 171

resistance. For example, endothelin-1 (see Chapter 17) constricts B. Renal Response to Decreased Blood Pressure
and nitric oxide (see Chapter 19) dilates blood vessels. By controlling blood volume, the kidney is primarily responsible
Blood pressure in a hypertensive patient is controlled by the for long-term blood pressure control. A reduction in renal perfu-
same mechanisms that are operative in normotensive subjects. sion pressure causes intrarenal redistribution of blood flow and
Regulation of blood pressure in hypertensive patients differs from increased reabsorption of salt and water. In addition, decreased
healthy patients in that the baroreceptors and the renal blood pressure in renal arterioles as well as sympathetic neural activity
volume-pressure control systems appear to be “set” at a higher (via β adrenoceptors) stimulates production of renin, which
level of blood pressure. All antihypertensive drugs act by interfer- increases production of angiotensin II (see Figure 11–1 and
ing with these normal mechanisms, which are reviewed below. Chapter 17). Angiotensin II causes (1) direct constriction of resis-
tance vessels and (2) stimulation of aldosterone synthesis in the
A. Postural Baroreflex adrenal cortex, which increases renal sodium absorption and intra-
Baroreflexes are responsible for rapid, moment-to-moment adjust- vascular blood volume. Vasopressin released from the posterior
ments in blood pressure, such as in transition from a reclining to pituitary gland also plays a role in maintenance of blood pressure
an upright posture (Figure 11–2). Central sympathetic neurons through its ability to regulate water reabsorption by the kidney
arising from the vasomotor area of the medulla are tonically active. (see Chapters 15 and 17).
Carotid baroreceptors are stimulated by the stretch of the vessel
walls brought about by the internal pressure (arterial blood pres-
sure). Baroreceptor activation inhibits central sympathetic dis-
charge. Conversely, reduction in stretch results in a reduction in
■ BASIC PHARMACOLOGY OF
baroreceptor activity. Thus, in the case of a transition to upright ANTIHYPERTENSIVE AGENTS
posture, baroreceptors sense the reduction in arterial pressure that
results from pooling of blood in the veins below the level of the All antihypertensive agents act at one or more of the four ana-
heart as reduced wall stretch, and sympathetic discharge is disin- tomic control sites depicted in Figure 11–1 and produce their
hibited. The reflex increase in sympathetic outflow acts through effects by interfering with normal mechanisms of blood pressure
nerve endings to increase peripheral vascular resistance (constric- regulation. A useful classification of these agents categorizes them
tion of arterioles) and cardiac output (direct stimulation of the according to the principal regulatory site or mechanism on which
heart and constriction of capacitance vessels, which increases they act (Figure 11–3). Because of their common mechanisms of
venous return to the heart), thereby restoring normal blood pres- action, drugs within each category tend to produce a similar spec-
sure. The same baroreflex acts in response to any event that lowers trum of toxicities. The categories include the following:
arterial pressure, including a primary reduction in peripheral vas-
cular resistance (eg, caused by a vasodilating agent) or a reduction 1. Diuretics, which lower blood pressure by depleting the body
in intravascular volume (eg, due to hemorrhage or to loss of salt of sodium and reducing blood volume and perhaps by other
and water via the kidney). mechanisms.

IC
2. Nucleus of the tractus solitarius
Brain- CP Sensory fiber
stem 1. Baroreceptor
in carotid sinus
Inhibitory interneurons
X
XI

XII Arterial blood pressure

3. Vasomotor
center
Motor fibers

5 6
Spinal
cord
4. Autonomic 5. Sympathetic
ganglion nerve ending 6. α or β
receptor

FIGURE 11–2 Baroreceptor reflex arc.

172 SECTION III Cardiovascular-Renal Drugs

Vasomotor center
Methyldopa
Clonidine
Guanabenz
Guanfacine

Sympathetic nerve terminals

Guanethidine
Guanadrel
Reserpine

Sympathetic ganglia
β-Receptors of heart Trimethaphan
Propranolol and
other β-blockers

Angiotensin α-Receptors of vessels Vascular smooth muscle

receptors of vessels Prazosin and Hydralazine Verapamil and other
Losartan and other α1-blockers Minoxidil calcium channel
other angiotensin Nitroprusside blockers
receptor blockers Diazoxide Fenoldopam

β-Receptors of juxtaglomerular
Kidney tubules cells that release renin
Thiazides, etc Propranolol and
other β-blockers

Angiotensin-
converting
enzyme
Renin
Angiotensin II Angiotensin I Angiotensinogen

Aliskiren
Captopril and
other ACE inhibitors

FIGURE 11–3 Sites of action of the major classes of antihypertensive drugs.

2. Sympathoplegic agents, which lower blood pressure by reduc- increased efficacy and, in some cases, decreased toxicity. (See Box:
ing peripheral vascular resistance, inhibiting cardiac function, Resistant Hypertension & Polypharmacy.)
and increasing venous pooling in capacitance vessels. (The lat-
ter two effects reduce cardiac output.) These agents are further
subdivided according to their putative sites of action in the DRUGS THAT ALTER SODIUM &
sympathetic reflex arc (see below).
3. Direct vasodilators, which reduce pressure by relaxing vascu-
WATER BALANCE
lar smooth muscle, thus dilating resistance vessels and—to Dietary sodium restriction has been known for many years to decrease
varying degrees—increasing capacitance as well. blood pressure in hypertensive patients. With the advent of diuretics,
4. Agents that block production or action of angiotensin and sodium restriction was thought to be less important. However, there
thereby reduce peripheral vascular resistance and (potentially) is now general agreement that dietary control of blood pressure is a
blood volume.
relatively nontoxic therapeutic measure and may even be preventive.
The fact that these drug groups act by different mechanisms Even modest dietary sodium restriction lowers blood pressure (though
permits the combination of drugs from two or more groups with to varying extents) in many hypertensive persons.
174 SECTION III Cardiovascular-Renal Drugs

Vasodilator
drugs

Decreased
systemic
vascular
resistance

Decreased 1 Decreased Increased

renal arterial sympathetic
sodium pressure nervous system
excretion outflow
2
Increased
renin
1 release
2
2

Increased Increased Increased Decreased

Increased Increased systemic heart cardiac venous
aldosterone angiotensin II vascular rate contractility capacitance
resistance

Sodium retention, Increased Increased

increased plasma arterial cardiac
volume pressure output

FIGURE 11–4 Compensatory responses to vasodilators; basis for combination therapy with β blockers and diuretics. 1 Effect blocked by
diuretics. 2 Effect blocked by β blockers.

doses (up to 100–200 mg of hydrochlorothiazide), when used hyperkalemia, particularly in patients with renal insufficiency and
as a single agent, lower doses (25–50 mg) exert as much anti- those taking ACE inhibitors or angiotensin receptor blockers;
hypertensive effect as do higher doses. In contrast to thiazides, spironolactone (a steroid) is associated with gynecomastia.
the blood pressure response to loop diuretics continues to
increase at doses many times greater than the usual therapeutic
dose. DRUGS THAT ALTER SYMPATHETIC
NERVOUS SYSTEM FUNCTION
Toxicity of Diuretics In many patients, hypertension is initiated and sustained at least in
In the treatment of hypertension, the most common adverse effect part by sympathetic neural activation. In patients with moderate to
of diuretics (except for potassium-sparing diuretics) is potassium severe hypertension, most effective drug regimens include an
depletion. Although mild degrees of hypokalemia are tolerated well agent that inhibits function of the sympathetic nervous system.
by many patients, hypokalemia may be hazardous in persons taking Drugs in this group are classified according to the site at which
digitalis, those who have chronic arrhythmias, or those with acute they impair the sympathetic reflex arc (Figure 11–2). This neuro-
myocardial infarction or left ventricular dysfunction. Potassium anatomic classification explains prominent differences in cardiovas-
loss is coupled to reabsorption of sodium, and restriction of dietary cular effects of drugs and allows the clinician to predict interactions
sodium intake therefore minimizes potassium loss. Diuretics may of these drugs with one another and with other drugs.
also cause magnesium depletion, impair glucose tolerance, and The subclasses of sympathoplegic drugs exhibit different pat-
increase serum lipid concentrations. Diuretics increase uric acid terns of potential toxicity. Drugs that lower blood pressure by
concentrations and may precipitate gout. The use of low doses actions on the central nervous system tend to cause sedation and
minimizes these adverse metabolic effects without impairing the mental depression and may produce disturbances of sleep, includ-
antihypertensive action. Potassium-sparing diuretics may produce ing nightmares. Drugs that act by inhibiting transmission through
 CHAPTER 11 Antihypertensive Agents 175

TABLE 11–2 Pharmacokinetic characteristics and dosage of selected oral antihypertensive drugs.
Bioavailability Suggested Usual Maintenance Reduction of Dosage Required in
Drug Half-life (h) (percent) Initial Dose Dose Range Moderate Renal Insufficiency1

Amlodipine 35 65 2.5 mg/d 5–10 mg/d No

Atenolol 6 60 50 mg/d 50–100 mg/d Yes
2
Benazepril 0.6 35 5–10 mg/d 20–40 mg/d Yes
Captopril 2.2 65 50–75 mg/d 75–150 mg/d Yes
Clonidine 8–12 95 0.2 mg/d 0.2–1.2 mg/d Yes
Diltiazem 3.5 40 120–140 mg/d 240–360 mg/d No
Guanethidine 120 3–50 10 mg/d 25–50 mg/d Possible
Hydralazine 1.5–3 25 40 mg/d 40–200 mg/d No
Hydrochlorothiazide 12 70 25 mg/d 25–50 mg/d No
Lisinopril 12 25 10 mg/d 10–80 mg/d Yes
3
Losartan 1–2 36 50 mg/d 25–100 mg/d No
Methyldopa 2 25 1 g/d 1–2 g/d No
Metoprolol 3–7 40 50–100 mg/d 200–400 mg/d No
Minoxidil 4 90 5–10 mg/d 40 mg/d No
4
Nebivolol 12 Nd 5 mg/d 10–40 mg/d No
Nifedipine 2 50 30 mg/d 30–60 mg/d No
Prazosin 3–4 70 3 mg/d 10–30 mg/d No
Propranolol 3–5 25 80 mg/d 80–480 mg/d No
Reserpine 24–48 50 0.25 mg/d 0.25 mg/d No
Verapamil 4–6 22 180 mg/d 240–480 mg/d No
1
Creatinine clearance ≥ 30 mL/min. Many of these drugs do require dosage adjustment if creatinine clearance falls below 30 mL/min.
2
The active metabolite of benazepril has a half-life of 10 hours.
3
The active metabolite of losartan has a half-life of 3–4 hours.
4
Nd, not determined.

autonomic ganglia (ganglion blockers) produce toxicity from CENTRALLY ACTING

inhibition of parasympathetic regulation, in addition to profound
sympathetic blockade and are no longer used. Drugs that act
SYMPATHOPLEGIC DRUGS
chiefly by reducing release of norepinephrine from sympathetic Centrally acting sympathoplegic drugs were once widely used in
nerve endings cause effects that are similar to those of surgical the treatment of hypertension. With the exception of clonidine,
sympathectomy, including inhibition of ejaculation, and hypoten- these drugs are rarely used today.
sion that is increased by upright posture and after exercise. Drugs
that block postsynaptic adrenoceptors produce a more selective
spectrum of effects depending on the class of receptor to which Mechanisms & Sites of Action
they bind. Although not discussed in this chapter, it should be These agents reduce sympathetic outflow from vasomotor centers
noted that renal sympathetic denervation is effective in lowering in the brainstem but allow these centers to retain or even increase
blood pressure in patients with hypertension resistant to antihyper- their sensitivity to baroreceptor control. Accordingly, the antihy-
tensive drugs. pertensive and toxic actions of these drugs are generally less depen-
Finally, one should note that all of the agents that lower blood dent on posture than are the effects of drugs that act directly on
pressure by altering sympathetic function can elicit compensatory peripheral sympathetic neurons.
effects through mechanisms that are not dependent on adrenergic Methyldopa (L-α-methyl-3,4-dihydroxyphenylalanine) is an
nerves. Thus, the antihypertensive effect of any of these agents analog of L-dopa and is converted to α-methyldopamine and
used alone may be limited by retention of sodium by the kidney α-methylnorepinephrine; this pathway directly parallels the synthesis
and expansion of blood volume. For this reason, sympathoplegic of norepinephrine from dopa illustrated in Figure 6–5. Alpha-
antihypertensive drugs are most effective when used concomi- methylnorepinephrine is stored in adrenergic nerve vesicles, where it
tantly with a diuretic. stoichiometrically replaces norepinephrine, and is released by nerve
184 SECTION III Cardiovascular-Renal Drugs

Angiotensinogen Kininogen

Renin Kallikrein
–
Aliskiren Increased
prostaglandin
Angiotensin I Bradykinin synthesis

Angiotensin-converting enzyme
(kininase II)

–
Angiotensin II Inactive
ACE metabolites
inhibitors
ARBs
– –
Vasoconstriction Aldosterone Vasodilation
secretion
Spironolactone,
eplerenone
–

Increased peripheral Increased sodium Decreased peripheral

vascular resistance and water retention vascular resistance

Increased Decreased
blood pressure blood pressure

FIGURE 11–5 Sites of action of drugs that interfere with the renin-angiotensin-aldosterone system. ACE, angiotensin-converting enzyme;
ARBs, angiotensin receptor blockers.

A parallel system for angiotensin generation exists in several bradykinin, a potent vasodilator, which works at least in part by
other tissues (eg, heart) and may be responsible for trophic stimulating release of nitric oxide and prostacyclin. The hypoten-
changes such as cardiac hypertrophy. The converting enzyme sive activity of captopril results both from an inhibitory action on
involved in tissue angiotensin II synthesis is also inhibited by ACE the renin-angiotensin system and a stimulating action on the
inhibitors. kallikrein-kinin system (Figure 11–5). The latter mechanism has
Three classes of drugs act specifically on the renin-angiotensin been demonstrated by showing that a bradykinin receptor antag-
system: ACE inhibitors; the competitive inhibitors of angiotensin onist, icatibant (see Chapter 17), blunts the blood pressure-
at its receptors, including losartan and other nonpeptide antago- lowering effect of captopril.
nists; and aliskiren, an orally active renin antagonist (see Chapter Enalapril is an oral prodrug that is converted by hydrolysis to
17). A fourth group of drugs, the aldosterone receptor inhibitors a converting enzyme inhibitor, enalaprilat, with effects similar to
(eg, spironolactone, eplerenone) are discussed with the diuretics. In those of captopril. Enalaprilat itself is available only for intrave-
addition, β blockers, as noted earlier, can reduce renin secretion. nous use, primarily for hypertensive emergencies. Lisinopril is a
lysine derivative of enalaprilat. Benazepril, fosinopril, moexipril,
perindopril, quinapril, ramipril, and trandolapril are other
ANGIOTENSIN-CONVERTING ENZYME long-acting members of the class. All are prodrugs, like enalapril,
(ACE) INHIBITORS and are converted to the active agents by hydrolysis, primarily in
the liver.
Captopril and other drugs in this class inhibit the converting Angiotensin II inhibitors lower blood pressure principally by
enzyme peptidyl dipeptidase that hydrolyzes angiotensin I to decreasing peripheral vascular resistance. Cardiac output and heart
angiotensin II and (under the name plasma kininase) inactivates rate are not significantly changed. Unlike direct vasodilators, these
 CHAPTER 11 Antihypertensive Agents 187

MANAGEMENT OF HYPERTENSIVE Treatment of Hypertensive Emergencies

EMERGENCIES The general management of hypertensive emergencies requires
monitoring the patient in an intensive care unit with continuous
Despite the large number of patients with chronic hypertension, recording of arterial blood pressure. Fluid intake and output must
hypertensive emergencies are relatively rare. Marked or sudden be monitored carefully and body weight measured daily as an indi-
elevation of blood pressure may be a serious threat to life, however, cator of total body fluid volume during the course of therapy.
and prompt control of blood pressure is indicated. Most fre- Parenteral antihypertensive medications are used to lower blood
quently, hypertensive emergencies occur in patients whose hyper- pressure rapidly (within a few hours); as soon as reasonable blood
tension is severe and poorly controlled and in those who suddenly pressure control is achieved, oral antihypertensive therapy should
discontinue antihypertensive medications. be substituted because this allows smoother long-term manage-
ment of hypertension. The goal of treatment in the first few hours
Clinical Presentation & Pathophysiology or days is not complete normalization of blood pressure because
Hypertensive emergencies include hypertension associated with chronic hypertension is associated with autoregulatory changes in
vascular damage (termed malignant hypertension) and hyperten- cerebral blood flow. Thus, rapid normalization of blood pressure
sion associated with hemodynamic complications such as heart may lead to cerebral hypoperfusion and brain injury. Rather, blood
failure, stroke, or dissecting aortic aneurysm. The underlying pressure should be lowered by about 25%, maintaining diastolic
pathologic process in malignant hypertension is a progressive arte- blood pressure at no less than 100–110 mm Hg. Subsequently,
riopathy with inflammation and necrosis of arterioles. Vascular blood pressure can be reduced to normal levels using oral medica-
lesions occur in the kidney, which releases renin, which in turn tions over several weeks. The drug most commonly used to treat
stimulates production of angiotensin and aldosterone, which fur- hypertensive emergencies is the vasodilator sodium nitroprusside.
ther increase blood pressure. Other parenteral drugs that may be effective include fenoldopam,
Hypertensive encephalopathy is a classic feature of malignant nitroglycerin, labetalol, calcium channel blockers, diazoxide, and
hypertension. Its clinical presentation consists of severe headache, hydralazine. Esmolol is often used to manage intraoperative and
mental confusion, and apprehension. Blurred vision, nausea and postoperative hypertension. Diuretics such as furosemide are
vomiting, and focal neurologic deficits are common. If untreated, administered to prevent the volume expansion that typically occurs
the syndrome may progress over a period of 12–48 hours to con- during administration of powerful vasodilators.
vulsions, stupor, coma, and even death.

SUMMARY Drugs Used in Hypertension

Pharmacokinetics,
Subclass Mechanism of Action Effects Clinical Applications Toxicities, Interactions

DIURETICS
• Thiazides: Block Na/Cl transporter in Reduce blood volume and poorly Hypertension, mild heart
Hydrochlorothiazide renal distal convoluted tubule understood vascular effects failure
• Loop diuretics: Block Na/K/2Cl transporter in Like thiazides • greater efficacy Severe hypertension, heart See Chapter 15
Furosemide renal loop of Henle failure
• Spironolactone Block aldosterone receptor in Increase Na and decrease K excretion Aldosteronism, heart
• Eplerenone renal collecting tubule • poorly understood reduction in failure, hypertension
heart failure mortality

SYMPATHOPLEGICS, CENTRALLY ACTING

• Clonidine, methyl Activate α2 adrenoceptors Reduce central sympathetic Hypertension • clonidine Oral • clonidine also patch •
dopa outflow • reduce norepinephrine also used in withdrawal Toxicity: sedation •
release from noradrenergic nerve from abused drugs methyldopa hemolytic
endings anemia

SYMPATHETIC NERVE TERMINAL BLOCKERS

• Reserpine Blocks vesicular amine Reduce all sympathetic effects, Hypertension but rarely Oral • long duration (days) •
transporter in noradrenergic especially cardiovascular, and used Toxicity: Reserpine: psychiatric
nerves and depletes reduce blood pressure depression, gastrointestinal
transmitter stores disturbances
• Guanethidine Interferes with amine release Same as reserpine Same as reserpine Guanethidine: Severe
and replaces norepinephrine orthostatic hypotension •
in vesicles sexual dysfunction

(continued )
188 SECTION III Cardiovascular-Renal Drugs

Pharmacokinetics,
Subclass Mechanism of Action Effects Clinical Applications Toxicities, Interactions

` BLOCKERS
• Prazosin Selectively block α1 Prevent sympathetic Hypertension • benign Oral • Toxicity: Orthostatic
• Terazosin adrenoceptors vasoconstriction • reduce prostatic hyperplasia hypotension
prostatic smooth muscle tone
• Doxazosin

a BLOCKERS
• Metoprolol, others Block β1 receptors; carvedilol Prevent sympathetic cardiac Hypertension • heart See Chapter 10
• Carvedilol also blocks α receptors stimulation • reduce renin secretion failure

• Propranolol: Nonselective prototype b blocker

• Atenolol: Very widely used b1-selective blocker

VASODILATORS
• Verapamil Nonselective block of L-type Reduce cardiac rate and output • Hypertension, angina, See Chapter 12
• Diltiazem calcium channels reduce vascular resistance arrhythmias

• Nifedipine, Block vascular calcium Reduce vascular resistance Hypertension, angina See Chapter 12
amlodipine, other channels > cardiac calcium
dihydropyridines channels
• Hydralazine Causes nitric oxide release Vasodilation • reduce vascular Hypertension • minoxidil Oral • Toxicity: Angina,
resistance • arterioles more also used to treat hair loss tachycardia • Hydralazine:
sensitive than veins • reflex Lupus-like syndrome
tachycardia
• Minoxidil Metabolite opens K channels Minoxidil: Hypertrichosis
in vascular smooth muscle

PARENTERAL AGENTS
• Nitroprusside Releases nitric oxide Powerful vasodilation Hypertensive emergencies Parenteral • short duration •
• Fenoldopam Activates D1 receptors Toxicity: Excessive
• Diazoxide Opens K channels hypotension, shock
• Labetalol α, β blocker

ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS

• Captopril, many Inhibit angiotensin- Reduce angiotensin II levels • Hypertension • heart Oral • Toxicity: Cough,
others converting enzyme reduce vasoconstriction and failure, diabetes angioedema • hyperkalemia
aldosterone secretion • increase • renal impairment
bradykinin • teratogenic

ANGIOTENSIN RECEPTOR BLOCKERS (ARBs)

• Losartan, many Block AT1 angiotensin Same as ACE inhibitors but no Hypertension • heart Oral • Toxicity: Same as ACE
others receptors increase in bradykinin failure inhibitors but less cough

RENIN INHIBITOR
• Aliskiren Inhibits enzyme activity of Reduces angiotensin I and II and Hypertension Oral • Toxicity: Hyperkalemia,
renin aldosterone renal impairment • potential
teratogen
 CHAPTER 11 Antihypertensive Agents 189

P R E P A R A T I O N S A V A I L A B L E

BETA-ADRENOCEPTOR BLOCKERS POSTGANGLIONIC SYMPATHETIC NERVE

Acebutolol (generic, Sectral) TERMINAL BLOCKERS
Oral: 200, 400 mg capsules
Guanadrel (Hylorel)
Atenolol (generic, Tenormin) Oral: 10, 25 mg tablets
Oral: 25, 50, 100 mg tablets
Guanethidine (Ismelin)
Parenteral: 0.5 mg/mL for injection
Oral: 10, 25 mg tablets
Betaxolol (Kerlone)
Reserpine (generic)
Oral: 10, 20 mg tablets
Oral: 0.1, 0.25 mg tablets
Bisoprolol (Zebeta)
Oral: 5, 10 mg tablets
Carteolol (Cartrol) ALPHA1–SELECTIVE ADRENOCEPTOR
Oral: 2.5, 5 mg tablets
Carvedilol (Coreg)
BLOCKERS
Oral: 3.125, 6.25, 12.5, 25 mg tablets; 10, 20, 40, 80 mg extended- Doxazosin (generic, Cardura)
release capsules Oral: 1, 2, 4, 8 mg tablets
Esmolol (BreviBloc) Prazosin (generic, Minipress)
Parenteral: 10, 250 mg/mL for injection Oral: 1, 2, 5 mg capsules
Labetalol (generic, Normodyne, Trandate) Terazosin (generic, Hytrin)
Oral: 100, 200, 300 mg tablets Oral: 1, 2, 5, 10 mg capsules and tablets
Parenteral: 5 mg/mL for injection
Metoprolol (generic, Lopressor)
Oral: 50, 100 mg tablets GANGLION-BLOCKING AGENTS
Oral extended-release (Toprol-XL): 25, 50, 100, 200 mg tablets
Mecamylamine (Inversine)
Parenteral: 1 mg/mL for injection
Oral: 2.5 mg tablets
Nadolol (generic, Corgard)
Oral: 20, 40, 80, 120, 160 mg tablets
Nebivolol (Bystolic)
Oral: 2.5, 5, 10 mg tablets
VASODILATORS USED IN HYPERTENSION
Penbutolol (Levatol) Diazoxide (Hyperstat IV)
Oral: 20 mg tablets Parenteral: 15 mg/mL ampule
Oral (Proglycem): 50 mg capsule; 50 mg/mL oral suspension (for
Pindolol (generic, Visken) insulinoma)
Oral: 5, 10 mg tablets
Fenoldopam (generic, Corlopam)
Propranolol (generic, Inderal) Parenteral: 10 mg/mL for IV infusion
Oral: 10, 20, 40, 60, 80, 90 mg tablets; 4, 8 mg/mL oral solution;
Intensol, 80 mg/mL solution Hydralazine (generic, Apresoline)
Oral sustained-release (generic, Inderal LA): 60, 80, 120, 160 mg Oral: 10, 25, 50, 100 mg tablets
capsules Parenteral: 20 mg/mL for injection
Parenteral: 1 mg/mL for injection Minoxidil (generic, Loniten)
Timolol (generic, Blocadren) Oral: 2.5, 10 mg tablets
Oral: 5, 10, 20 mg tablets Topical (generic, Rogaine): 2% lotion
Nitroprusside (generic, Nitropress)
Parenteral: 50 mg/vial
CENTRALLY ACTING SYMPATHOPLEGIC
DRUGS CALCIUM CHANNEL BLOCKERS
Clonidine (generic, Catapres) Amlodipine (generic, Norvasc)
Oral: 0.1, 0.2, 0.3 mg tablets Oral 2.5, 5, 10 mg tablets
Transdermal (Catapres-TTS): patches that release 0.1, 0.2, Clevidipine (Cleviprex)
0.3 mg/24 h Parenteral: 0.5 mg/mL emulsion for injection
Guanabenz (generic, Wytensin) Diltiazem (generic, Cardizem)
Oral: 4, 8 mg tablets Oral: 30, 60, 90, 120 mg tablets (unlabeled in hypertension)
Guanfacine (Tenex) Oral sustained-release (Cardizem CD, Cardizem SR, Dilacor XL): 60,
Oral: 1, 2 mg tablets 90, 120, 180, 240, 300, 360, 420 mg capsules
Methyldopa (generic) Parenteral: 5 mg/mL for injection
Oral: 250, 500 mg tablets
Parenteral (Methyldopate HCl): 50 mg/mL for injection
190 SECTION III Cardiovascular-Renal Drugs

Felodipine (generic, Plendil) Perindopril (Aceon)

Oral extended-release: 2.5, 5, 10 mg tablets Oral: 2, 4, 8 mg tablets
Isradipine (generic, DynaCirc) Quinapril (Accupril)
Oral: 2.5, 5 mg capsules; 5, 10 mg controlled-release tablets Oral: 5, 10, 20, 40 mg tablets
Nicardipine (generic, Cardene) Ramipril (Altace)
Oral: 20, 30 mg capsules Oral: 1.25, 2.5, 5, 10 mg capsules
Oral sustained-release (Cardene SR): 30, 45, 60 mg capsules Trandolapril (Mavik)
Parenteral (Cardene I.V.): 0.1, 2.5 mg/mL for injection Oral: 1, 2, 4 mg tablets
Nifedipine (generic, Adalat, Procardia)
Oral: 10, 20 mg capsules (off-label use in hypertension)
Oral extended-release (Adalat CC, Procardia-XL): 30, 60, 90 mg ANGIOTENSIN RECEPTOR BLOCKERS
tablets
Azilsartan (Edarbi)
Nisoldipine (Sular)
Oral: 40, 80 mg tablets
Oral extended-release: 8.5, 17, 25.5, 34 mg tablets
Candesartan (Atacand)
Verapamil (generic, Calan, Isoptin)
Oral: 4, 8, 16, 32 mg tablets
Oral: 40, 80, 120 mg tablets
Oral sustained-release (generic, Calan SR, Verelan): 120, 180, 240 mg Eprosartan (Teveten)
tablets; 100, 120, 180, 200, 240, 300, 360 mg capsules Oral: 600 mg tablets
Parenteral: 2.5 mg/mL for injection Irbesartan (Avapro)
Oral: 75, 150, 300 mg tablets
Losartan (Cozaar)
ANGIOTENSIN-CONVERTING ENZYME Oral: 25, 50, 100 mg tablets
INHIBITORS Olmesartan (Benicar)
Oral: 5, 20, 40 mg tablets
Benazepril (generic, Lotensin)
Telmisartan (Micardis)
Oral: 5, 10, 20, 40 mg tablets
Oral: 20, 40, 80 mg tablets
Captopril (generic, Capoten)
Valsartan (Diovan)
Oral: 12.5, 25, 50, 100 mg tablets
Oral: 40, 80, 160, 320 mg tablet
Enalapril (generic, Vasotec)
Oral: 2.5, 5, 10, 20 mg tablets
Parenteral (Enalaprilat): 1.25 mg/mL for injection
Fosinopril (generic, Monopril)
RENIN INHIBITOR
Oral: 10, 20, 40 mg tablets Aliskiren (Tekturna)
Lisinopril (generic, Prinivil, Zestril) Oral: 150, 300 mg tablets
Oral: 2.5, 5, 10, 20, 40 mg tablets
Moexipril (generic, Univasc)
Oral: 7.5, 15 mg tablets

REFERENCES Aronson S et al: The ECLIPSE trials: Comparative studies of clevidipine to nitro-
glycerin, sodium nitroprusside, and nicardipine for acute hypertension in
ACE Inhibitors in Diabetic Nephropathy Trialist Group: Should all patients with cardiac surgery patients. Anesth Alang 2008;107:1110.
type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting
August P: Initial treatment of hypertension. N Engl J Med 2003;348:610.
enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern
Med 2001;134:370. Bangalore S et al: Beta-blockers for primary prevention of heart failure in patients
with hypertension: Insights from a meta-analysis. J Am Coll Cardiol
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research
2008;52:1062.
Group: Major outcomes of high-risk hypertensive patients randomized to
angiotensin-converting enzyme inhibitor or calcium channel blockers vs Calhoun DA et al: Resistant hypertension: Diagnosis, evaluation, and treatment:
diuretic: The antihypertensive and lipid-lowering treatment to prevent heart A scientific statement from the American Heart Association Professional
attack trial. JAMA 2002;288:2981. Education Committee of the Council for High Blood Pressure Research.
Circulation 2008;117:e510.
Appel LJ et al: The importance of population-wide sodium reduction as a means
to prevent cardiovascular disease and stroke: A call to action from the Chobanian AV et al: The Seventh report of the Joint National Committee on
American Heart Association. Circulation 2011;123:1138. Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
JAMA 2003;289:2560.
Appel LJ et al: Intensive blood-pressure control in hypertensive chronic kidney
disease. N Engl J Med 2010;363:918. Egan BM et al: US trends in prevalence, awareness, treatment, and control of
hypertension, 1988-2008. JAMA 2010;303:2043.
Appel LJ et al: Effects of comprehensive lifestyle modification on blood pressure
control: Main results of the PREMIER clinical trial. JAMA Esler MD et al: Renal sympathetic denervation in patients with treatment-resistant
2003;289:2083. hypertension (The Symplicity HTN-2 Trial): A randomised controlled trial.
Lancet 2010;376:1903.
Aronow WS et al: ACCF/AHA 2011 Expert consensus document on hypertension
in the elderly: A report of the American College of Cardiology Foundation Garg J, Messerli AW, Bakris GL: Evaluation and treatment of patients with sys-
Task Force on Clinical Expert Consensus Documents. Circulation 2011; temic hypertension. Circulation 2002;105:2458.
123:2434. Hajjar I et al: Hypertension, white matter hyperintensities, and concurrent impair-
ments in mobility, cognition, and mood: The Cardiovascular Health Study.
Circulation 2011;123:858.
 CHAPTER 12 Vasodilators & the Treatment of Angina Pectoris 195

Ca2+
channel
Ca2+ – blockers

Ca2+ K+

Calmodulin ATP
+ β2 agonists

Ca2+ – Calmodulin complex

cAMP

+ +

MLCK* Myosin-LC kinase MLCK(PO4)2

(MLCK)
+ cGMP

Myosin
light chains Myosin-LC-PO4 Myosin-LC
(myosin-LC)
Actin

Contraction Relaxation

Vascular smooth muscle cell

FIGURE 12–1 Control of smooth muscle contraction and site of action of calcium channel-blocking drugs. Contraction is triggered (red
arrows) by influx of calcium (which can be blocked by calcium channel blockers) through transmembrane calcium channels. The calcium com-
bines with calmodulin to form a complex that converts the enzyme myosin light-chain kinase to its active form (MLCK∗). The latter phosphory-
lates the myosin light chains, thereby initiating the interaction of myosin with actin. Other proteins, calponin and caldesmon (not shown),
inhibit the ATPase activity of myosin during the relaxation of smooth muscle. Interaction with the Ca2+-calmodulin complex reduces their
interaction with myosin during the contraction cycle. Beta2 agonists (and other substances that increase cAMP) may cause relaxation in smooth
muscle (blue arrows) by accelerating the inactivation of MLCK and by facilitating the expulsion of calcium from the cell (not shown). cGMP
facilitates relaxation by the mechanism shown in Figure 12–2.

for triggering the interaction of actin with myosin in these to ischemic tissue. In variant angina, these two drug groups also
cells. This appears to be the mechanism of vasodilation caused increase myocardial oxygen delivery by reversing coronary artery
by β2 agonists, drugs that are not used in angina (because they spasm. The newer drugs, represented by ranolazine and ivabradine,
cause too much cardiac stimulation), and by fenoldopam, a D1 are discussed later.
agonist used in hypertensive emergencies.

■ BASIC PHARMACOLOGY OF NITRATES & NITRITES

DRUGS USED TO TREAT ANGINA Chemistry
These agents are simple nitric and nitrous acid esters of polyalco-
Drug Action in Angina hols. Nitroglycerin may be considered the prototype of the group.
The three drug groups traditionally used in angina (organic nitrates, Although nitroglycerin is used in the manufacture of dynamite,
calcium channel blockers, and β blockers) decrease myocardial oxygen the systemic formulations used in medicine are not explosive. The
requirement by decreasing the determinants of oxygen demand conventional sublingual tablet form of nitroglycerin may lose
(heart rate, ventricular volume, blood pressure, and contractility). In potency when stored as a result of volatilization and adsorption to
some patients, the nitrates and the calcium channel blockers may plastic surfaces. Therefore, it should be kept in tightly closed glass
cause a redistribution of coronary flow and increase oxygen delivery containers. Nitroglycerin is not sensitive to light.
196 SECTION III Cardiovascular-Renal Drugs

Blood vessel lumen

Nitrates
Nitrites

Capillary
Arginine Nitric oxide (NO)
endothelial
cells

Ca2+
Interstitium

Nitrates
NO
Nitrites
Ca2+ +
Vascular smooth Sildenafil
–
muscle cell
GTP cGMP GMP

Myosin
light chains Myosin-LC
(myosin-LC)
Actin

Contraction Relaxation

FIGURE 12–2 Mechanism of action of nitrates, nitrites, and other substances that increase the concentration of nitric oxide (NO) in
vascular smooth muscle cells. Steps leading to relaxation are shown with blue arrows. MLCK∗, activated myosin light-chain kinase (see
Figure 12–1). GC∗, activated guanylyl cyclase; PDE, phosphodiesterase; eNOS, endothelial nitric oxide synthase.

All therapeutically active agents in the nitrate group appear to molecule and ultimately inactivates the drug. Therefore, oral bio-
have identical mechanisms of action and similar toxicities, availability of the traditional organic nitrates (eg, nitroglycerin and
although susceptibility to tolerance may vary. Therefore, pharma- isosorbide dinitrate) is low (typically < 10–20%). For this rea-
cokinetic factors govern the choice of agent and mode of therapy son, the sublingual route, which avoids the first-pass effect, is
when using the nitrates. preferred for achieving a therapeutic blood level rapidly.
Nitroglycerin and isosorbide dinitrate both are absorbed effi-
H2C O NO2
ciently by this route and reach therapeutic blood levels within a
HC O NO2 few minutes. However, the total dose administered by this route
H2C O NO2 must be limited to avoid excessive effect; therefore, the total dura-
tion of effect is brief (15–30 minutes). When much longer dura-
Nitroglycerin
(glyceryl trinitrate) tion of action is needed, oral preparations can be given that
contain an amount of drug sufficient to result in sustained sys-
temic blood levels of the parent drug plus active metabolites.
Pharmacokinetics Other routes of administration available for nitroglycerin include
The liver contains a high-capacity organic nitrate reductase that transdermal and buccal absorption from slow-release preparations
removes nitrate groups in a stepwise fashion from the parent (described below).
198 SECTION III Cardiovascular-Renal Drugs

A B

10 mN
10 mN

K+ NTG
K+ NE NE K+

10 min
10 mN

C
NE NTG

10 min
10 mN

K+ Verapamil

FIGURE 12–3 Effects of vasodilators on contractions of human vein segments studied in vitro. A shows contractions induced by two vaso-
constrictor agents, norepinephrine (NE) and potassium (K+). B shows the relaxation induced by nitroglycerin (NTG), 4 μmol/L. The relaxation is
prompt. C shows the relaxation induced by verapamil, 2.2 μmol/L. The relaxation is slower but more sustained. (Modified and reproduced, with permis-
sion, from Mikkelsen E, Andersson KE, Bengtsson B: Effects of verapamil and nitroglycerin on contractile responses to potassium and noradrenaline in isolated human periph-
eral veins. Acta Pharmacol Toxicol 1978;42:14.)

nitrates are rarely of any clinical value. During recent decades, the corned beef. Thus, inadvertent exposure to large amounts of
use of amyl nitrite and isobutyl nitrite (not nitrates) by inhalation nitrite ion can occur and may produce serious toxicity.
as recreational (sex-enhancing) drugs has become popular with One therapeutic application of this otherwise toxic effect of
some segments of the population. Nitrites readily release nitric oxide nitrite has been discovered. Cyanide poisoning results from com-
in erectile tissue as well as vascular smooth muscle and activate plexing of cytochrome iron by the CN− ion. Methemoglobin iron
guanylyl cyclase. The resulting increase in cGMP causes dephospho- has a very high affinity for CN−; thus, administration of sodium
rylation of myosin light chains and relaxation (Figure 12–2), which nitrite (NaNO2) soon after cyanide exposure regenerates active
enhances erection. The pharmacologic approach to erectile dys- cytochrome. The cyanmethemoglobin produced can be further
function is are discussed in the Box: Drugs Used in the Treatment detoxified by the intravenous administration of sodium thiosulfate
−
of Erectile Dysfunction. (Na2S2O3); this results in formation of thiocyanate ion (SCN ), a
less toxic ion that is readily excreted. Methemoglobinemia, if
3. Action on platelets—Nitric oxide released from nitroglycerin excessive, can be treated by giving methylene blue intravenously.
stimulates guanylyl cyclase in platelets as in smooth muscle. The This antidotal procedure is now being replaced by hydroxocobala-
increase in cGMP that results is responsible for a decrease in platelet min, a form of vitamin B12, which also has a very high affinity for
aggregation. Unfortunately, recent prospective trials have estab- cyanide and converts it to another form of vitamin B12.
lished no survival benefit when nitroglycerin is used in acute myo-
cardial infarction. In contrast, intravenous nitroglycerin may be of Toxicity & Tolerance
value in unstable angina, in part through its action on platelets.
A. Acute Adverse Effects
4. Other effects—Nitrite ion reacts with hemoglobin (which The major acute toxicities of organic nitrates are direct extensions
contains ferrous iron) to produce methemoglobin (which contains of therapeutic vasodilation: orthostatic hypotension, tachycardia,
ferric iron). Because methemoglobin has a very low affinity for and throbbing headache. Glaucoma, once thought to be a con-
oxygen, large doses of nitrites can result in pseudocyanosis, tissue traindication, does not worsen, and nitrates can be used safely in
hypoxia, and death. Fortunately, the plasma level of nitrite result- the presence of increased intraocular pressure. Nitrates are con-
ing from even large doses of organic and inorganic nitrates is too traindicated, however, if intracranial pressure is elevated. Rarely,
low to cause significant methemoglobinemia in adults. In nursing transdermal nitroglycerin patches have ignited when external defi-
infants, the intestinal flora is capable of converting significant brillator electroshock was applied to the chest of patients in ven-
amounts of inorganic nitrate, eg, from well water, to nitrite ion. In tricular fibrillation. Such patches should be removed before use of
addition, sodium nitrite is used as a curing agent for meats, eg, external defibrillators to prevent superficial burns.
208 SECTION III Cardiovascular-Renal Drugs

SUMMARY Drugs Used in Angina Pectoris

Pharmacokinetics, Toxicities,
Subclass Mechanism of Action Effects Clinical Applications Interactions

NITRATES
• Nitroglycerin Releases nitric oxide in Smooth muscle relaxation, Angina: Sublingual form for High first-pass effect, so sublingual
smooth muscle, which acti- especially in vessels • other acute episodes • oral and dose is much smaller than oral
vates guanylyl cyclase and smooth muscle is relaxed but transdermal forms for pro- • high lipid solubility ensures rapid
increases cGMP not as markedly • vasodila- phylaxis • IV form for acute absorption • Toxicity: Orthostatic
tion decreases venous return coronary syndrome hypotension, tachycardia, headache •
and heart size • may increase Interactions: Synergistic hypotension
coronary flow in some areas with phosphodiesterase type 5
and in variant angina inhibitors (sildenafil, etc)

• Isosorbide dinitrate: Very similar to nitroglycerin, slightly longer duration of action

• Isosorbide mononitrate: Active metabolite of the dinitrate; used orally for prophylaxis

BETA BLOCKERS
• Propranolol Nonselective competitive Decreased heart rate, Prophylaxis of angina • for Oral and parenteral, 4–6 h duration of
antagonist at cardiac output, and blood other applications, see action • Toxicity: Asthma, atrioventricu-
β adrenoceptors pressure • decreases Chapters 10, 11, and 13 lar block, acute heart failure, sedation •
myocardial oxygen demand Interactions: Additive with all cardiac
depressants

• Atenolol, metoprolol, others: b1-Selective blockers, less risk of bronchospasm, but still significant
• See Chapters 10 and 11 for other b blockers and their applications

CALCIUM CHANNEL BLOCKERS

• Verapamil, Nonselective block of L-type Reduced vascular resistance, Prophylaxis of angina, hyper- Oral, IV, duration 4–8 h • Toxicity:
diltiazem calcium channels in vessels cardiac rate, and cardiac tension, others Atrioventricular block, acute heart
and heart force results in decreased failure; constipation, edema •
oxygen demand Interactions: Additive with other
cardiac depressants and hypotensive
drugs
• Nifedipine (a Block of vascular L-type Like verapamil and diltiazem; Prophylaxis of angina, hyper- Oral, duration 4–6 h • Toxicity: Excessive
dihydropyridine) calcium channels > cardiac less cardiac effect tension hypotension, baroreceptor reflex
channels tachycardia • Interactions: Additive with
other vasodilators

• Other dihydropyridines: Like nifedipine but slower onset and longer duration (up to 12 h or longer)

MISCELLANEOUS
• Ranolazine Inhibits late sodium current Reduces cardiac oxygen Prophylaxis of angina Oral, duration 6–8 h • Toxicity: QT inter-
in heart • also may modify demand • fatty acid oxidation val prolongation, nausea, constipation,
fatty acid oxidation modification may improve dizziness • Interactions: Inhibitors of
efficiency of cardiac oxygen CYP3A increase ranolazine concentra-
utilization tion and duration of action

• Ivabradine: Investigational inhibitor of sinoatrial pacemaker; reduction of heart rate reduces oxygen demand
 CHAPTER 12 Vasodilators & the Treatment of Angina Pectoris 209

P R E P A R A T I O N S A V A I L A B L E

NITRATES & NITRITES Nifedipine (Adalat, Procardia, others)

Oral: 10, 20 mg capsules
Amyl nitrite (generic) Oral extended-release (Procardia XL, Adalat CC): 30, 60, 90 mg
Inhalant: 0.3 mL capsules tablets
Isosorbide dinitrate (generic, Isordil) Nisoldipine (Sular)
Oral: 5, 10, 20, 30, 40 mg tablets; 5, 10 mg chewable tablets Oral extended-release: 8.5, 17, 25.5, 34 mg tablets
Oral sustained-release (Isochron, Dilatrate SR): 40 mg tablets and
Verapamil (generic, Calan, Isoptin)
capsules
Oral: 40, 80, 120 mg tablets
Sublingual: 2.5, 5 mg sublingual tablets
Oral sustained-release: 100, 120, 180, 240 mg tablets or capsules
Isosorbide mononitrate (Ismo, others) Parenteral: 2.5 mg/mL for injection
Oral: 10, 20 mg tablets; extended-release: 30, 60, 120 mg tablets
Nitroglycerin
Sublingual or buccal: 0.3, 0.4, 0.6 mg tablets; 0.4 mg/metered dose BETA BLOCKERS
aerosol spray See Chapter 10.
Oral sustained-release (generic, Nitro-Time): 2.5, 6.5, 9 mg capsules
Parenteral (generic): 5 mg/mL for IV administration; 100, 200,
400 mcg/mL in dextrose for IV infusion SODIUM CHANNEL BLOCKERS
Transdermal patches (generic, Nitrek, Nitro-Dur, Transderm-Nitro):
Ranolazine (Ranexa)
to release at rates of 0.1, 0.2, 0.3, 0.4, 0.6, or 0.8 mg/h
Oral: 500, 1000 mg extended-release tablets
Topical ointment (generic, Nitro-Bid): 20 mg/mL ointment (1 inch,
or 25 mm, of ointment contains about 15 mg nitroglycerin)
DRUGS FOR ERECTILE DYSFUNCTION
CALCIUM CHANNEL BLOCKERS Sildenafil (Viagra, Revatio)
Oral: 20 (approved for use in pulmonary arterial hypertension), 25,
Amlodipine (generic, Norvasc, AmVaz)
50, 100 mg tablets
Oral: 2.5, 5, 10 mg tablets
Tadalafil (Cialis, Adcirca)
Clevidipine (Cleviprex) (approved only for use in
Oral: 2.5, 5, 10, 20 mg tablets (20 mg approved for use in pulmonary
hypertensive emergencies)
hypertension)
Parenteral: 0.5 mg/mL for IV infusion
Vardenafil (Levitra)
Diltiazem (Cardizem, generic)
Oral: 2.5, 5, 10, 20 mg tablets
Oral: 30, 60, 90, 120 mg tablets
Oral sustained-release (Cardizem SR, Dilacor XL, others): 60, 90,
120, 180, 240, 300, 360, 420 mg capsules, tablets DRUGS FOR PERIPHERAL ARTERY DISEASE
Parenteral: 5 mg/mL for injection
Cilostazol (generic, Pletal)
Felodipine (generic, Plendil)
Oral: 50, 100 mg tablets
Oral extended-release: 2.5, 5, 10 mg tablets
Pentoxifylline (generic, Trental)
Isradipine (DynaCirc)
Oral: 400 mg controlled-release, extended-release tablets
Oral: 2.5, 5 mg capsules
Oral controlled-release: 5, 10 mg tablets
Nicardipine (Cardene, others)
Oral: 20, 30 mg capsules
Oral sustained-release (Cardene SR): 30, 45, 60 mg capsules
Parenteral (Cardene I.V.): 2.5 mg/mL

REFERENCES DeWitt CR, Waksman JC: Pharmacology, pathophysiology and management of

calcium channel blocker and beta-blocker toxicity. Toxicol Rev
Borer JS: Clinical effect of ‘pure’ heart rate slowing with a prototype If inhibitor: 2004;23:223.
placebo-controlled experience with ivabradine. Adv Cardiol 2006;43:54.
Fraker TD Jr, Fihn SD: 2007 Chronic angina focused update of the ACC/AHA
Carmichael P, Lieben J: Sudden death in explosives workers. Arch Environ Health 2002 guidelines for the management of patients with chronic stable angina.
1963;7:50. J Am Coll Cardiol 2007;50:2264.
Chaitman BR: Efficacy and safety of a metabolic modulator drug in chronic stable Ignarro LJ et al: Mechanism of vascular smooth muscle relaxation by organic
angina: Review of evidence from clinical trials. J Cardiovasc Pharmacol Ther nitrates, nitrites, nitroprusside, and nitric oxide: Evidence for the involve-
2004;9(Suppl 1):S47. ment of S-nitrosothiols as active intermediates. J Pharmacol Exp Ther
Chaitman BR et al: Effects of ranolazine, with atenolol, amlodipine, or diltiazem 1981;218:739.
on exercise tolerance and angina frequency in patients with severe chronic Kannam JP, Aroesty JM, Gersh BJ: Overview of the management of stable angina
angina. A randomized controlled trial. JAMA 2004;291:309. pectoris. UpToDate, 2010. http://www.uptodate.com.
Chen Z, Zhang J, Stamler JS: Identification of the enzymatic mechanism of Kast R et al: Cardiovascular effects of a novel potent and highly selective asaindole-
nitroglycerin bioactivation. Proc Nat Acad Sci 2002;99:8306. based inhibitor of Rho-kinase. Br J Pharmacol 2007;152:1070.
 CHAPTER 13 Drugs Used in Heart Failure 213

Myofibril syncytium

Digoxin
–
Interstitium
Cell membrane
Na+/K+-ATPase NCX Cav–L Cytoplasm
ATP –
Na+ + Ca2+ channel blockers
K+
Ca2+ β agonists
Trigger Ca2+

SERCA
ATP
CalS
CalS
Sarcoplasmic Ca2+ Ca2+
Ca2+ reticulum
CalS

CalS CalS
RyR ATP

Ca2+ Ca2+ sensitizers

Ca2+
+

Actin-tropomyosin- Myosin
Z troponin

Sarcomere

FIGURE 13–1 Schematic diagram of a cardiac muscle sarcomere, with sites of action of several drugs that alter contractility. Na+/K+-ATPase,
the sodium pump, is the site of action of cardiac glycosides. NCX is the sodium-calcium exchanger. Cav-L is the voltage-gated, L-type calcium
channel. SERCA (sarcoplasmic endoplasmic reticulum Ca2+-ATPase) is a calcium transporter ATPase that pumps calcium into the sarcoplasmic
reticulum (SR). CalS is calcium bound to calsequestrin, a high-capacity Ca2+-binding protein. RyR (ryanodine RyR2 receptor) is a calcium-activated
calcium channel in the membrane of the SR that is triggered to release stored calcium. Calcium sensitizers act at the actin-troponin-tropomyosin
complex where activator calcium brings about the contractile interaction of actin and myosin. Black arrows represent processes that initiate
contraction or support basal tone. Green arrows represent processes that promote relaxation.
214 SECTION III Cardiovascular-Renal Drugs

cardiac output and significantly reduced ejection fraction (< 45%;

normal > 60%), is typical of acute failure, especially that resulting Cardia
1 c perfo
from myocardial infarction. Diastolic dysfunction often occurs as rman
CO ce
a result of hypertrophy and stiffening of the myocardium, and 2
CO
although cardiac output is reduced, ejection fraction may be nor- NE, A B
mal. Heart failure due to diastolic dysfunction does not usually EF CO
ET
NE, A
respond optimally to positive inotropic drugs. ET
EF
“High-output” failure is a rare form of heart failure. In this NE, A
Afterload EF
ET
condition, the demands of the body are so great that even increased Afterload
cardiac output is insufficient. High-output failure can result from Afterload
hyperthyroidism, beriberi, anemia, and arteriovenous shunts. This Time
form of failure responds poorly to the drugs discussed in this chap-
ter and should be treated by correcting the underlying cause.
FIGURE 13–3 Vicious spiral of progression of heart failure.
The primary signs and symptoms of all types of heart failure
Decreased cardiac output (CO) activates production of neurohor-
include tachycardia, decreased exercise tolerance, shortness of mones (NE, norepinephrine; AII, angiotensin II; ET, endothelin), which
breath, and cardiomegaly. Peripheral and pulmonary edema (the cause vasoconstriction and increased afterload. This further reduces
congestion of congestive heart failure) are often but not always ejection fraction (EF) and CO, and the cycle repeats. The downward
present. Decreased exercise tolerance with rapid muscular fatigue spiral is continued until a new steady state is reached in which CO is
is the major direct consequence of diminished cardiac output. The lower and afterload is higher than is optimal for normal activity.
other manifestations result from the attempts by the body to com- Circled points 1, 2, and B represent points on the ventricular function
pensate for the intrinsic cardiac defect. curves depicted in Figure 13–4.
Neurohumoral (extrinsic) compensation involves two major
mechanisms (previously presented in Figure 6–7)—the sympa-
thetic nervous system and the renin-angiotensin-aldosterone hor-
monal response—plus several others. Some of the detrimental as heart failure. As a result, baroreceptor sensory input to the vaso-
well as beneficial features of these compensatory responses are motor center is reduced even at normal pressures; sympathetic
illustrated in Figure 13–2. The baroreceptor reflex appears to be outflow is increased, and parasympathetic outflow is decreased.
reset, with a lower sensitivity to arterial pressure, in patients with Increased sympathetic outflow causes tachycardia, increased car-
diac contractility, and increased vascular tone. Vascular tone is
further increased by angiotensin II and endothelin, a potent vaso-
constrictor released by vascular endothelial cells. Vasoconstriction
Cardiac output increases afterload, which further reduces ejection fraction and
cardiac output. The result is a vicious cycle that is characteristic of
heart failure (Figure 13–3). Neurohumoral antagonists and vaso-
dilators reduce heart failure mortality by interrupting the cycle
Carotid sinus firing Renal blood flow and slowing the downward spiral.
After a relatively short exposure to increased sympathetic drive,
complex down-regulatory changes in the cardiac β1-adrenoceptor–
Sympathetic Renin
G protein-effector system take place that result in diminished
discharge release stimulatory effects. Beta2 receptors are not down-regulated and
may develop increased coupling to the IP3-DAG cascade. It has
also been suggested that cardiac β3 receptors (which do not appear
Angiotensin II to be down-regulated in failure) may mediate negative inotropic
effects. Excessive β activation can lead to leakage of calcium from
Force the SR via RyR channels and contributes to stiffening of the ven-
Rate tricles and arrhythmias. Prolonged β activation also increases cas-
pases, the enzymes responsible for apoptosis. Increased angiotensin
Preload Afterload Remodeling
II production leads to increased aldosterone secretion (with
sodium and water retention), to increased afterload, and to
Cardiac output
(via compensation) remodeling of both heart and vessels (discussed below). Other
hormones are released, including natriuretic peptide, endothelin,
FIGURE 13–2 Some compensatory responses that occur during and vasopressin (see Chapter 17). Within the heart, failure-
congestive heart failure. In addition to the effects shown, sympathetic induced changes have been documented in calcium handling in
discharge facilitates renin release, and angiotensin II increases the SR by SERCA and phospholamban; in transcription factors
norepinephrine release by sympathetic nerve endings (dashed that lead to hypertrophy and fibrosis; in mitochondrial function,
arrows). which is critical for energy production in the overworked heart;
214 SECTION III Cardiovascular-Renal Drugs

cardiac output and significantly reduced ejection fraction (< 45%;

normal > 60%), is typical of acute failure, especially that resulting Cardia
1 c perfo
from myocardial infarction. Diastolic dysfunction often occurs as rman
CO ce
a result of hypertrophy and stiffening of the myocardium, and 2
CO
although cardiac output is reduced, ejection fraction may be nor- NE, A B
mal. Heart failure due to diastolic dysfunction does not usually EF CO
ET
NE, A
respond optimally to positive inotropic drugs. ET
EF
“High-output” failure is a rare form of heart failure. In this NE, A
Afterload EF
ET
condition, the demands of the body are so great that even increased Afterload
cardiac output is insufficient. High-output failure can result from Afterload
hyperthyroidism, beriberi, anemia, and arteriovenous shunts. This Time
form of failure responds poorly to the drugs discussed in this chap-
ter and should be treated by correcting the underlying cause.
FIGURE 13–3 Vicious spiral of progression of heart failure.
The primary signs and symptoms of all types of heart failure
Decreased cardiac output (CO) activates production of neurohor-
include tachycardia, decreased exercise tolerance, shortness of mones (NE, norepinephrine; AII, angiotensin II; ET, endothelin), which
breath, and cardiomegaly. Peripheral and pulmonary edema (the cause vasoconstriction and increased afterload. This further reduces
congestion of congestive heart failure) are often but not always ejection fraction (EF) and CO, and the cycle repeats. The downward
present. Decreased exercise tolerance with rapid muscular fatigue spiral is continued until a new steady state is reached in which CO is
is the major direct consequence of diminished cardiac output. The lower and afterload is higher than is optimal for normal activity.
other manifestations result from the attempts by the body to com- Circled points 1, 2, and B represent points on the ventricular function
pensate for the intrinsic cardiac defect. curves depicted in Figure 13–4.
Neurohumoral (extrinsic) compensation involves two major
mechanisms (previously presented in Figure 6–7)—the sympa-
thetic nervous system and the renin-angiotensin-aldosterone hor-
monal response—plus several others. Some of the detrimental as heart failure. As a result, baroreceptor sensory input to the vaso-
well as beneficial features of these compensatory responses are motor center is reduced even at normal pressures; sympathetic
illustrated in Figure 13–2. The baroreceptor reflex appears to be outflow is increased, and parasympathetic outflow is decreased.
reset, with a lower sensitivity to arterial pressure, in patients with Increased sympathetic outflow causes tachycardia, increased car-
diac contractility, and increased vascular tone. Vascular tone is
further increased by angiotensin II and endothelin, a potent vaso-
constrictor released by vascular endothelial cells. Vasoconstriction
Cardiac output increases afterload, which further reduces ejection fraction and
cardiac output. The result is a vicious cycle that is characteristic of
heart failure (Figure 13–3). Neurohumoral antagonists and vaso-
dilators reduce heart failure mortality by interrupting the cycle
Carotid sinus firing Renal blood flow and slowing the downward spiral.
After a relatively short exposure to increased sympathetic drive,
complex down-regulatory changes in the cardiac β1-adrenoceptor–
Sympathetic Renin
G protein-effector system take place that result in diminished
discharge release stimulatory effects. Beta2 receptors are not down-regulated and
may develop increased coupling to the IP3-DAG cascade. It has
also been suggested that cardiac β3 receptors (which do not appear
Angiotensin II to be down-regulated in failure) may mediate negative inotropic
effects. Excessive β activation can lead to leakage of calcium from
Force the SR via RyR channels and contributes to stiffening of the ven-
Rate tricles and arrhythmias. Prolonged β activation also increases cas-
pases, the enzymes responsible for apoptosis. Increased angiotensin
Preload Afterload Remodeling
II production leads to increased aldosterone secretion (with
sodium and water retention), to increased afterload, and to
Cardiac output
(via compensation) remodeling of both heart and vessels (discussed below). Other
hormones are released, including natriuretic peptide, endothelin,
FIGURE 13–2 Some compensatory responses that occur during and vasopressin (see Chapter 17). Within the heart, failure-
congestive heart failure. In addition to the effects shown, sympathetic induced changes have been documented in calcium handling in
discharge facilitates renin release, and angiotensin II increases the SR by SERCA and phospholamban; in transcription factors
norepinephrine release by sympathetic nerve endings (dashed that lead to hypertrophy and fibrosis; in mitochondrial function,
arrows). which is critical for energy production in the overworked heart;
 CHAPTER 13 Drugs Used in Heart Failure 215

and in ion channels, especially potassium channels, which facili- 100

tate arrhythmogenesis, a primary cause of death in heart failure.
Phosphorylation of RyR channels in the sarcoplasmic reticulum
2+
enhances and dephosphorylation reduces Ca release; studies in 80
animal models indicate that the enzyme primarily responsible

LV stroke work (g-m/m2)

for RyR dephosphorylation, protein phosphatase 1 (PP1), is up- Normal range
regulated in heart failure. These cellular changes provide many 60
potential targets for future drugs.
The most important intrinsic compensatory mechanism is A + Ino
myocardial hypertrophy. This increase in muscle mass helps Depressed
40 1
maintain cardiac performance. However, after an initial beneficial 2
effect, hypertrophy can lead to ischemic changes, impairment Vaso B
of diastolic filling, and alterations in ventricular geometry.
20
Remodeling is the term applied to dilation (other than that due to
passive stretch) and other slow structural changes that occur in the
Shock
stressed myocardium. It may include proliferation of connective
tissue cells as well as abnormal myocardial cells with some bio- 0
0 10 20 30 40
chemical characteristics of fetal myocytes. Ultimately, myocytes in
LV filling pressure (mm Hg)
the failing heart die at an accelerated rate through apoptosis, leav-
ing the remaining myocytes subject to even greater stress. FIGURE 13–4 Relation of left ventricular (LV) performance to
filling pressure in patients with acute myocardial infarction, an
important cause of heart failure. The upper line indicates the range
Pathophysiology of Cardiac Performance for normal, healthy individuals. At a given level of exercise, the heart
Cardiac performance is a function of four primary factors: operates at a stable point, eg, point A. In heart failure, function is
shifted down and to the right, through points 1 and 2, finally
1. Preload: When some measure of left ventricular performance reaching point B. A “pure” positive inotropic drug (+ Ino) would move
such as stroke volume or stroke work is plotted as a function of the operating point upward by increasing cardiac stroke work.
left ventricular filling pressure or end-diastolic fiber length, the A vasodilator (Vaso) would move the point leftward by reducing
resulting curve is termed the left ventricular function curve filling pressure. Successful therapy usually results in both effects.
(Figure 13–4). The ascending limb (< 15 mm Hg filling pres- (Modified and reproduced with permission, from Swan HJC, Parmley WW:
sure) represents the classic Frank-Starling relation described in Congestive heart failure. In: Sodeman WA Jr, Sodeman TM [editors]: Pathologic
physiology texts. Beyond approximately 15 mm Hg, there is a Physiology. Saunders, 1979.)
plateau of performance. Preloads greater than 20–25 mm Hg
result in pulmonary congestion. As noted above, preload is usu-
ally increased in heart failure because of increased blood volume
and venous tone. Because the function curve of the failing heart
4. Heart rate: The heart rate is a major determinant of cardiac
is lower, the plateau is reached at much lower values of stroke
output. As the intrinsic function of the heart decreases in fail-
work or output. Increased fiber length or filling pressure
ure and stroke volume diminishes, an increase in heart rate—
increases oxygen demand in the myocardium, as described in
through sympathetic activation of β adrenoceptors—is the first
Chapter 12. Reduction of high filling pressure is the goal of salt
compensatory mechanism that comes into play to maintain
restriction and diuretic therapy in heart failure. Venodilator
cardiac output.
drugs (eg, nitroglycerin) also reduce preload by redistributing
blood away from the chest into peripheral veins.
2. Afterload: Afterload is the resistance against which the heart
must pump blood and is represented by aortic impedance and
■ BASIC PHARMACOLOGY OF
systemic vascular resistance. As noted in Figure 13–2, as cardiac DRUGS USED IN HEART FAILURE
output falls in chronic failure, a reflex increase in systemic vas-
cular resistance occurs, mediated in part by increased sympa- Although digitalis is not the first drug and never the only drug
thetic outflow and circulating catecholamines and in part by
activation of the renin-angiotensin system. Endothelin, a potent used in heart failure, we begin our discussion with this group
vasoconstrictor peptide, is also involved. This sets the stage for because other drugs are discussed in more detail in other
the use of drugs that reduce arteriolar tone in heart failure. chapters.
3. Contractility: Heart muscle obtained by biopsy from patients
with chronic low-output failure demonstrates a reduction in DIGITALIS
intrinsic contractility. As contractility decreases in the patient,
there is a reduction in the velocity of muscle shortening, the
rate of intraventricular pressure development (dP/dt), and the Digitalis is the genus name for the family of plants that provide
stroke output achieved (Figure 13–4). However, the heart is most of the medically useful cardiac glycosides, eg, digoxin. Such
usually still capable of some increase in all of these measures of plants have been known for thousands of years but were used
contractility in response to inotropic drugs. erratically and with variable success until 1785, when William
 CHAPTER 13 Drugs Used in Heart Failure 215

and in ion channels, especially potassium channels, which facili- 100

tate arrhythmogenesis, a primary cause of death in heart failure.
Phosphorylation of RyR channels in the sarcoplasmic reticulum
2+
enhances and dephosphorylation reduces Ca release; studies in 80
animal models indicate that the enzyme primarily responsible

LV stroke work (g-m/m2)

for RyR dephosphorylation, protein phosphatase 1 (PP1), is up- Normal range
regulated in heart failure. These cellular changes provide many 60
potential targets for future drugs.
The most important intrinsic compensatory mechanism is A + Ino
myocardial hypertrophy. This increase in muscle mass helps Depressed
40 1
maintain cardiac performance. However, after an initial beneficial 2
effect, hypertrophy can lead to ischemic changes, impairment Vaso B
of diastolic filling, and alterations in ventricular geometry.
20
Remodeling is the term applied to dilation (other than that due to
passive stretch) and other slow structural changes that occur in the
Shock
stressed myocardium. It may include proliferation of connective
tissue cells as well as abnormal myocardial cells with some bio- 0
0 10 20 30 40
chemical characteristics of fetal myocytes. Ultimately, myocytes in
LV filling pressure (mm Hg)
the failing heart die at an accelerated rate through apoptosis, leav-
ing the remaining myocytes subject to even greater stress. FIGURE 13–4 Relation of left ventricular (LV) performance to
filling pressure in patients with acute myocardial infarction, an
important cause of heart failure. The upper line indicates the range
Pathophysiology of Cardiac Performance for normal, healthy individuals. At a given level of exercise, the heart
Cardiac performance is a function of four primary factors: operates at a stable point, eg, point A. In heart failure, function is
shifted down and to the right, through points 1 and 2, finally
1. Preload: When some measure of left ventricular performance reaching point B. A “pure” positive inotropic drug (+ Ino) would move
such as stroke volume or stroke work is plotted as a function of the operating point upward by increasing cardiac stroke work.
left ventricular filling pressure or end-diastolic fiber length, the A vasodilator (Vaso) would move the point leftward by reducing
resulting curve is termed the left ventricular function curve filling pressure. Successful therapy usually results in both effects.
(Figure 13–4). The ascending limb (< 15 mm Hg filling pres- (Modified and reproduced with permission, from Swan HJC, Parmley WW:
sure) represents the classic Frank-Starling relation described in Congestive heart failure. In: Sodeman WA Jr, Sodeman TM [editors]: Pathologic
physiology texts. Beyond approximately 15 mm Hg, there is a Physiology. Saunders, 1979.)
plateau of performance. Preloads greater than 20–25 mm Hg
result in pulmonary congestion. As noted above, preload is usu-
ally increased in heart failure because of increased blood volume
and venous tone. Because the function curve of the failing heart
4. Heart rate: The heart rate is a major determinant of cardiac
is lower, the plateau is reached at much lower values of stroke
output. As the intrinsic function of the heart decreases in fail-
work or output. Increased fiber length or filling pressure
ure and stroke volume diminishes, an increase in heart rate—
increases oxygen demand in the myocardium, as described in
through sympathetic activation of β adrenoceptors—is the first
Chapter 12. Reduction of high filling pressure is the goal of salt
compensatory mechanism that comes into play to maintain
restriction and diuretic therapy in heart failure. Venodilator
cardiac output.
drugs (eg, nitroglycerin) also reduce preload by redistributing
blood away from the chest into peripheral veins.
2. Afterload: Afterload is the resistance against which the heart
must pump blood and is represented by aortic impedance and
■ BASIC PHARMACOLOGY OF
systemic vascular resistance. As noted in Figure 13–2, as cardiac DRUGS USED IN HEART FAILURE
output falls in chronic failure, a reflex increase in systemic vas-
cular resistance occurs, mediated in part by increased sympa- Although digitalis is not the first drug and never the only drug
thetic outflow and circulating catecholamines and in part by
activation of the renin-angiotensin system. Endothelin, a potent used in heart failure, we begin our discussion with this group
vasoconstrictor peptide, is also involved. This sets the stage for because other drugs are discussed in more detail in other
the use of drugs that reduce arteriolar tone in heart failure. chapters.
3. Contractility: Heart muscle obtained by biopsy from patients
with chronic low-output failure demonstrates a reduction in DIGITALIS
intrinsic contractility. As contractility decreases in the patient,
there is a reduction in the velocity of muscle shortening, the
rate of intraventricular pressure development (dP/dt), and the Digitalis is the genus name for the family of plants that provide
stroke output achieved (Figure 13–4). However, the heart is most of the medically useful cardiac glycosides, eg, digoxin. Such
usually still capable of some increase in all of these measures of plants have been known for thousands of years but were used
contractility in response to inotropic drugs. erratically and with variable success until 1785, when William
 CHAPTER 13 Drugs Used in Heart Failure 217

A Control B Ouabain 10–7 mol/L C Ouabain 47 minutes

25 min

0
Membrane
mV
potential
–50

Calcium 10–4
detector L/Lmax
light 0

Contraction 3 mg

100 ms

FIGURE 13–5 Effects of a cardiac glycoside, ouabain, on isolated cardiac tissue. The top tracing shows action potentials evoked during the
control period (panel A), early in the “therapeutic” phase (B), and later, when toxicity is present (C). The middle tracing shows the light (L)
emitted by the calcium-detecting protein aequorin (relative to the maximum possible, Lmax) and is roughly proportional to the free intracellular
calcium concentration. The bottom tracing records the tension elicited by the action potentials. The early phase of ouabain action (panel B)
shows a slight shortening of action potential and a marked increase in free intracellular calcium concentration and contractile tension. The toxic
phase (panel C) is associated with depolarization of the resting potential, a marked shortening of the action potential, and the appearance of an
oscillatory depolarization, calcium increment, and contraction (arrows). (Unpublished data kindly provided by P Hess and H Gil Wier.)

be established. If allowed to progress, such a tachycardia may The most common cardiac manifestations of digitalis toxicity
deteriorate into fibrillation; in the case of ventricular fibrillation, include atrioventricular junctional rhythm, premature ventricular
the arrhythmia will be rapidly fatal unless corrected. depolarizations, bigeminal rhythm, and second-degree atrioven-
Autonomic actions of cardiac glycosides on the heart involve tricular blockade. However, it is claimed that digitalis can cause
both the parasympathetic and the sympathetic systems. In the virtually any arrhythmia.
lower portion of the dose range, cardioselective parasympathomi-
metic effects predominate. In fact, these atropine-blockable effects B. Effects on Other Organs
account for a significant portion of the early electrical effects of Cardiac glycosides affect all excitable tissues, including smooth
digitalis (Table 13–2). This action involves sensitization of the muscle and the central nervous system. The gastrointestinal tract
baroreceptors, central vagal stimulation, and facilitation of musca- is the most common site of digitalis toxicity outside the heart. The
rinic transmission at the cardiac muscle cell. Because cholinergic effects include anorexia, nausea, vomiting, and diarrhea. This
innervation is much richer in the atria, these actions affect atrial toxicity is caused in part by direct effects on the gastrointestinal
and atrioventricular nodal function more than Purkinje or ven- tract and in part by central nervous system actions.
tricular function. Some of the cholinomimetic effects are useful in Central nervous system effects include vagal and chemoreceptor
the treatment of certain arrhythmias. At toxic levels, sympathetic trigger zone stimulation. Less often, disorientation and hallucinations—
outflow is increased by digitalis. This effect is not essential for especially in the elderly—and visual disturbances are noted. The
typical digitalis toxicity but sensitizes the myocardium and exag- latter effect may include aberrations of color perception.
gerates all the toxic effects of the drug. Gynecomastia is a rare effect reported in men taking digitalis.

TABLE 13–2 Effects of digoxin on electrical properties of cardiac tissues.

Tissue or Variable Effects at Therapeutic Dosage Effects at Toxic Dosage

Sinus node ↓ Rate ↓ Rate

Atrial muscle ↓ Refractory period ↓ Refractory period, arrhythmias
Atrioventricular node ↓ Conduction velocity, ↑ refractory period ↓ Refractory period, arrhythmias
Purkinje system, ventricular muscle Slight ↓ refractory period Extrasystoles, tachycardia, fibrillation
Electrocardiogram ↑ PR interval, ↓ QT interval Tachycardia, fibrillation, arrest at extremely high dosage
 CHAPTER 13 Drugs Used in Heart Failure 217

A Control B Ouabain 10–7 mol/L C Ouabain 47 minutes

25 min

0
Membrane
mV
potential
–50

Calcium 10–4
detector L/Lmax
light 0

Contraction 3 mg

100 ms

FIGURE 13–5 Effects of a cardiac glycoside, ouabain, on isolated cardiac tissue. The top tracing shows action potentials evoked during the
control period (panel A), early in the “therapeutic” phase (B), and later, when toxicity is present (C). The middle tracing shows the light (L)
emitted by the calcium-detecting protein aequorin (relative to the maximum possible, Lmax) and is roughly proportional to the free intracellular
calcium concentration. The bottom tracing records the tension elicited by the action potentials. The early phase of ouabain action (panel B)
shows a slight shortening of action potential and a marked increase in free intracellular calcium concentration and contractile tension. The toxic
phase (panel C) is associated with depolarization of the resting potential, a marked shortening of the action potential, and the appearance of an
oscillatory depolarization, calcium increment, and contraction (arrows). (Unpublished data kindly provided by P Hess and H Gil Wier.)

be established. If allowed to progress, such a tachycardia may The most common cardiac manifestations of digitalis toxicity
deteriorate into fibrillation; in the case of ventricular fibrillation, include atrioventricular junctional rhythm, premature ventricular
the arrhythmia will be rapidly fatal unless corrected. depolarizations, bigeminal rhythm, and second-degree atrioven-
Autonomic actions of cardiac glycosides on the heart involve tricular blockade. However, it is claimed that digitalis can cause
both the parasympathetic and the sympathetic systems. In the virtually any arrhythmia.
lower portion of the dose range, cardioselective parasympathomi-
metic effects predominate. In fact, these atropine-blockable effects B. Effects on Other Organs
account for a significant portion of the early electrical effects of Cardiac glycosides affect all excitable tissues, including smooth
digitalis (Table 13–2). This action involves sensitization of the muscle and the central nervous system. The gastrointestinal tract
baroreceptors, central vagal stimulation, and facilitation of musca- is the most common site of digitalis toxicity outside the heart. The
rinic transmission at the cardiac muscle cell. Because cholinergic effects include anorexia, nausea, vomiting, and diarrhea. This
innervation is much richer in the atria, these actions affect atrial toxicity is caused in part by direct effects on the gastrointestinal
and atrioventricular nodal function more than Purkinje or ven- tract and in part by central nervous system actions.
tricular function. Some of the cholinomimetic effects are useful in Central nervous system effects include vagal and chemoreceptor
the treatment of certain arrhythmias. At toxic levels, sympathetic trigger zone stimulation. Less often, disorientation and hallucinations—
outflow is increased by digitalis. This effect is not essential for especially in the elderly—and visual disturbances are noted. The
typical digitalis toxicity but sensitizes the myocardium and exag- latter effect may include aberrations of color perception.
gerates all the toxic effects of the drug. Gynecomastia is a rare effect reported in men taking digitalis.

TABLE 13–2 Effects of digoxin on electrical properties of cardiac tissues.

Tissue or Variable Effects at Therapeutic Dosage Effects at Toxic Dosage

Sinus node ↓ Rate ↓ Rate

Atrial muscle ↓ Refractory period ↓ Refractory period, arrhythmias
Atrioventricular node ↓ Conduction velocity, ↑ refractory period ↓ Refractory period, arrhythmias
Purkinje system, ventricular muscle Slight ↓ refractory period Extrasystoles, tachycardia, fibrillation
Electrocardiogram ↑ PR interval, ↓ QT interval Tachycardia, fibrillation, arrest at extremely high dosage
218 SECTION III Cardiovascular-Renal Drugs

NSR PVB NSR PVB (not the USA). A group of β-adrenoceptor stimulants has also
been used as digitalis substitutes, but they may increase mortality
(see below).
V6

BIPYRIDINES
ST Inamrinone (previously called amrinone) and milrinone are
bipyridine compounds that inhibit phosphodiesterase isozyme 3
FIGURE 13–6 Electrocardiographic record showing digitalis- (PDE-3). They are active orally as well as parenterally but are
induced bigeminy. The complexes marked NSR are normal sinus available only in parenteral forms. They have elimination half-lives
rhythm beats; an inverted T wave and depressed ST segment are of 3–6 hours, with 10–40% being excreted in the urine.
present. The complexes marked PVB are premature ventricular beats
and are the electrocardiographic manifestations of depolarizations
evoked by delayed oscillatory afterpotentials as shown in Figure Pharmacodynamics
13–5. (Modified and reproduced, with permission, from Goldman MJ: Principles of The bipyridines increase myocardial contractility by increasing
Clinical Electrocardiography, 12th ed. Lange, 1986.) inward calcium flux in the heart during the action potential; they
may also alter the intracellular movements of calcium by influencing
the sarcoplasmic reticulum. They also have an important vasodilat-
ing effect. Inhibition of phosphodiesterase results in an increase in
C. Interactions with Potassium, Calcium, and Magnesium cAMP and the increase in contractility and vasodilation.
Potassium and digitalis interact in two ways. First, they inhibit The toxicity of inamrinone includes nausea and vomiting;
each other’s binding to Na+/K+-ATPase; therefore, hyperkalemia arrhythmias, thrombocytopenia, and liver enzyme changes have
reduces the enzyme-inhibiting actions of cardiac glycosides, also been reported in a significant number of patients. This drug
whereas hypokalemia facilitates these actions. Second, abnormal has been withdrawn in some countries. Milrinone appears less
cardiac automaticity is inhibited by hyperkalemia (see Chapter 14). likely to cause bone marrow and liver toxicity than inamrinone,
+
Moderately increased extracellular K therefore reduces the effects but it does cause arrhythmias. Inamrinone and milrinone are now
of digitalis, especially the toxic effects. used only intravenously and only for acute heart failure or severe
Calcium ion facilitates the toxic actions of cardiac glycosides by exacerbation of chronic heart failure.
accelerating the overloading of intracellular calcium stores that
appears to be responsible for digitalis-induced abnormal automa-
ticity. Hypercalcemia therefore increases the risk of a digitalis-in- BETA-ADRENOCEPTOR AGONISTS
duced arrhythmia. The effects of magnesium ion are opposite to
those of calcium. These interactions mandate careful evaluation of The general pharmacology of these agents is discussed in Chapter 9.
serum electrolytes in patients with digitalis-induced arrhythmias. The selective β1 agonist that has been most widely used in patients
with heart failure is dobutamine. This parenteral drug produces
an increase in cardiac output together with a decrease in ventricu-
lar filling pressure. Some tachycardia and an increase in myocar-
OTHER POSITIVE INOTROPIC dial oxygen consumption have been reported. Therefore, the
DRUGS USED IN HEART FAILURE potential for producing angina or arrhythmias in patients with
coronary artery disease is significant, as is the tachyphylaxis that
Istaroxime is an investigational steroid derivative that increases
+ + accompanies the use of any β stimulant. Intermittent dobutamine
contractility by inhibiting Na /K -ATPase (like cardiac glycosides)
2+ infusion may benefit some patients with chronic heart failure.
but in addition facilitates sequestration of Ca by the SR. The
Dopamine has also been used in acute heart failure and may be
latter action may render the drug less arrhythmogenic than
particularly helpful if there is a need to raise blood pressure.
digoxin. Istaroxime is in phase 2 clinical trials.
Drugs that inhibit phosphodiesterases, the family of enzymes
that inactivate cAMP and cGMP, have long been used in therapy
of heart failure. Although they have positive inotropic effects, DRUGS WITHOUT POSITIVE
most of their benefits appear to derive from vasodilation, as dis- INOTROPIC EFFECTS USED IN
cussed below. The bipyridines inamrinone and milrinone are the
most successful of these agents found to date, but their usefulness
HEART FAILURE
is limited. Levosimendan, a drug that sensitizes the troponin These agents—not positive inotropic drugs—are the first-line
system to calcium, also appears to inhibit phosphodiesterase and therapies for chronic heart failure. The drugs most commonly
to cause some vasodilation in addition to its inotropic effects. used are diuretics, ACE inhibitors, angiotensin receptor antago-
Some clinical trials suggest that this drug may be useful in patients nists, aldosterone antagonists, and β blockers (Table 13–1). In
with heart failure, and the drug has been approved in some countries acute failure, diuretics and vasodilators play important roles.
222 SECTION III Cardiovascular-Renal Drugs

Tachycardia limits filling time; therefore, bradycardic drugs may failure. Such patients can be usefully characterized on the basis of
be particularly useful, at least in theory. three hemodynamic measurements: arterial pressure, left ventricu-
lar filling pressure, and cardiac index. When filling pressure is
2
greater than 15 mm Hg and stroke work index is less than 20 g-m/m ,
MANAGEMENT OF ACUTE the mortality rate is high. Intermediate levels of these two variables
imply a much better prognosis.
HEART FAILURE Intravenous treatment is the rule in acute heart failure. Among
Acute heart failure occurs frequently in patients with chronic fail- diuretics, furosemide is the most commonly used. Dopamine or
ure. Such episodes are usually associated with increased exertion, dobutamine are positive inotropic drugs with prompt onset and
emotion, excess salt intake, nonadherence to medical therapy, or short durations of action; they are most useful in patients with
increased metabolic demand occasioned by fever, anemia, etc. A severe hypotension. Levosimendan has been approved for use in
particularly common and important cause of acute failure—with acute failure in Europe, and noninferiority has been demonstrated
or without chronic failure—is acute myocardial infarction. against dobutamine. Vasodilators in use in patients with acute
Patients with acute myocardial infarction are best treated with decompensation include nitroprusside, nitroglycerine, and
emergency revascularization using either coronary angioplasty and nesiritide. Reduction in afterload often improves ejection fraction,
a stent, or a thrombolytic agent. Even with revascularization, acute but improved survival has not been documented. A small subset
failure may develop in such patients. Many of the signs and symp- of patients in acute heart failure will have hyponatremia, presum-
toms of acute and chronic failure are identical, but their therapies ably due to increased vasopressin activity. A V1a and V2 receptor
diverge because of the need for more rapid response and the rela- antagonist, conivaptan, is approved for parenteral treatment of
tively greater frequency and severity of pulmonary vascular con- euvolemic hyponatremia. Several clinical trials have indicated that
gestion in the acute form. this drug and related V2 antagonists (tolvaptan) may have a ben-
Measurements of arterial pressure, cardiac output, stroke work eficial effect in some patients with acute heart failure and hypona-
index, and pulmonary capillary wedge pressure are particularly tremia. Thus far, vasopressin antagonists do not seem to reduce
useful in patients with acute myocardial infarction and acute heart mortality.

SUMMARY Drugs Used in Heart Failure

Pharmacokinetics, Toxicities,
Subclass Mechanism of Action Effects Clinical Applications Interactions

DIURETICS
• Furosemide Loop diuretic: Decreases NaCl Increased excretion of salt Acute and chronic heart Oral and IV • duration 2–4 h • Toxicity:
and KCl reabsorption in thick and water • reduces failure • severe hyperten- Hypovolemia, hypokalemia,
ascending limb of the loop of cardiac preload and sion • edematous orthostatic hypotension, ototoxicity,
Henle in the nephron (see afterload • reduces conditions sulfonamide allergy
Chapter 15) pulmonary and peripheral
edema
• Hydrochlorothiazide Decreases NaCl reabsorption Same as furosemide, but Mild chronic failure • mild- Oral only • duration 10–12 h • Toxicity:
in the distal convoluted tubule less efficacious moderate hypertension • Hyponatremia, hypokalemia,
hypercalciuria • has not hyperglycemia, hyperuricemia,
been shown to reduce hyperlipidemia, sulfonamide allergy
mortality

• Three other loop diuretics: Bumetanide and torsemide similar to furosemide; ethacrynic acid not a sulfonamide
• Many other thiazides: All basically similar to hydrochlorothiazide, differing only in pharmacokinetics

ALDOSTERONE ANTAGONISTS
• Spironolactone Blocks cytoplasmic aldoster- Increased salt and water Chronic heart failure • Oral • duration 24–72 h (slow onset
one receptors in collecting excretion • reduces remod- aldosteronism (cirrhosis, and offset) • Toxicity: Hyperkalemia,
tubules of nephron • possible eling • reduces mortality adrenal tumor) • hyperten- antiandrogen actions
membrane effect sion • has been shown to
reduce mortality

• Eplerenone: Similar to spironolactone; more selective antialdosterone effect; no significant antiandrogen action; has been shown to reduce mortality

(continued )
 CHAPTER 13 Drugs Used in Heart Failure 223

Pharmacokinetics, Toxicities,
Subclass Mechanism of Action Effects Clinical Applications Interactions

ANGIOTENSIN ANTAGONISTS
Angiotensin-converting Inhibits ACE • reduces AII Arteriolar and venous Chronic heart failure • Oral • half-life 2–4 h but given in large
enzyme (ACE) inhibitors: formation by inhibiting con- dilation • reduces aldoster- hypertension • diabetic doses so duration 12–24 h • Toxicity:
• Captopril version of AI to All one secretion • reduces renal disease • has been Cough, hyperkalemia, angioneurotic
cardiac remodeling shown to reduce mortality edema • Interactions: Additive with
other angiotensin antagonists
Angiotensin receptor Antagonize AII effects at AT1 Like ACE inhibitors Like ACE inhibitors • used Oral • duration 6–8 h • Toxicity:
blockers (ARBs): receptors in patients intolerant to Hyperkalemia; angioneurotic edema •
• Losartan ACE inhibitors • has been Interactions: Additive with other
shown to reduce mortality angiotensin antagonists

• Enalapril, many other ACE inhibitors: Like captopril

• Candesartan, many other ARBs: Like losartan

BETA BLOCKERS
• Carvedilol Competitively blocks β1 Slows heart rate • reduces Chronic heart failure: To Oral • duration 10–12 h • Toxicity:
receptors (see Chapter 10) blood pressure • poorly slow progression • reduce Bronchospasm, bradycardia,
understood effects • mortality in moderate and atrioventricular block, acute cardiac
reduces heart failure severe heart failure • many decompensation • see Chapter 10 for
mortality other indications in other toxicities and interactions
Chapter 10

• Metoprolol, bisoprolol, nebivolol: Select group of b blockers that have been shown to reduce heart failure mortality

CARDIAC GLYCOSIDE
• Digoxin Na+/K+-ATPase inhibition Increases cardiac Chronic symptomatic heart Oral, parenteral • duration 36–40 h •
2+
results in reduced Ca expul- contractility • cardiac failure • rapid ventricular Toxicity: Nausea, vomiting, diarrhea •
sion and increased Ca2+ stored parasympathomimetic rate in atrial fibrillation • cardiac arrhythmias
in sarcoplasmic reticulum effect (slowed sinus has not been definitively
heart rate, slowed shown to reduce mortality
atrioventricular
conduction)

VASODILATORS
Venodilators: Releases nitric oxide (NO) • Venodilation • reduces Acute and chronic heart Oral • 4–6 h duration • Toxicity:
• Isosorbide dinitrate activates guanylyl cyclase (see preload and ventricular failure • angina Postural hypotension, tachycardia,
Chapter 12) stretch headache • Interactions: Additive with
other vasodilators and synergistic
with phosphodiesterase type 5
inhibitors
Arteriolar dilators: Probably increases NO Reduces blood pressure Hydralazine plus nitrates Oral • 8–12 h duration • Toxicity:
• Hydralazine synthesis in endothelium (see and afterload • results in have reduced mortality Tachycardia, fluid retention, lupus-like
Chapter 11) increased cardiac output syndrome
Combined arteriolar and Releases NO spontaneously • Marked vasodilation • Acute cardiac decompen- IV only • duration 1–2 min • Toxicity:
venodilator: activates guanylyl cyclase reduces preload and sation • hypertensive emer- Excessive hypotension, thiocyanate
• Nitroprusside afterload gencies (malignant and cyanide toxicity • Interactions:
hypertension) Additive with other vasodilators

BETA-ADRENOCEPTOR AGONISTS
• Dobutamine Beta1-selective agonist • Increases cardiac Acute decompensated IV only • duration a few minutes
increases cAMP synthesis contractility, output heart failure • intermittent • Toxicity: Arrhythmias • Interactions:
therapy in chronic failure Additive with other sympathomimetics
reduces symptoms
• Dopamine Dopamine receptor agonist • Increases renal blood flow Acute decompensated IV only • duration a few minutes •
higher doses activate β and α • higher doses increase heart failure • shock Toxicity: Arrhythmias • Interactions:
adrenoceptors cardiac force and blood Additive with sympathomimetics
pressure

(continued )
224 SECTION III Cardiovascular-Renal Drugs

Pharmacokinetics, Toxicities,
Subclass Mechanism of Action Effects Clinical Applications Interactions
BIPYRIDINES
• Inamrinone, Phosphodiesterase type 3 Vasodilators; lower periph- Acute decompensated IV only • duration 3–6 h • Toxicity:
milrinone inhibitors • decrease cAMP eral vascular resistance • heart failure • increase Arrhythmias • Interactions: Additive
breakdown also increase cardiac mortality in chronic failure with other arrhythmogenic agents
contractility

NATRIURETIC PEPTIDE
• Nesiritide Activates BNP receptors, Vasodilation • diuresis Acute decompensated IV only • duration 18 minutes •
increases cGMP failure • has not been Toxicity: Renal damage, hypotension,
shown to reduce mortality may increase mortality

P R E P A R A T I O N S A V A I L A B L E

DIURETICS Fosinopril (generic, Monopril)

Oral: 10, 20, 40 mg tablets
See Chapter 15.
Lisinopril (generic, Prinivil, Zestril)
Oral: 2.5, 5, 10, 20, 30, 40 mg tablets
DIGITALIS Moexipril (generic, Univasc)
Oral: 7.5, 15 mg tablets
Digoxin (generic, Lanoxicaps, Lanoxin)
∗ Perindopril (Aceon)
Oral: 0.125, 0.25 mg tablets; 0.05, 0.1, 0.2 mg capsules ; 0.05 mg/mL
Oral: 2, 4, 8 mg tablets
elixir
Parenteral: 0.1, 0.25 mg/mL for injection Quinapril (generic, Accupril)
Oral: 5, 10, 20, 40 mg tablets
Ramipril (Altace)
DIGITALIS ANTIBODY Oral: 1.25, 2.5, 5, 10 mg capsules
Digoxin immune fab (ovine) (Digibind, DigiFab) Trandolapril (Mavik)
Parenteral: 38 or 40 mg per vial with 75 mg sorbitol lyophilized Oral: 1, 2, 4 mg tablets
powder to reconstitute for IV injection. Each vial will bind
approximately 0.5 mg digoxin or digitoxin.
ANGIOTENSIN RECEPTOR BLOCKERS
Candesartan (Atacand)
SYMPATHOMIMETICS MOST COMMONLY Oral: 4, 8, 16, 32 mg tablets
USED IN CONGESTIVE HEART FAILURE Eprosartan (Teveten)
Oral: 600 mg tablets
Dobutamine (generic)
Parenteral: 12.5 mg/mL for IV infusion Irbesartan (Avapro)
Oral: 75, 150, 300 mg tablets
Dopamine (generic, Intropin)
Parenteral: 40, 80, 160 mg/mL for IV injection; 80, 160, 320 mg/dL Losartan (Cozaar)
in 5% dextrose for IV infusion Oral: 25, 50, 100 mg tablets
Olmesartan (Benicar)
Oral: 5, 20, 40 mg tablets
ANGIOTENSIN-CONVERTING ENZYME Telmisartan (Micardis)
INHIBITORS Oral: 20, 40, 80 mg tablets
Benazepril (generic, Lotensin) Valsartan (Diovan)
Oral: 5, 10, 20, 40 mg tablets Oral: 40, 80, 160, 320 mg tablets
Captopril (generic, Capoten)
Oral: 12.5, 25, 50, 100 mg tablets
BETA BLOCKERS THAT HAVE REDUCED
Enalapril (generic, Vasotec, Vasotec I.V.)
Oral: 2.5, 5, 10, 20 mg tablets MORTALITY IN HEART FAILURE
Parenteral: 1.25 mg enalaprilat/mL Bisoprolol (generic, Zebeta, off-label use)
Oral: 5, 10 mg tablets
224 SECTION III Cardiovascular-Renal Drugs

Pharmacokinetics, Toxicities,
Subclass Mechanism of Action Effects Clinical Applications Interactions
BIPYRIDINES
• Inamrinone, Phosphodiesterase type 3 Vasodilators; lower periph- Acute decompensated IV only • duration 3–6 h • Toxicity:
milrinone inhibitors • decrease cAMP eral vascular resistance • heart failure • increase Arrhythmias • Interactions: Additive
breakdown also increase cardiac mortality in chronic failure with other arrhythmogenic agents
contractility

NATRIURETIC PEPTIDE
• Nesiritide Activates BNP receptors, Vasodilation • diuresis Acute decompensated IV only • duration 18 minutes •
increases cGMP failure • has not been Toxicity: Renal damage, hypotension,
shown to reduce mortality may increase mortality

P R E P A R A T I O N S A V A I L A B L E

DIURETICS Fosinopril (generic, Monopril)

Oral: 10, 20, 40 mg tablets
See Chapter 15.
Lisinopril (generic, Prinivil, Zestril)
Oral: 2.5, 5, 10, 20, 30, 40 mg tablets
DIGITALIS Moexipril (generic, Univasc)
Oral: 7.5, 15 mg tablets
Digoxin (generic, Lanoxicaps, Lanoxin)
∗ Perindopril (Aceon)
Oral: 0.125, 0.25 mg tablets; 0.05, 0.1, 0.2 mg capsules ; 0.05 mg/mL
Oral: 2, 4, 8 mg tablets
elixir
Parenteral: 0.1, 0.25 mg/mL for injection Quinapril (generic, Accupril)
Oral: 5, 10, 20, 40 mg tablets
Ramipril (Altace)
DIGITALIS ANTIBODY Oral: 1.25, 2.5, 5, 10 mg capsules
Digoxin immune fab (ovine) (Digibind, DigiFab) Trandolapril (Mavik)
Parenteral: 38 or 40 mg per vial with 75 mg sorbitol lyophilized Oral: 1, 2, 4 mg tablets
powder to reconstitute for IV injection. Each vial will bind
approximately 0.5 mg digoxin or digitoxin.
ANGIOTENSIN RECEPTOR BLOCKERS
Candesartan (Atacand)
SYMPATHOMIMETICS MOST COMMONLY Oral: 4, 8, 16, 32 mg tablets
USED IN CONGESTIVE HEART FAILURE Eprosartan (Teveten)
Oral: 600 mg tablets
Dobutamine (generic)
Parenteral: 12.5 mg/mL for IV infusion Irbesartan (Avapro)
Oral: 75, 150, 300 mg tablets
Dopamine (generic, Intropin)
Parenteral: 40, 80, 160 mg/mL for IV injection; 80, 160, 320 mg/dL Losartan (Cozaar)
in 5% dextrose for IV infusion Oral: 25, 50, 100 mg tablets
Olmesartan (Benicar)
Oral: 5, 20, 40 mg tablets
ANGIOTENSIN-CONVERTING ENZYME Telmisartan (Micardis)
INHIBITORS Oral: 20, 40, 80 mg tablets
Benazepril (generic, Lotensin) Valsartan (Diovan)
Oral: 5, 10, 20, 40 mg tablets Oral: 40, 80, 160, 320 mg tablets
Captopril (generic, Capoten)
Oral: 12.5, 25, 50, 100 mg tablets
BETA BLOCKERS THAT HAVE REDUCED
Enalapril (generic, Vasotec, Vasotec I.V.)
Oral: 2.5, 5, 10, 20 mg tablets MORTALITY IN HEART FAILURE
Parenteral: 1.25 mg enalaprilat/mL Bisoprolol (generic, Zebeta, off-label use)
Oral: 5, 10 mg tablets
 CHAPTER 13 Drugs Used in Heart Failure 225

Carvedilol (Coreg) OTHER DRUGS

Oral: 3.125, 6.25, 12.5, 25 mg tablets; 10, 20, 40, 80 mg extended-re-
lease capsules Hydralazine (generic) (see Chapter 11)
Metoprolol (Lopressor, Toprol XL) Isosorbide dinitrate (see Chapter 12)
Oral: 50, 100 mg tablets; 25, 50, 100, 200 mg extended-release Nitroglycerine (see Chapter 12)
tablets Hydralazine plus isosorbide dinitrate fixed dose (BiDil)
Parenteral: 1 mg/mL for IV injection Oral: 37.5 mg hydralazine + 20 mg isosorbide dinitrate tablets
Nebivolol (Bystolic) Inamrinone (generic)
Oral: 2.5, 5, 10 mg tablets Parenteral: 5 mg/mL for IV injection
Milrinone (generic, Primacor)
Parenteral: 1 mg/mL for IV injection
ALDOSTERONE ANTAGONISTS Nesiritide (Natrecor)
Spironolactone (generic, Aldactone) Parenteral: 1.58 mg powder to reconstitute for IV injection
Oral: 25, 50 mg tablets Bosentan (Tracleer)
Eplerenone (Inspra) Oral: 62.5, 125 mg tablets
Oral: 25, 50 mg tablets

∗
Digoxin capsules (Lanoxicaps) have greater bioavailability than digoxin tablets.

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tality in heart failure. N Engl J Med 2005;352:1539. Shekelle PG et al: Efficacy of angiotensin-converting enzyme inhibitors and beta
blockers in the management of left ventricular systolic dysfunction according
Colucci WS: Overview of the therapy of heart failure due to systolic dysfunction.
to race, gender, and diabetic status: A meta-analysis of major clinical trials. J
UpToDate, 2010. http://www.UpToDate.com.
Am Coll Cardiol 2003;41:1529.
CONSENSUS Trial Study Group: Effects of enalapril on mortality in severe con-
Taur Y, Frishman WH: The cardiac ryanodine receptor (RyR2) and its role in heart
gestive heart failure. N Engl J Med 1987;316:1429.
disease. Cardiol Rev 2005;13:142.
DeLuca L et al: Overview of emerging pharmacologic agents for acute heart failure
Taylor AL et al: Combination of isosorbide dinitrate and hydralazine in blacks with
syndromes. Eur J Heart Fail 2008;10:201.
heart failure. N Engl J Med 2004;351:2049.
Elkayam U et al: Vasodilators in the management of acute heart failure. Crit Care
Topalian S, Ginsberg F, Parrillo JE: Cardiogenic shock. Crit Care Med
Med 2008;36:S95.
2008;36:S66.
Ikeda Y, Hoshijima M, Chien KR: Toward biologically targeted therapy of calcium
van Veldhuisen DJ et al: Beta-blockade with nebivolol in elderly heart failure
cycling defects in heart failure. Physiology 2008;28:6.
patients with impaired and preserved left ventricular ejection fraction. Data
Jessup M et al: 2009 Focused update incorporated into the ACC/AHA 2005 from SENIORS (Study of Effects of Nebivolol Intervention on Outcomes
guidelines for the diagnosis and management of heart failure in adults. J Am and Rehospitalization in Seniors with Heart Failure). J Am Coll Cardiol
Coll Cardiol 2009;53:e1. 2009;53:2150.
Klapholtz M: β-Blocker use for the stages of heart failure. Mayo Clin Proc
2009;84:718.

CASE STUDY ANSWER

The patient has a low ejection fraction with systolic heart inhibitor was added (enalapril 20 mg twice daily), and over
failure. He was placed on a low-sodium diet and treated with the next few weeks, he continued to feel better. Because of
a diuretic (furosemide 40 mg twice daily). On this therapy, he continued shortness of breath on exercise, digoxin 0.25 mg/d
was less short of breath on exertion and could also lie flat was added with a further improvement in exercise tolerance.
without dyspnea. An angiotensin-converting enzyme (ACE) Addition of a β blocker and eplerenone is being considered.
228 SECTION III Cardiovascular-Renal Drugs

Superior
vena cava Phase 0
3
SA node 4

Atrium

AV node
Overshoot
1
0 2
Phase
0 3
mV

Purkinje 4

-100 Resting potential

Tricuspid
valve

Mitral
valve

Action potential phases

0: Upstroke Ventricle
1: Early-fast repolarization
2: Plateau R
3: Repolarization
4: Diastole
T

ECG
P

Q S
PR QT
200 ms

FIGURE 14–1 Schematic representation of the heart and normal cardiac electrical activity (intracellular recordings from areas indicated
and ECG). Sinoatrial (SA) node, atrioventricular (AV) node, and Purkinje cells display pacemaker activity (phase 4 depolarization). The ECG is the
body surface manifestation of the depolarization and repolarization waves of the heart. The P wave is generated by atrial depolarization, the
QRS by ventricular muscle depolarization, and the T wave by ventricular repolarization. Thus, the PR interval is a measure of conduction time
from atrium to ventricle, and the QRS duration indicates the time required for all of the ventricular cells to be activated (ie, the intraventricular
conduction time). The QT interval reflects the duration of the ventricular action potential.

Ionic Basis of Membrane Electrical Activity peptide chains that make up the channel proteins). Each type of
The transmembrane potential of cardiac cells is determined by the channel has its own type of gate (sodium, calcium, and some potas-
+
concentrations of several ions—chiefly sodium (Na ), potassium sium channels are each thought to have two types of gates). The
+ 2+ –
(K ), calcium (Ca ), and chloride (Cl )—on either side of the mem- channels primarily responsible for the cardiac action potential
brane and the permeability of the membrane to each ion. These (sodium, calcium, and several potassium) are opened and closed
water-soluble ions are unable to freely diffuse across the lipid cell (“gated”) by voltage changes across the cell membrane; that is, they
membrane in response to their electrical and concentration gradi- are voltage-sensitive. Most are also modulated by ion concentra-
ents; they require aqueous channels (specific pore-forming proteins) tions and metabolic conditions, and some potassium channels are
for such diffusion. Thus, ions move across cell membranes in primarily ligand- rather than voltage-gated.
response to their gradients only at specific times during the cardiac All the ionic currents that are currently thought to contribute to
cycle when these ion channels are open. The movements of the ions the cardiac action potential are illustrated in Figure 14–2. At rest,
produce currents that form the basis of the cardiac action potential. most cells are not significantly permeable to sodium, but at the start
Individual channels are relatively ion-specific, and the flux of ions of each action potential, they become quite permeable (see below).
through them is controlled by “gates” (flexible portions of the In electrophysiologic terms, the conductance of the fast sodium
 CHAPTER 14 Agents Used in Cardiac Arrhythmias 229

1
2
inward
outward 0 3
Phase 4 Gene/protein

Na+ current SCN5A/Nav 1.5

L-type CACNA1/Cav 1.2
Ca2+
current T-type CACNA1G,1/Cav 3.1, 3.2

transient lTO1 KCND3/ Kv 4.3

outward
lTO2 KCNA4/ Kv 1.4
current
lKs KCNA1/ KvLQT 1
delayed
rectifiers lKr KCNH2/ hERG
(lK)
lKur KCNA5/ Kv 1.5

lKP
lCl CFTR/CFTR
inward rectifier, lK1 KCNJ1/Kir 2.1
pacemaker current, lf HCN2, 4/HCN2, 4

Na+/Ca2+ exchange SLC8A1/NCX 1

Na+/K+-ATPase NKAIN1-4/Na, K-pump

FIGURE 14–2 Schematic diagram of the ion permeability changes and transport processes that occur during an action potential and the
diastolic period following it. Yellow indicates inward (depolarizing) membrane currents; blue indicates outward (repolarizing) membrane cur-
rents. Multiple subtypes of potassium and calcium currents, with different sensitivities to blocking drugs, have been identified. The right side of
the figure lists the genes and proteins responsible for each type of channel or transporter.

channel suddenly increases in response to a depolarizing stimulus. would drive Na+ into cells. Sodium does not enter the cell at rest
Similarly, calcium enters and potassium leaves the cell with each because sodium channels are closed; when sodium channels open,
+
action potential. Therefore, in addition to ion channels, the cell must the very large influx of Na accounts for phase 0 depolarization of
have mechanisms to maintain stable transmembrane ionic condi- the action potential. The situation for K+ in the resting cardiac cell
tions by establishing and maintaining ion gradients. The most is quite different. Here, the concentration gradient (140 mmol/L
important of these active mechanisms is the sodium pump, Na+/ inside; 4 mmol/L outside) would drive the ion out of the cell, but
+
K -ATPase, described in Chapter 13. This pump and other active the electrical gradient would drive it in; that is, the inward gradi-
ion carriers contribute indirectly to the transmembrane potential by ent is in equilibrium with the outward gradient. In fact, certain
maintaining the gradients necessary for diffusion through channels. potassium channels (“inward rectifier” channels) are open in the
In addition, some pumps and exchangers produce net current flow resting cell, but little current flows through them because of this
(eg, by exchanging three Na+ for two K+ ions) and hence are termed balance. The equilibrium, or reversal potential, for ions is deter-
“electrogenic.” mined by the Nernst equation:
When the cardiac cell membrane becomes permeable to a spe-
cific ion (ie, when the channels selective for that ion are open), Ce
Eion = 61 × log
movement of that ion across the cell membrane is determined by Ci
Ohm’s law: current = voltage ÷ resistance, or current = voltage ×
conductance. Conductance is determined by the properties of the where Ce and Ci are the extracellular and intracellular concentra-
individual ion channel protein. The voltage term is the difference tions, respectively, multiplied by their activity coefficients. Note
between the actual membrane potential and the reversal potential that raising extracellular potassium makes EK less negative. When
for that ion (the membrane potential at which no current would this occurs, the membrane depolarizes until the new EK is reached.
flow even if channels were open). For example, in the case of Thus, extracellular potassium concentration and inward rectifier
sodium in a cardiac cell at rest, there is a substantial concentration channel function are the major factors determining the membrane
+ +
gradient (140 mmol/L Na outside; 10–15 mmol/L Na inside) potential of the resting cardiac cell. The conditions required for
and an electrical gradient (0 mV outside; −90 mV inside) that application of the Nernst equation are approximated at the peak of
230 SECTION III Cardiovascular-Renal Drugs

the overshoot (using sodium concentrations) and during rest (using

potassium concentrations) in most nonpacemaker cardiac cells. If Effects of Potassium
the permeability is significant for both potassium and sodium, the
Nernst equation is not a good predictor of membrane potential, The effects of changes in serum potassium on cardiac action
but the Goldman-Hodgkin-Katz equation may be used: potential duration, pacemaker rate, and arrhythmias can
appear somewhat paradoxical if changes are predicted based
solely on a consideration of changes in the potassium electro-
PK × Ke + PNa × Nae
Emem = 61 × log chemical gradient. In the heart, however, changes in serum
PK × Ki + PNa × Nai
potassium concentration have the additional effect of alter-
ing potassium conductance (increased extracellular potas-
In pacemaker cells (whether normal or ectopic), spontaneous sium increases potassium conductance) independent of
depolarization (the pacemaker potential) occurs during diastole simple changes in electrochemical driving force, and this
(phase 4, Figure 14–1). This depolarization results from a gradual effect often predominates. As a result, the actual observed
increase of depolarizing current through special hyperpolarization- effects of hyperkalemia include reduced action potential
activated ion channels (If, also called Ih) in pacemaker cells. The duration, slowed conduction, decreased pacemaker rate, and
effect of changing extracellular potassium is more complex in a decreased pacemaker arrhythmogenesis. Conversely, the
pacemaker cell than it is in a nonpacemaker cell because the effect actual observed effects of hypokalemia include prolonged
on permeability to potassium is much more important in a pace- action potential duration, increased pacemaker rate, and
maker (see Box: Effects of Potassium). In a pacemaker—especially increased pacemaker arrhythmogenesis. Furthermore, pace-
an ectopic one—the end result of an increase in extracellular maker rate and arrhythmias involving ectopic pacemaker
potassium is usually to slow or stop the pacemaker. Conversely, cells appear to be more sensitive to changes in serum potas-
hypokalemia often facilitates ectopic pacemakers. sium concentration, compared with cells of the sinoatrial
node. These effects of serum potassium on the heart probably
The Active Cell Membrane contribute to the observed increased sensitivity to potassium
In normal atrial, Purkinje, and ventricular cells, the action channel-blocking antiarrhythmic agents (quinidine or sotalol)
potential upstroke (phase 0) is dependent on sodium current. during hypokalemia, eg, accentuated action potential prolon-
From a functional point of view, it is convenient to describe the gation and tendency to cause torsades de pointes.
behavior of the sodium current in terms of three channel states
(Figure 14–3). The cardiac sodium channel protein has been

Resting Activated Inactivated

Extracellular
Na+ Na+ Na+
+ + +

m m m m m m

+
h
Intracellular +
h h
potential (mV)

40 40 40
Membrane

0 0 0
-40 -40 -40
Threshold
-60 -60 -60

Recovery
+
FIGURE 14–3 A schematic representation of Na channels cycling through different conformational states during the cardiac action
potential. Transitions between resting, activated, and inactivated states are dependent on membrane potential and time. The activation gate is
shown as m and the inactivation gate as h. Potentials typical for each state are shown under each channel schematic as a function of time. The
dashed line indicates that part of the action potential during which most Na+ channels are completely or partially inactivated and unavailable
for reactivation.
232 SECTION III Cardiovascular-Renal Drugs

Molecular & Genetic Basis of Cardiac Arrhythmias

It is now possible to define the molecular basis of several congenital the LQT syndromes now raises the possibility that specific therapies
and acquired cardiac arrhythmias. The best example is the polymor- may be developed for individuals with defined molecular abnor-
phic ventricular tachycardia known as torsades de pointes (shown in malities. Indeed, preliminary reports suggest that the sodium chan-
Figure 14–8), which is associated with prolongation of the QT interval nel blocker mexiletine can correct the clinical manifestations of
(especially at the onset of the tachycardia), syncope, and sudden congenital LQT subtype 3 syndrome. It is likely that torsades de
death. This must represent prolongation of the action potential of at pointes originates from triggered upstrokes arising from early after-
least some ventricular cells (Figure 14–1). The effect can, in theory, be depolarizations (Figure 14–5). Thus, therapy is directed at correcting
attributed to either increased inward current (gain of function) or hypokalemia, eliminating triggered upstrokes (eg, by using β block-
decreased outward current (loss of function) during the plateau of ers or magnesium), or shortening the action potential (eg, by
the action potential. In fact, recent molecular genetic studies have increasing heart rate with isoproterenol or pacing)—or all of these.
identified up to 300 different mutations in at least eight ion channel The molecular basis of several other congenital cardiac arrhyth-
genes that produce the congenital long QT (LQT) syndrome mias associated with sudden death has also recently been identi-
( Table 14–1), and different mutations may have different clinical fied. Three forms of short QT syndrome have been identified that
implications. Loss-of-function mutations in potassium channel genes are linked to gain-of-function mutations in three different potas-
produce decreases in outward repolarizing current and are respon- sium channel genes (KCNH2, KCNQ1, and KCNJ2). Catecholaminergic
sible for LQT subtypes 1, 2, 5, 6, and 7. HERG and KCNE2 (MiRP1) genes polymorphic ventricular tachycardia, a disease that is characterized
encode subunits of the rapid delayed rectifier potassium current (IKr), by stress- or emotion-induced syncope, can be caused by genetic
whereas KCNQ1 and KCNE1 (minK) encode subunits of the slow mutations in two different proteins in the sarcoplasmic reticulum
delayed rectifier potassium current (IKs). KCNJ2 encodes an inwardly that control intracellular calcium homeostasis. Mutations in two
rectifying potassium current (IKir). In contrast, gain-of-function muta- different ion channel genes (HCN4 and SCN5A) have been linked to
tions in the sodium channel gene (SCN5A) or calcium channel gene congenital forms of sick sinus syndrome. The Brugada syndrome,
(CACNA1c) cause increases in inward plateau current and are respon- which is characterized by ventricular fibrillation associated with
sible for LQT subtypes 3 and 8, respectively. persistent ST-segment elevation, and progressive cardiac conduc-
Molecular genetic studies have identified the reason why con- tion disorder (PCCD), characterized by impaired conduction in the
genital and acquired cases of torsades de pointes can be so strik- His-Purkinje system and right or left bundle block leading to com-
ingly similar. The potassium channel IKr (encoded by HERG) is plete atrioventricular block, have both been linked to several loss-
blocked or modified by many drugs (eg, quinidine, sotalol) or elec- of-function mutations in the sodium channel gene, SCN5A. At least
trolyte abnormalities (hypokalemia, hypomagnesemia, hypocalce- one form of familial atrial fibrillation is caused by a gain-of-function
mia) that also produce torsades de pointes. Thus, the identification mutation in the potassium channel gene, KCNQ1.
of the precise molecular mechanisms underlying various forms of
Channels available, percent of maximum

Recovery time constant (ms)

100,000 Drug

100
10,000

Control 1000

100
Drug
Control
10

0 0
–120 –100 –80 –60 –120 –100 –80 –60
Resting membrane potential (mV) Resting membrane potential (mV)

FIGURE 14–4 Dependence of sodium channel function on the membrane potential preceding the stimulus. Left: The fraction of sodium
channels available for opening in response to a stimulus is determined by the membrane potential immediately preceding the stimulus. The
decrease in the fraction available when the resting potential is depolarized in the absence of a drug (control curve) results from the
voltage-dependent closure of h gates in the channels. The curve labeled Drug illustrates the effect of a typical local anesthetic antiarrhythmic
drug. Most sodium channels are inactivated during the plateau of the action potential. Right: The time constant for recovery from inactivation
after repolarization also depends on the resting potential. In the absence of drug, recovery occurs in less than 10 ms at normal resting poten-
tials (−85 to −95 mV). Depolarized cells recover more slowly (note logarithmic scale). In the presence of a sodium channel-blocking drug, the
time constant of recovery is increased, but the increase is far greater at depolarized potentials than at more negative ones.
234 SECTION III Cardiovascular-Renal Drugs

round trips through the pathway the reentrant impulse makes before
Early afterdepolarization
dying out, the arrhythmia may be manifest as one or a few extra beats
Prolonged (arises from the plateau)
0 mV plateau or as a sustained tachycardia.
For reentry to occur, three conditions must coexist, as indi-
cated in Figure 14–6. (1) There must be an obstacle (anatomic
or physiologic) to homogeneous conduction, thus establishing
a circuit around which the reentrant wavefront can propagate.
(2) There must be unidirectional block at some point in the
–70 circuit; that is, conduction must die out in one direction but
continue in the opposite direction (as shown in Figure 14–6, the
0.5 sec
impulse can gradually decrease as it invades progressively more
depolarized tissue until it finally blocks—a process known as dec-
0 mV remental conduction). (3) Conduction time around the circuit
Delayed afterdepolarization
(arises from the resting must be long enough that the retrograde impulse does not enter
potential) refractory tissue as it travels around the obstacle; that is, the con-
duction time must exceed the effective refractory period. It is
important to note that reentry depends on conduction that has
been depressed by some critical amount, usually as a result of
–70 injury or ischemia. If conduction velocity is too slow, bidirectional
block rather than unidirectional block occurs; if the reentering
FIGURE 14–5 Two forms of abnormal activity, early (top) and impulse is too weak, conduction may fail, or the impulse may
delayed afterdepolarizations (bottom). In both cases, abnormal arrive so late that it collides with the next regular impulse. On the
depolarizations arise during or after a normally evoked action poten- other hand, if conduction is too rapid—ie, almost normal—bidi-
tial. They are therefore often referred to as “triggered” automaticity; rectional conduction rather than unidirectional block will occur.
that is, they require a normal action potential for their initiation. Even in the presence of unidirectional block, if the impulse travels
around the obstacle too rapidly, it will reach tissue that is still
refractory. Representative electrocardiograms of important arrhyth-
multiple reentry circuits, determined by the varying properties of the mias are shown in Figures 14–7 and 14–8.
cardiac tissue, may meander through the heart in apparently random Slowing of conduction may be due to depression of sodium
paths. The circulating impulse often gives off “daughter impulses” current, depression of calcium current (the latter especially in the
that can spread to the rest of the heart. Depending on how many AV node), or both. Drugs that abolish reentry usually work by

Forward impulse Retrograde

obstructed and extinguished impulse
Purkinje twig

Depressed region

A. Normal conduction B. Unidirectional block

FIGURE 14–6 Schematic diagram of a reentry circuit that might occur in small bifurcating branches of the Purkinje system where they
enter the ventricular wall. A: Normally, electrical excitation branches around the circuit, is transmitted to the ventricular branches, and becomes
extinguished at the other end of the circuit due to collision of impulses. B: An area of unidirectional block develops in one of the branches, pre-
venting anterograde impulse transmission at the site of block, but the retrograde impulse may be propagated through the site of block if the
impulse finds excitable tissue; that is, the refractory period is shorter than the conduction time. This impulse then reexcites tissue it had previ-
ously passed through, and a reentry arrhythmia is established.
234 SECTION III Cardiovascular-Renal Drugs

round trips through the pathway the reentrant impulse makes before
Early afterdepolarization
dying out, the arrhythmia may be manifest as one or a few extra beats
Prolonged (arises from the plateau)
0 mV plateau or as a sustained tachycardia.
For reentry to occur, three conditions must coexist, as indi-
cated in Figure 14–6. (1) There must be an obstacle (anatomic
or physiologic) to homogeneous conduction, thus establishing
a circuit around which the reentrant wavefront can propagate.
(2) There must be unidirectional block at some point in the
–70 circuit; that is, conduction must die out in one direction but
continue in the opposite direction (as shown in Figure 14–6, the
0.5 sec
impulse can gradually decrease as it invades progressively more
depolarized tissue until it finally blocks—a process known as dec-
0 mV remental conduction). (3) Conduction time around the circuit
Delayed afterdepolarization
(arises from the resting must be long enough that the retrograde impulse does not enter
potential) refractory tissue as it travels around the obstacle; that is, the con-
duction time must exceed the effective refractory period. It is
important to note that reentry depends on conduction that has
been depressed by some critical amount, usually as a result of
–70 injury or ischemia. If conduction velocity is too slow, bidirectional
block rather than unidirectional block occurs; if the reentering
FIGURE 14–5 Two forms of abnormal activity, early (top) and impulse is too weak, conduction may fail, or the impulse may
delayed afterdepolarizations (bottom). In both cases, abnormal arrive so late that it collides with the next regular impulse. On the
depolarizations arise during or after a normally evoked action poten- other hand, if conduction is too rapid—ie, almost normal—bidi-
tial. They are therefore often referred to as “triggered” automaticity; rectional conduction rather than unidirectional block will occur.
that is, they require a normal action potential for their initiation. Even in the presence of unidirectional block, if the impulse travels
around the obstacle too rapidly, it will reach tissue that is still
refractory. Representative electrocardiograms of important arrhyth-
multiple reentry circuits, determined by the varying properties of the mias are shown in Figures 14–7 and 14–8.
cardiac tissue, may meander through the heart in apparently random Slowing of conduction may be due to depression of sodium
paths. The circulating impulse often gives off “daughter impulses” current, depression of calcium current (the latter especially in the
that can spread to the rest of the heart. Depending on how many AV node), or both. Drugs that abolish reentry usually work by

Forward impulse Retrograde

obstructed and extinguished impulse
Purkinje twig

Depressed region

A. Normal conduction B. Unidirectional block

FIGURE 14–6 Schematic diagram of a reentry circuit that might occur in small bifurcating branches of the Purkinje system where they
enter the ventricular wall. A: Normally, electrical excitation branches around the circuit, is transmitted to the ventricular branches, and becomes
extinguished at the other end of the circuit due to collision of impulses. B: An area of unidirectional block develops in one of the branches, pre-
venting anterograde impulse transmission at the site of block, but the retrograde impulse may be propagated through the site of block if the
impulse finds excitable tissue; that is, the refractory period is shorter than the conduction time. This impulse then reexcites tissue it had previ-
ously passed through, and a reentry arrhythmia is established.
 CHAPTER 14 Agents Used in Cardiac Arrhythmias 235

Panel 1: aVF
P R T
■ BASIC PHARMACOLOGY OF
Normal
sinus THE ANTIARRHYTHMIC AGENTS
rhythm

Mechanisms of Action
P' P' P' R P' P' P'
Panel 2:
Arrhythmias are caused by abnormal pacemaker activity or abnor-
V2
Atrial mal impulse propagation. Thus, the aim of therapy of the arrhyth-
flutter mias is to reduce ectopic pacemaker activity and modify conduction
or refractoriness in reentry circuits to disable circus movement.
S The major pharmacologic mechanisms currently available for
T T T
accomplishing these goals are (1) sodium channel blockade, (2)
V1 blockade of sympathetic autonomic effects in the heart, (3) pro-
longation of the effective refractory period, and (4) calcium chan-
nel blockade.
Panel 3: Before digitalis Antiarrhythmic drugs decrease the automaticity of ectopic pace-
Atrial S S S
makers more than that of the SA node. They also reduce conduction
fibrillation V
1 and excitability and increase the refractory period to a greater extent
in depolarized tissue than in normally polarized tissue. This is
accomplished chiefly by selectively blocking the sodium or calcium
After digitalis
channels of depolarized cells (Figure 14–9). Therapeutically useful
S S channel-blocking drugs bind readily to activated channels (ie, dur-
R R R
Panel 4: V1 ing phase 0) or inactivated channels (ie, during phase 2) but bind
Ventricular poorly or not at all to rested channels. Therefore, these drugs block
tachycardia
(starting at electrical activity when there is a fast tachycardia (many channel
arrow) activations and inactivations per unit time) or when there is signifi-
cant loss of resting potential (many inactivated channels during
rest). This type of drug action is often described as use-dependent
QS QS T T T or state-dependent; that is, channels that are being used frequently,
Panel 5: V4 or in an inactivated state, are more susceptible to block. Channels
Ventricular in normal cells that become blocked by a drug during normal
fibrillation
activation-inactivation cycles will rapidly lose the drug from the
receptors during the resting portion of the cycle (Figure 14–9).
Channels in myocardium that is chronically depolarized (ie, has a
FIGURE 14–7 Electrocardiograms of normal sinus rhythm and
some common arrhythmias. Major deflections (P, Q, R, S, and T) are
resting potential more positive than −75 mV) recover from block
labeled in each electrocardiographic record except in panel 5, in very slowly if at all (see also right panel, Figure 14–4).
which electrical activity is completely disorganized and none of these In cells with abnormal automaticity, most of these drugs reduce
deflections is recognizable. (Modified and reproduced, with permission, from the phase 4 slope by blocking either sodium or calcium channels,
Goldman MJ: Principles of Clinical Electrocardiography, 11th ed. McGraw-Hill, 1982.) thereby reducing the ratio of sodium (or calcium) permeability to
potassium permeability. As a result, the membrane potential during
phase 4 stabilizes closer to the potassium equilibrium potential. In
addition, some agents may increase the threshold (make it more
positive). β-Adrenoceptor–blocking drugs indirectly reduce the
further slowing depressed conduction (by blocking the sodium or phase 4 slope by blocking the positive chronotropic action of nor-
calcium current) and causing bidirectional block. In theory, accel- epinephrine in the heart.
erating conduction (by increasing sodium or calcium current) In reentry arrhythmias, which depend on critically depressed
would also be effective, but only under unusual circumstances conduction, most antiarrhythmic agents slow conduction fur-
does this mechanism explain the action of any available drug. ther by one or both of two mechanisms: (1) steady-state
Lengthening (or shortening) of the refractory period may also reduction in the number of available unblocked channels,
make reentry less likely. The longer the refractory period in tissue which reduces the excitatory currents to a level below that
near the site of block, the greater the chance that the tissue will required for propagation (Figure 14–4, left); and (2) prolonga-
still be refractory when reentry is attempted. (Alternatively, the tion of recovery time of the channels still able to reach the rested
shorter the refractory period in the depressed region, the less likely and available state, which increases the effective refractory period
it is that unidirectional block will occur.) Thus, increased disper- (Figure 14–4, right). As a result, early extrasystoles are unable to
sion of refractoriness is one contributor to reentry, and drugs may propagate at all; later impulses propagate more slowly and are
suppress arrhythmias by reducing such dispersion. subject to bidirectional conduction block.
236 SECTION III Cardiovascular-Renal Drugs

Polymorphic ventricular tachycardia

(torsade de pointes)

NSB

Prolonged QT interval

FIGURE 14–8 Electrocardiogram from a patient with the long QT syndrome during two episodes of torsades de pointes. The polymorphic
ventricular tachycardia is seen at the start of this tracing and spontaneously halts at the middle of the panel. A single normal sinus beat (NSB)
with an extremely prolonged QT interval follows, succeeded immediately by another episode of ventricular tachycardia of the torsades type.
The usual symptoms include dizziness or transient loss of consciousness. (Reproduced, with permission, from Basic and Clinical Pharmacology, 10th edition,
McGraw-Hill, 2007.)

By these mechanisms, antiarrhythmic drugs can suppress ecto- 4. Class 4 action is blockade of the cardiac calcium current. This
pic automaticity and abnormal conduction occurring in depolar- action slows conduction in regions where the action potential
ized cells—rendering them electrically silent—while minimally upstroke is calcium dependent, eg, the SA and AV nodes.
affecting the electrical activity in normally polarized parts of the
A given drug may have multiple classes of action as indicated
heart. However, as dosage is increased, these agents also depress
by its membrane and electrocardiographic (ECG) effects (Tables
conduction in normal tissue, eventually resulting in drug-in-
14–2 and 14–3). For example, amiodarone shares all four classes
duced arrhythmias. Furthermore, a drug concentration that is
of action. Drugs are usually discussed according to the predomi-
therapeutic (antiarrhythmic) under the initial circumstances of
nant class of action. Certain antiarrhythmic agents, eg, adenosine
treatment may become “proarrhythmic” (arrhythmogenic) dur-
and magnesium, do not fit readily into this scheme and are
ing fast heart rates (more development of block), acidosis
described separately.
(slower recovery from block for most drugs), hyperkalemia, or
ischemia.
SODIUM CHANNEL-BLOCKING
DRUGS (CLASS 1)
■ SPECIFIC ANTIARRHYTHMIC Drugs with local anesthetic action block sodium channels and
AGENTS reduce the sodium current, INa. They are the oldest group of anti-
arrhythmic drugs and are still widely used.

The most widely used scheme for the classification of antiarrhyth- PROCAINAMIDE (SUBGROUP 1A)
mic drug actions recognizes four classes:
1. Class 1 action is sodium channel blockade. Subclasses Cardiac Effects
of this action reflect effects on the action potential
duration (APD) and the kinetics of sodium channel By blocking sodium channels, procainamide slows the upstroke
blockade. Drugs with class 1A action prolong the APD of the action potential, slows conduction, and prolongs the QRS
and dissociate from the channel with intermediate duration of the ECG. The drug also prolongs the APD (a class 3
kinetics; drugs with class 1B action shorten the APD in action) by nonspecific blockade of potassium channels. The drug
some tissues of the heart and dissociate from the chan- may be somewhat less effective than quinidine (see below) in
nel with rapid kinetics; and drugs with class 1C action
suppressing abnormal ectopic pacemaker activity but more effec-
have minimal effects on the APD and dissociate from
the channel with slow kinetics. tive in blocking sodium channels in depolarized cells.
2. Class 2 action is sympatholytic. Drugs with this action O
reduce β-adrenergic activity in the heart. H C2H5
H2N C N CH2 CH2 N
3. Class 3 action manifests as prolongation of the APD. Most C2H5
drugs with this action block the rapid component of the
delayed rectifier potassium current, IKr. Procainamide
 CHAPTER 14 Agents Used in Cardiac Arrhythmias 237

Unblocked R A I

Blocked R-D A-D I-D

0
Sodium current (microamps / cm2)

–460

–920

–1380

–1840

–2300
0 1 2 3 4 5
Time (ms)

FIGURE 14–9 State- and frequency-dependent block of sodium channels by antiarrhythmic drugs. Top: Diagram of a mechanism for the
selective depressant action of antiarrhythmic drugs on sodium channels. The upper portion of the figure shows the population of channels
moving through a cycle of activity during an action potential in the absence of drugs: R (rested) → A (activated) → I (inactivated). Recovery
takes place via the I → R pathway. Antiarrhythmic drugs (D) that act by blocking sodium channels can bind to their receptors in the channels, as
shown by the vertical arrows, to form drug-channel complexes, indicated as R-D, A-D, and I-D. Binding of the drugs to the receptor varies with
the state of the channel. Most sodium channel blockers bind to the active and inactivated channel receptor much more strongly than to the
rested channel. Furthermore, recovery from the I-D state to the R-D state is much slower than from I to R. As a result, rapid activity (more activa-
tions and inactivations) and depolarization of the resting potential (more channels in the I state) will favor blockade of the channels and selec-
tively suppress arrhythmic cells. Bottom: Progressive reduction of inward sodium current (downward deflections) in the presence of a lidocaine
derivative. The largest curve is the initial sodium current elicited by a depolarizing voltage step; subsequent sodium current amplitudes are pro-
gressively reduced owing to prior accumulated block and block during each depolarization. (Adapted, with permission, from Starmer FC, Grant AO, Strauss
HC: Mechanisms of use-dependent block of sodium channels in excitable membranes by local anesthetics. Biophys J 1984;46:15.)

Procainamide has direct depressant actions on SA and AV nodes, of torsades de pointes arrhythmia and syncope. Excessive slow-
and these actions are only slightly counterbalanced by drug- ing of conduction can also occur. New arrhythmias can be
induced vagal block. precipitated.
A troublesome adverse effect of long-term procainamide
Extracardiac Effects therapy is a syndrome resembling lupus erythematosus and usu-
ally consisting of arthralgia and arthritis. In some patients,
Procainamide has ganglion-blocking properties. This action
pleuritis, pericarditis, or parenchymal pulmonary disease also
reduces peripheral vascular resistance and can cause hypotension,
occurs. Renal lupus is rarely induced by procainamide. During
particularly with intravenous use. However, in therapeutic con-
long-term therapy, serologic abnormalities (eg, increased anti-
centrations, its peripheral vascular effects are less prominent than
nuclear antibody titer) occur in nearly all patients, and in the
those of quinidine. Hypotension is usually associated with exces-
absence of symptoms, these are not an indication to stop drug
sively rapid procainamide infusion or the presence of severe
therapy. Approximately one third of patients receiving long-
underlying left ventricular dysfunction.
term procainamide therapy develop these reversible lupus-
related symptoms.
Toxicity Other adverse effects include nausea and diarrhea (in about
Procainamide’s cardiotoxic effects include excessive action poten- 10% of cases), rash, fever, hepatitis (< 5%), and agranulocytosis
tial prolongation, QT-interval prolongation, and induction (approximately 0.2%).
238 SECTION III Cardiovascular-Renal Drugs

TABLE 14–2 Membrane actions of antiarrhythmic drugs.

Block of Sodium Channels Refractory Period
Calcium Effect on
Depolarized Channel Pacemaker Sympatholytic
Drug Normal Cells Cells Normal Cells Depolarized Cells Blockade Activity Action

Adenosine 0 0 0 0 + 0 +
Amiodarone + +++ ↑↑ ↑↑ + ↓↓ +
Diltiazem 0 0 0 0 +++ ↓↓ 0
Disopyramide + +++ ↑ ↑↑ + ↓ 0
Dofetilide 0 0 ↑ ? 0 0 0
Dronedarone + + na na + na +
Esmolol 0 + 0 na 0 ↓↓ +++
Flecainide + +++ 0 ↑ 0 ↓↓ 0
Ibutilide 0 0 ↑ ? 0 0 0
Lidocaine 0 +++ ↓ ↑↑ 0 ↓↓ 0
Mexiletine 0 +++ 0 ↑↑ 0 ↓↓ 0
Procainamide + +++ ↑ ↑↑↑ 0 ↓ +
Propafenone + ++ ↑ ↑↑ + ↓↓ +
Propranolol 0 + ↓ ↑↑ 0 ↓↓ +++
Quinidine + ++ ↑ ↑↑ 0 ↓↓ +
Sotalol 0 0 ↑↑ ↑↑↑ 0 ↓↓ ++
Verapamil 0 + 0 ↑ +++ ↓↓ +
Vernakalant + + + + na 0 na

na, data not available.

Pharmacokinetics & Dosage of gastrointestinal (GI) or cardiac toxicity rises at plasma concen-
trations greater than 8 mcg/mL or NAPA concentrations greater
Procainamide can be administered safely by intravenous and intra-
than 20 mcg/mL.
muscular routes and is well absorbed orally. A metabolite
To control ventricular arrhythmias, a total procainamide dos-
(N-acetylprocainamide, NAPA) has class 3 activity. Excessive
age of 2–5 g/d is usually required. In an occasional patient who
accumulation of NAPA has been implicated in torsades de pointes
accumulates high levels of NAPA, less frequent dosing may be
during procainamide therapy, especially in patients with renal
possible. This is also possible in renal disease, where procainamide
failure. Some individuals rapidly acetylate procainamide and
elimination is slowed.
develop high levels of NAPA. The lupus syndrome appears to be
less common in these patients.
Procainamide is eliminated by hepatic metabolism to NAPA
Therapeutic Use
and by renal elimination. Its half-life is only 3–4 hours, which Procainamide is effective against most atrial and ventricular
necessitates frequent dosing or use of a slow-release formulation arrhythmias. However, many clinicians attempt to avoid long-
(the usual practice). NAPA is eliminated by the kidneys. Thus, term therapy because of the requirement for frequent dosing and
procainamide dosage must be reduced in patients with renal fail- the common occurrence of lupus-related effects. Procainamide is
ure. The reduced volume of distribution and renal clearance associ- the drug of second or third choice (after lidocaine or amiodarone)
ated with heart failure also require reduction in dosage. The in most coronary care units for the treatment of sustained ven-
half-life of NAPA is considerably longer than that of procainamide, tricular arrhythmias associated with acute myocardial infarction.
and it therefore accumulates more slowly. Thus, it is important to
measure plasma levels of both procainamide and NAPA, especially
in patients with circulatory or renal impairment.
QUINIDINE (SUBGROUP 1A)
If a rapid procainamide effect is needed, an intravenous load-
ing dose of up to 12 mg/kg can be given at a rate of 0.3 mg/kg/ Cardiac Effects
min or less rapidly. This dose is followed by a maintenance dosage Quinidine has actions similar to those of procainamide: it slows the
of 2–5 mg/min, with careful monitoring of plasma levels. The risk upstroke of the action potential, slows conduction, and prolongs
 CHAPTER 14 Agents Used in Cardiac Arrhythmias 239

TABLE 14–3 Clinical pharmacologic properties of antiarrhythmic drugs.

Effect on AV Usefulness in Arrhythmias
Nodal
Effect on SA Refractory QRS QT Supra–
Drug Nodal Rate Period PR Interval Duration Interval ventricular Ventricular Half-Life

Adenosine ↓↑ ↑↑↑ ↑↑↑ 0 0 ++++ ? < 10 s

1
Amiodarone ↓↓ ↑↑ Variable ↑ ↑↑↑↑ +++ +++ (weeks)
Diltiazem ↑↓ ↑↑ ↑ 0 0 +++ – 4–8 h
1,2 2 2
Disopyramide ↑↓ ↑↓ ↑↓ ↑↑ ↑↑ + +++ 7–8 h
Dofetilide ↓(?) 0 0 0 ↑↑ ++ None 7h
Dronedarone ↑ +++ – 24 h
Esmolol ↓↓ ↑↑ ↑↑ 0 0 + + 10 min
Flecainide None,↓ ↑ ↑ ↑↑↑ 0 +3 ++++ 20 h
Ibutilide ↓ (?) 0 0 0 ↑↑ ++ ? 6h
Lidocaine None1 None 0 0 0 None
4
+++ 1–2 h
1
Mexiletine None None 0 0 0 None +++ 12 h
1 2 2
Procainamide ↓ ↑↓ ↑↓ ↑↑ ↑↑ + +++ 3–4 h
Propafenone 0, ↓ ↑ ↑ ↑↑↑ 0 + +++ 5–7 h
Propranolol ↓↓ ↑↑ ↑↑ 0 0 + + 5h
Quinidine ↑↓1,2 ↑↓2 ↑↓2 ↑↑ ↑↑ + +++ 6h
Sotalol ↓↓ ↑↑ ↑↑ 0 ↑↑↑ +++ +++ 7h
Verapamil ↓↓ ↑↑ ↑↑ 0 0 +++ – 7h
Vernakalant ↑ ↑ +++ – 2h
1
May suppress diseased sinus nodes.
2
Anticholinergic effect and direct depressant action.
3
Especially in Wolff-Parkinson-White syndrome.
4
May be effective in atrial arrhythmias caused by digitalis.
5
Half-life of active metabolites much longer.

the QRS duration of the ECG, by blockade of sodium channels. and tinnitus (cinchonism) is observed at toxic drug concentra-
The drug also prolongs the action potential duration by blockade tions. Idiosyncratic or immunologic reactions, including thrombo-
of several potassium channels. Its toxic cardiac effects include cytopenia, hepatitis, angioneurotic edema, and fever, are observed
excessive QT-interval prolongation and induction of torsades rarely.
de pointes arrhythmia. Toxic concentrations of quinidine also
produce excessive sodium channel blockade with slowed Pharmacokinetics & Therapeutic Use
conduction throughout the heart.
Quinidine is readily absorbed from the GI tract and eliminated by
hepatic metabolism. It is rarely used because of cardiac and extra-
O CH3
cardiac adverse effects and the availability of better-tolerated anti-
arrhythmic drugs.

H N

N C
DISOPYRAMIDE (SUBGROUP 1A)
CH CH2

OH Cardiac Effects
Quinidine
The effects of disopyramide are very similar to those of procain-
amide and quinidine. Its cardiac antimuscarinic effects are even
Extracardiac Effects more marked than those of quinidine. Therefore, a drug that slows
Adverse GI effects of diarrhea, nausea, and vomiting are observed AV conduction should be administered with disopyramide when
in one third to one half of patients. A syndrome of headache, dizziness, treating atrial flutter or fibrillation.
240 SECTION III Cardiovascular-Renal Drugs

Channels blocked (%) Membrane potential (mV)

N 0
O
CH(CH3)2
H2N C C CH2 CH2 N
CH(CH3)2 –75 –70
–85 –80
–100

Disopyramide
100

Toxicity
Toxic concentrations of disopyramide can precipitate all of the
electrophysiologic disturbances described under quinidine. As a 0
result of its negative inotropic effect, disopyramide may precipi- 800
tate heart failure de novo or in patients with preexisting depression Time (ms)
of left ventricular function. Because of this effect, disopyramide is FIGURE 14–10 Computer simulation of the effect of resting
not used as a first-line antiarrhythmic agent in the USA. It should membrane potential on the blocking and unblocking of sodium channels
not be used in patients with heart failure. by lidocaine as the membrane depolarizes. Upper tracing: Action potentials
Disopyramide’s atropine-like activity accounts for most of its in a ventricular muscle cell. Lower tracing: Percentage of channels
symptomatic adverse effects: urinary retention (most often, but blocked by the drug. An 800 ms time segment is shown. Extra passage of
not exclusively, in male patients with prostatic hyperplasia), dry time is indicated by breaks in the traces. Left side: At the normal resting
mouth, blurred vision, constipation, and worsening of preexisting potential of –85 mV, the drug combines with open (activated) and
glaucoma. These effects may require discontinuation of the drug. inactivated channels during each action potential, but block is rapidly
reversed during diastole because the affinity of the drug for its receptor is
so low when the channel recovers to the resting state at –85 mV. Middle:
Pharmacokinetics & Dosage Metabolic injury is simulated, eg, ischemia due to coronary occlusion,
In the USA, disopyramide is only available for oral use. The typi- that causes gradual depolarization over time. With subsequent action
cal oral dosage of disopyramide is 150 mg three times a day, but potentials arising from more depolarized potentials, the fraction of channels
up to 1 g/d has been used. In patients with renal impairment, dos- blocked increases because more channels remain in the inactivated state
age must be reduced. Because of the danger of precipitating heart at less negative potentials (Figure 14–4, left), and the time constant for
failure, loading doses are not recommended. unblocking during diastole rapidly increases at less negative resting
potentials (Figure 14–4, right). Right: Because of marked drug binding,
conduction block and loss of excitability in this tissue result; that is, the
Therapeutic Use “sick” (depolarized) tissue is selectively suppressed.
Although disopyramide has been shown to be effective in a variety
of supraventricular arrhythmias, in the USA it is approved only for greater effects on cells with long action potentials such as Purkinje
the treatment of ventricular arrhythmias. and ventricular cells, compared with atrial cells. The rapid kinetics
at normal resting potentials result in recovery from block between
action potentials and no effect on conduction. The increased inac-
LIDOCAINE (SUBGROUP 1B) tivation and slower unbinding kinetics result in the selective
depression of conduction in depolarized cells. Little effect is seen
Lidocaine has a low incidence of toxicity and a high degree of on the ECG in normal sinus rhythm.
effectiveness in arrhythmias associated with acute myocardial
infarction. It is used only by the intravenous route.
Toxicity
CH3 Lidocaine is one of the least cardiotoxic of the currently used
O
H C2H5
sodium channel blockers. Proarrhythmic effects, including SA node
N C CH2 N arrest, worsening of impaired conduction, and ventricular arrhyth-
C2H5 mias, are uncommon with lidocaine use. In large doses, especially in
CH3 patients with preexisting heart failure, lidocaine may cause hypoten-
Lidocaine sion—partly by depressing myocardial contractility.
Lidocaine’s most common adverse effects—like those of other
local anesthetics—are neurologic: paresthesias, tremor, nausea of
Cardiac Effects central origin, lightheadedness, hearing disturbances, slurred speech,
Lidocaine blocks activated and inactivated sodium channels with and convulsions. These occur most commonly in elderly or other-
rapid kinetics (Figure 14–10); the inactivated state block ensures wise vulnerable patients or when a bolus of the drug is given too
248 SECTION III Cardiovascular-Renal Drugs

SUMMARY Antiarrhythmic Drugs

Mechanism of Clinical Pharmacokinetics, Toxicities,
Subclass Action Effects Applications Interactions

CLASS 1A
• Procainamide INa (primary) and IKr Slows conduction velocity and Most atrial and ventricu- Oral, IV, IM • eliminated by hepatic
(secondary) pacemaker rate • prolongs action lar arrhythmias • drug of metabolism to N-acetylprocainamide
blockade potential duration and dissociates second choice for most (NAPA; see text) and renal elimination •
from INa channel with intermedi- sustained ventricular NAPA implicated in torsades de pointes in
ate kinetics • direct depressant arrhythmias associated patients with renal failure • Toxicity:
effects on sinoatrial (SA) and atrio- with acute myocardial Hypotension • long-term therapy produces
ventricular (AV) nodes infarction reversible lupus-related symptoms
• Quinidine: Similar to procainamide but more toxic (cinchonism, torsades); rarely used in arrhythmias; see Chapter 52 for malaria
• Disopyramide: Similar to procainamide but significant antimuscarinic effects; may precipitate heart failure; not commonly used

CLASS 1B
• Lidocaine Sodium channel Blocks activated and inactivated Terminate ventricular IV • first-pass hepatic metabolism • reduce
(INa) blockade channels with fast kinetics • does tachycardias and prevent dose in patients with heart failure or liver
not prolong and may shorten ventricular fibrillation disease • Toxicity: Neurologic symptoms
action potential after cardioversion

• Mexiletine: Orally active congener of lidocaine; used in ventricular arrhythmias, chronic pain syndromes

CLASS 1C
• Flecainide Sodium channel Dissociates from channel with Supraventricular arrhythmias Oral • hepatic and kidney metabolism • half
(INa) blockade slow kinetics • no change in action in patients with normal life ∼ 20 h • Toxicity: Proarrhythmic
potential duration heart • do not use in
ischemic conditions
(post-myocardial infarction)

• Propafenone: Orally active, weak b-blocking activity; supraventricular arrhythmias; hepatic metabolism
• Moricizine: Phenothiazine derivative, orally active; ventricular arrhythmias, proarrhythmic. Withdrawn in USA.

CLASS 2
• Propranolol β-Adrenoceptor Direct membrane effects (sodium Atrial arrhythmias and Oral, parenteral • duration 4–6 h • Toxicity:
blockade channel block) and prolongation prevention of recurrent Asthma, AV blockade, acute heart failure
of action potential duration • infarction and sudden • Interactions: With other cardiac depres-
slows SA node automaticity and death sants and hypotensive drugs
AV nodal conduction velocity

• Esmolol: Short-acting, IV only; used for intraoperative and other acute arrhythmias

CLASS 3
• Amiodarone Blocks IKr, INa, ICa-L Prolongs action potential duration Serious ventricular Oral, IV • variable absorption and tissue
channels, and QT interval • slows heart rate arrhythmias and accumulation • hepatic metabolism,
β adrenoceptors and AV node conduction • low supraventricular elimination complex and slow •
incidence of torsades de pointes arrhythmias Toxicity: Bradycardia and heart block in
diseased heart, peripheral vasodilation,
pulmonary and hepatic toxicity •
hyper- or hypothyroidism. • Interactions:
Many, based on CYP metabolism
• Dofetilide IKr block Prolongs action potential, effective Maintenance or restora- Oral • renal excretion • Toxicity: Torsades de
refractory period tion of sinus rhythm in pointes (initiate in hospital) • Interactions:
atrial fibrillation Additive with other QT-prolonging drugs

• Sotalol: b-Adrenergic and IKr blocker, direct action potential prolongation properties, use for ventricular arrhythmias, atrial fibrillation
• Ibutilide: Potassium channel blocker, may activate inward current; IV use for conversion in atrial flutter and fibrillation
• Dronedarone: Amiodarone derivative; multichannel actions, reduces mortality in patients with atrial fibrillation
• Vernakalant: Investigational, multichannel actions in atria, prolongs atrial refractoriness, effective in atrial fibrillation

(continued)
 CHAPTER 14 Agents Used in Cardiac Arrhythmias 249

Mechanism of Clinical Pharmacokinetics, Toxicities,

Subclass Action Effects Applications Interactions

CLASS 4
• Verapamil Calcium channel Slows SA node automaticity and Supraventricular Oral, IV • hepatic metabolism • caution in
(ICa-L type) blockade AV nodal conduction velocity • tachycardias, patients with hepatic dysfunction • Toxicity
decreases cardiac contractility • hypertension, angina & Interactions: See Chapter 12
reduces blood pressure

• Diltiazem: Equivalent to verapamil

MISCELLANEOUS
• Adenosine Activates inward Very brief, usually complete Paroxysmal supraventric- IV only • duration 10–15 seconds• Toxicity:
rectifier IK • blocks ICa AV blockade ular tachycardias Flushing, chest tightness, dizziness •
Interactions: Minimal
• Magnesium Poorly understood • Normalizes or increases Torsades de pointes IV • duration dependent on dosage •
+
interacts with Na / plasma Mg2+ • digitalis-induced Toxicity: Muscle weakness in overdose
K+-ATPase, K+, and arrhythmias
Ca2+ channels
• Potassium Increases K+ perme- Slows ectopic pacemakers • slows Digitalis-induced arrhyth- Oral, IV • Toxicity: Reentrant arrhythmias,
+
ability, K currents conduction velocity in heart mias • arrhythmias associ- fibrillation or arrest in overdose
ated with hypokalemia

P R E P A R A T I O N S A V A I L A B L E

SODIUM CHANNEL BLOCKERS BETA BLOCKERS LABELED FOR USE AS

Disopyramide (generic, Norpace) ANTIARRHYTHMICS
Oral: 100, 150 mg capsules Acebutolol (generic, Sectral)
Oral controlled-release (generic, Norpace CR): 100, 150 capsules Oral: 200, 400 mg capsules
Flecainide (generic, Tambocor) Esmolol (Brevibloc)
Oral: 50, 100, 150 mg tablets Parenteral: 10 mg/mL, 250 mg/mL for IV injection
Lidocaine (generic, Xylocaine) Propranolol (generic, Inderal)
Parenteral: 100 mg/mL for IM injection; 10, 20 mg/mL for IV injec- Oral: 10, 20, 40, 60, 80, 90 mg tablets
tion; 40, 100, 200 mg/mL for IV admixtures; 2, 4, 8 mg/mL pre- Oral sustained-release: 60, 80, 120, 160 mg capsules
mixed IV (5% D/W) solution Oral solution: 4, 8 mg/mL
Mexiletine (Mexitil) Parenteral: 1 mg/mL for injection
Oral: 150, 200, 250 mg capsules
Procainamide (generic, Pronestyl, others)
Oral: 250, 375, 500 mg tablets and capsules ACTION POTENTIAL-PROLONGING AGENTS
Oral sustained-release (generic, Procan-SR): 250, 500, 750, 1000 mg Amiodarone (generic, Cordarone)
tablets Oral: 100, 200, 400 mg tablets
Parenteral: 500 mg/mL for injection Parenteral: 150 mg/3 mL for IV infusion
Propafenone (generic, Rythmol) Dofetilide (Tikosyn)
Oral: 150, 225, 300 mg tablets, capsules Oral: 125, 250, 500 mcg capsules
Quinidine sulfate [83% quinidine base] (generic) Dronedarone (Multac)
Oral: 200, 300 mg tablets Oral: 400 mg tablets
Oral sustained-release (Quinidex Extentabs): 300 mg tablets
Ibutilide (Corvert)
Quinidine gluconate [62% quinidine base] (generic) Parenteral: 0.1 g/mL solution for IV infusion
Oral sustained-release: 324 mg tablets
Parenteral: 80 mg/mL for injection Sotalol (generic, Betapace)
Oral: 80, 120, 160, 240 mg capsules
Quinidine polygalacturonate [60% quinidine base] (Cardioquin)
Oral: 275 mg tablets
 CHAPTER 14 Agents Used in Cardiac Arrhythmias 249

Mechanism of Clinical Pharmacokinetics, Toxicities,

Subclass Action Effects Applications Interactions

CLASS 4
• Verapamil Calcium channel Slows SA node automaticity and Supraventricular Oral, IV • hepatic metabolism • caution in
(ICa-L type) blockade AV nodal conduction velocity • tachycardias, patients with hepatic dysfunction • Toxicity
decreases cardiac contractility • hypertension, angina & Interactions: See Chapter 12
reduces blood pressure

• Diltiazem: Equivalent to verapamil

MISCELLANEOUS
• Adenosine Activates inward Very brief, usually complete Paroxysmal supraventric- IV only • duration 10–15 seconds• Toxicity:
rectifier IK • blocks ICa AV blockade ular tachycardias Flushing, chest tightness, dizziness •
Interactions: Minimal
• Magnesium Poorly understood • Normalizes or increases Torsades de pointes IV • duration dependent on dosage •
+
interacts with Na / plasma Mg2+ • digitalis-induced Toxicity: Muscle weakness in overdose
K+-ATPase, K+, and arrhythmias
Ca2+ channels
• Potassium Increases K+ perme- Slows ectopic pacemakers • slows Digitalis-induced arrhyth- Oral, IV • Toxicity: Reentrant arrhythmias,
+
ability, K currents conduction velocity in heart mias • arrhythmias associ- fibrillation or arrest in overdose
ated with hypokalemia

P R E P A R A T I O N S A V A I L A B L E

SODIUM CHANNEL BLOCKERS BETA BLOCKERS LABELED FOR USE AS

Disopyramide (generic, Norpace) ANTIARRHYTHMICS
Oral: 100, 150 mg capsules Acebutolol (generic, Sectral)
Oral controlled-release (generic, Norpace CR): 100, 150 capsules Oral: 200, 400 mg capsules
Flecainide (generic, Tambocor) Esmolol (Brevibloc)
Oral: 50, 100, 150 mg tablets Parenteral: 10 mg/mL, 250 mg/mL for IV injection
Lidocaine (generic, Xylocaine) Propranolol (generic, Inderal)
Parenteral: 100 mg/mL for IM injection; 10, 20 mg/mL for IV injec- Oral: 10, 20, 40, 60, 80, 90 mg tablets
tion; 40, 100, 200 mg/mL for IV admixtures; 2, 4, 8 mg/mL pre- Oral sustained-release: 60, 80, 120, 160 mg capsules
mixed IV (5% D/W) solution Oral solution: 4, 8 mg/mL
Mexiletine (Mexitil) Parenteral: 1 mg/mL for injection
Oral: 150, 200, 250 mg capsules
Procainamide (generic, Pronestyl, others)
Oral: 250, 375, 500 mg tablets and capsules ACTION POTENTIAL-PROLONGING AGENTS
Oral sustained-release (generic, Procan-SR): 250, 500, 750, 1000 mg Amiodarone (generic, Cordarone)
tablets Oral: 100, 200, 400 mg tablets
Parenteral: 500 mg/mL for injection Parenteral: 150 mg/3 mL for IV infusion
Propafenone (generic, Rythmol) Dofetilide (Tikosyn)
Oral: 150, 225, 300 mg tablets, capsules Oral: 125, 250, 500 mcg capsules
Quinidine sulfate [83% quinidine base] (generic) Dronedarone (Multac)
Oral: 200, 300 mg tablets Oral: 400 mg tablets
Oral sustained-release (Quinidex Extentabs): 300 mg tablets
Ibutilide (Corvert)
Quinidine gluconate [62% quinidine base] (generic) Parenteral: 0.1 g/mL solution for IV infusion
Oral sustained-release: 324 mg tablets
Parenteral: 80 mg/mL for injection Sotalol (generic, Betapace)
Oral: 80, 120, 160, 240 mg capsules
Quinidine polygalacturonate [60% quinidine base] (Cardioquin)
Oral: 275 mg tablets
250 SECTION III Cardiovascular-Renal Drugs

CALCIUM CHANNEL BLOCKERS MISCELLANEOUS

Diltiazem (generic, Cardizem, Dilacor) Adenosine (generic, Adenocard)
Oral: 30, 60, 90, 120 mg tablets; 60, 90, 120, 180, 240, 300, 340, Parenteral: 3 mg/mL for injection
420 mg extended- or sustained-release capsules (not labeled for use Magnesium sulfate
in arrhythmias) Parenteral: 125, 500 mg/mL for IV infusion
Parenteral: 5 mg/mL for IV injection
Verapamil (generic, Calan, Isoptin)
Oral: 40, 80, 120 mg tablets
Oral sustained-release (Calan SR, Isoptin SR): 100, 120, 180, 240 mg
capsules
Parenteral: 5 mg/2 mL for injection

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Fedida D: Vernakalant (RSD1235): A novel, atrial-selective antifibrillatory agent.
van Gelder I et al: A comparison of rate control and rhythm control in patients
Expert Opin Investig Drugs 2007;16:519.
with recurrent persistent atrial fibrillation. N Engl J Med 2002;347:1834.
Fuster V et al: ACC/AHA/ESC Guidelines for the management of patients with
Wehrens XHT, Lehnart SE, Marks AR: Ryanodine receptor-targeted anti-arrhyth-
atrial fibrillation. Circulation 2006;114:700.
mic therapy. NY Acad Sci 2005;1047:366.
Grant AO: Recent advances in the treatment of arrhythmias. Circ J 2003;67:651.
Wolbrette D et al: Dronedarone for the treatment of atrial fibrillation and atrial
Grant AO: Cardiac ion channels. Circ Arrhythmia Electrophysiol 2009;2:185. flutter: Approval and efficacy. Vasc Health Risk Manag 2010;6:517.
Hondeghem LM: Relative contributions of TRIaD and QT to proarrhythmia. Wyse DG et al: A comparison of rate control and rhythm control in patients with
J Cardiovasc Electrophysiol 2007;18:655. atrial fibrillation. N Engl J Med 2002;347:1825.
IRCCS Fondazione Salvatore Maugeri: Genetic mutations and inherited
arrhythmias. http://www.fsm.it/cardmoc.

CASE STUDY ANSWER

The patient has significant symptoms during recurrent epi- impairment of left ventricular function. Selection of a drug
sodes of atrial fibrillation. The peak heart rate is not particu- that is tolerated in heart failure and has documented ability to
larly high. Maintenance of sinus rhythm appears to be convert or prevent atrial fibrillation, eg, dofetilide or amio-
important in this patient. The echocardiogram demonstrates darone, would be appropriate.
252 SECTION III Cardiovascular-Renal Drugs

Proximal NaHCO3 NaCl NaCl Ca2+

Distal convoluted
convoluted (+PTH)
tubule
tubule
1
Proximal 4
straight tubule

7 K+
7
K+ H+
2
Ca2+
Collecting
Glomerulus H2O Mg2+ 7 tubule
Na+
Cortex ? 4 5 NaCl
K+ 3
(+aldosterone)
Outer medulla 2Cl−

K+

Diuretics H+
Thick 7
1 Acetazolamide ascending
limb
2 Osmotic agents (mannitol)
H2O 6
3 Loop agents (eg, furosemide) Thin (+ADH)
descending
limb Collecting
4 Thiazides 2 duct

5 Aldosterone antagonists 2 H2O

Thin
6 ADH antagonists ascending
limb
7 Adenosine Loop of
Henle
Inner medulla

FIGURE 15–1 Tubule transport systems and sites of action of diuretics. ADH, antidiuretic hormone; PTH, parathyroid hormone.

TABLE 15–1 Major segments of the nephron and their functions.

Primary Transporters
Water and Drug Targets at
Segment Functions Permeability Apical Membrane Diuretic with Major Action
Glomerulus Formation of glomerular filtrate Extremely high None None
Reabsorption of 65% of filtered Na+/K+/
1
Proximal convoluted Very high Na/H (NHE3), carbonic Carbonic anhydrase
tubule (PCT) CA2+, and Mg2+; 85% of NaHCO3, and anhydrase inhibitors
nearly 100% of glucose and amino Adenosine antagonists
acids. Isosmotic reabsorption of water. (under investigation)
Proximal tubule, straight Secretion and reabsorption of organic Very high Acid (eg, uric acid) and None
segments acids and bases, including uric acid and base transporters
most diuretics
Thin descending limb of Passive reabsorption of water High Aquaporins None
Henle’s loop
Thick ascending limb of Active reabsorption of 15–25% of Very low Na/K/2Cl (NKCC2) Loop diuretics
Henle’s loop (TAL) filtered Na+/K+/Cl−; secondary
reabsorption of Ca2+ and Mg2+
Distal convoluted tubule Active reabsorption of 4–8% of filtered Very low Na/Cl (NCC) Thiazides
+ − 2+
(DCT) Na and Cl ; Ca reabsorption under
parathyroid hormone control
Na+ reabsorption (2–5%) coupled to K+ K+-sparing diuretics
2
Cortical collecting tubule Variable Na channels (ENaC), K
+
(CCT) and H secretion channels,1 H+ Adenosine antagonists
transporter,1 aquaporins (under investigation)
2
Medullary collecting duct Water reabsorption under vasopressin Variable Aquaporins Vasopressin antagonists
control
1
Not a target of currently available drugs.
2
Controlled by vasopressin activity.
 CHAPTER 15 Diuretic Agents 253

Of the various solutes reabsorbed in the proximal tubule, the tubule is thus dependent on carbonic anhydrase activity. This
most relevant to diuretic action are NaHCO3 and NaCl. Of the enzyme can be inhibited by acetazolamide and other carbonic
currently available diuretics, only one group (carbonic anhydrase anhydrase inhibitors.
inhibitors, which block NaHCO3 reabsorption) acts predomi- Adenosine, which is released as a result of hypoxia and ATP
nantly in the PCT. In view of the large quantity of NaCl absorbed consumption, is a molecule with four different receptors and com-
in this segment, a drug that specifically blocked proximal tubular plex effects on Na+ transport in several segments of the nephron.
absorption of NaCl could be a particularly powerful diuretic. Although it reduces glomerular filtration rate (GFR) to decrease
Adenosine receptor antagonists, which are currently under intense energy consumption by the kidney, adenosine actually increases
+
clinical investigation, act mainly in the PCT and appear to induce proximal reabsorption of Na via stimulation of NHE3 activity. A
a NaCl, rather than a NaHCO3 diuresis. Sodium bicarbonate new class of drugs, the adenosine A1-receptor antagonists, have
+ +
reabsorption by the PCT is initiated by the action of a Na /H recently been found to significantly blunt both proximal tubule
exchanger (NHE3) located in the luminal membrane of the NHE3 activity and collecting duct NaCl reabsorption, and to
proximal tubule epithelial cell (Figure 15–2). This transport sys- have potent vasomotor effects in the renal microvasculature (see
+
tem allows Na to enter the cell from the tubular lumen in below, under Autacoids, Pharmacology of Diuretic Agents, and
+
exchange for a proton (H ) from inside the cell. As in all portions under Heart Failure).
+ + −
of the nephron, Na /K -ATPase in the basolateral membrane Because HCO3 and organic solutes have been largely removed
pumps the reabsorbed Na+ into the interstitium so as to maintain from the tubular fluid in the late proximal tubule, the residual
+ +
a low intracellular Na concentration. The H secreted into the luminal fluid contains predominantly NaCl. Under these condi-
−
lumen combines with bicarbonate (HCO3 ) to form H2CO3 (car- tions, Na+ reabsorption continues, but the H+ secreted by the
+ + − +
bonic acid), which is rapidly dehydrated to CO2 and H2O by Na /H exchanger can no longer bind to HCO3 . Free H causes
−
carbonic anhydrase. Carbon dioxide produced by dehydration of luminal pH to fall, activating a poorly defined Cl /base exchanger
+ +
H2CO3 enters the proximal tubule cell by simple diffusion where (Figure 15–2). The net effect of parallel Na /H exchange and
−
it is then rehydrated back to H2CO3, also facilitated by intracel- Cl /base exchange is NaCl reabsorption. As yet, there are no
+
lular carbonic anhydrase. After dissociation of H2CO3, the H is diuretic agents that are known to act on this conjoint process.
+ + −
available for transport by the Na /H exchanger, and the HCO3 Water is reabsorbed in the PCT in response to osmotic forces,
is transported out of the cell by a basolateral membrane trans- so luminal fluid osmolality remains nearly constant along its
porter (Figure 15–2). Bicarbonate reabsorption by the proximal length, and an impermeant solute like inulin rises in concentra-
tion as water is reabsorbed. If large amounts of an impermeant
solute such as mannitol (an osmotic diuretic) are present in the
tubular fluid, water reabsorption causes the concentration of the
Proximal
Lumen- convoluted Interstitium- solute to rise, so that as salt concentrations become diminished
urine tubule blood further, water reabsorption is prevented.
Organic acid secretory systems are located in the middle third of
Na+ the straight part of the proximal tubule (S2 segment). These systems
NHE3
ATP secrete a variety of organic acids (uric acid, nonsteroidal anti-inflam-
Na+ K+ matory drugs [NSAIDs], diuretics, antibiotics, etc) into the luminal
HCO3– + H+
+
H + HCO3
– fluid from the blood. These systems thus help deliver diuretics to the
luminal side of the tubule, where most of them act. Organic base
Na+
H2CO3
H2CO3
secretory systems (creatinine, choline, etc) are also present, in the early
(S1) and middle (S2) segments of the proximal tubule.
+ CA CA

H2O + CO2 CO2 + H2O LOOP OF HENLE

Cl– At the boundary between the inner and outer stripes of the outer
Base – medulla, the proximal tubule empties into the thin descending
limb of Henle’s loop. Water is extracted from the descending limb
of this loop by osmotic forces found in the hypertonic medullary
interstitium. As in the proximal tubule, impermeant luminal sol-
FIGURE 15–2 Apical membrane Na+/H+ exchange (via NHE3) utes such as mannitol oppose this water extraction and thus have
and bicarbonate reabsorption in the proximal convoluted tubule cell.
aquaretic activity. The thin ascending limb is relatively water-im-
Na+/K+-ATPase is present in the basolateral membrane to maintain
permeable but is permeable to some solutes.
intracellular sodium and potassium levels within the normal range.
Because of rapid equilibration, concentrations of the solutes are The thick ascending limb (TAL), which follows the thin limb of
approximately equal in the interstitial fluid and the blood. Carbonic Henle’s loop, actively reabsorbs NaCl from the lumen (about 25% of
anhydrase (CA) is found in other locations in addition to the brush the filtered sodium), but unlike the proximal tubule and the thin
border of the luminal membrane. descending limb of Henle’s loop, it is nearly impermeable to water.
254 SECTION III Cardiovascular-Renal Drugs

Thick Distal
ascending convoluted
Lumen- limb Interstitium- Lumen- tubule Interstitium-
urine blood urine blood

NKCC2 NCC
Na +
Na + Na+ Na+

K+ ATP ATP
–
2Cl–
K + Cl K+

K+ + R PTH
(+) Potential K+
–
Cl Ca 2+

Ca2+
Mg2+, Ca2+
Na+

Ca2+
FIGURE 15–3 Ion transport pathways across the luminal and
basolateral membranes of the thick ascending limb cell. The lumen ATP
positive electrical potential created by K+ back diffusion drives divalent H+
(and monovalent) cation reabsorption via the paracellular pathway.
NKCC2 is the primary transporter in the luminal membrane.

FIGURE 15–4 Ion transport pathways across the luminal and

Salt reabsorption in the TAL therefore dilutes the tubular fluid, and basolateral membranes of the distal convoluted tubule cell. As in all
it is called a diluting segment. Medullary portions of the TAL contrib- tubular cells, Na+/K+ ATPase is present in the basolateral membrane.
ute to medullary hypertonicity and thereby also play an important NCC is the primary sodium and chloride transporter in the luminal
role in concentration of urine by the collecting duct. membrane. (R, parathyroid hormone [PTH] receptor.)
The NaCl transport system in the luminal membrane of the
TAL is a Na+/K+/2Cl− cotransporter (called NKCC2 or NK2CL)
(Figure 15–3). This transporter is selectively blocked by diuretic
agents known as “loop” diuretics (see later in chapter). Although the
COLLECTING TUBULE SYSTEM
+ + −
Na /K /2Cl transporter is itself electrically neutral (two cations and The collecting tubule system that connects the DCT to the renal
two anions are cotransported), the action of the transporter contrib- pelvis and the ureter consists of several sequential tubular segments:
utes to excess K+ accumulation within the cell. Back diffusion of this the connecting tubule, the collecting tubule, and the collecting duct
+
K into the tubular lumen causes a lumen-positive electrical poten- (formed by the connection of two or more collecting tubules).
tial that provides the driving force for reabsorption of cations— Although these tubule segments may be anatomically distinct, the
including magnesium and calcium—via the paracellular pathway. physiologic gradations are more gradual, and in terms of diuretic
Thus, inhibition of salt transport in the TAL by loop diuretics, activity it is easier to think of this complex as a single segment of the
which reduces the lumen-positive potential, causes an increase in nephron containing several distinct cell types. The collecting tubule
urinary excretion of divalent cations in addition to NaCl. system is responsible for only 2–5% of NaCl reabsorption by the
kidney. Despite this small contribution, it plays an important role
in renal physiology and in diuretic action. As the final site of NaCl
DISTAL CONVOLUTED TUBULE reabsorption, the collecting system is responsible for tight regulation
+
Only about 10% of the filtered NaCl is reabsorbed in the distal of body fluid volume and for determining the final Na concentra-
convoluted tubule (DCT). Like the TAL of Henle’s loop, this seg- tion of the urine. Furthermore, the collecting system is the site at
ment is relatively impermeable to water, and NaCl reabsorption which mineralocorticoids exert a significant influence. Lastly, this is
+
further dilutes the tubular fluid. The mechanism of NaCl trans- the most important site of K secretion by the kidney and the site
+
port in the DCT is an electrically neutral thiazide-sensitive Na at which virtually all diuretic-induced changes in K+ balance occur.
−
and Cl cotransporter (NCC, Figure 15–4). The mechanism of NaCl reabsorption in the collecting tubule
+
Because K does not recycle across the apical membrane of the system is distinct from the mechanisms found in other tubule seg-
DCT as it does in the TAL, there is no lumen-positive potential ments. The principal cells are the major sites of Na+, K+, and
in this segment, and Ca2+ and Mg2+ are not driven out of the water transport (Figures 15–5 and 15–6), and the intercalated
+
tubular lumen by electrical forces. Instead, Ca2+ is actively reab- cells (α, β) are the primary sites of H (α cells) or bicarbonate (β
2+
sorbed by the DCT epithelial cell via an apical Ca channel and cells) secretion. The α and β intercalated cells are very similar,
+
except that the membrane locations of the H+-ATPase and Cl/HCO3−
2+
basolateral Na /Ca exchanger (Figure 15–4). This process is
regulated by parathyroid hormone. exchanger are reversed. Principal cells do not contain apical
254 SECTION III Cardiovascular-Renal Drugs

Thick Distal
ascending convoluted
Lumen- limb Interstitium- Lumen- tubule Interstitium-
urine blood urine blood

NKCC2 NCC
Na +
Na + Na+ Na+

K+ ATP ATP
–
2Cl–
K + Cl K+

K+ + R PTH
(+) Potential K+
–
Cl Ca 2+

Ca2+
Mg2+, Ca2+
Na+

Ca2+
FIGURE 15–3 Ion transport pathways across the luminal and
basolateral membranes of the thick ascending limb cell. The lumen ATP
positive electrical potential created by K+ back diffusion drives divalent H+
(and monovalent) cation reabsorption via the paracellular pathway.
NKCC2 is the primary transporter in the luminal membrane.

FIGURE 15–4 Ion transport pathways across the luminal and

Salt reabsorption in the TAL therefore dilutes the tubular fluid, and basolateral membranes of the distal convoluted tubule cell. As in all
it is called a diluting segment. Medullary portions of the TAL contrib- tubular cells, Na+/K+ ATPase is present in the basolateral membrane.
ute to medullary hypertonicity and thereby also play an important NCC is the primary sodium and chloride transporter in the luminal
role in concentration of urine by the collecting duct. membrane. (R, parathyroid hormone [PTH] receptor.)
The NaCl transport system in the luminal membrane of the
TAL is a Na+/K+/2Cl− cotransporter (called NKCC2 or NK2CL)
(Figure 15–3). This transporter is selectively blocked by diuretic
agents known as “loop” diuretics (see later in chapter). Although the
COLLECTING TUBULE SYSTEM
+ + −
Na /K /2Cl transporter is itself electrically neutral (two cations and The collecting tubule system that connects the DCT to the renal
two anions are cotransported), the action of the transporter contrib- pelvis and the ureter consists of several sequential tubular segments:
utes to excess K+ accumulation within the cell. Back diffusion of this the connecting tubule, the collecting tubule, and the collecting duct
+
K into the tubular lumen causes a lumen-positive electrical poten- (formed by the connection of two or more collecting tubules).
tial that provides the driving force for reabsorption of cations— Although these tubule segments may be anatomically distinct, the
including magnesium and calcium—via the paracellular pathway. physiologic gradations are more gradual, and in terms of diuretic
Thus, inhibition of salt transport in the TAL by loop diuretics, activity it is easier to think of this complex as a single segment of the
which reduces the lumen-positive potential, causes an increase in nephron containing several distinct cell types. The collecting tubule
urinary excretion of divalent cations in addition to NaCl. system is responsible for only 2–5% of NaCl reabsorption by the
kidney. Despite this small contribution, it plays an important role
in renal physiology and in diuretic action. As the final site of NaCl
DISTAL CONVOLUTED TUBULE reabsorption, the collecting system is responsible for tight regulation
+
Only about 10% of the filtered NaCl is reabsorbed in the distal of body fluid volume and for determining the final Na concentra-
convoluted tubule (DCT). Like the TAL of Henle’s loop, this seg- tion of the urine. Furthermore, the collecting system is the site at
ment is relatively impermeable to water, and NaCl reabsorption which mineralocorticoids exert a significant influence. Lastly, this is
+
further dilutes the tubular fluid. The mechanism of NaCl trans- the most important site of K secretion by the kidney and the site
+
port in the DCT is an electrically neutral thiazide-sensitive Na at which virtually all diuretic-induced changes in K+ balance occur.
−
and Cl cotransporter (NCC, Figure 15–4). The mechanism of NaCl reabsorption in the collecting tubule
+
Because K does not recycle across the apical membrane of the system is distinct from the mechanisms found in other tubule seg-
DCT as it does in the TAL, there is no lumen-positive potential ments. The principal cells are the major sites of Na+, K+, and
in this segment, and Ca2+ and Mg2+ are not driven out of the water transport (Figures 15–5 and 15–6), and the intercalated
+
tubular lumen by electrical forces. Instead, Ca2+ is actively reab- cells (α, β) are the primary sites of H (α cells) or bicarbonate (β
2+
sorbed by the DCT epithelial cell via an apical Ca channel and cells) secretion. The α and β intercalated cells are very similar,
+
except that the membrane locations of the H+-ATPase and Cl/HCO3−
2+
basolateral Na /Ca exchanger (Figure 15–4). This process is
regulated by parathyroid hormone. exchanger are reversed. Principal cells do not contain apical
 CHAPTER 15 Diuretic Agents 255

Lumen- Collecting Interstitium- increase in the transepithelial electrical potential and a dramatic
+ +
urine tubule blood increase in both Na reabsorption and K secretion.
The collecting tubule system is also the site at which the final
Cl–
urine concentration is determined. In addition to their role in con-
+ +
Principal cell trol of Na absorption and K secretion (Figure 15–5), principal
ENaC cells also contain a regulated system of water channels (Figure
+ R Aldosterone
15–6). Antidiuretic hormone (ADH, also called arginine vasopres-
Na+ sin, AVP) controls the permeability of these cells to water by regulat-
+ ing the insertion of pre-formed water channels (aquaporin-2,
Na+
+ AQP2) into the apical membrane. Vasopressin receptors in the vas-
K ATP culature and central nervous system (CNS) are V1 receptors, and
K+ those in the kidney are V2 receptors. V2 receptors act via a G pro-
tein-coupled, cAMP-mediated process. In the absence of ADH, the
collecting tubule (and duct) is impermeable to water, and dilute
Intercalated cell urine is produced. ADH markedly increases water permeability, and
this leads to the formation of a more concentrated final urine. ADH
HCO3– also stimulates the insertion of urea transporter UT1 molecules into
ATP the apical membranes of collecting duct cells in the medulla.
Cl–
H+ Urea concentration in the medulla plays an important role
maintaining the high osmolarity of the medulla and in the con-
centration of urine. ADH secretion is regulated by serum osmola-
FIGURE 15–5 Ion transport pathways across the luminal and lity and by volume status. A new class of drugs, the vaptans (see
basolateral membranes of collecting tubule and collecting duct cells.
under Agents That Alter Water Excretion), are ADH antagonists.
Inward diffusion of Na+ via the epithelial sodium channel (ENaC)
leaves a lumen-negative potential, which drives reabsorption of Cl−
and efflux of K+. (R, aldosterone receptor.)

Lumen- Collecting Interstitium-

urine tubule blood
+
cotransport systems for Na and other ions, unlike cells in other
nephron segments. Principal cell membranes exhibit separate ion
channels for Na+ and K+. Since these channels exclude anions,
+ + AQP2
transport of Na or K leads to a net movement of charge across
+
the membrane. Because Na entry into the principal cell pre- H2O
V2
+ R
dominates over K secretion into the lumen, a 10–50 mV lumen-
negative electrical potential develops. Sodium that enters the
principal cell from the tubular fluid is then transported back to the
blood via the basolateral Na+/K+-ATPase (Figure 15–5). The
H2O
10–50 mV lumen-negative electrical potential drives the transport
−
of Cl back to the blood via the paracellular pathway and draws V2
+ +
K out of cells through the apical membrane K channel. Thus, cAMP R ADH
+
there is an important relationship between Na delivery to the
+ +
collecting tubule system and the resulting secretion of K .
+ H2O
Upstream diuretics increase Na delivery to this site and enhance
+ +
K secretion. If Na is delivered to the collecting system with an
− −
anion that cannot be reabsorbed as readily as Cl (eg, HCO3 ), the
+
lumen-negative potential is increased, and K secretion is enhanced. AQP2 AQP3,4
This mechanism, combined with enhanced aldosterone secretion H2O
+ H2O
due to volume depletion, is the basis for most diuretic-induced K
wasting. Adenosine antagonists, which act upstream at the proximal
FIGURE 15–6 Water transport across the luminal and basolateral
tubule, but also at the collecting duct, are perhaps the only diuretics
+ membranes of collecting duct cells. Above, low water permeability
that violate this principle (see below). Reabsorption of Na via the exists in the absence of antidiuretic hormone (ADH). Below, in the
+
epithelial Na channel (ENaC) and its coupled secretion of K is presence of ADH, aquaporins are inserted into the apical membrane,
regulated by aldosterone. This steroid hormone, through its actions greatly increasing water permeability. (AQP2, apical aquaporin water
on gene transcription, increases the activity of both apical mem- channels; AQP3,4, basolateral aquaporin water channels; V2, vaso-
+ +
brane channels and the basolateral Na /K -ATPase. This leads to an pressin V2 receptor.)
 CHAPTER 15 Diuretic Agents 255

Lumen- Collecting Interstitium- increase in the transepithelial electrical potential and a dramatic
+ +
urine tubule blood increase in both Na reabsorption and K secretion.
The collecting tubule system is also the site at which the final
Cl–
urine concentration is determined. In addition to their role in con-
+ +
Principal cell trol of Na absorption and K secretion (Figure 15–5), principal
ENaC cells also contain a regulated system of water channels (Figure
+ R Aldosterone
15–6). Antidiuretic hormone (ADH, also called arginine vasopres-
Na+ sin, AVP) controls the permeability of these cells to water by regulat-
+ ing the insertion of pre-formed water channels (aquaporin-2,
Na+
+ AQP2) into the apical membrane. Vasopressin receptors in the vas-
K ATP culature and central nervous system (CNS) are V1 receptors, and
K+ those in the kidney are V2 receptors. V2 receptors act via a G pro-
tein-coupled, cAMP-mediated process. In the absence of ADH, the
collecting tubule (and duct) is impermeable to water, and dilute
Intercalated cell urine is produced. ADH markedly increases water permeability, and
this leads to the formation of a more concentrated final urine. ADH
HCO3– also stimulates the insertion of urea transporter UT1 molecules into
ATP the apical membranes of collecting duct cells in the medulla.
Cl–
H+ Urea concentration in the medulla plays an important role
maintaining the high osmolarity of the medulla and in the con-
centration of urine. ADH secretion is regulated by serum osmola-
FIGURE 15–5 Ion transport pathways across the luminal and lity and by volume status. A new class of drugs, the vaptans (see
basolateral membranes of collecting tubule and collecting duct cells.
under Agents That Alter Water Excretion), are ADH antagonists.
Inward diffusion of Na+ via the epithelial sodium channel (ENaC)
leaves a lumen-negative potential, which drives reabsorption of Cl−
and efflux of K+. (R, aldosterone receptor.)

Lumen- Collecting Interstitium-

urine tubule blood
+
cotransport systems for Na and other ions, unlike cells in other
nephron segments. Principal cell membranes exhibit separate ion
channels for Na+ and K+. Since these channels exclude anions,
+ + AQP2
transport of Na or K leads to a net movement of charge across
+
the membrane. Because Na entry into the principal cell pre- H2O
V2
+ R
dominates over K secretion into the lumen, a 10–50 mV lumen-
negative electrical potential develops. Sodium that enters the
principal cell from the tubular fluid is then transported back to the
blood via the basolateral Na+/K+-ATPase (Figure 15–5). The
H2O
10–50 mV lumen-negative electrical potential drives the transport
−
of Cl back to the blood via the paracellular pathway and draws V2
+ +
K out of cells through the apical membrane K channel. Thus, cAMP R ADH
+
there is an important relationship between Na delivery to the
+ +
collecting tubule system and the resulting secretion of K .
+ H2O
Upstream diuretics increase Na delivery to this site and enhance
+ +
K secretion. If Na is delivered to the collecting system with an
− −
anion that cannot be reabsorbed as readily as Cl (eg, HCO3 ), the
+
lumen-negative potential is increased, and K secretion is enhanced. AQP2 AQP3,4
This mechanism, combined with enhanced aldosterone secretion H2O
+ H2O
due to volume depletion, is the basis for most diuretic-induced K
wasting. Adenosine antagonists, which act upstream at the proximal
FIGURE 15–6 Water transport across the luminal and basolateral
tubule, but also at the collecting duct, are perhaps the only diuretics
+ membranes of collecting duct cells. Above, low water permeability
that violate this principle (see below). Reabsorption of Na via the exists in the absence of antidiuretic hormone (ADH). Below, in the
+
epithelial Na channel (ENaC) and its coupled secretion of K is presence of ADH, aquaporins are inserted into the apical membrane,
regulated by aldosterone. This steroid hormone, through its actions greatly increasing water permeability. (AQP2, apical aquaporin water
on gene transcription, increases the activity of both apical mem- channels; AQP3,4, basolateral aquaporin water channels; V2, vaso-
+ +
brane channels and the basolateral Na /K -ATPase. This leads to an pressin V2 receptor.)
 CHAPTER 15 Diuretic Agents 257

to CO2 at the luminal membrane and rehydration of CO2 to TABLE 15–3 Carbonic anhydrase inhibitors used
H2CO3 in the cytoplasm as previously described. By blocking orally in the treatment of glaucoma.
carbonic anhydrase, inhibitors blunt NaHCO3 reabsorption and
Drug Usual Oral Dosage
cause diuresis.
Carbonic anhydrase inhibitors were the forerunners of modern Dichlorphenamide 50 mg 1–3 times daily
diuretics. They were discovered in 1937 when it was found that Methazolamide 50–100 mg 2–3 times daily
bacteriostatic sulfonamides caused an alkaline diuresis and hyper-
chloremic metabolic acidosis. With the development of newer
agents, carbonic anhydrase inhibitors are now rarely used as
diuretics, but they still have several specific applications that are
discussed below. The prototypical carbonic anhydrase inhibitor is sites other than the kidney. The ciliary body of the eye secretes
−
acetazolamide. HCO3 from the blood into the aqueous humor. Likewise, forma-
−
tion of cerebrospinal fluid by the choroid plexus involves HCO3
−
secretion. Although these processes remove HCO3 from the
Pharmacokinetics blood (the direction opposite of that in the proximal tubule), they
The carbonic anhydrase inhibitors are well absorbed after oral are similarly inhibited by carbonic anhydrase inhibitors.
administration. An increase in urine pH from the HCO3− diuresis
is apparent within 30 minutes, is maximal at 2 hours, and persists
for 12 hours after a single dose. Excretion of the drug is by secre- Clinical Indications & Dosage (Table 15–3)
tion in the proximal tubule S2 segment. Therefore, dosing must be A. Glaucoma
reduced in renal insufficiency. The reduction of aqueous humor formation by carbonic anhy-
drase inhibitors decreases the intraocular pressure. This effect is
Pharmacodynamics valuable in the management of glaucoma, making it the most
Inhibition of carbonic anhydrase activity profoundly depresses common indication for use of carbonic anhydrase inhibitors.
−
HCO3 reabsorption in the PCT. At its maximal safe dosage, 85% Topically active agents, which reduce intraocular pressure without
−
of the HCO3 reabsorptive capacity of the superficial PCT is producing renal or systemic effects, are available (dorzolamide,
inhibited. Some HCO3− can still be absorbed at other nephron brinzolamide).
sites by carbonic anhydrase–independent mechanisms, so the
overall effect of maximal acetazolamide dosage is only about 45% B. Urinary Alkalinization
−
inhibition of whole kidney HCO3 reabsorption. Nevertheless, Uric acid and cystine are relatively insoluble and may form stones
−
carbonic anhydrase inhibition causes significant HCO3 losses and in acidic urine. Therefore, in cystinuria, a disorder of cystine reab-
hyperchloremic metabolic acidosis (Table 15–2). Because of sorption, solubility of cystine can be enhanced by increasing uri-
reduced HCO3− in the glomerular filtrate and the fact that nary pH from 7.0 to 7.5 with carbonic anhydrase inhibitors. In
−
HCO3 depletion leads to enhanced NaCl reabsorption by the the case of uric acid, pH needs to be raised only to 6.0 or 6.5. In
−
remainder of the nephron, the diuretic efficacy of acetazolamide the absence of HCO3 administration, these effects of acetazol-
decreases significantly with use over several days. amide last only 2–3 days, so prolonged therapy requires oral
−
At present, the major clinical applications of acetazolamide HCO3 . Excessive urinary alkalinization can lead to stone forma-
involve carbonic anhydrase–dependent HCO3− and fluid transport at tion from calcium salts (see below), so urine pH should be fol-
lowed during treatment with acetazolamide.

C. Metabolic Alkalosis
Metabolic alkalosis is generally treated by correction of abnor-
+
TABLE 15–2 Changes in urinary electrolyte patterns malities in total body K , intravascular volume, or mineralocorti-
and body pH in response to diuretic coid levels. However, when the alkalosis is due to excessive use of
drugs. diuretics in patients with severe heart failure, replacement of intra-
Urinary Electrolytes
vascular volume may be contraindicated. In these cases, acetazol-
+
amide can be useful in correcting the alkalosis as well as producing
Group NaCl NaHCO3 K Body pH
a small additional diuresis for correction of volume overload.
Carbonic anhydrase + +++ + ↓ Acetazolamide can also be used to rapidly correct the metabolic
inhibitors
alkalosis that may appear following the correction of respiratory
Loop agents ++++ 0 + ↑ acidosis.
Thiazides ++ + + ↑
Loop agents plus +++++ + ++ ↑ D. Acute Mountain Sickness
thiazides Weakness, dizziness, insomnia, headache, and nausea can occur in
K+-sparing agents + (+) − ↓ mountain travelers who rapidly ascend above 3000 m. The symp-
+, increase; −, decrease; 0, no change; ↓, acidosis; ↑, alkalosis. toms are usually mild and last for a few days. In more serious cases,
268 SECTION III Cardiovascular-Renal Drugs

2+
because Ca reabsorption in the proximal tubule would be effect of thiazides was previously thought to be mediated through
enhanced. Thus, saline must be administered simultaneously with plasma volume reduction, with an associated fall in GFR, leading
2+
loop diuretics if an effective Ca diuresis is to be maintained. The to enhanced proximal reabsorption of NaCl and water and
usual approach is to infuse normal saline and furosemide (80–120 decreased delivery of fluid to the downstream diluting segments.
+
mg) intravenously. Once the diuresis begins, the rate of saline However, in the case of Li -induced NDI, it is now known that
infusion can be matched with the urine flow rate to avoid volume HCTZ causes increased osmolality in the inner medulla
depletion. Potassium chloride may be added to the saline infusion (papilla) and a partial correction of the Li+-induced reduction in
as needed. aquaporin-2 expression. HCTZ also leads to increased expression
+
of Na transporters in the DCT and CCT segments of the
nephron. Thus, the maximum volume of dilute urine that can be
DIABETES INSIPIDUS produced is significantly reduced in NDI. Dietary sodium restric-
tion can potentiate the beneficial effects of thiazides on urine
Diabetes insipidus is due to either deficient production of ADH volume in this setting. Serum Li+ levels must be carefully moni-
(neurogenic or central diabetes insipidus) or inadequate respon- tored in these patients, because diuretics may reduce renal clear-
+ +
siveness to ADH (nephrogenic diabetes insipidus [NDI]). ance of Li and raise plasma Li levels into the toxic range (see
Administration of supplementary ADH or one of its analogs is Chapter 29). Lithium-induced polyuria can also be partially
effective only in central diabetes insipidus. Thiazide diuretics can reversed by amiloride, which blocks Li+ entry into collecting duct
+
reduce polyuria and polydipsia in both types of diabetes insipidus. cells, much as it blocks Na entry. As mentioned above, thiazides
Lithium, used in the treatment of manic-depressive disorder, is a are also beneficial in other forms of nephrogenic diabetes insipi-
common cause of NDI, and thiazide diuretics have been found to dus. It is not yet clear whether this is via the same mechanism that
+
be very helpful in treating it. This seemingly paradoxic beneficial has been found in Li -induced NDI.

SUMMARY Diuretic Agents

Mechanism of Pharmacokinetics,
Subclass Action Effects Clinical Applications Toxicities, Interactions

CARBONIC ANHYDRASE INHIBITORS

• Acetazolamide, Inhibition of the enzyme Reduces reabsorption of HCO3−, causing Glaucoma, mountain sick- Oral and topical preparations
others prevents dehydration of self-limited diuresis • hyperchloremic ness, edema with alkalosis available • duration of action ∼
H2CO3 and hydration of metabolic acidosis reduces body pH, 8–12 h • Toxicity: Metabolic acido-
CO2 in the proximal convo- reduces intraocular pressure sis, renal stones, hyperammone-
luted tubule mia in cirrhotics

• Brinzolamide, dorzolamide: Topical for glaucoma

LOOP DIURETICS
• Furosemide Inhibition of the Na/K/2Cl Marked increase in NaCl excretion, some Pulmonary edema, periph- Oral and parenteral preparations
transporter in the ascend- K wasting, hypokalemic metabolic alka- eral edema, hypertension, • duration of action 2–4 h
ing limb of Henle’s loop losis, increased urine Ca and Mg acute hypercalcemia or • Toxicity: Ototoxicity, hypovolemia,
hyperkalemia, acute renal K wasting, hyperuricemia,
failure, anion overdose hypomagnesemia

• Bumetanide, torsemide: Sulfonamide loop agents like furosemide

• Ethacrynic acid: Not a sulfonamide but has typical loop activity and some uricosuric action

THIAZIDES
• Hydrochlorothia- Inhibition of the Na/Cl Modest increase in NaCl excretion • some Hypertension, mild heart fail- Oral • duration 8–12 h • Toxicity:
zide transporter in the distal K wasting • hypokalemic metabolic ure, nephrolithiasis, nephro- Hypokalemic metabolic alkalosis,
convoluted tubule alkalosis • decreased urine Ca genic diabetes insipidus hyperuricemia, hyperglycemia,
hyponatremia

• Metolazone: Popular for use with loop agents for synergistic effects
• Chlorothiazide: Only parenteral thiazide available (IV)
• Chlorthalidone: Long half-life (50–60 h) due to binding to red blood cells

(continued)
 CHAPTER 15 Diuretic Agents 269

Mechanism of Pharmacokinetics,
Subclass Action Effects Clinical Applications Toxicities, Interactions

POTASSIUM-SPARING DIURETICS
• Spironolactone Pharmacologic antagonist Reduces Na retention and K wasting in Aldosteronism from any Slow onset and offset of effect
of aldosterone in collect- kidney • poorly understood antagonism cause • hypokalemia due to • duration 24–48 h •Toxicity:
ing tubules • weak antago- of aldosterone in heart and vessels other diuretics • postmyocar- Hyperkalemia, gynecomastia
nism of androgen dial infarction (spironolactone, not eplerenone)
receptors • additive interaction with other
K-retaining drugs
• Amiloride Blocks epithelial sodium Reduces Na retention and K wasting Hypokalemia from other Orally active • duration 24 h
channels in collecting • increases lithium clearance diuretics • reduces lithium- • Toxicity: Hyperkalemic
tubules induced polyuria metabolic acidosis

• Eplerenone: Like spironolactone, more selective for aldosterone receptor

• Triamterene: Mechanism like amiloride, much less potent, more toxic

OSMOTIC DIURETICS
• Mannitol Physical osmotic effect on Marked increase in urine flow, reduced Renal failure due to increased IV administration • Toxicity:
tissue water distribution brain volume, decreased intraocular solute load (rhabdomyolysis, Nausea, vomiting, headache
because it is retained in pressure, initial hyponatremia, then chemotherapy), increased
the vascular compartment hypernatremia intracranial pressure,
glaucoma

VASOPRESSIN (ADH) ANTAGONISTS

• Conivaptan Antagonist at V1a and V2 Reduces water reabsorption, increases Hyponatremia, congestive IV only, usually continuous
ADH receptors plasma Na concentration, vasodilation heart failure • Toxicity: Infusion site reactions,
thirst, polyuria, hypernatremia
• Tolvaptan Selective antagonist at V2 Reduces water reabsorption, increases Hyponatremia, SIADH Oral • duration 12–24 h • Toxicity:
ADH receptors plasma Na concentration Polyuria (frequency), thirst,
hypernatremia

P R E P A R A T I O N S A V A I L A B L E

Acetazolamide (generic, Diamox) Dichlorphenamide (Daranide)

Oral: 125, 250 mg tablets Oral: 50 mg tablets
Oral sustained-release: 500 mg capsules Dorzolamide (Trusopt) (For ocular conditions)
Parenteral: 500 mg powder for injection Ophthalmic: 2% solution
Amiloride (generic, Midamor, combination drugs1) Eplerenone (Inspra)
Oral: 5 mg tablets Oral: 25, 50 mg tablets
1
Bendroflumethiazide (Naturetin, combination drugs ) Ethacrynic acid (Edecrin)
Oral: 5, 10 mg tablets Oral: 25, 50 mg tablets
Brinzolamide (Azopt) (For ocular conditions) Parenteral: 50 mg IV injection
Ophthalmic: 1% suspension Furosemide (generic, Lasix, others)
Bumetanide (generic, Bumex) Oral: 20, 40, 80 mg tablets; 8, 10 mg/mL oral solutions
Oral: 0.5, 1, 2 mg tablets Parenteral: 10 mg/mL for IM or IV injection
Parenteral: 0.5 mg/2 mL ampule for IV or IM injection Hydrochlorothiazide (generic, Esidrix, Hydro-DIURIL, combination
1
Chlorothiazide (generic, Diuril) drugs )
Oral: 250, 500 mg tablets; 250 mg/5 mL oral suspension Oral: 12.5 mg capsules; 25, 50, 100 mg tablets; 10, 100 mg/mL
Parenteral: 500 mg for injection solution
Chlorthalidone (generic, Hygroton, Thalitone, combination Hydroflumethiazide (generic, Saluron)
1
drugs ) Oral: 50 mg tablets
Oral: 25, 50, 100 mg tablets Indapamide (generic, Lozol)
Conivaptan (Vaprisol) Oral: 1.25, 2.5 mg tablets
Parenteral: 5 mg/mL; 20 mg/100 mL D5W for IV injection Mannitol (generic, Osmitrol)
Demeclocycline (Declomycin) Parenteral: 5, 10, 15, 20% solution, for injection
Oral: 150 mg tablets and capsules; 300 mg tablets
 CHAPTER 15 Diuretic Agents 269

Mechanism of Pharmacokinetics,
Subclass Action Effects Clinical Applications Toxicities, Interactions

POTASSIUM-SPARING DIURETICS
• Spironolactone Pharmacologic antagonist Reduces Na retention and K wasting in Aldosteronism from any Slow onset and offset of effect
of aldosterone in collect- kidney • poorly understood antagonism cause • hypokalemia due to • duration 24–48 h •Toxicity:
ing tubules • weak antago- of aldosterone in heart and vessels other diuretics • postmyocar- Hyperkalemia, gynecomastia
nism of androgen dial infarction (spironolactone, not eplerenone)
receptors • additive interaction with other
K-retaining drugs
• Amiloride Blocks epithelial sodium Reduces Na retention and K wasting Hypokalemia from other Orally active • duration 24 h
channels in collecting • increases lithium clearance diuretics • reduces lithium- • Toxicity: Hyperkalemic
tubules induced polyuria metabolic acidosis

• Eplerenone: Like spironolactone, more selective for aldosterone receptor

• Triamterene: Mechanism like amiloride, much less potent, more toxic

OSMOTIC DIURETICS
• Mannitol Physical osmotic effect on Marked increase in urine flow, reduced Renal failure due to increased IV administration • Toxicity:
tissue water distribution brain volume, decreased intraocular solute load (rhabdomyolysis, Nausea, vomiting, headache
because it is retained in pressure, initial hyponatremia, then chemotherapy), increased
the vascular compartment hypernatremia intracranial pressure,
glaucoma

VASOPRESSIN (ADH) ANTAGONISTS

• Conivaptan Antagonist at V1a and V2 Reduces water reabsorption, increases Hyponatremia, congestive IV only, usually continuous
ADH receptors plasma Na concentration, vasodilation heart failure • Toxicity: Infusion site reactions,
thirst, polyuria, hypernatremia
• Tolvaptan Selective antagonist at V2 Reduces water reabsorption, increases Hyponatremia, SIADH Oral • duration 12–24 h • Toxicity:
ADH receptors plasma Na concentration Polyuria (frequency), thirst,
hypernatremia

P R E P A R A T I O N S A V A I L A B L E

Acetazolamide (generic, Diamox) Dichlorphenamide (Daranide)

Oral: 125, 250 mg tablets Oral: 50 mg tablets
Oral sustained-release: 500 mg capsules Dorzolamide (Trusopt) (For ocular conditions)
Parenteral: 500 mg powder for injection Ophthalmic: 2% solution
Amiloride (generic, Midamor, combination drugs1) Eplerenone (Inspra)
Oral: 5 mg tablets Oral: 25, 50 mg tablets
1
Bendroflumethiazide (Naturetin, combination drugs ) Ethacrynic acid (Edecrin)
Oral: 5, 10 mg tablets Oral: 25, 50 mg tablets
Brinzolamide (Azopt) (For ocular conditions) Parenteral: 50 mg IV injection
Ophthalmic: 1% suspension Furosemide (generic, Lasix, others)
Bumetanide (generic, Bumex) Oral: 20, 40, 80 mg tablets; 8, 10 mg/mL oral solutions
Oral: 0.5, 1, 2 mg tablets Parenteral: 10 mg/mL for IM or IV injection
Parenteral: 0.5 mg/2 mL ampule for IV or IM injection Hydrochlorothiazide (generic, Esidrix, Hydro-DIURIL, combination
1
Chlorothiazide (generic, Diuril) drugs )
Oral: 250, 500 mg tablets; 250 mg/5 mL oral suspension Oral: 12.5 mg capsules; 25, 50, 100 mg tablets; 10, 100 mg/mL
Parenteral: 500 mg for injection solution
Chlorthalidone (generic, Hygroton, Thalitone, combination Hydroflumethiazide (generic, Saluron)
1
drugs ) Oral: 50 mg tablets
Oral: 25, 50, 100 mg tablets Indapamide (generic, Lozol)
Conivaptan (Vaprisol) Oral: 1.25, 2.5 mg tablets
Parenteral: 5 mg/mL; 20 mg/100 mL D5W for IV injection Mannitol (generic, Osmitrol)
Demeclocycline (Declomycin) Parenteral: 5, 10, 15, 20% solution, for injection
Oral: 150 mg tablets and capsules; 300 mg tablets
270 SECTION III Cardiovascular-Renal Drugs

Methazolamide (generic, Neptazane) (For ocular conditions) Spironolactone (generic, Aldactone , combination drugs1)
Oral: 25, 50 mg tablets Oral: 25, 50, 100 mg tablets
Methyclothiazide (generic, Aquatensen, Enduron) Tolvaptan (Samsca)
Oral: 2.5, 5 mg tablets Oral: 15, 30 mg tablets
Metolazone (Mykrox, Zaroxolyn) (Note: Bioavailability of Mykrox is Torsemide (Demadex)
greater than that of Zaroxolyn.) Oral: 5, 10, 20, 100 mg tablets
Oral: 0.5 (Mykrox); 2.5, 5, 10 mg (Zaroxolyn) tablets Parenteral: 10 mg/mL for injection
Nesiritide (Natrecor) Triamterene (Dyrenium)
Parenteral: 1.5 mg vial for dilution into 250 mL IV solution Oral: 50, 100 mg capsules
(6 mcg/mL) Trichlormethiazide (generic, Diurese, Naqua, others)
Polythiazide (Renese, combination drugs1) Oral: 2, 4 mg tablets
Oral: 1, 2, 4 mg tablets
Quinethazone (Hydromox)
Oral: 50 mg tablets

1
Combination drugs: see Table 15-6

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