Table 32-2.

Classification of Antihypertensive Drugs by Their

Primary Site or Mechanism of Action
Diuretics (Chapter 28)
1. Thiazides and related agents (hydrochlorothiazide,
chlorthalidone, etc.)
2. Loop diuretics (furosemide, bumetanide, torsemide, ethacrynic
acid)
3. K+-sparing diuretics (amiloride, triamterene, spironolactone)
Sympatholytic drugs (Chapters 9, 10, and 33)
1. b Adrenergic antagonists (metoprolol, atenolol, etc.)
2. a Adrenergic antagonists (prazosin, terazosin, doxazosin,
phenoxybenzamine, phentolamine)
3. Mixed adrenergic antagonists (labetalol, carvedilol)
4. Centrally acting agents (methyldopa, clonidine, guanabenz,
guanfacine)
5. Adrenergic neuron blocking agents (guanadrel, reserpine)
Ca2+ channel blockers (Chapters 31, 32, 33, and 34) (verapamil,
diltiazem, nimodipine, felodipine, nicardipine, isradipine,
amlodipine)
Angiotensin converting enzyme inhibitors (Chapters 30 and 31),
(captopril, enalapril, lisinopril, quinapril, ramipril, benazepril,
fosinopril, moexipril, perindopril, trandolapril)
Angiotensin II-receptor antagonists (Chapters 30 and 33)
(losartan, candesartan, irbesartan, valsartan, telmisartan,
eprosartan)
Vasodilators (Chapter 33)
1. Arterial (hydralazine, minoxidil, diazoxide, fenoldopam)
2. Arterial and venous (nitroprusside)
 
Table 32-3. Hemodynamic Effects of Long-Term Administration of Antihypertensive Agents

HEART RATE CARDIAC TOTAL PLASMA PLASMA

OUTPUT PERIPHERAL VOLUME RENIN
RESISTANCE ACTIVITY

Diuretics ↔ ↔ ↓ -↓ ↑

Sympatholytic agents

Centrally acting -↓ -↓ ↓ -↑ -↓

Adrenergic neuron blockers -↓ ↓ ↓ ↑ -↑

α Adrenergic antagonists -↑ -↑ ↓ -↑ ↔

β Adrenergic antagonists

No ISA* ↓ ↓ -↓ -↑ ↓

ISA ↔ ↔ ↓ -↑ -↓

Arteriolar vasodilators ↑ ↑ ↓ ↑ ↑

Ca2+ channel blockers ↓ or ↑ ↓ or ↑ ↓ -↑ -↑

ACE inhibitors ↔ ↔ ↓ ↔ ↑

AT1-receptor antagonists ↔ ↔ ↓ ↔ ↑

Changes are indicated as follows: ↑, increased; ↓, decreased; -↑, increased or no change; -↓,
decreased or no change; ↔, unchanged.
*
ISA, intrinsic sympathomimetic activity. ACE, angiotensin converting enzyme; AT 1, the type 1 receptor
for angiotensin II.
Table 33-1. Vasodilator Drugs Used to Treat Heart Failure

DRUG CLASS EXAMPLES MECHANISM OF VASODILATING PRELOAD AFTERLOAD

ACTION REDUCTION REDUCTION

Organic nitrates Nitroglycerin, NO-mediated vasodilation +++ +

isosorbide dinitrate

Nitric oxide donors Nitroprusside NO-mediated vasodilation +++ +++

Angiotensin-converting Captopril, enalapril, Inhibition of Ang II generation, ++ ++

enzyme inhibitors lisinopril decreased bradykinin degradation

Angiotensin receptor Losartan, Blockade of AT1 receptors ++ ++

blockers candesartan

Phosphodiesterase Milrinone, Inhibition of cyclic AMP ++ ++

inhibitors inamrinone degradation

Direct-acting K+-channel Hydralazine Unknown + +++

agonist

Minoxidil Hyperpolarization of vascular + +++

 smooth muscle cells

α1 Adrenergic Doxazosin, prazosin Selective α1 adrenergic receptor +++ ++

antagonists blockade

Nonselective α Phentolamine Nonselective α adrenergic receptor +++ +++

adrenergic antagonists blockade

Vasodilating β/α1 Carvedilol, labetalol Selective α1 adrenergic receptor ++ ++

adrenergic antagonists blockade

Ca2+ channel blockers Amlodipine, Inhibition of L-type Ca2+ channels + +++

nifedipine, felodipine

β adrenergic agonists Isoproterenol Stimulation of vascular β2 + ++

adrenergic receptors

ABBREVIATIONS: Ang II, angiotensin II; AT 1, type 1 Ang II receptor; NO, nitric oxide.

Table 33-2. Potential Roles of Aldosterone in the Pathophysiology of

Heart Failure

MECHANISM PATHOPHYSIOLOGICAL EFFECT

Increased Na+ and water Edema, elevated cardiac filling pressures

retention

K+ and Mg2+ loss Arrhythmogenesis and risk of sudden

cardiac death

Reduced myocardial Potentiation of norepinephrine effects:

norepinephrine uptake myocardial remodeling and
arrhythmogenesis

Reduced baroreceptor Reduced parasympathetic activity and risk

sensitivity of sudden cardiac death

Myocardial fibrosis, fibroblast Remodeling and ventricular dysfunction

proliferation

Alterations in Na+ channel Increased excitability and contractility of

expression cardiac myocytes

Table 33-3. Causes of Diuretic Resistance in Heart Failure

Noncompliance with medical regimen; excess dietary Na +

intake

Decreased renal perfusion and glomerular filtration rate due

to:

Excessive intravascular volume depletion and hypotension

due to aggressive diuretic or vasodilator therapy

Decline in cardiac output due to worsening heart failure,

arrhythmias, or other primary cardiac causes

Selective reduction in glomerular perfusion pressure

following initiation (or dose increase) of ACE inhibitor
therapy

Nonsteroidal antiinflammatory drugs

Primary renal pathology (e.g., cholesterol emboli, renal

artery stenosis, drug-induced interstitial nephritis,
obstructive uropathy)

Reduced or impaired diuretic absorption due to gut wall

edema and reduced splanchnic blood flow
 Na+ and Ca2+ enter the cardiac
myocyte via the Na+ channel and the L-type Ca2+ channel during each cycle of membrane
depolarization, triggering the release, through the ryanodine receptor (RyR), of larger amounts of
Ca2+ from internal stores in the sarcoplasmic reticulum (SR). The resulting increase in
intracellular Ca2+ interacts with troponin C and activates interactions between actin and myosin
that result in sarcomere shortening. The electrochemical gradient for Na+ across the sarcolemma
is maintained by active transport of Na+ out of the cell by the sarcolemmal Na+,K+-ATPase. The
bulk of cytosolic Ca2+ is pumped back into the SR by a Ca2+-ATPase, SERCA2. The remainder is
removed from the cell by either a sarcolemmal Ca2+-ATPase or a high capacity Na+-Ca2+
exchange protein, NCX. NCX exchanges three Na+ for every Ca2+, using the electrochemical
potential of Na+ to drive Ca2+ extrusion. The direction of Na+-Ca2+ exchange may reverse briefly
during depolarization, when the electrical gradient across the sarcolemma is transiently reversed.
 Receptor agonists and phosphodiesterase inhibitors, by increasing intracellular cyclic AMP
levels, activate PKA, which phosphorylates target proteins, including phospholamban, the 
subunit of the L-type Ca2+ channel and regulatory components of the RyR, as well as TnI, the
inhibitory subunit of troponin (not shown). The effect of these phosphorylations is a positive
inotropic effect: a faster rate of tension development to a higher level of tension, followed by a
faster rate of relaxation. indicates site of cardiac glycoside binding. See text for mechanism of
positive inotropic effect of cardiac glycosides.
Table 34-1. Drug-Induced Cardiac Arrhythmias

ARRHYTHMIA DRUG LIKELY MECHANISM TREATMENT* CLINICAL FEATURES

Sinus bradycardia Digoxin ↑Vagal tone Antidigoxin Atrial tachycardia may

antibodies also be present

AV block Temporary
pacing

Sinus bradycardia Verapamil Ca2+ channel block Ca2+

AV block Diltiazem Temporary

pacing

Sinus bradycardia β-Blockers Sympatholytic Isoproterenol

AV block Clonidine Temporary

pacing

Methyldopa

Sinus tachycardia β-Blocker Upregulation of β- β-Blockade Hypertension, angina

withdrawal receptors with chronic also possible
therapy; more
receptors available for
agonist after
withdrawal of blocker

Any other
tachycardia

↑ Ventricular rate Quinidine Conduction slowing in AV nodal QRS complexes often

in atrial flutter atrium, with blockers widened at fast rates
enhanced (quinidine)
or unaltered AV
conduction

Flecainide

Propafenone

↑ Ventricular rate Digoxin ↓ accessory pathway IV procainamide Ventricular rate can

in atrial fibrillation refractoriness exceed 300/min
in patients with
WPW syndrome

Verapamil DC
 cardioversion

Multifocal atrial Theophylline ?↑ Intracellular Ca2+ Withdraw Often in advanced

tachycardia and DADs theophylline lung disease

?Verapamil

Polymorphic VT Quinidine EAD-related triggered Cardiac pacing Hypokalemia,

with ↑ QT interval activity bradycardia frequent
(torsades de
pointes)

Sotalol Isoproterenol Related to ↑ plasma

concentrations,
except for quinidine

Procainamide Magnesium

Disopyramide

Dofetilide

Ibutilide

"Noncardioactive"
drugs (see text)

Amiodarone (rare)

Frequent or Flecainide Conduction slowing in Na+ bolus Most often in patients

difficult to reentrant circuits reported with advanced
terminate VT effective in myocardial scarring
("incessant" VT) some cases

Propafenone

Quinidine (rarer)

Atrial tachycardia Digoxin DAD-related triggered Antidigoxin Coexistence of

with AV block; activity (±↑ vagal antibodies abnormal impulses
ventricular tone) with abnormal sinus
bigeminy and or AV nodal function
others

Ventricular Inappropriate use Severe hypotension Cardiac Misdiagnosis of VT as

fibrillation of IV verapamil and/or myocardial resuscitation PSVT → inappropriate
ischemia (DC use of verapamil
cardioversion)
*
In each of these cases, recognition and withdrawal of the offending drug(s) are mandatory.
ABBREVIATIONS: AV, atrioventricular; DAD, delayed afterdepolarization; DC, direct current; EAD, early
afterdepolarization; WPW, Wolff-Parkinson-supraventricular tachycardia; IV, intravenous; ↑, increase;
↓, decrease; ?, unclear.

Table 34-2. A Mechanistic Approach to Antiarrhythmic Therapy

ARRHYTHMIA COMMON MECHANISM ACUTE CHRONIC THERAPY a

THERAPY a

Premature atrial, Unknown None indicated None indicated

nodal, or ventricular
depolarizations

Atrial fibrillation Disorganized 1. Control 1. Control ventricular

"functional" reentry ventricular response: AV nodal
response: AV block b
nodal block b

Continual AV node 2. Restore sinus 2. Maintain normal

stimulation → irregular, rhythm: DC rhythm: K+ channel
often rapid, ventricular cardioversion block Na+ channel block
rate with τrecovery > 1 second

Atrial flutter Stable reentrant circuit Same as atrial Same as atrial

in the right atrium fibrillation fibrillation

Ventricular rate often AV nodal blocking drugs

rapid and irregular especially desirable to
avoid ↑ ventricular rate

Ablation in selected
cases c

Atrial tachycardia Enhanced automaticity, Same as atrial Same as atrial

DAD-related fibrillation fibrillation
automaticity, or reentry
within the atrium

Ablation of tachycardia
"focus" c

AV nodal reentrant Reentrant circuit within * Adenosine *AV nodal block

tachycardia (PSVT) or near AV node
 AV nodal block Flecainide

Less commonly: Propafenone

↑ vagal tone
(digitalis,
edrophonium,
phenylephrine)

*Ablation c

Arrhythmias
associated with
WPW syndrome:

1. AV reentry (PSVT) Reentry (Figure 34-7) Same as AV K+ channel block

nodal reentry

Na+ channel block with

τrecovery > 1 second

Ablation c

2. Atrial fibrillation Very rapid rate due to *DC Ablation c

with atrioventricular nondecremental cardioversion
conduction via properties of accessory
accessory pathway pathway

* Procainamide K+ channel block

Na+ channel block with

trecovery > 1 second (AV
nodal blockers can be
harmful)

VT in patients with Reentry near the rim of Lidocaine *ICD d

remote myocardial the healed myocardial
infarction infarction

Amiodarone * Amiodarone

Procainamide K+ channel block

DC cardioversion Na+ channel block

VT in patients DADs triggered by ↑ Adenosine e Verapamil e

without structural sympathetic tone
heart disease
 Verapamil e β-Blockers e

β-Blockers e

DC cardioversion

VF Disorganized reentry *DC *ICD d

cardioversion

Lidocaine * Amiodarone

Amiodarone K+ channel block

Procainamide Na+ channel block

Torsades de pointes, EAD-related triggered Pacing β-Blockade

congenital or activity
acquired; (often
drug-related)

Magnesium Pacing

Isoproterenol
*
Indicates treatment of choice.
a
Acute drug therapy is administered intravenously; chronic therapy implies long-term
oral use.
b
AV nodal block can be achieved clinically by adenosine, Ca 2+ channel block, β adrenergic
receptor blockade, or increased vagal tone (a major antiarrhythmic effect of digitalis
glycosides).
c
Ablation is a procedure in which tissue responsible for the maintenance of a tachycardia
is identified by specialized recording techniques and then selectively destroyed, usually
by high-frequency radio waves delivered through a catheter placed in the heart.
d
ICD, implanted cardioverter/defibrillator. A device that can sense VT or VF and deliver
pacing and/or cardioverting shocks to restore normal rhythm.
e
These may be harmful in reentrant VT and so should be used for acute therapy only if
the diagnosis is secure.
ABBREVIATIONS: DAD, delayed afterdepolarization; EAD, early afterdepolarization; WPW,
Wolff-Parkinson-White; PSVT, paroxysmal supraventricular tachycardia; VT, ventricular
tachycardia; VF, ventricular fibrillation.

Table 34-3. Major Electrophysiological Actions of Antiarrhythmic Drugs

Na+ CHANNEL BLOCK

DRUG τ RECOVERY 1, STATE ↑APD Ca2+ AUTONOMIC EFFECTS OTHER EFFECTS

 SECONDS DEPENDENCE1 CHANNEL
BLOCK

Lidocaine 0.1 I>O

Phenytoin 0.2 I

Mexiletine * 0.3

Tocainide * 0.4 O>I

Procainamide 1.8 O √ Ganglionic blockade 3: Metabolite pr

(especially intravenous) APD

Quinidine 3 O √ (x) α-Blockade, vagolytic

Disopyramide a 9 O √ Anticholinergic

Moricizine ~10 O≈I

Propafenone a 11 O≈I √ β-Blockade (variable

clinical effect)

Flecainide * 11 O (x) (x)

β-Blockers:

Propanolola β-Blockade Na+ channel blo

vitro

Sotalol a √ β-Blockade

Amiodarone 1.6 I √ (x) Noncompetitive β- Antithyroid acti

blockade

Dofetilide √

Ibutilide √

Verapamil * √

Diltiazem * √

Digoxin √:Vagal stimulation √: Inhibition of N

ATPase

Adenosine √ √:Adenosine receptor √: Activation of

activation outward K+ curr

Magnesium ?√ Mechanism not

understood
√indicates an effect that is important in mediating the clinical action of a drug.
(x)indicates a demonstrable effect whose relationship to drug action in patients is less well established.
*
indicates drugs prescribed as racemates, and the enantiomers are thought to exert similar electrophysiological effects.
a
indicates racemates for which clinically relevant differences in the electrophysiological properties of individual enantiom
have been reported (see text).
One approach to classifying drugs is:
Class Major action
I Na+ channel block
II β-blockade
III action potential prolongation (usually by K + channel block)
IV Ca2+ channel block
Drugs are listed here according to this scheme. It is important to bear in mind, however, that many drugs exert multiple e
that contribute to their clinical actions. It is occasionally clinically useful to subclassify Na + channel blockers by their rates
recovery from drug-induced block (τ recovery) under physiological conditions. Since this is a continuous variable and can be
modulated by factors such as depolarization of the resting potential, these distinctions can become blurred: class Ib, τ recov
class Ia, τrecovery 1-10 s; class Ic, τrecovery > 10 s. These class and subclass effects are associated with distinctive ECG changes,
characteristic "class" toxicities, and efficacy in specific arrhythmia syndromes (see text).
1
These data are dependent on experimental conditions, including species and temperature. The τ recovery values cited here a
from Courtney (1987), with the exception of moricizine, which was found by Lee and Rosen (1991) to have a value slightly
than that for flecainide. The state-dependence is from Snyders et al., (1991).
ABBREVIATIONS: O, Open state blocker; I, inactivated state blocker; APD, action potential duration.