Antihypertensive Drugs and Vasodilators: John W. Sear

Chapter
23
ANTIHYPERTENSIVE DRUGS
AND VASODILATORS
John W. Sear
HISTORICAL PERSPECTIVE
SITES AND MECHANISMS OF ANTIHYPERTENSIVE AND
VASODILATOR DRUGS
BASIC PHARMACOLOGY AND MECHANISMS OF ACTION OF
INDIVIDUAL DRUG CLASSES
Calcium Channel Blockers
Blockers
Angiotensin-Converting Enzyme Inhibitors and
Angiotensin Receptor Antagonists
Diuretics
Centrally Acting Agents
2-Adrenoreceptor Agonists
-Adrenoreceptor Antagonists
Nitrovasodilators
Other Vasodilator
PHARMACOKINETICS, PHARMACODYNAMICS, AND ADVERSE
EFFECTS
Blockers
Angiotensin-Converting Enzyme Inhibitors
Angiotensin II Receptor Antagonists
Diuretics
Vasodilators
PHARMACOTHERAPY OF HYPERTENSION
HYPERTENSION AND ANESTHESIA
PULMONARY VASODILATORS
EMERGING DEVELOPMENTS
Endothelin and Endothelin Blockade
Worldwide there are probably more than 1 billion people with

raised blood pressure.1 It is one of the most common chronic
medical conditions internationally (U.S. National Center for
Health Statistics, 2005), and occurs almost twice as often in
African-Americans than in Caucasian-Americans. The incidence of hypertension increases with age, with a slightly
greater incidence in men than in women.2 In the United
States, hypertension affects about 25% of all adults older than
40 years of age. More importantly, the prevalence of undiagnosed hypertension is about 1 in 15. In the United Kingdom,
there are about 7.5 million patients suffering from raised
blood pressure; but importantly 80% to 85% of these patients
are either not treated or are being inadequately treated.
Blood pressure has been classified into four categories in
the JNC VII Report (Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood
Pressure; 7th Report) based on systolic (left) and diastolic
(right) pressures3:
Normotension <120 and <80mmHg
Pre-hypertension 120-139 or 80-89mmHg
Stage I hypertension 140-159 or 90-99mmHg
Stage II hypertension >160 or 100mmHg
In addition, patients with isolated systolic hypertension
(ISH) are classified into ISH 1 (140-159/<90mmHg) and
ISH 2 (>160/<90mmHg).
Many patients with hypertension have associated metabolic disorders (decreased high density lipoproteins; increased
triglycerides; increased urates; and reduced glucose tolerance). These all contribute to the increased cardiovascular risk
associated with high blood pressure, and to the possible development of type 2 diabetes mellitus. These additional comorbidities influence the choice of drug therapy for treatment of
raised blood pressure.
In the United States, present strategies for treatment
include initiation of treatment if blood pressure is more than
20mmHg systolic or 10mmHg diastolic above the target
pressure. Many studies have shown monotherapy to be generally inadequate and to be associated with an increased incidence of cardiovascular events occurring early after starting
treatment. The use of combination therapy is not new, in that
it originates from the mid-1960s when studies showed the
efficacy of fixed doses of reserpine, hydrochlorothiazide, and
hydralazine.
Section III CARDIOVASCULAR AND PULMONARY SYSTEMS
HISTORICAL PERSPECTIVE
The causes of arterial hypertension are multiple, but can be
divided into three distinct subgroups (Table 23-1). There are
various ways of reducing the blood pressure and hence of
treating hypertension. The history of the treatment of raised
blood pressure shows how different drugs have been used to
act on different effector sites or receptors. The dates of introduction of some of these early antihypertensive therapies are
listed in Table 23-2.
One of the earliest treatments for hypertension was that
described by Pauli using the sedative and hypotensive properties of sodium thiocyanate to obtain relief from the subjective
symptoms of hypertension.4 Another drug used for the treatment of malignant hypertension was sodium nitroprusside.5,6
In the 1930s, the beneficial effects of extracts of Rauwolfia
serpentina were first described with its first clinical use in
1955.7,8 In the 1940s, sympathectomy was used to treat high
blood pressure, often preceded by use of tetra-ethylammonium
as a prognosticator to judge the likely success of the surgery,
but was associated with a fairly high surgical mortality.
Real advances in management came with the introduction
of ganglion blocking drugs (e.g., as mecamylamine, pempidine, hexamethonium, and pentolinium) in the 1950s. Other
drugs introduced over the next decade included reserpine (a
rauwolfia alkaloid) and hydralazine.9 The combination of a
ganglion blocker and general anesthesia resulted in the development of significant bradycardias and hypotension. Diuretics were also introduced for treatment of hypertension
(initially chlorothiazide). The reduction in circulating fluid
volume produced by the natriuresis enhanced the hypotensive
effect of ganglion blocking agents and reduced some side
effects of drugs such as reserpine. These synergistic interactions between drugs allowed a smaller dose of each drug and
hence a less severe side-effect profile.
In the late 1950s and 1960s, two new important classes of
drugs were introducedadrenergic neuron blockers and the
first generation of -adrenoceptor blockers (see Chapter 13).
Table 23-1. Causes of Hypertension

Essential
Secondary
Chronic kidney disease
Coarctation of the aorta
Cushing disease and other conditions leading to excess levels of
glucocorticoid (including steroid therapy)
Obstructive uropathy
Pheochromocytoma
Primary aldosteronism and other mineralocorticoid excess states
Renovascular hypertension
Sleep apnea
Thyroid/parathyroid disease
Drugs
Secondary to Na+ and water retention, sodium salts of drugs,
steroid treatment (mineralocorticoids, glucocorticoids, oral
contraceptive pill); NSAIDs
Vasoconstrictor drugs such as sympathomimetics
Monoamine oxidase inhibitors through interaction with amines
including dietary tyramine
Rebound hypertension following acute withdrawal of clonidine,
-methyl DOPA, and blockers
NSAIDs, Nonsteroidal anti-inflammatory drugs.
406
The antihypertensive effect of adrenergic neuron blockers

(bretylium being the first) depends on inhibition of transmitter release from adrenergic nerve terminals in response to
sympathetic nerve impulses. This results in a decrease in
cardiac output, decrease in peripheral vascular resistance, and
increase in venous capacitance. The main side effects of
neuron blockade was postural hypotension, exertional hypotension, and hypotension in hot environments (all due to a
failure of sympathetically mediated circulatory control).
-Methyl DOPA (a false transmitter), introduced in 1961,
reduces blood pressure by inhibition of norepinephrine synthesis. A slowly developing antihypertensive effect develops
after repeated administration of small doses that do not exert
a significant pressor effect. It is not established whether its
hypotensive action is due to a peripheral effect (from impaired
neuroeffector transmission) or to a central effect (involving
the norepinephrine synapses in the medulla oblongata).
First-generation monoamine oxidase inhibitors (MAOIs),
such as pargyline, were introduced in 1963. The antihypertensive effect of MAOIs has a slow onset that persists for a
considerable period after cessation of treatment. In time, tolerance develops, probably due to fluid accumulation. The
underlying mechanism for their antihypertensive effect is
probably due to a change in composition of the monoamine
stores of adrenergic neurons with a relative increase in amines
other than norepinephrine (in particular, dopamine).
Other centrally acting drugs introduced in the 1960s
include the 2adrenoceptor agonist clonidine and the second
generation of adrenergic neuron blockers typified by bethanidine and debrisoquine. One of the first -adrenergic blocking
drugs introduced into clinical practice was pronethalol in
1962, followed by propranolol in 1965, alprenolol in 1967,
and oxprenolol and practolol in 1968.
Table 23-2. Drugs Used in Treatment of Hypertension

from Mid-1930s to 1966
1930sSedative drugs (barbiturates, bromides, cannabis
preparations)
1940sSurgical sympathectomy (bilateral thoracolumbar
ganglionectomy)
1944Salt-free diet (rice and fruit)
1945Nitroprusside and thiocyanate salts
1950Hexamethonium (the first of a series of improved ganglionblocking drugs)
1952Phenoxybenzamine and phentolamine (both used for
treatment of hypertension, although introduced primarily for
treatment of pheochromocytoma)
1953Benefit of combination therapy recognized: pentolinium
(ganglion blocker); hydralazine (vasodilator); reserpine and other
rauwolfia alkaloids
1957Mecamylamine (ganglion blocker) and chlorothiazide.
Although chlorothiazide only had weak antihypertensive effects, its
use was associated with a marked potentiation of the effect of
other antihypertensive drugs
1959Bretylium, the first adrenergic neuron blocker
1960Guanethidine
1961-Methyl-DOPA (the first of the drugs that act through
production of false transmitters)
1962Diazoxide (vasodilator)
1963Monoamine oxidase inhibitors
1965Propranolol, followed by oxprenolol and practolol; also
bethanidine (second-generation adrenergic neuron blocker)
1966Clonidine (centrally acting antihypertensive agent);
desbrisoquine
Chapter 23 Antihypertensive Drugs and Vasodilators

At the same time, a major controversy and debate developed regarding whether antihypertensive drugs should be
withdrawn from patients before anesthesia and surgery
because of their effects in obtunding the normal mechanisms
of cardiovascular control. The value of maintaining therapy
was emphasized in a series of controlled studies of treated
and untreated hypertensive patients.10 Patients with wellcontrolled hypertension maintained on their drugs up to and
including the morning of surgery experienced less cardiovascular instability than their untreated counterparts, especially
in the postoperative period.
SITES AND MECHANISMS OF ANTIHYPERTENSIVE

AND VASODILATOR DRUGS
The main center for neurogenic control of vascular tone and
hence blood pressure is the vasomotor center in the midbrain.
This affects both the sympathetic ganglia and parasympathetic nerves (Figure 23-1). There are two different central
neural control systems involved in blood pressure regulation:
neurogenic control (as outlined previously) and arterial baroreceptor reflexes.
Other humoral and endocrine control systems include the
renin-angiotensin-aldosterone system; atrial natriuretic peptides; renal control of Na+ and water excretion; eicosanoids;
the kallikrein-kinin system; adrenal steroids (both glucocorticoids and mineralocorticoids); the endothelin system; and
medullipin in patients with hypertension secondary to uremia
and renal failure.
There are three main mechanisms by which drugs act in
treatment of high blood pressure: (1) effects on the autonomic nervous system, (2) inhibition of the renin-angiotensinaldosterone system, and (3) peripheral vasodilation. Based on
these mechanisms, there are a number of potential sites of
action for antihypertensive agents (Table 23-3).
Based on the three main antihypertensive mechanisms and
the multiple sites at which drugs can act, there are different
physiologic approaches to the reduction of blood pressure
(Table 23-4) .11 Most drugs currently available do not act by
a single mechanism. Within this physiologic approach to lowering blood pressure by vasodilation, the drugs available can
be divided into three main subgroups (Table 23-5). Most of
these vasodilator drugs act either on the arterial or venous
circulations, with very few acting on both (Table 23-6).
Vasomotor center
2-Adrenoceptor agonists
Imidazoline receptor agonists
Sympathetic nerve terminals
Adrenergic neuron blockers
Sympathetic ganglia
Ganglion blockers
-Adrenoreceptors on heart
-Adrenoreceptor antagonists
Angiotensin
receptors
on vessels
ACE inhibitors
AT1, receptor
antagonists
Vascular smooth
muscle
Diuretics
Vasodilators
Nitrovasodilators
Calcium channel
openers
-Adrenoreceptors
on vessels
1-Adrenoceptor
antagonists
1 antagonists
Adrenal cortex
ACE inhibitors
AT1 receptor antagonists
Kidney tubules
Diuretics
ACE inhibitors
Juxtaglomerular cells that release renin

-Adrenoreceptor antagonists
Direct renin inhibitor
A
Neurogenic Control of Vascular Tone
Cortex
Hypothalamus
Vasomotor center
Sympathetic ganglia
Parasympathetic ganglia
Adrenergic nerves
Cholinergic
receptors
Adrenergic receptors (1, 2)
Endothelium
Calcium channels
EDRF (NO)
Figure 23-1 A, Sites of action within the body of drugs that can be used
for the treatment of high blood pressure. B, Mechanisms of the neurogenic
control of vascular tone via the vasomotor center. EDRF, Endothelial derived
relaxing factor; NO, nitric oxide.
BASIC PHARMACOLOGY AND MECHANISMS OF

ACTION OF INDIVIDUAL DRUG CLASSES
These drugs have a direct, dose-related effect on three separate functions of the heart (conduction, contraction, and ino
tropy), and on peripheral and coronary vascular tone. When
used to treat high blood pressure, the major effect of these
drugs is arterial vasodilation by blockade of Ca2+ influx
through L type voltage-gated Ca2+ channels in the smooth
muscle cells of resistance vessels. They also reduce the increase
in intracellular Ca2+ in response to membrane depolarization,
and the secondary Ca2+-induced Ca2+ release from intracellular stores. Some calcium channel blockers also reduce heart
Table 23-3. Sites of Action of Antihypertensive Agents

Vasomotor center
Sympathetic nerve terminals
adrenoceptor on heart
Sympathetic ganglia
Angiotensin receptors on vessels
adrenoceptors on vessels
Vascular smooth muscle
Adrenal cortex
Kidney tubules
Juxtaglomerular cells that release renin
407

Table 23-4. Physiologic Strategies for Reduction of Blood
Pressure
Decrease Systemic Vascular Resistance
Decreased sympathetic vascular motor tone
Decreased central sympathetic activity
Blockade of ganglionic transmission
Impairment of vascular neuroeffector transmission
Decreased vascular reactivity
Relaxation of vascular smooth muscle
Decrease of Na+ content of vascular tissue
Decreased humorally mediated vasoconstriction
Inhibition of vasoconstrictor release
Blockade of action of vasoconstrictors
Decrease Cardiac Output
Decreased sympathetic cardiac tone
Decreased central sympathetic activity
Blockade of sympathetic ganglionic transmission
Impairment of cardiac neuroeffector transmission
Decreased cardiac reactivity
Increased vagal activity
Depression of myocardial reactivity directly
Decreased cardiac return
Decreased venomotor tone (and thereby increased venous
capacitance)
Decreased circulating fluid volume
Adapted from Bowman WC, Rand MJ. Textbook of Pharmacology. 2nd ed. Oxford:
Blackwell Scientific; 1980:23.26-23.
Table 23-5. Drugs and Their Physiologic Mechanisms

for Lowering Blood Pressure
Neurogenically Acting Hypotensive Agents
Central depression of catecholaminesrauwolfia alkaloids,
alpha-methyl-DOPA, 2 agonists, monoxidine
Ganglion blockerspentolinium, hexamethonium, trimetaphan
Adrenergic nerve blockersguanethidine, bethanidine, bretylium,
monoamine oxidase inhibitors
Neurogenically Acting Vasodilators Acting
on Adrenergic Receptors
1 blockersprazosin, indoramin, doxazosin, and related
compounds
1, 2 blockersphentolamine, phenoxybenzamine
1, 1 blockerslabetalol, carvedilol, nebivolol
2 agonistsisoproterenol
Other Vasodilators
Renin-angiotensin system antagonistsangiotensin-converting
enzyme inhibitors, angiotensin II receptor antagonists, direct
renin inhibitors
Nitrovasodilatorsnitric oxide, sodium nitroprusside,
nitroglycerin, isosorbide dinitrate, isosorbide mononitrate
Other vasodilatorshydralazine, minoxidil
rate and myocardial contractility, which leads to decreased

cardiac output and blood pressure.
There are three classes of calcium channel blockers. Difference in subunit structure of Ca2+ channels in vascular and
cardiac tissues might explain the different selectivity of the
drugs. The dihydropyridines act mainly on vascular smooth
muscle of resistance vessels, while the non-dihydropyridines
act on the myocardium. All three classes act on voltage-gated
Ca2+ channels that are made up of five subunits (1, 2, , ,
and ). The 2 and subunit dimer and subunit are transmembrane, while the unit is located intracellularly. The 1
subunit forms the transmembrane ion channel.
408
Table 23-6. Sites of Action of Vasodilator Drugs

ARTERIOLAR
BOTH
Prazosin
Nitroprusside
Phentolamine
Phenoxybenzamine
Tolazoline
Hydralazine
Diazoxide
Calcium channel blockers
Angiotensin-converting enzyme inhibitors
VENODILATORS
Nitroglycerin
Dihydropyridines (e.g., nifedipine and nicardipine) bind to

the extracellular domain of the L-type voltage-gated Ca2+
channel (CaV1) in the cell membrane, so inhibiting Ca2+
influx.10 These drugs primarily affect resistance vessels with
minimal effects on veins due to the low density of L-type Ca2+
channels in capacitance vessels.
Phenylalkylamines (e.g., verapamil) act mainly on the heart
where inhibition of voltage-gated Ca2+ channels is frequencydependent. The phenylalkylamines probably enter the cell
and bind internally to produce their effects.12
Benzothiazepines (e.g., diltiazem) bind on the extracellular
side of the L-type channel.13 Their effects are seen more on
vascular compared with cardiac smooth muscle.
Blockers
There are at least three distinct subtypes of receptors (1,
2, and 3), each of which has different tissue distributions.
Both 1 and 2 agonists mediate their cellular effects through
increases in cyclic adenosine monophosphate (cAMP).
receptors are G proteincoupled receptors that traverse the
lipid cell membrane seven times. The N-terminal end of the
protein is extracellular and the C-terminal end intracellular.
The region conferring receptor coupling is thought to lie
in the third cytoplasmic loop between the fifth and sixth
transmembrane segments (for further detail of this receptor,
see Chapter 1).
1 receptors are present mainly in heart muscle. The ligandreceptor complex is coupled to a Gs-protein, which in turn
activates adenylyl cyclase to produce cAMP. The cAMP activates a protein kinase A, leading to enhanced influx of Ca2+
and, in turn, muscle contraction.
2 receptors exist in several sites. Some of these receptors
can be identified in heart muscle (hence the rationale for use
of salbutamol in some patients with low output states).
However, they are more abundant in bronchial and peripheral
vascular smooth muscle, where they lead to bronchodilation
and vasodilation respectively.
3 receptors are present in adipose tissue and heart muscle.
In contrast to 1 and 2 adrenoceptors, activation of 3 leads
to a decrease in inotropic state of the myocardium via a Gi
proteindependent pathway. Thus, as well as having an effect
on thermogenesis, 3 activation can lead to cardiodepressant
effects.14
ACTION OF BLOCKERS AT THE ADRENERGIC RECEPTOR
Administration of some blockers restore receptor responsiveness to catecholamines after receptor desensitization,

leading to normal GRK2 activity (G proteincoupled receptor kinase 2; also known as BARK1, or adrenoceptor kinase
1) and receptor protein subunit G1 levels. Other blockers
allow intracellular signaling to return toward normal despite
concurrent catecholamine stimulation. A third class of
blockers (including metoprolol and carvedilol) have an additional property in reversing the effects of cardiac remodeling.
These differences in action could explain why some blockers
protect myocytes more effectively than others, and why all are
not equally effective in reducing perioperative ischemia, myocardial infarction, and cardiac mortality.15,16
receptors can exist in three distinct activation
states: stabilized and inactivated, nonstabilized and inactivated, or stabilized and activated. Normally there is a dynamic
equilibrium between the activated and the two inactivated
states. Drugs that stabilize the receptor in the activated state
are either partial or full agonists; drugs that push the equilibrium toward the inactivated state are either full or partial
agonists; drugs that block access to the receptor binding site
without affecting the state of equilibrium are termed neutral
(competitive) antagonists (see Chapter 1).
At the molecular level, some blockers incompletely stabilize the activated state of the receptor, leading to a coupling of the receptor to the G intracellular protein (these are
therefore partial agonistsbucindilol, xamoterol). They
block the effects of potent agonists while generating lowlevel adrenoceptor stimulation on their own. Other
blockers stabilize the receptor in the inactivated state, thus
leading to receptor upregulation rather than the desensitization and downregulation seen with xamoterol. Such drugs
are inverse agonists (metoprolol, nebivolol, sotalol). However,
most of the blockers are neutral or competitive antagonists,
in that they bind to the receptor without affecting its activation state.
These different molecular actions give rise to drugs with
different clinical profiles. Thus the 1 selective blockers (acebutolol, atenolol, bisoprolol, celiprolol, esmolol, xamoterol)
diminish detrimental cardiac remodeling while preserving the
protective effects of 2 activation; the 1, 2, and 1 blockers
(e.g., bucinodilol, carvedilol, labetalol) decrease arterial vascular tone and serve as effective afterload reducing drugs, as
well as blocking the deleterious effects of sympathetic hyperactivity. The partial inverse agonists (metoprolol and nebivolol) might reduce receptor desensitization while maintaining
functional receptor responsiveness.
adrenoceptor blocking drugs act as receptors by competitive antagonism. Their action to reduce blood pressure is by
both decreasing cardiac output (through their effects on contractility and heart rate) and by inhibiting renin release from
the kidneys.There are several ways of classifying the pharmacologic effects of the adrenoceptor blockers, depending on
their receptor specificity; the presence of either intrinsic sympathomimetic or vasodilator activity, and their lipophilicity or
hydrophilicity (Table 23-7).
The 1 selective agents such as atenolol, bisoprolol, and
metoprolol are cardioselective, although this selectivity is
reduced at higher doses. The pure adrenoceptor blocking
drugs do not cause vasodilation. These agents diminish the
detrimental effects of myocardial remodeling while preserving the protective effects of 2 activity.17,18
Nonselective (1 and 2) agents have similar effects to the
selective agents on blood pressure.
Table 23-7. Classification and Relative Potency of Blockers

Used for Treatment of Hypertension
ANTAGONISTS*
Selective
Atenolol (1)
Metoprolol (3)
Esmolol (0.02), landiolol
Bisoprolol
Nonselective
Propranolol (1)
Timolol (10)
Nadolol
Sotalol (0.1)
PARTIAL AGONISTS (ISA)*

Acebutolol
Practolol
Oxprenolol (1)
Alprenolol
Pindolol (20)
*Number enclosed in parentheses indicates potency relative to propranolol at the

1 receptor.
Vasodilators = labetalol (0.25), celiprolol, carvedilol, nebivolol.
ISA, Intrinsic sympathomimetic activity.
Partial agonists (pindolol) result in less resting bradycardia

and some peripheral vasodilation.
Vasodilator activity is also produced by drugs with antagonist action at receptors (labetalol, celiprolol, carvedilol), or
by agents that promote endothelial nitric oxide production via
the L-arginine-NO pathway (nebivolol).19 The use of these
drugs with vasodilatory properties can be advantageous when
treating hypertension. One of the first drugs of this type
(celiprolol) is formulated as a racemic mixture, is hydrophilic,
and acts as a 1 antagonist, mild 2 agonist, and weak vasodilator.20 Celiprolol also causes an increase in myocardial inducible NO synthase activity.
Angiotensin-Converting Enzyme Inhibitors and

Angiotensin Receptor Antagonists
Renin is a protease synthesized in the kidney and catalyzes
the production of angiotensin I from angiotensinogen (a 225
amino acid pro-hormone). Angiotensin-converting enzyme
(ACE) then biotransforms angiotensin I to angiotensin II
the latter being a vasoconstrictor through action at angio
tensin receptors. The molecular mechanism of action for
angiotensin II is through coupling to the phospholipase C Gq
proteinIP3 transduction pathway. Angiotensin II also affects
norepinephrine kinetics through facilitation of its release and
prevention of its reuptake at sympathetic nerve terminals.
The renin-angiotensin pathway can therefore be interrupted
at two separate sites (both leading to vasodilation): direct
inhibition of ACE and angiotensin receptor antagonism
(Figure 23-2).
ACE inhibition occurs both in the plasma and in the vascular endothelium. Inhibition also has an effect to reverse
arteriolar hypertrophy that occurs in hypertension, and reduce
left ventricular hypertrophy. ACE inhibitors decrease conversion of angiotensin I to angiotensin II thereby reducing vasoconstrictor effects, aldosterone secretion, and sympathetic
activation (all of which lead to hypertension). Angiotensin II
acts on AT1 receptors via Gq to activate phospholipase C.
This has the effect of increasing intracellular diacyl glycerol
(DAG) and IP3, which increase Ca2+ release from the sarcoplasmic reticulum (SR) to cause vasoconstriction of the efferent arteriole.21 Stimulation of the AT2 receptor leads to
409

Angiotensinogen
ACE inhibitor
Renin
Angiotensin I
Angiotensin II
Norepinephrine
Epinephrine
Inactive
peptides
Angiotensin
converting
enzyme
Bradykinins
Aldosterone
Na+ : H2O
Hypotension
Hypertension
Figure 23-2 Mechanisms of action of angiotensin-converting enzyme inhibitors with inhibition of conversion of angiotensin I to angiotensin II, and
inhibition of the breakdown of bradykinin to inactive peptides.
AT1
PLC
DAG
Ca2+
IP3
Vasoconstriction
AT2
Proliferation of
smooth muscle;
ventricular remodelling
Figure 23-3 Mechanism of action of angiotensin II receptor blockers (at

the AT1 and AT2 angiotensin receptors). DAG, Diacylglycerol; IP3, inositol
trisphosphate; PLC, phospholipase C.
smooth muscle proliferation and ventricular remodeling

(Figure 23-3).
Both ACE inhibitors and AT receptor antagonists produce
arterial vasodilation not only by limiting the direct effects of
angiotensin II on vascular smooth muscle but also by minimizing its ability to increase sympathetic vascular tone. Their
action is also accompanied by an increase in parasympathetic
tone. They also decrease the effect of aldosterone on the distal
convoluted tubule of the nephron, so promoting salt and
water loss. They also block breakdown of bradykinin, which,
in turn, contributes to the vasodilator effects of the drugs.
ACE inhibitors prevent the breakdown of kinins, and the
increased concentration of bradykinin is probably responsible
for the unwanted side effects of cough and allergic reactions.
Other side effects of ACE inhibitors include diarrhea. On
the other hand, the angiotensin receptor antagonists prevent
the vasoconstrictor effects of angiotensin II without affecting
ACE activity.10 So, in contrast to ACE inhibitors, they do
not affect kinin production (and hence cough is not a prominent side effect of these drugs). These drugs act as selective
blockers at the AT1 receptors, with no effect on AT2
receptors.
Diuretics
The action of diuretics to reduce blood pressure is twofold.
First, they cause an initial decrease in intravascular volume,
although compensatory mechanisms are activated and this
effect is reduced over time. They have a secondary mechanism
410
to reduce blood pressure by direct arterial vasodilation.

The exact mechanism involved is not clear but might be
through a decrease in Ca2+ entry into smooth muscle cells and
through stimulating local vasodilator prostaglandin formation. Although the decrease in intravascular volume and total
body Na+ occurs within weeks of the start of diuretic therapy,
an increase in renin release causes them to return to normal.
The antihypertensive effects of diuretics are not just related
to their effects on Na+ and water balance, because more effective diuretic agents (e.g., furosemide) are not very effective
hypotensive agents.
There are three main classes of diuretics:
1. Thiazides inhibit Na+/Cl co-transporters in the proximal
diluting segment of the distal collecting tubule and early
collecting duct. The diuretic effect of the thiazides (except
metolazone and indapamide) is less effective in patients
with renal impairment.22 If used long term, thiazides
inhibit maximal reabsorption of Na+ to about 3% to 5%
of the filtered load.
2. Loop diuretics have a short duration of action and hence are
rarely used as first-line drugs for treatment of hypertension. They act on the medullary and cortical thick ascending limb segments of the nephron to prevent Na+, Cl, and
water reabsorption. There is some debate as to whether
they also have other actions, such as systemic vasodilation
and a reduction in left ventricular filling pressure secondary to preload reduction due to venodilation. However,
they are useful if volume expansion contributes in part to
the etiology of the hypertension (in patients with renal
failure or from use of vasodilator drugs).
3. Of the potassium-sparing diuretics, both amiloride and triamterene have weak antihypertensive effects. However,
spironolactone (an aldosterone antagonist) can be useful as
an antihypertensive treatment in primary or secondary
hyperaldosteronism, or if the hypertension is treatmentresistant. This class of diuretics has relatively weak natriuretic effects with a maximal excretion of only about 1%
to 2% of filtered Na+ load.23
Centrally Acting Agents

Most centrally acting antihypertensive drugs are no longer
widely used. However, identifying their sites of action illustrates the diversity of approaches used to reduce blood
pressure.
Reserpine acts to deplete neuronal stores of catecholamines both centrally and peripherally at the postganglionic
neuron. Its mechanism of action is related to inhibition of
norepinephrine and dopamine uptake into terminal synaptic
vesicles, leading to increased breakdown of norepinephrine
and reduced conversion of dopamine to norepinephrine.
Although reserpine crosses the blood-brain barrier, this is
probably not the site of its antihypertensive effect.
Bethanidine, guanethidine, and debrisoquin are selective
postganglionic neuron blockers that act to inhibit release
of norepinephrine from peripheral sympathetic nerve terminals. Although the exact mechanism of action of these drugs
is not clear, there is evidence that the drugs must be actively
taken up into neurons where they accumulate in synaptic
vesicles, causing norepinephrine depletion. Their antihypertensive effects are through reduced adrenergic synaptic
transmission.
2 Receptor agonists have several distinct pharmacologic
effectssedation, analgesia, and hypotension. The 2 adrenoceptor is coupled to a Gi protein complex, which inhibits
adenylyl cyclase, and Ca2+ and K+ ion channels. The net result
of 2 agonist binding is reduced cAMP production, hyperpolarization, and decreased intracellular Ca2+. 2 Receptors
occur both presynaptically and postsynaptically. Stimulation
of presynaptic 2 receptor decreases central sympathetic
outflow. Agonist stimulation of postsynaptic 2 receptors
mediates the sedative and analgesic effects.24
Some of the earliest antihypertensive therapies were based
on drugs acting on the control mechanisms in the central
nervous system (CNS). There are 2 adrenoceptors in the
locus coeruleus in the floor of the fourth ventricle, where 2
agonists act to cause sedation. The locus coeruleus also has
afferent connections from the rostral ventrolateral medullary
nuclei and efferent connections to noradrenergic fibers connecting to the thalamus and elsewhere. The 2 agonists
also block salivary gland secretion. Effects in the nucleus
tractus solitarius lead to inhibition of sympathetic activity and
reduce peripheral vasoconstriction. These drugs are no longer
widely used in the treatment of hypertension, with the exception of -methyl DOPA for treatment of preeclampsia of
pregnancy.
Excessive hypotension secondary to 2 agonist therapy can
be reversed by vasopressors and inotropes. The use of ephedrine, phenylephrine, and dobutamine, but not norepinephrine, can be accompanied by an enhanced pressor response
due to the effects of these agents.
There are three main classes of 2 agonists: (1) the phenylethylates (-methyl DOPA, guanabenz), (2) the imidazolines
(clonidine, dexmedetomidine, mivazerol), and (3) the
oxaloazepines.
-Methyl DOPA is converted in noradrenergic neurons to
the false transmitter -methyl norepinephrine, which is a
potent 2 agonist. It stimulates brainstem postsynaptic 2
receptors to decrease sympathetic tone and systemic vascular
resistance.
Clonidine acts as a presynaptic 2 agonist on receptors in
the brainstem, leading to reduction in sympathetic outflow
and an increase in vagal activity. After intravenous dosing,
there can be an initial transient hypertensive response due to
peripheral vasoconstriction through 1 and 2B interactions.
In contrast to 2 agonists such as -methyl DOPA, imidazoline compounds produce hypotension following direct intramedullary injection. This led to the proposal of the presence
of nonadrenergic receptors in the lateral reticular nuclei of
the ventrolateral medulla (VLM). Two types of nonadrenergic
imidazoline receptors have been identified: I1 receptors in
brain and I2 receptors in brain, pancreas, and kidney. A
number of the 2 agonists also have activity at I1 receptors. It
is likely that they mediate their effects through a G protein
coupled mechanism that results in an increase in arachidonic
acid and the subsequent release of prostaglandins. This led to
the development of two specific I2 receptor agonists with
more ideal hemodynamic profiles: monoxidine and rilmenidine. Both drugs have weaker affinity for central adrenoreceptors than -methyl DOPA and clonidine. Other 2 agonists
include dexmedetomidine, which has a greater selectivity and
specificity for 2 receptors than clonidine (2:1 1620:1
-Methyl DOPA
clonidine, dexmedetomidine
I1-Imidazoline
receptors
2-Adrenoceptors
Salivary
glands
Locus
coeruleus
Dry mouth
Sedation
Moxonidine
Nucleus
tractus
solitarius
Rostral ventral
lateral medulla
Inhibition of
sympathetic
activity
Reduced vasoconstriction
Figure 23-4 Mechanisms of action of 2 adrenoreceptor agonists and I1
imidazoline receptor agonists.
compared with 200:1); and mivazerol (119:1) (Figure 23-4).

This latter sympatholytic drug has been examined for a role
in myocardial protection, but there are no published studies
examining its use in the treatment of perioperative
hypertension.25
Monoxidine is a selective imidazoline receptor agonist that
stimulates I1 receptors in the VLM, thereby decreasing sympathetic outflow and lowering blood pressure. In contrast to
some other drugs, its use is not associated with a reflex
tachycardia.
Agonists of the 1 adrenoreceptor leads to an increased intracellular Ca2+. The 1 agonist-receptor interaction leads to
activation of phospholipase C (linked to Gq), which increases
hydrolysis of phosphatidylinositol bisphosphate (PIP2) and
increases synthesis of two second messengers: DAG and
1,4,5-inositol trisphosphate (IP3). DAG activates protein
kinase C while IP3 increases the intracellular Ca2+ concentration by releasing Ca2+ from the SR. There is also evidence
that IP3 causes an increase in the Ca2+ sensitivity of the contractile proteins. The phosphorylated product of IP3 (IP4
1,3,4,5-inositol tetraphosphate) has been suggested as the
messenger that enhances Ca2+ flux across the cell membrane,
causing vasoconstriction.
The 1 selective antagonists block 1 receptors to prevent
Ca2+ increases, thus leading to smooth muscle relaxation in
arterioles and venous capacitance vessels.
There are two types of 1 antagonists:
1. Selective 1 antagonists: doxazosin, terazosin, prazosin,
and indoramin
2. Nonselective 1 antagonists: phentolamine and phenoxybenzamine
While the selective antagonists act in a competitive manner,
phenoxybenzamine combines irreversibly with the 1 receptors and so has a prolonged duration of effect. Phentolamine
is a short-acting, reversible antagonist.
Nitrovasodilators
Nitric oxide (NO) was identified as the endotheliumdependent relaxing factor by Furchgott and Zawadski in
411

L-arginine
Endothelial
cell
Constitutive
nitric oxide
synthase
NO donors
Nitroglycerin
Sodium nitroprusside
NO
NO
Guanylyl cyclase
GTP
Smooth
muscle
cell
cGMP
[Ca2+]
Relaxation
Figure 23-5 Mechanism of action of nitric oxide and nitric oxide donors
on vascular smooth muscle. cGMP, cyclic guanosine monophosphate;
GMP, Guanine monophosphate; GTP, guanine triphosphate; NO, nitric oxide.
1980,26 and its mechanism defined by Palmer etal.27 NO is

an endogenous vasodilator that causes renal vasodilatation,
leading to a diuresis and natriuresis and resulting in reduced
blood pressure. There is some suggestion that deficiency in
NO could contribute to the etiology of high blood pressure.
NO stimulates guanylyl cyclase to produce cyclic guanosine monophosphate (cGMP), which activates PKG (cGMPdependent protein kinase). PKG then activates MLCP
(myosin light chain phosphatase) to dephosphorylate myosin
light chains, and hence produce vascular relaxation.28 NO also
activates sarcoplasmic and endoplasmic reticular Ca2+-ATPase
to enhance reuptake of Ca2+, an effect that is cyclic GMP
independent. NO might also activate K+ channels, resulting
in membrane hyperpolarization, thus closing voltage-gated
Ca2+ channels (Figure 23-5).
There are a number of NO donors. Some vasodilators
release NO spontaneously (sodium nitroprusside), while
others (organic nitrates such as nitroglycerin) need active
reduction of the nitrate radical by intracellular sulfhydryl
groups. All NO donors are potentiated by phosphodiesterase-5
inhibitors that reduce hydrolysis of cyclic GMP (see later).29
Nitrites act as both arterial and venous dilators. They are
usually associated with a reflex increase in heart rate; hence
they are often coadministered with blockers.
Sodium nitroprusside (SNP) is broken down in red cells
with liberation of cyanide and NO. SNP has a rapid onset of
action and is of short duration (1-2 minutes). While breaking
down to form NO, SNP interacts with oxyhemoglobin to
form cyan-methemoglobin and cyanide.30 The latter is converted to thiocyanate through transsulfation by the liver
enzyme rhodanase, with thiosulfate acting as the sulphur
donor. There are still issues over the total safe dose of SNP.
Prolonged administration leads to accumulation of thiocyanate and cyanide, with the development of venous hyperoxemia and metabolic acidosis.
Nitrates undergo denitration to produce NO, their active
component. Denitration can involve reaction with sulfydryl
groups or depends on the action of glutathione-S-transferase,
cytochrome P450, and xanthine oxidoreductase. A stepwise
412
increase in the dose of infused nitrate leads to a reduction in

venous tone and central venous pressure. This is accompanied
by a gradual decrease in systemic pressure. Administration
of bolus doses of nitrates cause significant and immediate
decreases in arterial pressure.
Glyceryl trinitrate (GTN) or nitroglycerin acts as an NO
donor, with a greater action on venous rather than arteriolar
vessels. Its use can lead to tachyphylaxis due to a decrease in
NO formation through generation of superoxide and peroxynitrite free radicals that inhibit aldehyde dehydrogenase.
Without this enzyme, the conversion of organic nitrates and
GTN to NO is impaired. In addition to decreasing blood
pressure, GTN also reduces preload and myocardial oxygen
demand. GTN is a coronary vasodilator (including relaxation
of stenosed vessels) and brings about an increased collateral
coronary flow, improved subendocardial perfusion, and
improved diastolic function. Because nitroglycerin undergoes
extensive first-pass metabolism after oral dosing, nitrates are
administered orally as isosorbide dinitrate (ISDN) and its
metabolite isosorbide mononitrate (ISMN). Although the
main uses of GTN, ISMN, and ISDN are as antianginal
drugs, they can also be used by titration for the control of
blood pressure in the cardiac patient.
Adenosine stimulates purinergic receptors (P1 and P2) on
endothelial cells to stimulate NO production. Adenosine also
has direct effects on smooth muscle via a G proteincoupled
pathway and activates ATPsensitive K+ channels, leading to
membrane hyperpolarization and relaxation.31,32 Adenosine
receptor blockers prevent Ca2+ entry during phase 1 of the
action potential, thus causing vascular relaxation. Although
predominantly a coronary vasodilator, it can decrease blood
pressure. It is not absorbed from the gut and is therefore
given by the intravenous route. The half-life after intravenous
dosing is less than 10 seconds. It is intracellularly phosphorylated to AMP and then deaminated to inosine, hypoxanthine,
xanthine, and uric acid. Both theophylline and other xanthines
are antagonists at both P1 and P2 receptors; hence their concurrent use increases dose requirements for adenosine. The
uptake of adenosine into coronary endothelial cells is inhibited
by dipyridamole.
Other Vasodilator
Minoxidil opens ATP-sensitive K+ channels in vascular smooth
muscle, hyperpolarizes the cell membrane, and closes voltagegated Ca2+ channels, leading to smooth muscle relaxation and
vasodilation.33
Hydralazine acts by promoting the influx of K+ into vascular smooth muscle cells, thereby causing hyperpolarization
and muscle relaxation.34 It can also cause arterial vasodilation
by promoting smooth muscle relaxation through activation of
guanylyl cyclase, leading to an increase in cyclic GMP. Other
mechanisms of action include inhibition of Ca2+ release from
the SR, reduction in Ca2+ stores in the SR, and stimulation of
NO formation by the vascular endothelium.
Diazoxide is chemically similar to thiazide diuretics but
causes Na+ retention. It is a powerful antihypertensive agent
due to peripheral vasodilation secondary to opening K+
channels.
Nicorandil promotes vasodilation of both systemic and
coronary arteries by opening ATP-sensitive K+ channels,
hyperpolarization of the membrane, and reduced opening of

voltage-gated Ca2+ channels and therefore vascular smooth
muscle relaxation. This is enhanced by the local production
of NO from a nitrate-like action that also causes
venodilation.35
Ganglionic blockers formerly played a significant role in the
modulation of blood pressure. Now only trimethaphan is used
(rarely) in hypertensive emergencies or for the production of
controlled hypotension during surgery. Ganglionic blockers
act by inhibiting autonomic activity at both sympathetic and
parasympathetic ganglia. The decrease in sympathetic outflow
causes vasodilation.
Magnesium affects vascular tone by diverse mechanisms; it
acts as a Ca2+ channel antagonist, stimulates production of
vasodilator prostaglandins and NO, and alters the response of
vascular endothelium to vasoactive agonists.36
Endothelin receptor antagonists reduce blood pressure by
blocking the actions of endothelins. Endothelins act on both
ET-A and ET-B receptors. Endothelin 1 (ET-1) causes vasoconstriction through activation of both types of receptor
on vascular smooth muscle cells. The receptors are coupled
to Gq, with activation leading to increased synthesis and
release of IP3 and Ca2+ release from the SR.37,38 ET-1 synthesis
and release is stimulated by a number of mediators: angiotensin II, arginine vasopressin, thrombin, cytokines, reactive
oxygen species, and shear forces on the endothelium. Mixed
ET-receptor antagonists lower arterial blood pressure and
prevent vascular and myocardial hypertrophy. Use of these
drugs has also been studied in the treatment of pulmonary
hypertension.
Peripheral dopamine agonists cause selective vasodilation of
a number of vascular beds (splanchnic, cerebral, and coronary
circulations) and can therefore be used in the treatment of
hypertension. There are two subtypes of peripheral DA
receptors. DA1 receptors are postsynaptic Gs protein-coupled
receptors and cause vasodilation following increased intracellular cAMP and reduced intracellular calcium. The DA2
receptor is presynaptic and is coupled to Gi protein, leading
to reduced cyclic AMP, with membrane hyperpolarization and
reduced norepinephrine release. The effects of dopamine on
various catecholamine receptors are dose-dependent: DA1
interactions occur at low doses, 1 at moderate doses, and 1
with high doses (see Chapter 22).
Fenoldopam is a selective DA1 dopamine agonist without
adrenergic receptor agonist properties. It is more potent than
dopamine at DA1 receptors and is useful for control of blood
pressure. It also has no agonist effects at the DA2, receptor.
As such, it causes a decrease in blood pressure without increases
in heart rate or contractility due to adrenergic effects. An
advantage of the drug is that it does not cross the blood-brain
barrier. It is available in the United States and some European
countries, where it is recommended for acute or emergency
control of blood pressure in the perioperative period.39
Phosphodiesterases catalyze the hydrolysis of cyclic nucleotides. Phosphodiesterase inhibitors (PDEIs) block the hydrolysis of cAMP or cGMP, so prolonging the effects on smooth
muscle of signaling pathways involving these second messengers.40,41 An increase in cAMP (or cGMP) leads to phosphorylation of myosin light chain kinase, leading to a reduction of
its activity due to reduced affinity for the Ca2+-calmodulin
complex. The resulting reduced phosphorylation of myosin
light chains leads to smooth muscle relaxation and vasodilatation. There are five subtypes of phosphodiesterase; PCE3 is
Adenylyl
cyclase
1
Gs
PDE
inhibitors
cAMP
ATP
Phosphodiesterase
5AMP
Ca2+
Protein
kinase
Ca2+
Figure 23-6 Mechanism of action of phosphodiesterase (PDE) inhibitors.

1, 1 Adrenoceptor; Gs, stimulatory subunit of the G protein complex; cAMP,
cyclic adenosine monophosphate; 5AMP, 5 adenosine monophosphate.
inhibited by milrinone and enoximone, and PDE5 is inhibited

by sildenafil and related compounds (see later).
PDE3 inhibition prevents the breakdown of cAMP. Specific
phosphodiesterases also hydrolyze cGMP, which might contribute to the vasodilator effect of PDE5 inhibitors. As a
result of the inhibition of cyclic nucleotide breakdown, PDEIs
cause a decrease in systemic vascular resistance and a small
but significant fall in arterial pressure (Figure 23-6).
Prostaglandins PGE1 and PGI2 (prostacyclin) have direct
vasodilator actions via prostanoid receptors on vascular
smooth muscle involving stimulation of cAMP. Although they
decrease systemic vascular resistance (and therefore blood
pressure), their main effect is on pulmonary vascular resistance (see later).
A number of other drugs are also vasodilators. These include
ganglion-blocking neuromuscular blocking drugs (tubocurarine derivatives), general anesthetics, and histamine.
PHARMACOKINETICS, PHARMACODYNAMICS, AND

ADVERSE EFFECTS
All calcium channel blockers are effective in reducing blood
pressure, although there is some controversy over the adverse
effects of short-acting drugs.42 In general, they are all well
tolerated and are becoming the first-line treatment for patients
aged older than 55 years. The actions of the three classes of
calcium channel blocking drugs differ. The relationship
between vasodilation and negative inotropy is about 1:1 for
both diltiazem and verapamil, 10:1 for nifedipine, and up to
1000:1 for the newer dihydropyridines.43 In the same way, the
side effects of calcium channel blockers differ according to
the class of drug.
Verapamil (a phenylalkylamine) is a racemic mixture that
is well absorbed orally and has high presystemic metabolism
(about 85%; L-enantiomer >D-enantiomer). Metabolism is
extensive by O-demethylation (25%) and N-dealkylation
(40%) followed by conjugation. Some of the metabolites are
active, especially nor-verapamil, which has about one-fifth to
one-tenth the activity of the parent drug. Verapamil has a
half-life of about 5 hours (range 2-7 hours), which can be
prolonged in patients with liver disease. The clearance of
L-verapamil is greater than that of the D-enantiomer,
413
NO2
R1 OOC
CH3
COO CH2 R2
N
CH3
Figure 23-7 Structure of the dihydropyridine calcium entry blockers. R1 and

R2 = side-chains at the 1 and 4 positions of the pyridine ring.
although the half-lives of the two enantiomers are similar.

There is greater free fraction of L-verapamil, and hence it has
a greater volume of distribution. Verapamil is excreted in the
urine (70%; as metabolites and unchanged drug) and feces.
Diltiazem (a benzothiazepine) is well absorbed orally
(>90%), but has a smaller fraction undergoing presystemic
metabolism (about 50%). Diltiazem is extensively metabolized, and some of these metabolites are active.
All dihydropyridines (nifedipine, amlodipine, felodipine,
isradipine, nicardipine, lacidipine, lercanidipine, nisoldipine)
are well absorbed by the oral route (>90%), but because of
their significant presystemic metabolism, sublingual dosing is
preferable for some (e.g., nifedipine). Presystemic metabolism
of nifedipine results in inactive metabolites with half-lives of
about 9 hours, while that of the parent drug is about 2 to 6
hours, with plasma protein binding of more than 90% and a
small volume of distribution (0.3-1.2L/kg). Metabolites are
excreted in both the urine (80%) and feces.
Chemical substitutions in nifedipine at the R1 position,
with introduction of long side chains (as amlodipine), produce
drugs with a longer duration of action and a half-life of up to
30 to 40 hours (felodipine 12-36 hours; isradipine 2-8 hours;
nicardipine 3-12 hours; amlodipine 35-60 hours) (Figure
23-7). The dihydropyridines are metabolized by hepatic cytochrome P450 (mainly CYP 3A4), and hence there are many
examples of drug-drug interactions either with CYP 3A4
inhibitors (the -azoles, -avirs, erythromycin, clarithromycin)
or with other drugs competing for metabolism by the same
isoform (e.g., midazolam, alfentanil, cyclosporin). Nifedipine
shows a bimodal polymorphism of metabolism by CYP 3A4/5.
The calcium channel blockers all demonstrate age-related
kinetics due to reduction in cardiac output (and liver blood
flow), leading to increased bioavailability and decreased systemic clearance. Other side effects of dihydropyridine include
vasodilation with flushing, headaches, ankle edema, and reflex
tachycardia. The use of calcium channel blockers is contraindicated in patients with heart failure due to their negative
inotropic effects (especially the non-dihydropyridines), and
slowing of sinoatrial and atrioventricular node conduction,
leading to bradycardia and heart block. Pronounced antihypertensive effects are mainly observed with the dihydropyridines. The decrease in blood pressure is accompanied
by reflex tachycardia and increased myocardial oxygen
utilization.
ADVERSE DRUG INTERACTIONS
Dihydropyridines increase plasma digoxin concentrations

by inhibiting its tubular secretion by interaction with
P-glycoprotein.
Verapamil can worsen cardiac failure in affected patients,
causing hypotension due to both vasodilation and negative
414
inotropy. If verapamil is given in combination with a blocker,

patients can develop hypotension, asystole, and an increased
incidence of arrhythmias.
Diltiazem reduces cardiac output and hepatic clearance of
flow-limited drugs, such as propranolol and cyclosporin A. All
non-dihydropyridines (diltiazem and verapamil) can cause
bradycardia and heart block when administered in conjunction with blockers. They can also exacerbate congestive
heart failure through negative inotropic effects.
NEW CALCIUM CHANNEL BLOCKERS
Clevidipine (an intravenous dihydropyridine) is characterized

by rapid onset of action, vascular selectivity and unique pharmacokinetics. Unlike other drugs in this class, it is not metabolized in the liver but undergoes breakdown of an ester-linkage
in blood and extravascular tissues to produce inactive carboxylic acid metabolites. This leads to a rapid onset of effect
(within 60 seconds) and short duration of action. It is highly
protein bound (>99.5%) with a small volume of distribution
(0.5-0.6L/kg) and high clearance (0.105L/kg/min). The
rapid offset relates partly to its short elimination half-life
(about 15 minutes). After infusions of up to 12 hours, the
context-sensitive half-time of the drug is less than 2 minutes.
Drug metabolism does not involve CYP enzymes, and hence
its elimination is not affected by hepatic or renal disease, and
there are no significant drug-drug interactions documented
to date.44 Clevidipine might be useful for emergency control
of blood pressure by careful titration of an intravenous
infusion.45,46
Blockers
There are two main chemical structural types of blockers:
(1) amino-oxypropanol derivatives (propranolol, timolol,
pindolol, metoprolol, atenolol, esmolol, and carvedilol)
and hydroxyaminoethyl compounds (sotalol and labetalol).
Although described in Table 23-7 as 1 selective blocking
drugs, metoprolol, celiprolol, and bisoprolol all show 2
antagonism at high doses. Most blockers are well absorbed
when given orally, although atenolol and sotalol, being more
polar, have lower oral absorption (about 50%). Carvedilol,
metoprolol, and propranolol all undergo extensive presystemic metabolism; bisoprolol shows no presystemic metabolism and is only metabolized by about 50%. Both atenolol and
sotalol are eliminated in urine mostly unchanged. The principal kinetics and dynamics of some commonly used blocking agents for treatment of hypertension are summarized in
Table 23-8.
Propranolol is a nonselective -blocking drug (although
1 activity >2 activity), with some membrane-stabilizing
activity (MSA). It is highly lipid soluble and can therefore
cross the blood-brain barrier, which can result in druginduced depression. Propranolol undergoes extensive hepatic
metabolism with less than 4% drug excreted unchanged in the
urine and feces.
Oxprenolol is a 1-selective blocker with intrinsic sympathomimetic activity (ISA) and MSA. Like propranolol, it is extensively metabolized with less than 5% excreted unchanged in
the urine.
Metoprolol is a highly selective 1 drug with no MSA
and no ISA. Metoprolol shows polymorphism with regard
to its metabolism; some of the metabolites (especially

Table 23-8. Pharmacokinetics and Pharmacodynamics of Common Beta Blockers
ORAL
ABSN (%)
BIOAVAIL
ABILITY(%)
T1/2 (HR)
PLASMA
PROTEIN
(%)
Acebutolol
Atenolol
Bisoprolol
Carvedilol
Celiprolol
Labetalol
Metoprolol*
>50
40-50
>95
25
30-70
>95
50-70
30-50
>90
80-90
R30; S15
>85
15-90
40-50
3-6
6-7
9-13
7-10
4-6
3-4
3-7*
26
<3
30
98
30
50
5-10
Nadolol
Nebivolol*
30-40
?
>95
12-96
17-24
12-19*
30
?
Oxprenolol
90
20-70
1-2
80
Pindolol
Propranolol
Timolol*
Esmolol
>95
>95
>95
N/A
85-90
5-50
50
N/A
3-4
3-6
2-5
0.14-0.18
40
80-95
80
55
METABOLIC
ROUTE
1
SELECTIVITY
ISA
MSA
VASODILATION
OTHER
100% H
10% H
50% H
H
Minimal
90% H
90% H,
gut
Minimal
Extensive
H
Extensive
H
H
100% H
80%H
Rbcesterase
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
No
No
No
No
No
No
Yes
No
No
Yes
No
No
No
No
No
No
Yes
Yes
Yes
No
Nil
Nil
Nil
Yes1
Yes2
Yes3
Nil
No
Yes
No
No
No
No
No
Yes
Nil
Yes4
No
Yes
Yes
No
Nil
No
No
No
Yes
Yes
No
No
No
Yes
Yes
No
No
No
No
No
No
Nil
Nil
Nil
Nil
*, Drug showing polymorphism; ABSN, absorption; H, hepatic; ISA, intrinsic sympathomimetic activity; MSA, membrane stabilizing activity; plasma protein (%), plasma
protein binding; Yes1, 1, 2 antagonism; Yes2, 2 agonism; Yes3, 1 and 2 antagonism, some ISA at 2.
-OH-metoprolol and O-desmethyl-metoprolol) are active

at the 1 receptor. There can also be extrahepatic
metabolism.
Pindolol is excreted in the urine as both unchanged drug
(40%) and metabolites following oxidation and glucuronide
conjugation.
Atenolol has properties similar to those of metoprolol. It is
eliminated by renal excretion (90%) as unchanged drug.
Being hydrophilic, there are few central nervous system side
effects due to minimal blood-brain barrier transfer.
Bisoprolol is a 1-selective blocker that is well absorbed
orally. Elimination is via the kidney (50% unchanged and 50%
as an active metabolite) following hepatic biotransformation.
Nadolol is a (1-selective blocker that is eliminated solely
by the kidney. Hence its use is contraindicated in patients with
renal impairment.
Timolol is a nonselective blocker that is eliminated
by both hepatic metabolism and renal excretion (20% as
unchanged drug).
Bextalol is a cardioselective blocker that is well absorbed
and undergoes minimal presystemic metabolism. It has a halflife of 13 to 24 hours and is metabolized by hepatic hydroxylation with little conjugation. The hydroxyl-metabolite is
excreted in the urine, together with 10% to 17% unchanged
drug.
Acebutolol, carteolol, penbutolol, and pindolol are all nonselective agents with some ISA. Acebutolol is biotransformed
by hydrolysis and N-acetylation in the liver to an active
metabolite, diacetolol, which has a long half-life of 10 to 14
hours. There can also be some drug metabolism in the gut
following oral dosing.
Celiprolol is a third-generation selective 1 blocker with no
MSA. This agent has some ISA at the 2 receptor, manifest
as weak bronchodilation and vasodilation.
output that is not compensated for by baroreflex mechanisms,

and where there might be a resetting of the reflex. Some of
the drugs (those that are lipophilic) can also have a central
effect to reduce sympathetic outflow. Another antihypertensive effect can be through inhibition of renin release from the
kidney.
ANTIHYPERTENSIVE EFFECT OF BLOCKERS
Because of differences in pharmacologic profiles, different

adrenoceptor blockers have varied side-effect profiles, but there
are some common features:
The exact mechanism by which blockers reduce blood pressure is unclear. They could act through reduction in cardiac
NEW BLOCKERS
Carvedilol (1, 1, 2 blocker) has a unique carbazole moiety.

It is a nonselective agent that also blocks the 1 receptor.
Carvedilol has some MSA but no ISA. It exerts a greater clinical effect than other blockers in the management of congestive cardiac failure and postmyocardial infarction. It is also an
antioxidant with antiarrhythmic, antiapoptotic, and antiproliferative properties that influence carbohydrate and lipid
metabolism.47 Carvedilol is metabolized by CYP 2D6 to an
active metabolite (a 4-hydroxy-phenol). Drug elimination is
via the biliary route and excretion in the feces. Carvedilol has
an elimination half-life of 7 to 10 hours.
Nebivolol is formulated as a racemic mixture. It is highly
lipophilic and rapidly absorbed, with a peak effect of 0.5 to 2
hours. It has vasodilating properties that are mediated by
stimulation of the L-arginine-NO pathway. It is only available
as an oral preparation and undergoes extensive metabolism by
glucuronidation, and N-dealkylation and oxidation by CYP
P450 2D6 with less than 0.5% excreted unchanged. Because
of genetic polymorphism of CYP 2D6, bioavailability varies
from about 12% in fast metabolizers to 96% in poor metabolizers, and the terminal half- life from 11 hours to 30+ hours,
respectively.19,48,49 Both carvedilol and nebivolol reduce blood
pressure through a decrease in systemic vascular resistance
rather than the proposed decrease in cardiac output (see
later).47,49
ADVERSE EFFECTS OF BLOCKERS
415

All blockers have negative inotropic effects and can cause
acute left ventricular failure when given in large doses to
patients with impaired left ventricular function.
All blockers can exacerbate intermittent claudication and
Raynauds phenomenon in patients with coexisting peripheral vascular disease.
Large doses of blockers can cause bradycardia leading to
syncope.
Nonselective blockers that interact with 2 receptors can
result in bronchospasm in patients with asthma or chronic
obstructive pulmonary disease due to blockade of 2
receptors.
Blockade can cause significant blood lipid effects leading
to increased triglycerides and decreased high-density lipoprotein cholesterol.
Lipophilic blockers that can cross the blood-brainbarrier can cause central nervous system effects leading
to depression, sleep disturbances, vivid dreams, and
hallucinations.
Sudden withdrawal of blockers results in increased catecholamine sensitivity; this upregulation can produce tachycardia, acute hypertension, and palpitations.
There are also important drug interactions involving
blockers:
Cimetidine (a CYP inhibitor) decreases hepatic first-pass
metabolism of propranolol and metoprolol, and the hepatic
metabolism of bisoprolol.
Carvedilol increases plasma concentrations of digoxin and
the risk of toxicity.
Concurrent administration of blockers and verapamil
increases risk of bradyarrhythmias and heart failure.
Avoid use of sotalol in conjunction with other drugs that
prolong the QT interval (e.g., amiodarone, disopyramide,
procainamide, quinidine).
All blockers can potentiate the effects of insulin and other
oral hypoglycemic drugs, and block the normal sympathetic
responses to hypoglycemia. Some evidence suggests that
this effect is more pronounced with nonselective
blockers.
Angiotensin-Converting Enzyme Inhibitors

Both captopril and enalapril are well absorbed orally, but
absorption is decreased to 50% if taken in the presence of
food. Captopril has limited presystemic metabolism (3%14%), has a half-life of 1 to 2 hours, and has plasma protein
binding of 30%. It undergoes both hepatic and renal elimination with 50% excreted unchanged and 50% transformed to
inactive metabolites.
Enalapril is the orally administered prodrug of the active
compound enalaprilat (available for intravenous use), which
is formed when enalapril undergoes extensive presystemic
metabolism. Enalapril has a half-life of less than 1 hour, but
enalaprilat has a long half-life of 35 hours. Enalaprilat is
excreted unchanged in urine.
Lisinopril shows slow and poor oral absorption (<25%) and
is eliminated unchanged in the urine. It has a half-life of about
12 hours and low protein binding (3%-10%).
Ramipril is modestly well absorbed (about 60%), and
undergoes some presystemic metabolism. Like enalapril, it is
metabolized to the active form ramiprilat, which in turn
undergoes partial excretion in the bile.
416
Other ACE inhibitor prodrugs include quinalopril and

perindopril. The long half-lives of all the ACE inhibitors
relate to their extensive binding to ACE in the plasma.
Angiotensin II Receptor Antagonists

Angiotensin II receptor antagonists act as competitive antagonists at the AT-1 receptor: currently they are only formulated
as oral medications. Candesartan is rapidly and completely
de-esterified during absorption of candesartan axetil. It is
highly protein bound, and undergoes part metabolism, and
part excretion in the bile. Unchanged drug is excreted in the
urine. Candesartan has a half-life of about 10 hours, with a
peak concentration at 3 to 4 hours.
Irbesartan is also rapidly and completely absorbed after
oral dosing, and undergoes minimal presystemic metabolism.
The drug is 90% bound to plasma proteins. It is metabolized
by oxidation (CYP 2C9) and glucuronidation with a half-life
of 12 hours. There are interactions between candesartan
and other drugs metabolized by CYP 2CP in vitro, although
no significant changes in disposition have been reported
in vivo.
Losartan is well absorbed after oral administration, but
undergoes extensive presystemic metabolism by CYP 2C9
and 3A4. The parent drug has a half-life of 2 hours, but there
is an active metabolite (with a half-life of about 8 hours). Peak
concentrations of drug and metabolite occur at about 1 and 4
hours respectively. Losartan is inactivated by further metabolism with two inactive metabolites excreted in the bile. Systemic bioavailability is double in patients with liver disease,
but there is no change after oral dosing in patients with renal
dysfunction.
Valsartan has a low systemic bioavailability (25%) reduced
even further (to 15%) if administered with food. The drug is
extensively protein bound (95%), and mostly excreted in the
bile and feces (83%) with 13% eliminated in the urine. There
is no effect of renal failure on valsartan disposition. It has a
half-life of about 6 hours.
Other drugs of this class are mainly longer acting (due to
longer elimination half-lives): eprosartan (5-9 hours), olmesartan (about 13 hours), and telmisartan (16-23 hours).
ADVERSE EFFECTS AND DRUG INTERACTIONS
Hypotension is associated with intravascular volume depletion due to accompanying diuretic therapy.
ACE inhibitors can cause renal impairment and hyperkalemia especially in patients with renal artery stenosis as perfusion of the affected kidney depends on the local production
of angiotensin. Rashes are seen in about 10% of patients and
can be accompanied by fever and eosinophilia. Rarely this is
associated with episodes of angioneurotic edema.
Coadministration of NSAIDs (cyclooxygenase inhibitors)
can reduce the hypotensive effects of ACE inhibitors. ACE
inhibitors can inhibit the excretion of lithium, and can result
in lithium toxicity. Angiotensin II receptor antagonists can
cause hypotension if coadministered with diuretics. They
should be used with caution in patients with renal failure,
because they rarely lead to hyperkalemia.
Because these drugs do not affect the breakdown of kinins
(as is seen with the ACE inhibitors), patients do not develop
episodes of coughing, and rarely develop angioneurotic
edema.
Diuretics
Diuretics are discussed in more detail in Chapter 34.
Thiazides are all absorbed when given orally and are
excreted unchanged by the kidney. Half- lives range between
3 and 90 hours. Chlorthalidone is well absorbed (60%-70%)
with negligible presystemic metabolism. Unlike some other
thiazides, it has a long half-life (50-90 hours), with protein
binding of 75%.
Loop diuretics act by inhibiting Na+ and K+ reabsorption
in the ascending loop of Henle by inhibiting Na+/K+/Cl
co-transport. Furosemide is poorly absorbed (50%-65%), with
poorer absorption in the presence of heart failure, is excreted
mainly unchanged in the urine, has a plasma half-life of about
1 hour, and high protein binding (96%-98%). Bumetanide
drug is well absorbed following oral administration (65%95%). About 60% is excreted unchanged in the urine, with
the rest being metabolized by the liver and excreted in urine
and bile. Bumetamide has a half-life of 1.5 hours, volume of
distribution of 9.5 to 35L, and high protein binding (95%).
As is seen with furosemide and the thiazides, bumetamide, in
the presence of hypokalemia, potentiates the effects of glycosides and other antiarrhythmic drugs, thus increasing the incidence of arrhythmias.
Diazoxide is well absorbed orally (85%-95%), and
has a long half-life (20-40 hours) and high protein binding
(90%).
Amiloride shows poor oral absorption, with no presystemic
metabolism. It has low protein binding, with a large volume
of distribution (5L/kg). Amiloride is almost completely
excreted unchanged in urine and has a plasma half-life of 6 to
9 hours.
Spironolactone is an aldosterone antagonist that is well
absorbed orally with a short half-life of 10 minutes. It is
metabolized in the liver to the active compound canrenone,
which has a half-life of 16 hours and is excreted by the kidney.
Protein binding is high (98%). Because of the long half-life
of its metabolite, spironolactone has a long duration of action
with the maximum effect of the drug taking some days to be
reached.
Triamterene undergoes incomplete (30%-83%) although
rapid absorption from the gut. There is some presystemic
metabolism, and it is extensively biotransformed in the liver
before urinary excretion and variable biliary excretion. The
elimination half-life is about 2 hours, with protein binding of
45%-70%.
ADVERSE EFFECTS AND DRUG INTERACTIONS
There are important side effects of all diuretics. Prolonged

use of thiazides (especially in older adults) can lead to hyponatremia and hypokalemia, and an increased plasma uric acid
concentration. Prolonged hypokalemia, in turn, leads to
impaired glucose tolerance due to inhibition of insulin release,
as well as enhancing digitalis toxicity. Whereas thiazides cause
a reduction in Ca2+ excretion, the loop diuretics increase Ca2+
excretion.
Both groups of diuretics reduce clearance of lithium by the
kidney (which increases the risk of toxicity as the latter has a
narrow therapeutic range). Hypokalemia potentiates the
effects of cardiac glycosides, as well as altering the effects of
antiarrhythmic drugs, leading to ventricular arrhythmias
(torsade de pointes).
All the potassium-sparing diuretics (amilioride, spironolactone, and triamterene) potentiate additively the potassiumsparing effects of ACE inhibitors, and therefore their
coadministration can be dangerous. The potassium-sparing
diuretics can also lead to hyperkalemia in patients also receiving potassium supplements or in patients with renal failure.
These diuretics can also cause renal failure when coadministered to patients receiving NSAIDs. Spironolactone interferes
with the assay of digitalis. Triamterene inhibits the urinary
excretion of the antiparkinsonian drug amantadine.
There are no available data to suggest that 2 agonists are
useful for the rapid control of blood pressure in the perioperative period. They are used in special circumstances for treatment of chronic hypertension.
Clonidine is the archetypal drug of this group. It is moderately lipid soluble, shows complete absorption after oral
dosing, but undergoes limited presystemic metabolism (up to
25%). Clonidine has a peak effect at 60 to 90 minutes and
peak plasma concentration at 1 to 3 hours. Clonidine has a
long half-life (12-24 hours), protein binding of 20% to 40%,
and a large volume of distribution (2-4L/kg). It is eliminated
by both hepatic metabolism and renal excretion.
Dexmedetomidine was introduced into clinical practice more
recently, although principally as a sedative rather than antihypertensive. It is the D-enantiomer of medetomidine. Dexmedetomidine has a volume of distribution of 100L and
clearance of about 40L/hour. There is high protein binding
to albumin and 1 glycoprotein, and undergoes extensive
hepatic biotransformation. Dexmedetomidine also has a weak
inhibitory effect on CYP 2D6 mediated metabolism in vitro.
-Methyl DOPA is incompletely absorbed following oral
dosing and has variable (10%-60%) bioavailability. It has low
protein binding (10%-15%), a half-life of 6 to 12 hours, and
is eliminated through both the biliary tract and the kidney.
An important issue with these drugs is that all 2 agonists
have significant side-effect profiles. Central 2 agonists (e.g.,
clonidine) cause decreased sympathetic activity, leading to
postural or exertional hypotension. Other side effects include
ejaculation failure and an effect on the central nervous system
mediated sedation and drowsiness. Significant side effects of
-methyl DOPA include orthostatic hypotension, dizziness,
sedation, dryness of the mouth, nasal congestion, headaches,
and impotence. Rebound hypertension can occur on withdrawal, but occurs less frequently than after cessation of clonidine. It can also cause a reversible positive Coombs test
hemolytic anemia. I1 receptor agonists (monoxidine) can
cause dry mouth, nausea, fatigue, dizziness, and headaches.
PHENTOLAMINE AND PHENOXYBENZAMINE
Phentolamine is a competitive nonselective antagonist of 1

receptors, with a half- life of 3 to 13 hours and protein binding
of 54%. Little more is known about its pharmacokinetics or
metabolism, although it is excreted mainly unchanged by the
kidney. Phentolamine has equal efficacy at 1 and 2 receptors, and is a 5-hydroxy-tryptamine (serotonin) antagonist.
Phenoxybenzamine is a haloalkylamine that acts as a noncompetitive, irreversible antagonist. The half-life is 18 to 24
417

hours, but the duration of effect depends on the cellular turnover of receptorswith evidence of drug action for 3 to 4
days. It is biotransformed probably in the liver. The slow
onset of effect is due to the need for initial conversion of its
ring structure to a reactive carbonium ion, which covalently
binds to the 1 receptor.
There are common adverse effects for both drugs (similar
to those of other drugs that decrease sympathetic outflow),
namely vasodilation leading to a reflex tachycardia, orthostatic
hypotension secondary to venous pooling, nasal congestion,
and ejaculatory failure. Headaches, lethargy, dizziness, nausea,
and urinary frequency also occur.
Although labetalol is normally classified as a -receptor
antagonist, it also shows nonspecific -receptor antagonist
properties.
Prazocin, doxazocin, and terazocin are all absorbed orally (up
to 65% for doxazocin), undergo some presystemic hepatic
metabolism, and are then mostly broken down in the liver by
dealkylation followed by conjugation. All three drugs have
high protein binding (90%-98%).
Although the half-lives of the drugs vary (prazocin, 2-4
hours; doxazocin, 9-12 hours; terazocin, 11 hours), their therapeutic effects lasts longer (prazocin about 10 hours; doxazocin about 30 hours). Terazocin is eliminated unchanged in the
urine and feces. There is need to reduce dosage of all three
agents in patients with renal failure. This is not due to drug
or metabolite accumulation but to increased drug sensitivity.
The exact mechanism is unclear but may be due to increased
absorption, decreased first-pass metabolism, altered drug
binding, or decreased volume of drug distribution.
Indoramin is also well orally absorbed (>90%), but undergoes almost complete metabolism by presystemic metabolism.
Indoramin has variable protein binding (72%-92%), a halflife of 2 to 10 hours, and might have active metabolites.
The antihypertensive effects of 1 blocking drugs are
enhanced by coadministration with other antihypertensive
agents, especially diuretics and blockers. 1 Blockers should
not be given in conjunction with MAOIs.
Vasodilators
HYDRALAZINE
Hydralazine is well absorbed orally, undergoes presystemic

metabolism, and shows extensive metabolism (65%-90%) by
acetylation (with a bimodal distribution). The half-life of
hydralazine is 3 to 7 hours; because acetylation by NAT-2
occurs mainly during presystemic metabolism, the subsequent
rate of drug clearance is not directly related to the rate of
acetylation. There is a bimodal distribution of clearance; slow
acetylators are at risk of developing a lupus-type condition.
However, acetylator status does not appear to affect the halflife. Hydralazine has high protein binding (87%) and a large
volume of distribution (3.6L/kg).
The ratio of fast:slow acetylators in the population is
racially determined. In Europe, the ratio is about 40:60; in
Japan 85:15; and in the Inuit population 95:5. The consequences of this bimodal metabolic profile are twofold: first,
slow acetylators can have an enhanced response to treatment;
second, they can also have an increased risk of drug toxicity.
The difference between fast and slow acetylators is not dependent on kinetic properties but rather on the amount of the
NAT-2 isoform expressed. A reduced dose of hydralazine is
418
indicated in the presence of renal and hepatic disease, regardless of the metabolic phenotype.
NICORANDIL
Nicorandil acts as a mixed vasodilator with part nitrate-like

action and part K+ channel opening effect.50 After oral twicedaily dosing, steady-state concentrations are reached by 96 to
120 hours, although there is an onset of effect by 30 minutes
after dosing. Nicorandil undergoes extensive hepatic metabolism to an inactive denitrated metabolite that is excreted in
the urine and has a short half-life (1 hour) and high clearance
(about 1.1L/min).
Side effects associated with the use of nicorandil include
headache in 25% to 50% of patients on starting the drug, as
well as dizziness, nausea, and vomiting.
MINOXIDIL
Another arterial vasodilator (like hydralazine), minoxidil is

well absorbed orally and has an elimination half-life of 3 to 4
hours. The duration of effect of a single dose is 8 to 12 hours.
It is mainly prescribed in patients with resistant hypertension,
but is often accompanied by significant side effects. These
include hirsutism (therefore the drug is usually only prescribed in males), and peripheral edema due to fluid retention.
Because it is a powerful vasodilator, other adverse effects
include skin flushing, headache, reflex tachycardia, and associated palpitations. To overcome the edema and tachycardia,
the drug is often coadministered with a blocker and a
diuretic.
NITRATES
Glyceryl trinitrate (or nitroglycerin) undergoes extensive

hepatic presystemic metabolism when given orally, and is
therefore usually given by the sublingual route, by which it is
well absorbed and rapidly taken up into the circulation. Buccal
administration has a similar effect, and this route is used for
more prolonged action over a few hours. When given intravenously, there is drug breakdown by the cells of the vascular
endothelium. Nitroglycerin is broken down (bioactivated) to
1,2 glyceryl nitrate and NO by hepatic mitochondrial aldehyde dehydrogenase. Tolerance develops over time as the
enzyme is depleted by continuous exposure.
Isosorbide dinitrate (ISDN) is absorbed in the gut and extensively metabolized to active metabolites especially the mononitrate ISMN, which also shows good oral absorption but, in
contrast to ISDN, has low presystemic metabolism. The halflives of these nitrates are a few minutes for nitroglycerin, 1
hour for ISDN, and 4 hours for ISMN. Protein binding
differs for the three agents (ISMN < 5%, for ISDN 30%, and
nitroglycerin 60%). There are also differences in their
volumes of distribution (ISMN 3L/kg; ISDN 1-8L/kg;
nitroglycerin 0.7L/kg).
Sodium nitroprusside is effective within 30 to 40 seconds of
infusion, and offset is similarly rapid. It is broken down in the
liver to cyanide and thiocyanate; together with the parent
drug, both are excreted in the urine. Dose reduction is indicated for all nitrates in patients with renal or hepatic disease.
There may be tolerance to vasodilatory effects of nitrates with
prolonged dosing especially when given transdermally. The
safe doses of nitroprusside are less than 1.5g/kg/min during
hypotensive anesthesia and up to 8g/kg/min to treat hypertensive crises.

PHOSPHODIESTERASE INHIBITORS
The peripheral actions of the PDEIs are mediated by PDE3.

There are two main chemical classes of inhibitorsthe bipyridines (amrinone and milrinone) and the imidazolones (enoximone). These drugs cause vasodilation by increasing the
intracellular cAMP in vascular smooth muscle, leading to
activated outward Ca2+ transport and hence a decrease in
intracellular Ca2+ concentration.
Amrinone has an elimination half-life of 2 to 4 hours, clearance of 4 to 9mL/kg/min, and a small volume of distribution
(1.3L/kg). It has low protein binding (20%) and its elimination is not affected by renal disease. On the other hand,
milrinone in healthy patients has an intermediate protein
binding 70%, terminal half-life of 2 hours, clearance of 2 to
3mL/kg/min, and volume of distribution of 0.4 to 0.5L/kg;
its terminal half-life is increased in patients with renal dysfunction. Enoximone has a higher clearance (10mL/kg/min),
protein binding (70%-85%), and longer terminal half-life of
6 to 7 hours. The action of enoximone is increased in renal
failure due to the accumulation of the active sulfoxide
metabolite.51
Other nonspecific PDEIs include the methylxanthines
(e.g., theophylline and aminophylline) and the benzylisoquinoline, papaverine.
PHARMACOTHERAPY OF HYPERTENSION
Current first-line drugs for the treatment of high blood pressure are diuretics, ACE inhibitors and angiotensin II receptor
blockers, and calcium channel blockers; the latter three groups
of drugs potentiate the effect of the diuretics. Joint National
Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure 7th Report (JNC VII) indicates
that thiazides are the first choice for treatment of uncomplicated hypertension, while combination therapy has greater
efficacy than doubling of single drug dosage.52 However,
calcium channel blockers are an effective treatment in hypertensive patients for the prevention of stroke, but have little
effect on the incidence of heart failure, major cardiovascular
events, and cardiovascular and total mortality.53
Blockers for the treatment of hypertension should be
reserved for patients with associated coronary artery disease
or tachycardia/tachyarrhythmias.54-56 In comparisons with
other treatments, blockers show a greater ability to reduce
the incidence of stroke (29% vs 17%) but no difference in
prevention of coronary events and heart failure.57 In patients
with associated heart failure, thiazides, ACE inhibitors, aldosterone receptor blockers (spironolactone), and low-dose
titrated blockers are indicated. In patients with renal impairment, ACE inhibitors and angiotensin II receptor antagonists
are the drugs of choice.58
A Cochrane Review of randomized trials of at least 1 year
duration compared thiazides, blockers, calcium channel
blockers, ACE inhibitors, 1 blockers, and angiotensin II
receptor blockers as first-line therapies for patients with
uncomplicated hypertension. The review concluded, Lowdose thiazides reduced all cause mortality and morbidity (as
stroke, coronary heart disease, cardiovascular events); ACE
inhibitors and calcium channel blockers might be similarly
effective but the evidence is less robust; and high-dose thiazides and blockers are inferior to low-dose thiazides.59
HYPERTENSION AND ANESTHESIA

Present anesthetic practice dictates that all antihypertensive
therapies (with the possible exception of high-dose ACE
inhibitors and angiotensin II receptor antagonists) are maintained up to the time of surgery. Not all investigators agree
that ACE inhibitors and angiotensin II receptor antagonists
should be withheld.60,61 However, preoperative evaluation for
patients with hypertension should include the measurement
of plasma K+ concentrations, especially in patients receiving
diuretics or renin-angiotensin system antagonists.
One of the present controversies is which groups of patients
(if any) should the surgery be cancelled because of raised
blood pressure? There are few data on the influence of coexisting hypertension on cardiovascular outcome following
noncardiac surgery. None of the scoring systems used to categorize patient risk include hypertension as a factor. However,
a recent study of outcome from Switzerland identified an
increased incidence of cardiovascular complications (11.2% vs
4.6%; adjusted odds ratio 1.38 [1.27-1.49]) in the hypertensive subgroup.62 These results are in keeping with the metaanalysis of Howell and colleagues63 (odds ratio 1.35 [1.17-1.56])
for perioperative cardiovascular complications of cardiac
mortality, myocardial infarction and heart failure, and
arrhythmias.
The 2007 American College of Cardiology/American
Heart Association (ACC/AHA) guidelines offer few substantive recommendations as to which hypertensive patients
should be canceled to allow treatment before surgery, or how
long such treatment should be continued before surgery.64
Indeed the ACC/AHA Guidelines list uncontrolled systemic
hypertension as a low-risk factor for cardiac complications.
Observational data agree that stage 1 or 2 hypertension is not
an independent risk factor for perioperative cardiovascular
complications, and hence there is no scientific evidence to
support postponing these patients in the absence of target
organ damage. However, the case for stage 3 (SAP 180 and/
or DAP 110mmHg) hypertension is less clear. The ACC/
AHA guidelines recommend control of blood pressure before
surgery, but this is not supported by a large body of data
relating exclusively to patients with these levels of blood
pressure.
Based on clinical studies and practice, there is no evidence
to cancel and treat hypertensive patients other than those with
documented target organ damage. Blood pressure control
should be optimized before surgery in patients in whom
hypertension is associated with accompanying significant risk
factors such as diabetes mellitus, coronary artery disease,
peripheral vascular disease, impaired renal function, smoking,
or hypercholesterolemia.65,66
Isolated systolic hypertension (ISH) is frequent in older adults.
It is characterized by increased systolic pressure as well as
pulse pressure due to increased large artery stiffness secondary
to aging. There are also often associations with obesity and
reduced physical activity. In nonsurgical patients with ISH,
there is a clear association with increased prevalence of silent
myocardial ischemia. The influence of ISH on perioperative
outcomes has not been well studied, although a recent study
(PROMISEPerioperative Myocardial Ischemia in Isolated
Systolic Hypertension) showed no increased incidence of
myocardial ischemia in ISH patients.67
419

In patients with white coat hypertension, as many repeat
blood pressures as possible should be obtained to inform clinical decisions. Starting a normally normotensive patient with
white coat hypertension on inappropriate therapy can be dangerous. If surgery is to be deferred to allow white coat hypertension to be treated, it is unclear how long treatment should
be given before surgery.
PULMONARY VASODILATORS
The pulmonary circulation is normally a low pressure, low
resistance circuit (see Chapters 21 and 25). Pulmonary hypertension is defined as mean pulmonary artery pressure greater
than 20mmHg or systolic pulmonary artery pressure greater
than 30mmHg.
The causes of pulmonary hypertension are 50% idiopathic,
and the remaining 50% is associated with connective tissue
disorders, congenital heart disease, portal hypertension, infection with human immunodeficiency virus, or intake of appetite suppressant drugs such as fenfluramine or dexfenfluamine.
The hypertension can be aggravated by hypoxic vasoconstriction and hence these patients should receive supplemental
oxygen, while avoiding causative drugs.
Hypoxic pulmonary vasoconstriction (HPV; see Chapter
25) is mediated by the endothelium. The exact mechanism is
not well defined, but the redox theory proposes the coordinated action of a redox sensor (within the proximal mitochondrial electron transport chain) that generates a diffusible
mediator (probably a reactive oxygen species such as hydrogen peroxide) that regulates an effector protein (either a
voltage-gated K+ or Ca2+ channel). The subsequent inhibition
of oxygen-sensitive K+ KV1.5 and KV 2.1 channels depolarizes
pulmonary artery smooth muscle and activates voltage-gated
Ca2+ channels. This leads to an influx of Ca2+ causing
vasoconstriction.68
Hypoxic pulmonary vasoconstriction can be modulated by
a number of variables. The reflex activity decreases with
increases in pulmonary artery pressure, cardiac output, left
atrial pressure, and central blood volume. Drugs also modulate the reflex and interfere with ventilation/perfusion matching (Table 23-9). Other perioperative conditions that impair
the response include hypocapnia and hypothermia. When
Table 23-9. Effect of Vasoactive and Other Drugs

on the Hypoxic Pulmonary Vasoconstrictor Reflex
DRUG
Hydralazine
Nifedipine
Verapamil
Nitroglycerin
Sodium nitroprusside
Nicardipine
Labetalol
Inhaled anesthetics
Intravenous anesthetics
ketamine and propofol
Thoracic epidural
420
hypoxic pulmonary vasoconstriction is inhibited, there is an

increase in alveolar-arterial oxygen gradient.
Until recently, the prognosis for patients with pulmonary
hypertension was poor (with a survival of 5-6 years) even with
treatment, and the only useful treatment was chronic calcium
channel blockers. This has changed with the introduction
of nitric oxide, prostacyclin analogs, PDEIs, and lung transplantation. Other useful therapies include inotropic drugs
that can cause some right ventricular adaptation secondary to
an increase in systolic function. Conversely these patients
tolerate adrenoceptor blockade poorly. Diuretics can also
help by decreasing pericardial and pleural effusions, as well as
improving right ventricular volumes and left ventricular diastolic function.
A classification of pulmonary vasodilators is shown in
Table 23-10. There is no vasodilator that acts solely on the
pulmonary vasculature. Adenosine, acetylcholine, nitroglycerin, and prostacyclin have the best ratio of pulmonary to
systemic effects. Most drugs used to attempt a reduction in
pulmonary blood pressure are not without significant side
effects: systemic hypotension, pulmonary hypertension (druginduced decrease in systemic blood pressure can increase pulmonary artery pressure by increasing cardiac output and
sympathetic tone), decreased myocardial contractility, and
hypoxemia. Because of these side effects, there have been a
number of new treatments assessed since the mid-1990s.
Inhaled nitric oxide (iNO) readily diffuses from the alveoli
to the vascular smooth muscle where it activates guanylyl
cyclase to increase cGMP, causing pulmonary vasodilation.
NO has little effect on the systemic circulation. It can be
administered in doses ranging from 5 to 80ppm. About 33%
of patients with pulmonary hypertension show little or no
response to iNO due to a nonreactive pulmonary circulation,
rapid NO inactivation, abnormalities of the guanylyl cyclase
system, or rapid breakdown of cGMP (although this can be
inhibited by addition of dipyridamole). The main adverse
effects of iNO are inhibition of platelet function, and rebound
hypoxemia and pulmonary hypertension.
Prostanoid pulmonary vasodilators can be administered by
a variety of different routesintravenous (epoprostenol,
treprostinil, iloprost); subcutaneous (treprostinil); inhalation
(iloprost); oral (beraprost). Prostacyclin (PGI2) is endog
enously synthesized, predominantly by endothelial cells
including the pulmonary vascular endothelium. Prostacyclin
produces vasodilation in low-resistance beds such as the pulmonary circulation.69 It not only stimulates the endothelial
release of NO, but in turn, NO enhances PGI2 synthesis in
EFFECT
None
Inhibition
Inhibition
Inhibition
Inhibition
None
None
None to slight inhibition
None
No direct effect; but changes
likely attributable to
alterations in cardiac function
Table 23-10. Classification of Pulmonary Vasodilators

Direct-actinghydralazine, nitroglycerin, sodium nitroprusside
(through activation of guanylyl cyclase)
-Adrenoceptor antagoniststolazoline, phentolamine
-Adrenoceptor agonistsisoproterenol (isoprenaline) (activation of
adenylyl cyclase)
Calcium channel blockersnifedipine, diltiazem
ProstaglandinsPGE1 and prostacyclin
Adenosine
Endothelin receptor antagonists
Indirect-acting vasodilatorssuch as acetylcholine, which causes the
release of nitric oxide

smooth muscle cells of the pulmonary artery. PGI2 is spontaneously broken down by plasma hydrolysis to an inactive
6-keto metabolite, with a half- life of about 6 minutes. Animal
studies show PGI2 to have a high clearance (90-100mL/kg/
min), a volume of distribution of 357mL/kg, and a half-life
of 2.7 minutes.70 Delivery of PGI2 by aerosol causes minimal
systemic effects, but dramatic and rapid improvement in arterial oxygenation and lowering of pulmonary artery pressure.
Phosphodiesterase Inhibitors.
Both NO and atrial natriuretic peptide (ANP) activate smooth

muscle cell guanylyl cyclase to decrease intracellular Ca2+ with
muscle relaxation, inhibition of cell proliferation, and activation of apoptosis. There is evidence that phosphodiesterase
(PDE) is overexpressed in pulmonary hypertension, leading
to an increased degradation of cGMP. There is also decreased
expression on NO synthase. Hence therapy has focused on
the efficacy of PDE5 inhibitors, which cause pulmonary vasodilation. PDE5 is located in the corpus cavernosus, vascular
smooth muscle, and platelets.
Sildenafil reduces pulmonary vascular resistance. It has
high oral bioavailability, with onset of effect within 15 minutes
and peak hemodynamic effect at 2 hours. Sildenafil has a halflife of about 4 hours and is metabolized by two separate routes
involving CYP 3A4 (major) and 2C9 (minor). Both pathways
are influenced by CYP inhibitors and inducers. The drug is
effective in reducing pulmonary artery pressure in both adults
and children.
Tadalafil has a longer half-life and is hence viewed as a
once-per-day drug.
For the effective treatment of pulmonary hypertension,
combination therapies are often the most efficacious.
Novel Pulmonary Vasodilators.
A number of therapies are under evaluation in vitro and in

animal modelsthese include potassium channel openers,
antiproliferative drugs, rapamycin, and statins.
EMERGING DEVELOPMENTS
remikiren. Both drugs are formulated for oral use only. Aliskiren is a piperidine derivative that is poorly absorbed, with an
oral bioavailability of only 2.5%. Peak concentrations are seen
at 1 to 3 hours. Aliskiren has a half-life of 24 to 40 hours, and
protein binding of 47% to 51%. It is partly metabolized
(about 19%) in the liver by CYP 3A4 to O-demethylated and
carboxylic acid derivatives. The remainder of the drug is
excreted unchanged in the feces.
Remikiren has a similar low bioavailability (<6%), a half-life
of 1.5 hours, and clearance similar to hepatic blood flow. The
effect lasts about 24 hours. It is recommended that the dose
of both drugs be reduced in patients with renal impairment.74,75 Ivabradine is a specific sinus node inhibitor that
slows heart rate without having negative inotropic effects by
inhibition of If (funny channel) currents. The effects of
ivabradine on heart rate also lead to an increased diastolic
time and hence coronary flow. It is an alternative to blocker
or a heart rate-limiting calcium channel blocker and also has
antianginal action when given with a blocker. It has some
antihypertensive effect through its action on heart rate. Use
of ivabradine can be accompanied by the development of
significant side effects: visual symptoms, blurring of vision,
headache, dizziness, and bradycardia.76
Natriuretic Peptides
Natriuretic peptides (atrial and brain natriuretic peptides,
ANP and BNP) act via transmembrane NP-receptors (NP-A,
NP-B). Agonists binding to NP-A receptors cause vasodilation with increased glomerular filtration rate and enhanced
Na+ and water excretion, while NP-B receptor stimulation
inhibits renin production. These peptides reduce blood pressure through vasodilation of both the arterial and venous
systems (Figure 23-8). A number of new therapeutic
approaches are being developed related to these peptides.
These include neural endopeptidase (NEP) inhibitors
(e.g., candoxatril), vasopeptidase inhibitors (e.g., omapatrilat,
which inhibits both ACE and NEP), exogenous ANP and
BNP (e.g., Nesiritide; recombinant BNP), and exogenous
ANP as a coronary vasodilator.
Direct Renin Inhibitors
Endothelin and Endothelin Blockade
Direct renin inhibitors are a new class of drugs that act as

nonpeptide renin inhibitors by binding competitively to
renin and blocking the generation of angiotensin I from
angiotensinogen. Direct renin inhibitors act on the juxtaglomerular cells of the kidney where the hormone is produced.
They cause arterial and venous dilatation by blocking formation of angiotensin, and cause downregulation of sympathetic
adrenergic activity and promotion of Na+ and water excretion
by the kidneys. Aliskiren can be used in patients when ACE
inhibitors or angiotensin receptor antagonists (ARAs) are not
tolerated. It has additive antihypertensive effects when combined with ARAs. Unlike ACE inhibitors and ARAs, they do
not appear to cause a compensatory rise in plasma renin and
produce a more complete block of the pathway.71,72 They
appear to possess fewer side effects than either ACE inhibitors
or ARAs, and are recommended as a third-line treatment
for hypertension (especially where resistant to other
therapies).73There are few kinetic data available for the two
currently available direct renin inhibitors, aliskiren and
Endothelins are vasoconstrictors found in endothelial cells

that were first discovered in 1985 and identified in 1988.77
Transmembrane NP receptors
NP-A
NP-B
Vasodilation
Inhibition of renin
production
Increased GFR
Enhanced Na+ and

water excretion
Figure 23-8 Possible mechanisms of action of natriuretic peptides (NP).
Atrial and brain natriuretic peptides interact with NP-A and NP-B receptors
to reduce blood pressure by vasodilation and enhanced salt and water
excretion.
421

There are four distinct endothelin peptides (1, 2, 3, and 4).
ET-1 and ET-3 are the endothelins present in vascular endothelial cells; ET-2 and ET-4 are found in the kidneys and
intestines, and ET-3 is also found in the intestines, brain,
lungs, and adrenal glands.
ET-1 is synthesized as a 212 residue precursor (prepro-ET)
that undergoes cleavage by an atypical endopeptidase of the
metalloprotease type to big ET-1 and subsequently ET-1.
This latter cleavage occurs both intracellularly and on the
surface of endothelial and smooth muscle cells. The stimuli
to endothelin synthesis include the release of any of a series
of noxious vasoconstrictor mediatorsincluding activated
platelets, endotoxins, thrombin, various cytokines, cell and
tumor growth factors, angiotensin II, antidiuretic hormone,
and adrenaline, as well as other stimuli such as hypoxia and
insulin.
Inhibitors to synthesis include NO, natriuretic peptides,
prostaglandins PGE2 and PGI2, and heparin. It is probable
that endothelin-1 is stored as a preformed molecule in the
endothelial cells, while the release mechanism is poorly
understood. Endothelin-1 is a 21 amino acid peptide with
vasoconstrictor and mitogenic properties, being a growth
factor for both vascular smooth muscle and fibroblasts. The
release of ET-1 appears to be stimulated by hypoxemia
and inhibited by NO. There are two distinct endothelin
receptors: ET-A and ET-B; both are G proteincoupled
with ET-1 preferentially activating ET-A. This receptor is,
in turn, coupled to three or more second messengers
(including phospholipase C, protein kinase C, and IP3).
The mRNA for endothelin ET-A receptors is expressed in
many human tissues, including vascular smooth muscle,
heart, lungs, and kidney. Stimulation of ET-A receptors
brings about vasoconstriction and cell proliferation, while
ET-B stimulation causes release of NO and prostacyclin.78
Patients with pulmonary hypertension can have enhanced
pulmonary production and increased circulating levels of
endothelin-1.79,80
There are two broad classes of blockersselective to
one or other receptor, and nonselective. All are undergoing evaluation in patients with pulmonary hypertension.
They have beneficial effects in the management of the
condition by reducing vascular resistance and altering vascular remodeling.78
Bosentan can be given as either a continuous infusion or as
an oral preparation. The orally active preparation of this nonselective endothelin blocker has a half-life of about 7 hours.
It is metabolized by CYP, and is an inducer of CYP 4AA
and 2C9.81
Sitaxentan is an endothelin blocker with a specificity of
A:B receptors of 6500:1 (this compares with a ratio of 20:1
for bosentan; a blocker is said to be selective if the ratio is
greater than 100:1). Sitaxentan is also orally active and rapidly
absorbed with a Tmax of 1 to 4 hours. Its elimination half-life
is about 10 hours, and it is metabolized by CYP 2C9 and 3A4.
The compound has also been shown to be a competitive
inhibitor of CYP 2C9, 2C19, and 3A4/5.
Ambrisentan is another nonselective blocker with an A:B
specificity of 77:1. It has a high oral bioavailability and a long
half-life, therefore making it a once a day drug.
Darusentan is an endothelin A receptor antagonist that
reduces both systolic and diastolic pressures. It might be a
useful therapy in patients with refractory hypertension.
422
KEY POINTS
Pharmacologic control of blood pressure can occur
through central or peripheral actions, primarily effects
on the sympathetic autonomic nervous system, or on the
tone of the peripheral vasculature.
Interactions with four classes of adrenergic receptors
1, 2, 1, and 2can modulate blood pressure.
Antagonists at the 1 receptor counteract the
hypertensive effects of 1 agonists, as well as reduce
the vascular hypertrophy seen in hypertension.
Antagonists at 1 and 2 receptors reduce heart rate and
modulate sympathetic effects.
-adrenoceptor blockers include two classesthe
aminooxypropanols (propranolol, metoprolol, esmolol,
carvedilol) and the hydroxyaminoethyls (sotalol and
labetalol). Pharmacologically there are three classes:
partial agonists (bucindolol and xamoterol); inverse
agonists (metoprolol, bisoprolol, nebivolol, sotalol) that
stabilize the receptor in an inactive state; and neutral
(competitive) antagonists (carvedilol, propranolol)
that bind to the receptor without selectivity for active
or inactive state. Further functional classification
distinguishes antagonists as 1 selective or nonselective,
as having intrinsic sympathomimetic activity (ISA), or as
having membrane stabilizing actions.
Antagonists at 1 receptors reduce myocardial remodeling
while preserving 2 mediated cardiac protection.
Selective 1 blockers also have negative inotropic and
chronotropic effects.
For the treatment of hypertension, -adrenoceptor
blockers with inverse agonist activity, or those with
associated 1 adrenceptor blocking activity (labetalol,
carvedilol), might be preferred.
Most peripheral vasodilators act through regulation of
intracellular Ca2+ concentration in vascular smooth
muscle. Vasodilators increase intracellular cAMP or cGMP,
and bring about vasodilation by phosphorylation of
phospholamban and promotion of increased uptake of
Ca2+ into the sarcoplasmic reticulum.
Calcium blockers block Ca2+ entry through L-type
voltage-gated Ca2+ channels, leading to vasodilation. The
three structural classes of blockersphenylalkylamines
(verapamil), benzothiazepines (diltiazem), and
dihydropyridines (nifedipine)have two main actions,
vasodilation and negative inotropy.
Nitrosovasodilators either cause spontaneous release of
nitric oxide or undergo active reduction prior to nitric
oxide release. Nitric oxide activates guanylyl cyclase
to produce cGMP that activates protein kinase G
and activates myosin light chain phosphatase, which de
phosphorylates light chains to produce muscle relaxation.
Inhibition of the renin-angiotensin system can occur
through direct inhibition of angiotensin converting
enzyme (ACE), angiotensin II receptor antagonism, or
direct renin inhibition.
Endothelins activate ET-A receptors to cause
vasoconstriction and smooth muscle proliferation;
endothelin antagonists mainly block the ET-A receptor to
cause vasodilation.

Potassium channel openers act by decreasing membrane
potential through the efflux of K+, thus reducing the
activity of voltage-gated Ca2+ channels.
Magnesium is a calcium channel blocker that also acts
as an antihypertensive agent by stimulating production
of prostaglandin E1 and nitric oxide, and by altering the
vascular smooth muscle response to vasoactive agents.
The eicosanoids (prostaglandins E1 and E2; and
prostaglandin I2, known as prostacyclin) bind specific
prostanoid receptors, leading to increased intracellular
cAMP, activation of protein kinase A, and inhibition of
smooth muscle contraction.
Treatment options for pulmonary hypertension include
calcium channel blockers; direct acting nitrovasodilators
(e.g., nitroglycerin rather than nitroprusside); inhaled
nitric oxide; endothelin blockers; prostanoids
(prostacyclin); and phosphodiesterase 5 inhibitors
(sildenafil and cogeners).
Key References
Chobanian AV, Bakris GL, Black HR, et al. Seventh Report of the
Joint National Committee on Prevention, Detection, Evaluation
and Treatment of High Blood Pressure. Hypertension. 2003;42:
1206-1252. An updated report on the medical aspects of the
prevention and management of hypertension. (Ref. 3)
Fleisher LA, Beckman JA, Brown KA, et al. AAC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for
Non-Cardiac Surgery. A report of the American College of
Cardiology/American Heart Association Taskforce on Practice
Guidelines. (Writing Committee to update the 2002 Guidelines
on Perioperative Cardiovascular Evaluation for Non-Cardiac
Surgery). Circulation. 2007;116:1971-1996. A set of guidelines for
cardiovascular evaluation and care of the patient undergoing noncardiac surgery. (Ref. 64)
Howell SJ, Foex P, Sear JW. Hypertension and perioperative cardiac
risk. Br J Anaesth. 2004;92:570-583. Evidence for an association
between hypertensive disease, elevated arterial pressure, and perioperative cardiac outcome are reviewed using a systematic review
and metaanalysis of 30 observational studies. (Ref. 63)
Kirsten R, Nelson K, Kirsten D, et al. Clinical pharmacokinetics of
vasodilators. Part I. Clin Pharmacokin. 1998;34:457-482. Part II.
Clin Pharmacokin. 1998;35:9-36. Two review papers defining the
mechanism of action and pharmacokinetic properties of vasodilator drugs used in the treatment of hypertension. (Refs. 10 and 40)
Kroen C. Does elevated blood pressure at the time of surgery
increase perioperative cardiac risk? Proceedings of the 2nd
Annual Cleveland Clinic Perioperative Medicine Summit. Cleve
Clinic J Med. 2006;33:s5-s6. Elevated blood pressure by itself has
not been shown to increase the incidences of perioperative cardiac
events; however, target organ damage caused by chronic hypertension can confer increased cardiac risk. A useful review of some
of those issues relating to the assessment and treatment of the
patient with hypertension. (Ref. 65)
Law MR, Morris JK, Wald NJ. Use of blood pressure lowering
drugs in the prevention of cardiovascular disease: metaanalysis of
147 randomised trials in the context of expectations from prospective epidemiological studies. Br Med J. 2009;338:b1665. doi:
10.1136/bmj.b1665. A meta-analysis of 147 randomized trials
showing that all classes of blood pressure lowering drugs have a
similar effect in reducing coronary heart disease events and stroke
for a given reduction in blood pressure. (Ref. 57)
Sear JW. Perioperative control of hypertension: when will it
adversely affect perioperative outcome? Curr Hypertens Rep.
2008;10:480-487. A review of the effects of increased blood pressure on perioperative outcomes. Only patients with a blood pressure 180/110mmHg (stage II of JNC VII) or 140/90mmHg
plus target organ damage (stage I) need be canceled for institution
of treatment before to noncardiac surgery. (Ref. 66)
Wright JM, Musini VM. First-line drugs for hypertension. Cochrane

Database Syst Rev. 2009;8(3):CD0018419. This review sets out to
quantify the benefits and harms of the major first-line antihypertensive drug classes: thiazides, blockers, calcium channel blockers, ACE inhibitors, blockers, and angiotensin II receptor
blockers. First-line low-dose thiazides reduce all morbidity and
mortality outcomes. First-line ACE inhibitors and calcium
channel blockers might be similarly effective but the evidence is
less robust. First-line high-dose thiazides and first-line blockers
are inferior to first-line low-dose thiazides. (Ref. 59)
References
1. Danaei G, Finucane MM, Lin JK, et al. National, regional and global
trends in systolic blood pressure since 1980: systematic analysis of
health examination surveys and epidemiological studies with 786
country-years and 5.4 million participants. Lancet. 2011;377:
568-577.
2. Borzecki AM, Wong AT, Hickey EC, Ash AS, Berlowitz DR. Hypertension control: how well are we doing? Arch Intern Med. 2003;
163:2705-2711.
3. Chobanian AV, Bakris GL, Black HR, et al. Seventh Report of the
Joint National Committee on Prevention, Detection, Evaluation
and Treatment of High Blood Pressure. Hypertension. 2003;42:
1206-1252.
4. Pauli W. Ueber ionenwirkungen und ihre therapeutische verwendung. Much Med Wschr. 1903;50:153.
5. Johnson CC. The actions and toxicity of sodium nitroprusside. Arch
Int Pharmacodyn. 1929;35:480.
6. Page IH, Corcoran AC, Dustan HP, Koppanyi T. Cardiovascular
actions of sodium nitroprusside in animals and hypertensive patients.
Circulation. 1955;11:188-198.
7. Sen G, Bose KC. Rauwolfia serpentina, a new Indian drug for insanity and high blood pressure. Indian Med World. 1931;2:194-201.
8. Vakil EJ. A clinical trial of rauwolfia serpentina in essential hypertension. Br Heart J. 1949;11:350.
9. Wilkinson EL, Beckman H, Hecht HH. Cardiovascular and renal
adjustments to a hypotensive agent (1-hydrazinophthalazine: CIBA
BA-5968; apresoline). J Clin Invest. 1952;31:872-879.
10. Kirsten R, Nelson K, Kirsten D, Heintz B. Clinical pharmacokinetics
of vasodilators. Part I. Clin Pharmacokin. 1998;34:457-482.
11. Bowman WC, Rand MJ. The cardiovascular system. In: Textbook
of Pharmacology. 2nd ed. Oxford: Blackwell Scientific; 1980:
23.26-23.58.
12. Klockner U, Isenberg G. Myocytes isolated from porcine coronary
arteries: reduction of currents through L-type Ca-channels by
verapamil-type Ca-antagonists. J Physiol Pharmacol. 1991;42:
163-179.
13. Kurokawa J, Adachi-Akahane S, Nagao T. 1,5-Benzothiazepine
binding domain is located on the extracellular side of the cardiac
L-type Ca2+ channel. Mol Pharmacol. 1997;51:262-268.
14. Skeberdis VA. Structure and function of beta3- adrenergic receptors.
Medicinia (Kaunus). 2004;40:407-413.
15. Groenning BA, Nilsson JC, Sondergaard l, et al. Anti-modeling
effects on the left ventricle during beta-blockade with metoprolol in
the treatment of chronic heart failure. JACC. 2000;36:2072-2080.
16. Udelson JE. Ventricular remodeling in heart failure and the effect of
beta-blockade. Am J Cardiol. 2004;93:43b-48B.
17. Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlledrelease metoprolol on total mortality, hospitalizations, and wellbeing in patients with heart failure: the Metoprolol CR/XL
Randomized Intervention Trial in Congestive Heart Failure
(MERIT-HF). JAMA. 2000;83:1295-1302.
18. Ahmet I , Krawczyk M, Zhu W, et al. Cardioprotective and survival
benefits of long-term combined therapy with beta2 adrenoreceptor
(AR) agonist and beta1 AR blocker in dilated cardiomyopathy postmyocardial infarction. J Pharmacol Exp Ther. 2008;325:491-499.
19. Prisant LM. Nebivolol: pharmacologic profile of an ultraselective,
vasodilatory beta1-blocker. J Clin Pharmacol. 2008;48:225-239.
20. Milne RJ, Buckley M. Celiprololan updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy
in cardiovascular disease. Drugs. 1991;41:941-969.
423

21. Carpenter CL. Actin cytoskeleton and cell signaling. Crit Care Med.
2000;28:(suppl 4):N94-N99.
22. Shimizu T, Yoshtomi K, Nakamura M, Imai M. Site and mechanism
of actions of trichlormethiazide in rabbit distal nephron segments
perfused in vitro. J Clin Invest. 1988;82:721-730.
23. Rose BD. Diuretics. Kidney International. 1991;39:336-352.
24. Maze M, Tranquilli W. Alpha2-adrenoceptor agonists: defining the
role in clinical anesthesia. Anesthesiology. 1991;74:581-605.
25. Oliver MF, Goldman L, Julian DG, Holme I. Effect of mivazerol on
perioperative cardiac complications during non-cardiac surgery in
patients with coronary heart disease: the European Mivazerol Trial
(EMIT). Anesthesiology. 1999;91:951-961.
26. Furchgott RF, Zawadski JV. The obligatory role of the endothelial
cells in the relaxation of arterial smooth muscle by acetylcholine.
Nature. 1980;288:373-376.
27. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts
for the biological activity of endothelium-derived relaxing factor.
Nature. 1987;327:524-526.
28. Cohen RA, Adachi T. Nitric-oxide-induced vasodilation: regulation
by physiologic s-glutathionation and pathologic oxidation of the sarcoplasmic endoplasmic calcium ATPase. Trends Cardiovasc Med.
2006;16:109-114.
29. Yamamoto T, Bing RJ. Nitric oxide donors. Proc Soc Exp Biol Med.
2000;225:200-206.
30. Friederich JA, Butterworth JFT. Sodium nitroprusside: twenty years
and counting. Anesth Analg. 1995;81:152-162.
31. Hein TW, Kuo L. cAMP independent dilation of coronary arterioles
to adenosine: role of nitric oxide, G proteins and K(ATP) channels.
Circ Res. 1999;85:634-642.
32. Sabouni MH, Hussain T, Cushing DJ, Mustafa SJ. G proteins subserve relaxation mediated by adenosine receptors in human coronary
artery. J Cardiovasc Pharmacol. 1991;18:696-702.
33. Leblanc N, Wilde DW, Keef KD, Hume JR. Electrophysiological
mechanism of minoxidil sulfate-induced vasodilation of rabbit portal
vein. Circ Res. 1989;65:1102-1111.
34. Ellershaw DC, Gurne AM. Mechanisms of hydralazine induced vasodilation in rabbit aorta and pulmonary artery. Br J Pharmacol. 2001;
134:621-623.
35. Simpson D, Wellington K. Nicorandil: a review of its use in the
management of stable angina pectoris, including high-risk patients.
Drugs. 2004;64:1941-1955.
36. Guerrero-Romero F, Rodriguez-Moran M. The effect of lowering
blood pressure by magnesium supplementation in diabetic hypertensive adults with low serum magnesium levels: a randomized, doubleblind, placebo controlled clinical trial. Human Hypertens. 2009;
23:245-251.
37. Spieker LE, Noll G, Luscher TF. Therapeutic potential for endothelin receptor antagonists in cardiovascular disorders. Am J Cardiovasc Drugs. 2001;1:293-303.
38. Barton M, Yanagisawa M. Endothelin: 20 years from discovery to
therapy. Can J Physiol Pharmacol. 2008;86:485-498.
39. Brogden RN, Markham A. Fenoldopam: a review of its pharmacodynamic and pharmacokinetic properties and intravenous potential
in the management of hypertensive urgencies and emergencies.
Drugs. 1997;54:634-650.
40. Kirsten R, Nelson K, Kirsten D, Heintz B. Clinical pharmacokinetics
of vasodilators. Part II. Clin Pharmacokin. 1998;35:9-36.
41. Corbin JD, Francis SH. Cyclic GMP phosphdiesterase-5: target of
silfenadil. J Biol Chem. 1999;274:13729-13732.
42. Furberg CD, Psaty BM, Meyer JV. Nifedipine. Dose-related increase
in mortality in patients with coronary heart disease. Circulation.
1995;92:1326-1331.
43. Godfraind T, Salomone S, Dessy C, Verhelst B, Dion R, Schoevaerts
JC. Selectivity scale of calcium antagonists in the human cardiovascular system based on in vitro studies. J Cardiovasc Pharmacol.
1992;20(suppl 5):S34-S41.
44. Peacock WF, Angeles JE, Soto KM, Lumb PD, Varon J. Parenteral
clevidipine for the acute control of blood pressure in the critically ill
patient: a review. Ther Clin Risk Manag. 2009;5:627-634.
45. Erikson AL, DeGrado JR, Fanikos JR. Clevidipine: a short-acting
intravenous dihydropyridine calcium channel blocker for the management of hypertension. Pharmacotherapy. 2010;30:515-528.
46. Deeks ED, Keating GM, Keams J. Clevidipine: a review of its use in
the management of acute hypertension. Am J Cardiovasc Drugs.
2009;9:117-134.
424
47. Stroe AF, Gheorghiaede M. Carvedilol: beta-blockade and beyond.

Rev Cardiovasc Med. 2004;5:s18-s27.
48. Moen MD, Wagstaff AJ. Nebivolol: a review of its use in the management of hypertension and chronic heart failure. Drugs. 2006;66:
1389-1409.
49. Munzel T, Gori T. Nebivolol: the somewhat-different betaadrenergic receptor blocker. J Am Coll Cardiol. 2009;54:14911499.
50. Andersson KE. Clinical pharmacology of potassium channel openers.
Pharmacol Toxicol. 1992;70:244-254.
51. Lehtonen LA, Antila S, Pentikinen PJ. Pharmacokinetics and pharmacodynamics of intravenous inotropic agents. Clin Pharmacokinet.
2004;43:187-203.
52. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination
therapy versus monotherapy in reducing blood pressure: metaanalysis on 11,000 participants from 42 trials. Am J Med. 2009;
122:290-300.
53. Opie LH, Schall R. Evidence-based evaluation of calcium channel
blockers for hypertension: equality of mortality and cardiovascular
risk relative to conventional therapy. J Am Coll Cardiol. 2002;39:315322. Erratum in: J Am Coll Cardiol. 2002;39:1409-1410.
54. De Caterina AR, Leone AM. The role of beta-blockers in first line
therapy in hypertension. Curr Atheroscler Rep. 2011;13:147-153.
55. Ram CV. Beta-blockers in hypertension. Am J Cardiol. 2010;106:
1819-1825.
56. Ong HT. Beta-blockers in hypertension and cardiovascular disease.
Br Med J. 2007;334:946-949.
57. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs
in the prevention of cardiovascular disease: meta-analysis of 147
randomised trials in the context of expectations from prospective
epidemiological studies. Br Med J. 2009;338:b1665. doi: 10.1136/
bmj.b1665.
58. Staessen JA, Wang J, Bianchi G, Birkenhger WH. Essential hypertension. Lancet. 2003;361:1629-1641.
59. Wright JM, Musini VM. First-line drugs for hypertension. Cochrane
Database Syst Rev. 2009;8(3):CD001841.
60. Sear JW, Jewkes C, Tellez J-C, Foex P. Does the choice of antihypertensive therapy influence haemodynamic responses to induction,
laryngoscopy and intubation? Br J Anaesth. 1994;73:303-308.
61. Bertrand M, Godet G, Meersschaert K, Brun L, Salcedo E, Coriat
P. Should the angiotensin II antagonists be discontinued before
surgery? Anesth Analg. 2001;92:26-30.
62. Beyer K, Taff P, Halfon P, et al. Hypertension and intra-operative
incidents: a multicentre study of 125,000 surgical procedures in Swiss
hospitals. Anaesthesia. 2009;64(5):494-502.
63. Howell SJ, Foex P, Sear JW. Hypertension and perioperative cardiac
risk. Br J Anaesth. 2004;92:570-583.
64. Fleisher LA, Beckman JA, Brown KA, et al. AAC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery. A report of the American College of Cardiology/
American Heart Association Taskforce on Practice Guidelines.
(Writing Committee to update the 2002 Guidelines on Perioperative
Cardiovascular Evaluation for Non-Cardiac Surgery). Circulation.
2007;116:1971-1996.
65. Kroen C. Does elevated blood pressure at the time of surgery increase
perioperative cardiac risk? Proceedings of the 2nd Annual Cleveland
Clinic Perioperative Medicine Summit. Cleve Clinic J Med. 2006;
33:s5-s6.
66. Sear JW. Perioperative control of hypertension: when will it adversely
affect perioperative outcome? Curr Hypertens Rep. 2008;10:480487.
67. Fayad AA, Yang HY, Ruddy TD, Waters JM, Wells GA. Perioperative myocardial ischemia and isolated systolic hypertension in noncardiac surgery. Can J Anesth. 2011;58:428-435.
68. Archer SL, Wu XC, Thebaud B, et al. O2 sensing in the human
ductus arteriosus: redox-sensitive K+ channels are regulated by
mitochondria-derived hydrogen peroxide. Biol Chem. 2004;385:
205-216.
69. Lowson SM, Doctor A, Walsh BK, Doorley PA. Inhaled prostacyclin
for the treatment of pulmonary hypertension after cardiac surgery.
Crit Care Med. 2002;30:2762-2764.
70. Vane JR, Botting RM. Pharmacodynamic profile of prostacyclin. Am
J Cardiol. 1995;75:A3-A10.
71. Barrios V, Escobar C. Aliskiren in the management of hypertension.
Am J Cardiovasc Drugs. 2010;10:349-358.

72. Duggan ST, Chwieduk CM, Curran MP. Aliskiren: a review of its
use as monotherapy and as combination therapy in the management
of hypertension. Drugs. 2010;70:2011-2049.
73. Oh BH, Mitchell J, Herron JR, Chung J, Khan M, Keefe DL. Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and
sustained 24-hour blood pressure control in patients with hypertension. J Am Coll Cardiol. 2007;49:1157-1163.
74. Oparil S, Yarrows SA, Patel S, Zhang J, Satlin A. Dual inhibition of
the renin system by aliskiren and valsartan. Lancet. 2007;370:
221-229.
75. Reboldi G, Gentile G, Angeli F, Verdecchia I. Pharmacokinetics,
pharmacodynamics and clinical evaluation of aliskiren for hypertension treatment. Exp Opinion Drug Metab Toxicol. 2011;7:115-128.
76. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K. Efficacy of
ivabradine, a new selective If inhibitor compared with atenolol in
patients with chronic stable angina. Europ Heart J. 2005;26:
2529-2536.
77. Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular and endothelial cells. Nature.
1988;332:411-415.
78. Rich S, Mclaughlin W. Endothelin receptor blockers in cardiovascular disease. Circulation. 2003;108:2184-2190.
79. Stewart DL, Levy RD, Cernacek P, Langleben D. Increased plasma
endothelin-1 in pulmonary hypertension: marker or mediator of
disease. Ann Int Med. 1991;114:464-469.
80. Giaid A, Yanagisawa M, Langleban D, et al. Expression of
endothelin-1 in the lungs of patients with pulmonary hypertension.
New Engl J Med. 1993;328:1732-1739.
81. Yuan JX, Aldinger AM, Juhaszova M, et al. Dysfunctional voltagegated K+ channels in pulmonary artery smooth muscle cells of
patients with primary pulmonary hypertension. Circulation. 1998;
98:1400-1406.
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Chapter

Worldwide there are probably more than 1 billion people with

Section III CARDIOVASCULAR AND PULMONARY SYSTEMS

Table 23-1. Causes of Hypertension

The antihypertensive effect of adrenergic neuron blockers

Table 23-2. Drugs Used in Treatment of Hypertension

Chapter 23 Antihypertensive Drugs and Vasodilators

SITES AND MECHANISMS OF ANTIHYPERTENSIVE

Juxtaglomerular cells that release renin

Adrenergic receptors (1, 2)

BASIC PHARMACOLOGY AND MECHANISMS OF

Table 23-3. Sites of Action of Antihypertensive Agents

Section III CARDIOVASCULAR AND PULMONARY SYSTEMS

Table 23-5. Drugs and Their Physiologic Mechanisms

rate and myocardial contractility, which leads to decreased

Table 23-6. Sites of Action of Vasodilator Drugs

Dihydropyridines (e.g., nifedipine and nicardipine) bind to

ACTION OF BLOCKERS AT THE ADRENERGIC RECEPTOR

Chapter 23 Antihypertensive Drugs and Vasodilators

Table 23-7. Classification and Relative Potency of Blockers

PARTIAL AGONISTS (ISA)*

*Number enclosed in parentheses indicates potency relative to propranolol at the

Partial agonists (pindolol) result in less resting bradycardia

Angiotensin-Converting Enzyme Inhibitors and

Section III CARDIOVASCULAR AND PULMONARY SYSTEMS

Figure 23-3 Mechanism of action of angiotensin II receptor blockers (at

smooth muscle proliferation and ventricular remodeling

to reduce blood pressure by direct arterial vasodilation.

Centrally Acting Agents

Chapter 23 Antihypertensive Drugs and Vasodilators

compared with 200:1); and mivazerol (119:1) (Figure 23-4).

Section III CARDIOVASCULAR AND PULMONARY SYSTEMS

1980,26 and its mechanism defined by Palmer etal.27 NO is

increase in the dose of infused nitrate leads to a reduction in

Chapter 23 Antihypertensive Drugs and Vasodilators

Figure 23-6 Mechanism of action of phosphodiesterase (PDE) inhibitors.

inhibited by milrinone and enoximone, and PDE5 is inhibited

PHARMACOKINETICS, PHARMACODYNAMICS, AND

Section III CARDIOVASCULAR AND PULMONARY SYSTEMS

Figure 23-7 Structure of the dihydropyridine calcium entry blockers. R1 and

although the half-lives of the two enantiomers are similar.

ADVERSE DRUG INTERACTIONS

Dihydropyridines increase plasma digoxin concentrations

inotropy. If verapamil is given in combination with a blocker,

NEW CALCIUM CHANNEL BLOCKERS

Clevidipine (an intravenous dihydropyridine) is characterized

Chapter 23 Antihypertensive Drugs and Vasodilators

-OH-metoprolol and O-desmethyl-metoprolol) are active

output that is not compensated for by baroreflex mechanisms,

ANTIHYPERTENSIVE EFFECT OF BLOCKERS

Because of differences in pharmacologic profiles, different

Carvedilol (1, 1, 2 blocker) has a unique carbazole moiety.

ADVERSE EFFECTS OF BLOCKERS

Section III CARDIOVASCULAR AND PULMONARY SYSTEMS

Angiotensin-Converting Enzyme Inhibitors

Other ACE inhibitor prodrugs include quinalopril and

Angiotensin II Receptor Antagonists

ADVERSE EFFECTS AND DRUG INTERACTIONS