63: Miscellaneous Antihypertensives and Pharmacologically
Related Agents
Jerome DeRoos Francis
INTRODUCTION
Hypertension is one of the commonest chronic medical problems and one of the most readily
amenable to pharmacotherapy. Beginning in the 1960s, when asymptomatic hypertension was
linked to significant adverse effects such as stroke, myocardial infarction, and sudden death,
antihypertensive pharmacotherapeutics began being used. The first generation included centrally
acting, sympatholytics, direct vasodilators, sodium nitroprusside, and diuretics. Unfortunately, these
often had significant adverse events, leading to the development of β-adrenergic antagonists,
calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin
receptor blockers (ARBs), and, more recently, direct renin inhibitors (DRIs). This chapter reviews the
first-generation antihypertensives, as well ACEIs, ARBs, and DRIs. In general, the majority of
antihypertensives manifest clinical signs and symptoms in terms of the degree of hypotension
produced. Particular attention will be placed on mechanisms of action and unique toxicologic
considerations for each of these xenobiotics.
CLONIDINE AND OTHER CENTRALLY ACTING
ANTIHYPERTENSIVES
Clonidine is an imidazoline compound that was synthesized in the early 1960s. Because of its potent
peripheral α2-adrenergic agonist effects, it was initially studied as a potential topical nasal
decongestant. However, hypotension was a common adverse event, which redirected its
consideration for other therapeutic applications.105 Clonidine is the best understood and the most
commonly used of all the centrally acting antihypertensives, a group that includes methyldopa,
guanfacine, and guanabenz. Although these drugs differ chemically and structurally, they all
decrease blood pressure in a similar manner. The imidazoline compounds oxymetazoline and
tetrahydrozoline, which are used as ophthalmic topical vasoconstrictors and nasal decongestants,
produce similar systemic effects when ingested.105
Since 1985, the increased efficacy and improved adverse event profiles of the newer
antihypertensives have diminished the use of the α2-adrenergic agonists in routine hypertension
management. However, their use is increasing as a result of a wide variety of applications, including
attention-deficit/hyperactivity disorder (ADHD), peripheral nerve and spinal anesthesia, and as an
adjunct in the management of opioid, ethanol, and nicotine withdrawal.120,127,130,224 In addition, abuse of
clonidine may be a growing problem in opioid dependent patients, and it has been used in criminal
acts of chemical submission.20,145
Although centrally acting α2-adrenergic agonist exposure is relatively uncommon, it may cause
significant toxicity, particularly in children. One report from two large pediatric hospitals identified 47
children requiring hospitalization for unintentional clonidine ingestions over a 5-year
period.266 Significant clonidine poisoning has also resulted from formulation and dosing errors in
children.211,241 Imidazolines used as ocular vasoconstrictors have resulted in significant systemic
toxicity, especially when ingested.109,150,137,202
Pharmacology
Clonidine and the other centrally acting antihypertensives exert their hypotensive effects primarily via
stimulation of presynaptic α2-adrenergic receptors in the brain.78,194,218,257This central α2-adrenergic
receptor agonism enhances the activity of inhibitory neurons in the vasoregulatory regions of the
central nervous system (CNS), notably the nucleus tractus solitarius in the medulla, resulting in
decreased norepinephrine release.217 This results in decreased sympathetic outflow from the
intermediolateral cell columns of the thoracolumbar spinal tracts into the periphery2,256 and reduces
the heart rate, vascular tone, and, ultimately, arterial blood pressure.186,256 This centrally mediated
sympatholytic effect is modulated by nitric oxide and γ-aminobutyric acid (GABA), which may explain
some of the clinical variability that occurs among patients who have overdosed with clonidine.37,87,234,260
Pharmacokinetics
Clonidine is well absorbed from the gastrointestinal (GI) tract (~ 75%) with an onset of action within
30 to 60 minutes. The peak serum concentration occurs at 2 to 3 hours and lasts as long as 8
hours.59 Clonidine has 20% to 40% protein binding and an apparent volume of distribution of 3.2 to
5.6 L/kg.138 The majority of clonidine is eliminated unchanged via the kidneys.143
Clonidine is available in both oral and patch form. The patch, referred to as the clonidine transdermal
therapeutic system, allows slow, continuous delivery of drug over a prolonged period of time,
typically one week. This formulation, however, offers unique clinical challenges. Each patch contains
significantly more drug than is typically delivered during the prescribed duration of use. For example,
while a patch that delivers 0.1 mg/day of clonidine contains a total of 2.5 mg, the product that
delivers 0.3 mg/day and contains a total of 7.5 mg.36 Even after one week of use, between 35% and
50% and, in some instances, as much as 70%, of the drug remains in the patch.36,98 Puncturing the
outer membrane layer or backing opens the drug reservoir and allows a significant amount of the
drug to be released rapidly. In addition, patients do not perceive this delivery system as a
medication, and they may not exercise appropriate precautions. For example, discarding a used
patch in an open wastebasket provides toddlers, who often are fascinated with stickers and other
adhesive objects, an opportunity to remove the patch and apply, taste, or ingest it. Numerous reports
of toxicity in both adults and children have resulted from dermal exposure, mouthing, or ingesting
one clonidine patch, emphasizing this concern.36,47,98,102,124,204,205
Guanabenz and guanfacine are structurally and pharmacologically very similar to each other. They
are well absorbed orally, achieving peak concentrations within 3 to 5 hours, and both have large
volumes of distribution (4–6 L/kg for guanfacine, 7–17 L/kg for guanabenz).109,237 Whereas guanabenz
is metabolized predominantly in the liver and undergoes extensive first-pass effect, guanfacine is
eliminated equally by the liver and kidney.109,237 The metabolism of neither drug results in the
production of significant active metabolites.
Whereas clonidine, guanabenz, and guanfacine are all active drugs with direct α2-adrenergic agonist
effects, methyldopa is a prodrug. It enters the CNS, probably by an active transport mechanism,
before it is converted into its pharmacologically active degradation products.22 α-
Methylnorepinephrine is the most significant of its metabolites, although α-methyldopamine and α-
methylepinephrine may also be important.75,101,210These metabolites are direct α2-adrenergic agonists
and impart their hypotensive effect as do the other centrally acting antihypertensives. Approximately
50% of an oral dose of methyldopa is absorbed, and peak serum concentrations are achieved in 2 to
3 hours.170However, because methyldopa requires metabolism into its active form, these
concentrations have little correlation with its clinical effects. Methyldopa has a small volume of
distribution (0.24 L/kg) and little protein binding (15%).170 It is eliminated in the urine, both as parent
compound and after hepatic sulfation.179
Pathophysiology
In therapeutic oral dosing, clonidine and the other centrally acting antihypertensives have little effect
on the peripheral α2 receptors, the peripheral sympathetic nervous system, or the normal circulatory
responses that occur with exercise or the Valsalva maneuver.169,183However, when serum
concentrations increase above 2 ng/mL, as in the setting of intravenous (IV) administration or oral
overdose, peripheral postsynaptic α2-adrenergic stimulation may occur, causing increased
norepinephrine release and producing vasoconstriction and hypertension.44,53,173,243 This hypertension
is short lived, however, because the potent centrally mediated sympathetic inhibition becomes the
predominant effect, and hypotension ensues.4,154,168,210 Imidazoline specific binding sites are identified
both in the rostral ventrolateral medulla and in coronary artery vascular smooth muscle and may be
important in the clinical effects of these xenobiotics although there exact function has not been
elucidated.210,248 Direct stimulation of these imidazoline binding sites appears to lower blood pressure
independent of central α2-adrenergic effects.24,62Therefore, although their precise physiologic
relationship has not been clearly elucidated, more evidence supports the concept that both
imidazoline and α2-adrenergic receptors modulate the ability of clonidine, and presumably other
centrally acting antihypertensives, to inhibit central norepinephrine release and the cardiovascular
effects.25,62,99,163
Clinical Manifestations
Although the majority of the published cases involve clonidine, the signs and symptoms of poisoning
with any centrally acting antihypertensive are similar. The CNS and cardiovascular toxicity reflect an
exaggeration of their pharmacologic action. Common signs include CNS depression, bradycardia,
hypotension, and (occasionally) hypothermia.6,192,227,253 Most patients who ingest clonidine or the other
similarly acting drugs manifest symptoms rapidly, typically within 30 to 90 minutes.266 The exception
may be methyldopa, a prodrug, which requires metabolism to be activated, possibly delaying toxicity
for hours.227,270
CNS depression is the most frequent clinical finding and may vary from mild lethargy to
coma.149,154,182,203 In addition, severely obtunded patients may experience decreased ventilatory effort
and hypoxia.4 Respirations may be slow and shallow, with intermittent deep, sighing breaths. Various
other terms are used to describe this phenomenon, including gasping, Cheyne-Stokes respirations,
and periodic apnea.6,10,124,154 This hypoventilation is characteristically responsive to tactile stimuli in
children, although mechanical ventilation may be required in severe cases.4,6,103,124 The associated
CNS depression typically resolves over 12 to 36 hours.10,182 Other manifestations of this CNS
depression include hypotonia, hyporeflexia, and irritability.44,154,239 The cranial nerve examination often
demonstrates miotic pupils that may remain reactive to light.4,6,245 Two unusual case reports describe
seizures in the setting of clonidine poisoning,44,146 the mechanism of which is unclear.
Hypothermia is associated with overdoses involving centrally acting antihypertensives.6,154,192,210 This is
thought to be a consequence of α-adrenergic effects within the thermoregulatory center, although
other authors suggest that these drugs activate central serotonergic pathways that alter normal
thermoregulation.138,161 Although this phenomenon may last several hours, it rarely requires treatment
and responds well to passive rewarming.44,192
Sinus bradycardia may occur in up to 50% of patients who ingest clonidine and it results from the
combination of an exaggerated centrally mediated sympatholytic effect, a centrally mediated
increase in vagal tone, or a direct stimulation of α2-adrenergic receptors on the
myocardium.55,132,239,256,266,267
Other conduction abnormalities, including first degree heart block, type 1 and 2 Mobitz
atrioventricular block, and complete heart block, are described both in overdose and after
therapeutic dosing.123,182,218,220,254,267 It appears that very young patients and patients who have
underlying sinus node dysfunction, concurrent sympatholytic drug therapy, or chronic kidney disease
(CKD) are at particular risk of developing bradydysrhythmia after central antihypertensive
ingestion.31,239,247
Hypotension is the major cardiovascular manifestation of central antihypertensive
toxicity.6,36,182,222,239,266 While studies have suggested a dose-response relationship between the history
of the quantity of the centrally acting antihypertensive ingested and the severity of the clinical
manifestations, clonidine ingestions as small as 0.2 mg have resulted in clinically severe poisoning,
mandating the necessity to individually assess each exposure; the presence of any symptoms
should prompt immediate medical evaluation.18,182 Fatalities from any of these xenobiotics are rare,
with few published reports from the American Association of Poison Control Centers (AAPCC)
database29(Chap. 136).
After deaths of four children who were prescribed clonidine were reported, concerns that there was a
causal association between combination clonidine–methylphenidate therapy and sudden death were
raised.35,71 Fortunately, closer scrutiny of these cases revealed significant confounders, and a formal
investigation by the US Food and Drug Administration (FDA) concluded that there was inadequate
evidence to confirm this association.71,199,242,266
Withdrawal
Abrupt cessation of central antihypertensive therapy may result in withdrawal that is characterized by
excessive sympathetic activity. Symptoms include agitation, insomnia, tremor, palpitations,
tachycardia, and hypertension, that begin between 16 and 48 hours after cessation of
therapy.95,206 Ventricular tachycardia and myocardial infarction may occur in patients with clonidine
withdrawal.19,172,193 The frequency and severity of symptoms appear to be greater in patients treated
with higher doses for several months and in those with the most severe pretreatment
hypertension.206 Shorter-acting drugs such as clonidine and guanabenz are more frequently
associated with withdrawal.30,82,201,269 Due to the prolonged and continuous exposures, children being
treated with extended release guanfacine formulations and transdermal patches, may be placed at
greater risk of developing withdrawal upon cessation. The mechanism for this hyperadrenergic
phenomenon appears to involve an increase in CNS noradrenergic activity in the setting of
decreased α2-receptor sensitivity.65 Reasonable treatment strategies include administering clonidine
or benzodiazepines, via either the oral or IV route, followed by a closely monitored tapering of the
dosing over several weeks. Animal and human data suggest that β-adrenergic antagonists, including
labetalol, are contraindicated in clonidine withdrawal.9,117 Esmolol exacerbates this paradoxical
hypertension in a manner similar to that which occurs when these xenobiotics are used in cocaine
toxicity by inducing unopposed α1-receptor stimulation (Chap. 78).
Diagnostic Testing
Clonidine and other centrally acting antihypertensives are not routinely included in serum or urine
toxicologic assays. Consequently, management decisions should be based on clinical parameters.
No electrolyte or hematologic abnormalities are associated with this exposure. Because of the
potential for bradydysrhythmia and hypoventilation, 12-lead electrocardiography (ECG) and
continuous cardiac and pulse oximetry monitoring are recommended.
Management
Appropriate therapy begins with particular focus on the patient’s respiratory and hemodynamic
status. Administration of activated charcoal (AC) is the primary mode of GI decontamination in most
cases of ingestion. Patients often present after the onset of symptoms rather than immediately after
ingestion, and patients respond well to supportive care. In cases involving clonidine patch
ingestions, whole-bowel irrigation appears to be an effective intervention.102
All patients with CNS depression should be evaluated for hypoxia and hypoglycemia. Those with
respiratory compromise, including apnea, often respond well to simple auditory or tactile
stimulation.4,6,103,124 Significant arousal during preparation for intubation often precludes the need for
mechanical ventilation.4 Endotracheal intubation should be performed if clinically indicated.
Patients with isolated hypotension should initially be treated with IV boluses of crystalloid: 20 mL/kg
in children and 500 to 1000 mL in adults. Bradycardia is typically mild and usually does not require
any therapy if adequate peripheral perfusion exists. If the symptomatic bradycardia occurs,
then atropine is often effective and redosing may be required.4,6,149,239
It is likely that naloxone was first used in clonidine-poisoned patients because of their clinical
findings of CNS and respiratory depression and miosis is similar to opioid-poisoned
patients.174 Clonidine-poisoned patients, particularly children, may have increased arousal,
respiratory effort, heart rate, and blood pressure after naloxone administration.10,129,174,245 The
mechanism for this may relate to modulation of CNS sympathetic outflow by endogenous CNS
opioids.26,70,116,222
This concept is supported by a clinical study in which clonidine administration to hypertensive
patients for 3 days resulted in a significant decrease in blood pressure. Subsequent administration of
0.4 mg of naloxone parenterally reversed the decrease in blood pressure and heart rate in almost
60% of the patients.69 Because of the short duration of effects of naloxone (20–60 minutes) redosing
or continuous infusion may be required. As with some synthetic opioids, such as propoxyphene and
fentanyl, clinical improvement may occur only after high doses (4–10 mg) of naloxone,124,152 and some
patients have no response regardless of dose used.149,266
Early onset hypertension is typically self limited and therapy should be cautiously undertaken. If
hypertension is severe or prolonged, then treatment with a short acting and titratable
antihypertensive such as IV nicardipine and sodium nitroprusside is appropriate.154 Esmolol may
exacerbate this paradoxical hypertension in a manner similar to that which occurs when these
xenobiotics are used in cocaine toxicity by inducing unopposed α1-receptor stimulation (Chap. 78).
Although oral nifedipine has been used,58its inability to titrate and its unpredictable efficacy make its
use inappropriate as well.
CENTRAL IMIDAZOLINE AGONISTS
Moxonidine and related rilmenidine are also known as second-generation centrally acting
antihypertensives and are the newest class of antihypertensives available in the United
States.62 They are structurally similar to clonidine, but selectively attach at I1-imidazoline binding sites
which are found predominantly in the rostral ventrolateral medulla, and they have much less affinity
for the α2-adrenergic receptor.66 The exact molecular structure of these imidazoline binding sites has
not been determined nor has the exact physiologic cascade or effect of ligand binding at these sites.
Therefore these sites are not currently termed “receptors.” Although the exact mechanism of action
is still being investigated, binding at these I1-imidazoline specific sites ultimately leads to sympathetic
outflow from the medulla, vasodilation, and reduction in blood pressure. Nitric oxide or GABA
mechanisms may be involved in their central effects.190,191 Therapeutically, moxonidine is used both
as monotherapy or in combination with the antihypertensives. Patients with diabetes or metabolic
syndrome may particularly benefit from moxonidine because of its positive effects on insulin
resistance, impaired glucose tolerance, and hyperlipidemia.62,72There is one published overdose
resulted in initial hypertension and somnolence suggesting that weak α2-adrenergic receptor affinity
is overwhelmed in overdose.148 This patient subsequently had two seizures that were responsive to
benzodiazepines however never developed any hypotension.148
OTHER SYMPATHOLYTIC ANTIHYPERTENSIVES
Several other xenobiotics also exert their antihypertensive effect by decreasing the effects of the
sympathetic nervous system. Often termed sympatholytics, they can be classified as ganglionic
blockers, presynaptic adrenergic blockers, or α1-adrenergic antagonists, depending on their
mechanism of action. These drugs are rarely used clinically, and little is known about their effects in
overdose.
Presynaptic Adrenergic Antagonists
These xenobiotics exert their sympatholytic action by decreasing norepinephrine release from
presynaptic nerve terminals. Whereas guanethidine and guanadrel interfere with the action potential
that triggers norepinephrine release,224 reserpine depletes norepinephrine, serotonin, and other
catecholamines from the presynaptic nerve terminals, probably by direct binding and inactivation of
catecholamine storage vesicles.84Adverse events limit their clinical usefulness. These effects include
a high incidence of orthostatic and exercise-induced hypotension, diarrhea, increased gastric
secretions, and impotence.179 In addition, this hypotensive effect may be prolonged for as long as
one week.119,225 Because of its ability to cross the blood–brain barrier, reserpine may also deplete
central catecholamines and produce drowsiness, extrapyramidal symptoms, hallucinations, migraine
headaches, or depression.142 In overdose, an extension of their pharmacologic effects is expected.
Patients with severe orthostatic hypotension should be anticipated and treated with IV crystalloid
boluses and a direct-acting vasopressor. If reserpine is involved, significant CNS depression should
also be anticipated.142
Peripheral α1-Adrenergic Antagonists
The selective α1-adrenergic antagonists include prazosin, terazosin, and doxazosin. The α1 receptor
is a postsynaptic receptor primarily located on vascular smooth muscle, although they are also found
in the eye and in the GI and genitourinary tracts.49,107 In fact, these xenobiotics provide first line
pharmacologic therapy for patients with urinary dysfunction secondary to benign prostatic
hyperplasia.136 They produce arterial smooth muscle relaxation, vasodilation, and a reduction of the
blood pressure. Although better tolerated than ganglionic blockers and peripheral adrenergic neuron
blockers, they may still produce significant symptoms of postural hypotension, including
lightheadedness, syncope, or palpitations, particularly after the first dose or if the dosing is rapidly
increased.17 Hypotension and CNS depression ranging from lethargy to coma are reported in
overdose.135,140,216 In addition, priapism may occur.140,208 Treatment includes supportive care, IV
crystalloid boluses, and a vasopressor, with phenylephrine being a logical initial choice.
Direct Vasodilators
Hydralazine, Minoxidil, and Diazoxide.
These xenobiotics produce vascular smooth muscle relaxation independent of innervation or known
pharmacologic receptors.60,118,126 This vasodilatory effect has been attributed to stimulation of nitric
oxide release from vascular endothelial cells. The nitric oxide then diffuses into the underlying
smooth muscle cells, stimulating guanylate cyclase to produce cyclic guanosine monophosphate
(cGMP). This second messenger indirectly inhibits calcium entry into the smooth muscle cells,
producing vasodilation.215 Minoxidil, however, also has direct potassium channel activation
effects.128,176 It has been proposed that the opening of these adenosine triphosphate linked potassium
channels results in potassium influx and cell depolarization, thereby reducing calcium influx and
ultimately relaxing vascular smooth muscle.33
As this vasodilation occurs, the baroreceptor reflexes, which remain intact, produce an increased
sympathetic outflow to the myocardium, resulting in an increase in heart rate and contractile force.
Typically, these xenobiotics are used therapeutically in patients with severe, refractory hypertension
and in conjunction with a β-adrenergic antagonist to diminish reflex tachycardia.
Hydralazine, minoxidil, and diazoxide are effective orally, but sodium nitroprusside is only used
IV. Minoxidil is also used topically in a 2% solution to promote hair growth, and significant poisoning
has occurred in suicidal adults who have ingested this formulation.68,160 Diazoxide, although
previously used to rapidly reduce blood pressure in hypertensive emergencies, is rarely used for this
indication now as a consequence of its poor ability to titrate and its variable, and occasionally
profound, hypotensive effect.125
Adverse effects associated with daily hydralazine use include several immunologic phenomena such
as hemolytic anemia, vasculitis, acute glomerulonephritis, and most notably a lupuslike
syndrome.196 Minoxidil may cause changes on ECG, both in therapeutic doses and in overdose.
Sinus tachycardia, ST segment depression, and T-wave inversion are all reported.94,198,232 There also
appears to be an association with supratherapeutic doses of minoxidil and left ventricular multifocal,
subacute necrosis, and subsequent fibrosis.96,97 The significance of either of these changes is
unknown; they typically resolve with either continued therapy or as other toxic manifestations
resolve.94,97,232
The common toxic manifestations of these xenobiotics in overdose are an extension of their
pharmacologic action. Symptoms may include lightheadedness, syncope, palpitations, and
nausea.3,147 Signs may be isolated to tachycardia alone,198,232 flushing, or alterations in mental status,
which is related to the degree of hypotension.160 Based on AAPCC annual poison data, in recent
years, the majority of reported exposures to this class of drugs may have involved the topical
formulation of minoxidil29 (Chap. 136).
After appropriate GI decontamination, routine supportive care should be performed with special
consideration to maintaining adequate mean arterial pressure. If IV crystalloid boluses are
insufficient, then a peripherally acting α-adrenergic agonist, such as norepinephrine
or phenylephrine, is an appropriate next therapy. Dopamine andepinephrine should be avoided to
prevent an exaggerated myocardial response and tachycardia from β-adrenergic stimulation.
Nitroprusside.
Sodium nitroprusside is effectively a prodrug, exerting its vasodilatory effects only after its
breakdown and the release of nitric oxide. The nitroprusside molecule also contains five cyanide
radicals that, although gradually released, occasionally produce cyanide or thiocyanate
toxicity.178,219 Physiologic methemoglobin can bind the liberated cyanide. The binding capacity of
physiologic methemoglobin is about 175 µg/kg of cyanide, corresponding to a little less than 500
µg/kg of infused sodium nitroprusside. These cyanide moieties are rapidly cleared, both by
interacting with various sulfhydryl groups in the surrounding tissues and blood and enzymatically in
the liver by rhodanese, which couples them to thiosulfate-producing thiocyanate.76 This cyanide
detoxification process in healthy adults occurs at a rate of about 1 µg/kg/min, which corresponds to a
sodium nitroprusside infusion rate of 2 µg/kg/min.51,219 It is limited by the sulfur donor availability, so
factors that reduce these stores, such as poor nutrition in infants and toddlers, critical illness,
surgery, and diuretic use, place patients at risk for developing cyanide toxicity.40,51The hemolysis
associated with cardiopulmonary bypass may place the patient at particular risk because the
elevated free hemoglobin may accelerate the release of cyanide from the sodium nitroprusside
moiety.40 Therefore, depending on the balance of cyanide release (eg, rate of sodium nitroprusside
infusion) and the rate of cyanide detoxification (eg, sulfur donor stores), cyanide toxicity may develop
within hours. Infusion rates greater than 4 µg/kg/min of nitroprusside for greater than 12 hours may
overwhelm the capacity of rhodanese for detoxifying cyanide.207 Signs and symptoms of cyanide
toxicity include alteration in mental status; anion gap metabolic acidosis; and in late stages,
hemodynamic instability. If cyanide poisoning does occur, then hydroxycobalamin is the current
treatment of choice for treatment (Chap. 126).
One method of preventing cyanide toxicity from sodium nitroprusside is to expand the thiosulfate
pool available for detoxification by the concomitant administration of sodium
thiosulfate.51,92,164,219 Dosing of 1 g sodium thiosulfate for every 100 mg of nitroprusside is typically
sufficient to prevent cyanide accumulation.207 Unfortunately, the thiocyanate formed may accumulate,
particularly in patients with renal insufficiency, and produce thiocyanate toxicity.76,219 Simultaneous
infusion of thiosulfate does not interfere with the vasodilatory effects of sodium
nitroprusside.104 Needless to say, the potential of sodium nitroprusside to produce cyanide poisoning,
in addition to the introduction of other equally effective and rapidly titratable antihypertensives, has
greatly reduced its use.
Thiocyanate is almost exclusively renally eliminated, with an elimination half-life of 3 to 7 days. It is
postulated that a continuous sodium nitroprusside infusion of 2.5 µg/kg/min in patients with normal
renal function could produce thiocyanate toxicity within 7 to 14 days, although it may be as short as
3 to 6 days or as little as 1 µg/kg/min in patients with CKD who are not receiving hemodialysis.219 The
symptoms of thiocyanate toxicity begin to appear at serum concentrations of 60 µg/mL (1 mmol/L);
are very nonspecific; and they may include nausea, vomiting, fatigue, dizziness, confusion, delirium,
and seizures.76Thiocyanate toxicity may produce life-threatening effects, such as hemodynamic and
intracranial pressure elevation, when serum concentrations are above 200 µg/mL.51,76,92,249 Anion gap
metabolic acidosis and hemodynamic instability do not occur with thiocyanate toxicity. Although
cyanide or thiocyanate concentrations are not typically useful in the management of patients with
cyanide toxicity, they may be beneficial for monitoring critically ill patients who are at risk of
thiocyanate poisoning. Hemodialysis clears thiocyanate from the serum and should be strongly
considered in patients with significant clinical manifestations of thiocyanate toxicity.64,153,166
Another therapy used to prevent cyanide toxicity from sodium nitroprusside is a simultaneous
infusion of hydroxocobalamin.128 Dosing of 25 mg/h has successfully reduced cyanide poisoning in
humans.48,270 As with thiosulfate, simultaneous infusion ofhydroxocobalamin does not interfere with
the vasodilatory effects of sodium nitroprusside.104 Because of the relative higher cost
of hydroxocobalamin as well its interactions with some laboratory tests, thiosulfate should remain the
mainstay of prophylaxis against sodium nitroprusside-induced cyanide toxicity (Antidotes in Depth:
A40 and A41).
Diuretics
Diuretics can be divided into three main groups: (1) the thiazides and related compounds, including
hydrochlorothiazide and chlorthalidone, (2) the loop diuretics, including furosemide, bumetanide,
and ethacrynic acid, and (3) the potassium-sparing diuretics, including amiloride, triamterene,
and spironolactone. Two other groups of diuretics—the carbonic anhydrase inhibitors, such
as acetazolamide, and osmotic diuretics (eg, mannitol)—are not used as antihypertensive agents.
The thiazides produce their diuretic effect by inhibition of sodium and chloride reabsorption in the
distal convoluted tubule. Loop diuretics, in contrast, inhibit the coupled transport of sodium,
potassium, and chloride in the thick ascending limb of the loop of Henle. Although their exact
antihypertensive mechanism is unclear, an increased urinary excretion of sodium, potassium, and
magnesium results from the use of loop diuretics. Potassium-sparing diuretics act either as
aldosterone antagonists, such asspironolactone, or as renal epithelial sodium channel antagonists,
such as triamterene, in the late distal tubule and collecting duct.114
The majority of toxicity associated with diuretics is metabolic and occurs during chronic therapy or
overuse.264 Hyponatremia develops within the first 2 weeks of initiation of diuretic therapy in more
than 67% of susceptible patients, and female sex, old age, and malnourishment are the greatest risk
factors.8,235 Symptoms of severe hyponatremia (< 120 mEq/L) may include headache, nausea,
vomiting, confusion, seizures, or coma (Chap. 19). The osmotic demyelination syndrome, formally
known as central pontine myelinolysis, is reported during rapid correction of severe hyponatremia
secondary to diuretic abuse.46
Other electrolyte abnormalities associated with diuretic use include hypokalemia and
hypomagnesemia, which may precipitate ventricular dysrhythmias such as torsade de pointes and
sudden death. This is an extremely controversial topic, with several excellent studies providing
conflicting results.21,77,185,228,230 Although it is unclear how great a risk, if any, diuretic use may be, it
remains prudent to monitor and correct the patient’s potassium concentration.108,228,262 This is
particularly important in elderly patients and for those patients who concomitantly use digoxin, in
which setting hypokalemia is clearly associated with dysrhythmias (Chap. 65).28,240 Potassium-sparing
diuretics may cause hyperkalemia, particularly in the setting of renal insufficiency or when combined
with other hyperkalemia-producing drugs such as ACEIs.118
Thiazide diuretics are associated with inducing hyperglycemia, particularly in patients with diabetes
mellitus. This is a result of depletion of total body potassium stores. Because insulin secretion is
dependent on transmembrane potassium fluxes, this decrease in potassium concentration reduces
the amount of insulin secreted.144 This effect is dose dependent and reversible either by potassium
supplementation or discontinuation of the thiazide diuretic.39,100 This association has lead to significant
work and discussion about the routine use of thiazide diuretics as first-line antihypertensives in the
treatment of uncomplicated patients.52,90,166 In addition, thiazides are less well tolerated than any other
antihypertensive drug class leading to significant noncompliance.165
Thiazide diuretics are also associated with inducing hyperuricemia, renal calculi, and gout.34,91,93 This
is because the renal elimination of uric acid is extremely dependent on intravascular and urinary
volume so diuretic-induced volume depletion reduces uric acid filtration and increases its proximal
tubule resorption.226,238
Several unusual reactions are associated with thiazide diuretic use, including pancreatitis;
cholecystitis; and hematologic abnormalities, such as hypercoagulability, thrombocytopenia, and
hemolytic anemia.61,63,212,214,252,261
Despite the widespread use of these xenobiotics, acute overdoses are distinctly rare.139Major signs
and symptoms include GI distress, brisk diuresis, possible hypovolemia and electrolyte
abnormalities, and altered mental status.139 Typically, the diuresis is short lived because of the limited
duration of effect and the rapid clearance of the majority of diuretics. Assessment should focus on
fluid and electrolyte status, which should be corrected as needed. If hyperkalemia is unexpectedly
discovered, either the ingestion of a potassium-sparing xenobiotic or, more likely, an overdose of
potassium supplements, which are frequently prescribed in conjunction with thiazide and loop
diuretics, should be considered.111,112 Altered mental status, including coma, may result from diuretic
overdose without evidence of any fluid or electrolyte abnormalities.17,18,139,213 Postulated mechanisms
include a direct drug effect and induction of transient cerebral ischemia due to hypotension.180
Angiotensin-Converting Enzyme Inhibitors
ACEIs are among the most widely prescribed antihypertensives. At the time of this writing, there are
10 ACEIs approved by the US FDA for the treatment of hypertension (Table 63–1). In general, they
are well absorbed from the GI tract, reaching peak serum concentrations within 1 to 4
hours. Enalapril and ramipril are prodrugs and require hepatic metabolism to produce their active
forms. Elimination is primarily via the kidneys.
TABLE 63–1. Antihypertensives and Pharmacologically Related Agents
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All ACEIs have a common core structure of a 2-methylpropanolol-L-proline moiety.81 This structure
binds directly to the active site of ACE, which is found in the lung and vascular endothelium,
preventing the conversion of angiotensin I to angiotensin II. Because angiotensin II is a potent
vasoconstrictor and stimulant of aldosterone secretion, vasodilation; decreased peripheral vascular
resistance; decreased blood pressure; increased cardiac output; and a relative increase in renal,
cerebral, and coronary blood flow occur.81 This hypotensive response may be severe in select
patients after their initial dose, resulting in syncope and cardiac ischemia.42,106 Patients with
renovascular-induced hypertension and patients who are hypovolemic from concomitant diuretic use
appear to be at greatest risk.106 Overall, however, these drugs are well tolerated and have a very low
incidence of side effects. Some reported adverse effects include rash, dysgeusia, neutropenia,
hyperkalemia, chronic cough, and angioedema.56,81,246 Because of their interference with the renin–
angiotensin system, ACEIs are potential teratogens and should never be used by pregnant women
or women of childbearing age.13
ACEI-Induced Angioedema.
Angioedema is an inflammatory reaction in which there is increased capillary blood flow and
permeability, resulting in an increase in interstitial fluid. If this process is confined to the superficial
dermis, urticaria develops; if the deeper layers of the dermis or subcutaneous tissue are involved,
angioedema results. Angioedema most commonly involves the periorbital, perioral, or oropharyngeal
tissues.199 This swelling may progress rapidly over minutes and result in complete airway obstruction
and death.80,85,223 The pathogenesis of acquired angioedema involves multiple vasoactive substances,
including histamine, prostaglandin D2, leukotrienes, and bradykinin.110 Because ACE also inactivates
bradykinin and substance P, ACE inhibition results in elevations in bradykinin concentrations that
appear to be the primary cause of both ACEI angioedema and cough (Fig. 63–1).5,113 There is no
evidence that the ACEI angioedema phenomenon is immunoglobulin E (IgE) mediated.5
FIGURE 63–1.
An overview of the normal function of the renin-angiotensin-aldosterone system (RAAS) and the mechanisms of
action of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and direct renin
inhibitors (DRIs) on that system. PVR = peripheral vascular resistance.
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Although the literature is replete with reports of ACEI angioedema, the overall incidence is only
approximately 0.1%, and it is idiosyncratic.73,113,231 One-third of these reactions occur within hours of
the first dose and another third occur within the first week.151,231 It is important to remember that the
remaining third of cases may occur at any time during therapy, even after years.41 Women, African
Americans, and patients with a history of idiopathic angioedema appear to be at greater risk.151,184 In
addition, there is evidence that patients who develop ACEI angioedema are at increased subsequent
risk of developing angioedema from any etiology.16
Treatment varies depending on the severity and rapidity of the swelling. Because of its propensity to
involve the tongue, face, and oropharynx, the airway must remain the primary focus of management.
A nasopharyngeal airway is often helpful. If there is any potential for or suggestion of airway
compromise, then endotracheal intubation should be performed. Severe tongue and oropharyngeal
swelling may make orotracheal or nasotracheal intubation extremely difficult, if not impossible. If this
is a concern, then fiberoptic nasal intubation may be an attractive option, provided that the resources
are available. Other techniques, including retrograde intubation over a guidewire that was passed
through the cricothyroid membrane and emergent cricothyrotomy, may also be
considered.207 However, the most important aspect of airway management in patients experiencing
ACEI angioedema is early risk assessment for airway obstruction and rapid intervention before the
development of severe and obstructive swelling.2
Because ACEI angioedema is not an IgE-mediated phenomenon pharmacologic therapy targeting
an allergic cascade, such as epinephrine, diphenhydramine, and corticosteroids, should not be
expected to be effective. However, when the history is unclear, these medications should not be
withheld in order to ensure providing life-saving therapy to someone having a severe IgE-mediated
allergic reaction.
Newer treatment modalities developed to target various points along the cascade of events
associated with hereditary angioedema may be beneficial in the treatment of ACEI angioedema.
Hereditary angioedema results from a genetically mediated defect in C1 inhibitor resulting in limited
activity of this enzyme and an increase in kallikrein concentrations. Kallikrein is a protease that
cleaves kininogen into bradykinin. The end result is very similar to the cause of ACEI angioedema,
namely an activation of vascular bradykinin B2 receptors.13 Several new treatments have been
developed to target specific steps in the development of hereditary angioedema, including Berinert,
a C1 esterase inhibitor, ecallantide, a kallikrein inhibitor, and icatibant, a bradykinin B2 receptor
antagonist. Case reports of successful treatment of ACEI angioedema with these xenobiotics are
few.14,79,177 However, one case series of eight patients with ACEI angioedema who where treated with
30 mg subcutaneous icatibant had more rapid improvement in their signs and symptoms as well as
no need for subsequent steroid ordiphenhydramine use.14 While further evidence is needed, icatibant
may be a reasonable treatment for ACEI angioedema; however, its significant cost should limit its
use only in patients with rapidly progressive or severe angioedema.
Fresh frozen plasma (FFP) which contains ACE has also been proposed as treatment for ACEI
angioedema. FFP infusion will elevate ACE concentrations and lead to the degradation of
accumulated bradykinin. Clinical use of FFP for the successful treatment of both hereditary and
ACEI angioedema is reported.122,189,200,263 In these case reports, doses range from 1 to 5 units of FFP
(200–250 mL/unit) with most using an infusion of 2 units of FFP as initial, and typically definitive,
treatment.200
All patients with mild or rapidly resolving angioedema should be observed for several hours to
ensure that the swelling does not progress or return. Outpatient therapy with a short course of oral
antihistamines and corticosteroids should be considered if there is any question as to whether ACEI
therapy produced the angioedema because allergic-mediated angioedema will benefit from this
treatment. Patients developing angioedema from ACEI therapy should be instructed to discontinue
them permanently and to consult their primary care physicians about other antihypertensive options.
Because this is a mechanistic and not allergic adverse effect, the use of any other ACEIs is
contraindicated.
Angiotensin-Converting Enzyme Inhibitor Overdose.
The toxicity of ACEIs in overdose appears to be limited.43,141 Although several reports of overdoses
involving ACEIs are published, the majority of the cases reported manifested toxicity of a
coingestant.54,89,262 Hypotension may occur in select patients,11,12,131 but deaths are rarely reported in
isolated ACEI ingestions.187,235 Other patients may remain asymptomatic despite high serum drug
concentrations.131
Treatment should focus on supportive care and on identifying any coingestants that may be more
toxic, particularly other antihypertensives such as β-adrenergic antagonists and calcium channel
blockers. In most cases, AC alone is sufficient GI decontamination. IV crystalloid boluses are often
effective in correcting hypotension, although in rare cases, catecholamines may be
required.7,83 Naloxone may also be effective in reversing the hypotensive effects of ACEIs. ACEIs
may inhibit the metabolism of enkephalins and potentiate their opioid effects, which include lowering
blood pressure.57,167 In a controlled human volunteer study, continuous naloxone infusion effectively
blunted the hypotensive response of captopril.1 In one case report, naloxone appeared to be
effective in reversing symptomatic hypotension secondary to a captopril overdose.258 In another
published case, naloxone was ineffective.11 Although its role in the setting of ACEI overdose remains
unclear, naloxone may obviate the need for large quantities of crystalloid or vasopressors and
should therefore be considered.
Angiotensin II Receptor Blockers
ARBs were first introduced in 1995, and currently, six members of this class are marketed in the
United States. These xenobiotics are rapidly absorbed from the GI tract, reaching peak serum
concentrations in 1 to 4 hours, and then are eliminated either unchanged in the feces or after
undergoing hepatic metabolism via the mixed function oxidase system eliminated in the bile.156,157,158,
and 159,181
Although these xenobiotics are similar to ACEIs in that they decrease the effects of angiotensin II
rather than decrease the formation of angiotensin II, they act by antagonizing angiotensin II at the
type 1 angiotensin (AT-1) receptor (Fig. 63–1).123 This allows the drugs to inhibit the vasoconstrictive-
and aldosterone-promoting effects of angiotensin II and reduce blood pressor by blunting both the
sympathetic as well as the renin–angiotensin systems.156 Despite the mechanistic evidence that
ARBs do not affect bradykinin degradation and therefore should have a much lower incidence of
angioedema when compared to ACEIs, serious cases of angioedema associated with ARB therapy
have been reported.38,151,255 In addition, there is a significantly higher incidence of angioedema
associated with ARBs when compared to other antihypertensives, such a β-adrenergic
antagonists.250
Similar to ACEIs, ARBs should never be used by pregnant patients because of their teratogenic
potential.13,229 In addition, when initiating the xenobiotic, up to 1% develop of patients first-dose
orthostatic hypotension.86
There have been few published reports of overdoses involving ARBs. Adverse signs and symptoms
reflect orthostatic or absolute hypotension and include palpitations, diaphoresis, dizziness, lethargy,
or confusion.74,162,233 Hypotension should be treated with crystalloid boluses and catecholamine
therapy.162,233 Patients who are chronically taking ARBs may exhibit significant hypotension during
induction of general anesthesia that has been refractory to traditional vasoconstrictor therapy, such
as norepinephrine, ephedrine, and phenylephrine, but appear to respond to vasopressin.23,27,67
One promising new treatment for hypotension produced by ARBs and ACEIs is methylene
blue.155,171,251 This treatment was first explored in patients placed on cardiopulmonary bypass
(CPB).186,236,251 During CPB systemic blood pressure and peripheral vascular resistance decrease due
to a number of factors, including acute hemodilution, citrate use in the cardioplegia, a poorly defined
inflammatory response that results in nitric oxide release, and an increase in circulating
bradykinin.45,50,268 This increase in bradykinin, which also mediates its vasodilatory effects via nitric
oxide, occurs because bradykinin metabolism is primarily in pulmonary tissue and CPB mechanically
bypasses the pulmonary system.45,50 ACEIs and ARBs exacerbate this vasodilation by inhibiting
bradykinin metabolism.197 In a double blinded placebo controlled study of 30 patients taking ACEIs
who were undergoing elective cardiac surgery requiring CPB, administration of methylene blue at
the onset of CPB resulted in an increase in mean arterial pressure and systemic vascular resistance
and less use of phenylephrine and norepinephrine.155 A reasonable starting dose of methylene blue,
when used as a vasopressor, appears to be 2 mg/kg with subsequent intermittent boluses or
possibly continuous infusions starting at 0.5 mg/kg/h.115,155
DIRECT RENIN INHIBITORS
Direct renin inhibitors (DRIs) such as aliskiren exert their antihypertensive effects via the renin-
angiotensin-aldosterone system (RAAS) by directly inhibiting circulating renin.265Unfortunately, all
RAAS acting antihypertensives such as ACEIs, ARBs, and DRIs induce a compensatory increase in
serum renin concentrations; however, only DRIs are able to blunt the physiologic effects of this
rise.32,221,265 Aliskiren is well tolerated and is an effective antihypertensive both as monotherapy and in
combination with other antihypertensives, including hydrochlorothiazide, calcium channel blockers,
and β-adrenergic antagonists.144 However, significant controversy surrounds aliskiren use when
combined ARBs or ACEIs after a clinical trial was halted due to an increased incidence of ischemic
stroke, acute kidney injury, hyperkalemia, and hypotension was noted in patients with diabetes and
CKD.188 There are no reported cases of poisoning or overdose; however, hypotension should be
anticipated and treatment that includes supportive care, including IV crystalloid and catecholamines,
seems reasonable.
SUMMARY
These xenobiotics are not often associated with severe poisonings, either because of limited
use, as with most of the sympatholytics and direct vasodilators, or because of limited toxicity,
as with diuretics, ACEIs, ARBs, and DRIs.
Severe clonidine poisoning classically presents as the opioid toxidrome producing profound
CNS depression and bradycardia.
Clonidine withdrawal manifests as CNS agitation, tachycardia, and hypertension and should
be treated with clonidine or benzodiazepines.
Nitroprusside infusions greater than 4 µg/kg/min may result in cyanide poisoning which can
be prevented with coadministration of thiosulfate or hydroxycobalamin.
Because of the pathogenesis of ACEI-induced angioedema, it is unlikely to respond to
“typical” allergic treatment such as antihistamines, epinephrine, and steroids. Rather, focus
should be on definitive airway management in patients with rapidly progressing swelling or
symptoms.
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