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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