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CNS stimulant
PATHOPHYSIOLOGY
Caffeine has many effects in the body. The three most commonly documented effects
are (1) adenosine receptor antagonism, (2) phosphodiesterase inhibition, and (3)
enhanced intracellular calcium levels.[13] Adenosine receptor antagonism leads to
vasoconstriction, hypertension, tremor, and agitation. These effects are frequently
seen in caffeine overdose.[72] These effects are the reverse of those seen with adenosine
agonist activity, such as arterial vasodilation, inhibition of catecholamine release, and
slowing of cardiac pacemaker cells.[13][50]
Caffeine inhibits phosphodiesterases, causing increased levels of cyclic AMP, which
results in increased levels of catecholamines. Muscle contractility is enhanced through
increased intracellular calcium levels and increased permeability of the sarcoplasmic
reticulum to calcium.[50][75] Stimulation of gastric acid and intestinal secretions and
lowering of lower esophageal sphincter tone by caffeine commonly result in diarrhea
and abdominal cramping.[50]
Beneficial effects of caffeine include bronchodilation and vasodilation in the
treatment of apnea in premature infants. Although caffeine-induced vasodilation may
lower blood pressure, caffeine-induced medullary stimulation and increased
catecholamine release offset this effect.
Phenylpropanolamine and ephedrine act primarily via increased β1- and β2-adrenergic
receptor agonist activity and enhanced release of catecholamines.[36]
Phenylpropanolamine is as potent as ephedrine but causes less central nervous system
(CNS) stimulation. Phenylephrine is a selective α1-adrenergic receptor agonist.[36] It is
a derivative of epinephrine and produces similar therapeutic and adverse effects.
Peripheral vasoconstriction and tachycardia are the most common adverse effects.
Table 36–3 compares the α- and β-adrenergic receptor activity and CNS stimulation
of caffeine and other nonprescription sympathomimetics. Chronic misuse of these
agents may lead to cardiovascular abnormalities, such as vasculitis, stroke syndrome,
cardiomyopathy, hypertension, and dysrhythmias.
Table 36-3 -- Actions of Selected Sympathomimetic Agents at Peripheral
Adrenergic Receptors in the Central Nervous System
Alpha-Adrenergic
Beta-Adrenergic
CNS
Substance
Response
Response
Stimulation
Amphetamine
++
++
+++
Caffeine
++
+
+
Ephedrine
++
+++
++
Phenylephrine
++++
0
+
Phenylpropanolamine
+++
+
+++
+, week activity.
++++, strongest activity.
Oral preparations of these drugs are the most common forms available, but each of
these agents may also be used intravenously. Phenylephrine is also available as a
nonprescription inhaler. Phenylpropanolamine and caffeine may be sold on the street
falsely as cocaine or amphetamines. In these cases, the agents may be snorted,
ingested, or taken intravenously.
CLINICAL PRESENTATION
All the nonprescription sympathomimetics (i.e., caffeine, ephedrine,
phenylpropanolamine, and phenylephrine) share some similar clinical features when
taken in excessive amounts. Common symptoms include nausea, vomiting, diarrhea,
abdominal pain, tremors, anxiety, agitation, and headaches.[1] Less common but more
severe symptoms include delirium, seizures, hypertensive crisis, intracerebral
hemorrhage, and myocardial infarction. Debate still exists as to whether or not a
single dose of caffeine or phenylpropanolamine can result in clinically significant
hypertension.[44][57][59] However, hypertensive crisis is documented in significant acute
overdoses.[29] Phenylpropanolamine differs from caffeine in that
phenylpropanolamine-induced hypertension is associated with a reflex bradycardia.[36]
Caffeine overdose is most commonly associated with tachycardia. Although severe
toxicity and death may be caused by any of these agents in an overdose situation,
ephedrine, phenylpropanolamine, and phenylephrine appear to have more reported
cardiovascular complications than caffeine.[10][25][50][51][58]
Although hyperthermia is frequently seen with severe overdose of the
psychostimulants (amphetamines, methamphetamines, and cocaine), it is rarely seen
in caffeine overdoses. Sympathomimetic overdoses, however, can cause severe
hyperthermia that may be lethal if untreated.[7][11] The hyperthermia is thought to be
due to activation of specific dopamine receptors.[11] Increased motor activity and
stimulant-induced seizures are also possible causes of hyperthermia after
sympathomimetic overdose.
Acute Toxicity
In adults, ingestion of 500–1000 mg of caffeine may result in nausea, vomiting,
diarrhea, tremors, and agitation.[1][50] Most patients have sinus tachycardia and a mild
hypertension. Increases in cardiac output and glomerular filtration rate (GFR) can
increase urine production. Dehydration and hypokalemia are common. Death due to
caffeine overdose is rare but can result from the spontaneous vomiting that occurs
with ingestion of large amounts. Caffeine-related deaths from dysrhythmias, seizures,
and neurologic effects have been reported.[17][20][43] The estimated lethal dose of caffeine
in an untreated adult is 5–10 g,[12][50] and in children 78 mg/kg has caused serious
symptoms.[47][50][66] This may be due to the slower elimination of caffeine by children.
Table 36–4 summarizes the clinical effects of over-the-counter sympathomimetics.
Table 36-4 -- Clinical Effects of Caffeine Toxicity
Mild and Common
Sinus tachycardia
Severe and Uncommon
Seizure
Reflex bradycardia with phenylpropanolamine Hypertensive crisis
Hypertension
Hyperthermia
Nausea, vomiting, diarrhea, cramps
Myocardial infarction/chest pain
CNS agitation, anxiety
Delirium
Palpitations
Intracerebral hemorrhage
Chronic Toxicity
Chronic excessive ingestions of over-the-counter sympathomimetic and caffeine
frequently result in tachycardia, hypertension, and palpitations. Myocardial infarction,
vasculitis, cardiomyopathy, and dysrhythmias (paroxysmal atrial tachycardia,
premature ventricular contractions, bigeminy, ventricular tachycardia, and ventricular
fibrillation) have been reported in large and chronic overdoses.[3][17][37][47][50][81] A cerebral
vasculitis from chronic use and misuse of ephedrine may cause an acute intracerebral
hemorrhage.[80] Chronic use and misuse may also lead to sustained hypertension and
subsequent hemorrhage.[5] With chronic use, certain individuals may tolerate
extremely large ingestions with minimal side effects, although others may experience
severe symptoms at a fraction of the dose
DIFFERENTIAL DIAGNOSIS
Multiple medical and psychological conditions may mimic sympathomimetic toxicity
( Table 36–5 ). Serious medical conditions, including sepsis, intracranial hemorrhage,
metabolic disorders, myocardial infarction, and primary dysrhythmias, must be
excluded when patients present with signs of stimulant overdose. Psychiatric
complications such as mania, anxiety, and panic attacks must also be considered in
the differential diagnosis. Sympathomimetic abuse and overdoses may exacerbate preexisting psychiatric, neurologic, and cardiac conditions.[25][40][52]
Table 36-5 -- Differential Diagnosis of Caffeine Toxicity
Other drugs
MAO inhibitors
Cocaine
Amphetamines
Theophylline
PCP
LSD
Anticholinergics
Cardiac abnormalities
Cardiomyopathy
Hypertensive crisis
Myocardial infarction
Primary dysrhythmia
Metabolic dysfunction
Hyperthyroidism
Pheochromocytoma
Hypoxia
Hypoglycemia
Hyperthermia/sepsis
Psychiatric disorders
Anxiety
Mania
Panic disorder
Sleep disorder
CNS disturbances
Intracranial hemorrhage
Headache: migraine or tension
TREATMENT ( Table36–6 )
Acute Overdose
Treatment in all cases is supportive with attention to airway, breathing, and
circulation. Oral activated charcoal, 1–2 g/kg of body weight is the primary mode of
gastrointestinal decontamination. Gastric lavage may be considered if the patient
presents to the emergency department within 1 hour after ingestion, has ingested a
potentially life-threatening amount of drug, and does not have nausea and vomiting.
Table 36-6 -- Treatment Essentials in Caffeine Toxicity
Effect
Therapy
Dose (Adult)
Decontamination Activated charcoal
50–100 g PO
Dysrhythmia
Diazepam: 5–10 mg IV q 5–10 min
Benzodiazepines
Lorazepam: 1–2 mg IV q 5 min
Esmolol
Esmolol: LD 500 μg/kg IV over 1 min;
follow with 50 μg/kg/min IV infusion;
titrate up q 5 min to a max of 200
μg/kg/min prn
Effect
Hypertension
Therapy
Dose (Adult)
Lidocaine
Lidocaine: 1–1.5 mg/kg IV bolus over 2–
3 min; may repeat dose of 0.5 mg/kg in
5–10 min up to a total of 3 mg/kg
Procainamide
Procainamide: LD 15–18 mg/kg given as
slow infusion over 25–30 min;
maintenance dose 1–6 mg/min by
continuous IV infusion
Benzodiazepines
Diazepam: 5–10 mg IV q 5–10 min
Lorazepam: 1–2 mg IV q 5 min
Seizures
Sodium nitroprusside
Sodium nitroprusside: 0.5 μg/kg/min,
increase by 0.5 μg q 5 min until desired
effect; maximum dose of 10 μg/kg/min
Benzodiazepines
Diazepam: 5–10 mg IV q 5–10 min
Lorazepam: 1–2 mg IV q 5 min
Phenobarbital
Nausea/vomiting Rehydration if
necessary
Potassium/electrolyte
replacement
Phenobarbital: 10–20 mg/kg IV given at a
rate of 25–50 mg/min
Titrate crystalloids to maintain urine
output of 1–2 mL/kg/hr
Replace electrolytes as needed.
Antiemetics
Metoclopromide
Metoclopromide: Adult= 5–10 mg IV,
PO, or IM up to a maximum dose of 1
mg/kg
Pediatric: 0.1 mg/kg to maximum 10 mg
dose
Ondansetron
Ondansetron
Adult: 0.15 mg/kg IV (maximum 8 mg
dose)
Pediatric: ≤40 kg 0.15 mg/kg/IV
>40 kg 4 mg IV
Intravenous crystalloids are indicated for significant vomiting or diarrhea, and
electrolyte losses should be replaced. Urine output should be maintained at 1–2
mL/kg/hour.
Rhabdomyolysis may result in acute intrinsic renal failure, which may be avoided
with intravenous (IV) crystalloids and IV mannitol, 0.5–1 g/kg over 5–10 minutes to
maintain urine output of 1–2 mL/kg/hour. With significant aciduria the addition of
sodium bicarbonate to maintain a urine pH value greater than 6.0 may protect the
renal tubules and improve the prognosis of acute renal failure associated with
rhabdomyolyisis.[34][65] If these treatments fail to produce diuresis or if electrolyte
abnormalities persist, hemodialysis may be required.
Caffeine may produce hypokalemia directly by activation of the Na+/K+-ATPase pump
or secondarily by induction of emesis and diuresis.[61][67] Metabolic acidosis and
catecholamine-induced intracellular shifts of potassium may also potentiate
electrolyte abnormalities.[67] Potassium and other electrolytes should be monitored and
replaced as needed.
An antiemetic such as metoclopromide or ondansetron may be considered if
protracted vomiting occurs. Temperature should be monitored closely. Stimulantinduced hyperthermia should be treated aggressively utilizing fans, ice water lavage,
and ice water baths when necessary. Benzodiazepines such as diazepam and
lorazepam should be given to patients who are agitated, hypertensive, or tachycardic.
Benzodiazepines are frequently underutilized and often will decrease blood pressure
and heart rate without further complications. Benzodiazepines may decrease or stop
agitation, which can contribute to the development of rhabdomyolysis. The dose
should be titrated intravenously to effect. The patient should be monitored for
respiratory depression.
The over-the-counter sympathomimetics may precipitate seizures in overdose.[43]
Intravenous diazepam or lorazepam should be administered until seizures subside. If
seizures persist, phenobarbital should be administered.
With hypertensive crisis unresponsive to benzodiazepines, sodium nitroprusside is the
drug of choice because of its short duration of action. The dose can be titrated to
maintain a normal blood pressure. Phentolamine, an α-adrenergic receptor antagonist,
has a longer duration of action and cannot be titrated as easily to effect.
Nitroglycerine should be considered in cases with myocardial ischemia and infarction.
Beta-adrenergic receptor antagonists should be avoided in a hypertensive crisis
because unopposed α-adrenergic receptor agonist effects may result in further
increases in blood pressure and adverse cardiac effects. Although labetolol blocks
both α1- and β2-adrenergic receptors, its α1-adrenergic antagonist effect is one-fifth to
one-tenth that of its β-adrenergic receptor antagonism. Use of labetolol may still result
in unopposed α-adrenergic receptor agonism and further increases in blood pressure,
and is not recommended. Reflex bradycardia should resolve with treatment of
hypertension.
Chronic Toxicity
Treatment of chronic stimulant overdoses is more complicated because of the lack of
well-controlled, long-term studies on chronic abuse of stimulants other than caffeine.
Most data is extrapolated from acute toxicity or individual case reports. Chronic
ingestion of caffeine is usually benign, but a withdrawal syndrome may be
encountered if caffeine is stopped abruptly.[26][73] Headaches, lethargy, and agitation are
the most commonly encountered effects. Reintroduction of caffeine followed by a
gradual taper should relieve symptoms and prevent any further withdrawal symptoms.
Diet aids containing phenylpropanolamine are frequently abused by women.[10][14][17][46]
Increasing doses over months to years may be used to maintain diet and weight.
Tolerance to these products develops readily, and large amounts may be ingested
daily.[64] Prolonged and excessive misuse or abuse of these products has led to
cardiomyopathy.[10] Hemorrhagic stroke and intracerebral hemorrhage may be
encountered with both acute or chronic misuse or abuse of phenylpropanolamine and
ephedrine.[15][25][35][42][51][77] Phenylpropanolamine-induced psychosis or relapsing of
underlying psychiatric conditions has been documented.[52][68] Standard medical
therapies are recommended for these complications.
Antiarrhythmic
KARL A. SPORER
The action potential of a ventricular or Purkinje fiber ( Fig. 41–1 ) is generated by the
flux of ions through specific channels in the cell membrane. Membrane depolarization
results from the net influx of positive charges (sodium [Na+] and calcium [Ca2+]), and
repolarization occurs secondary to the net efflux of positive charges (potassium [K+]) (
Table 41–1 ).
Figure 41-1 EKG recording of ventricular muscle cell action potential. (Redrawn from Tan HL, Hou JY, et al:
Electrophysiologic mechanisms of the long QT interval syndromes and torsade de pointes. Ann Intern Med 1995;
122:701–714.)
Table 41-1 -- Major Ion Currents Underlying the Cardiac Action Potential *
Effect of Current on Action
Action Potential Phase
Current Direction
Potential
Phase 0 (upstroke; inward >
outward currents)
Phase 1 (initial
repolarization; outward >
inward currents)
Phase 2 (plateau; inward ∼
outward currents)
INa
Inward
ITO
Outward
ICa
Inward
Slow inactivation maintains early
plateau phase
INaCa
Inward
May assist in maintenance of
plateau phase
ITO
Rapid upstroke or action potential
in atrial, ventricular, and Purkinje
fibers
Rapid early repolarization after
overshoot of action potential
Residual slowly inactivating
Outward outward current during plateau
phase
Action Potential Phase
Phase 3 (rapid repolarization;
outward > inward currents)
Current Direction
IK
Outward
Effect of Current on Action
Potential
Delayed rectifier repolarizes
membrane to near resting potential
Phase 4 (Diastole; Inward ∼
Maintains high negative resting
IK1
Outward
or > outward currents)
potential near -90 mV
From Tan AHL, Hou CJY, Lauer MR, Sung RJ: Electrophysiologic mechanisms of the
long QT interval syndromes and torsades de pointes. Ann Intern Med 1995; 122:701–
714.
*
INa, Fast inward sodium current; ITO, transient outward potassium current; Ica, slow inward L type calcium channel;
INaCA, electrogenic sodium-calcium exchange current; IK, outward delayed rectifier potassium; IK1, outward potassium
current that exhibits anomalous (inward-going) rectification.
Phase 0 depolarization is mainly caused by the opening of the fast Na+ channels,
allowing the influx of Na+ from a high concentration gradient toward a low
concentration gradient. Phase 1 is a small depolarization mediated by the transient
outward current of K+.
The plateau phase, or phase 2, is maintained by the relatively slow influx of
Ca2+through the L-type Ca2+channel. The rapid repolarization of phase 3 is generated
by the efflux of K+ through the delayed rectifier K+ channel. The Na+/K+ adenosine
triphosphatase (ATP) pump and the Na+ concentration–dependent electrogenic
Na+/Ca2+exchange pump function between action potentials to maintain electrolyte
balance.
Na+ channel blockers will slow the phase 0 rapid upstroke and prolong the length of
the entire action potential. For a given resting membrane potential, depolarization is
associated with a reduced rate of voltage change and reduced maximum voltage. In
addition, the higher threshold requires a greater stimulus to initiate the action
potential. Clinically, this is manifested as Q-Tc prolongation in therapeutic
concentrations and QRS widening in toxic concentrations. In higher doses, the Na+
channel blockade diminishes cardiac output; and in even higher concentrations it will
also slow the heart rate.
Ca2+ channel blockers in toxic doses will develop bradycardia from the slowing of
atrial and ventricular action potentials. In addition, the slow and diminished action
potential along with the low intracellular Ca2+ concentration will manifest as a
diminished cardiac output, relative bradycardia, and peripheral vasodilation.
K+ channel blockers prolong the action potential by slowing the efflux of K+. In
addition to prolonging the action potential, this will also increase the resting
membrane potential. There are currently no pure K+ channel blockers, and thus their
clinical effects in isolation have not been determined.
The treatment of toxicity due to Ca2+ channel blockers and β-adrenergic receptor
antagonists is covered in Chapters 43 and 42 , respectively.
CLASS IA: QUINIDINE, PROCAINAMIDE, DISOPYRAMIDE
Essentials
•
Lethargy, confusion, coma
•
Widened QRS and Q-Tc intervals
•
Hypotension without tachycardia
•
Anticholinergic symptoms (primarily from disopyramide)
The action potential of a ventricular or Purkinje fiber results from the rapid flux of
Na+, Ca2+, and K+ through various transmembrane channels (see Fig. 41–1 and Table
41–1 ).[63] Antidysrhythmics work by partially blocking the function of specific ion
channels and thus slowing various phases of the action potential. In the exaggerated
response of toxicity, the surface electrocardiographic (EKG) abnormalities can be
predicted.
Quinidine, procainamide, and disopyramide are antidysrhythmic drugs in the class IA
category and function as antidysrhythmics by blocking both the Na+ and K+ cardiac
channels.
Pharmacology/Pathophysiology
Pharmacology
See Tables 41–2 and 41–3 .
Table 41-2 -- Modified Vaughan-Williams Classification of Antidysrhythmic
Drugs
Class
Pharmacologic Effect
Antidysrhythmic Drug
IA
Depresses rapid action potential upstroke and
decreases conduction velocity (Na+ channel
Quinidine, procainamide,
blockade) and significantly prolongs
disopyramide
+
repolarization (K channel blockade)
IB
Depresses rapid action potential upstroke in
Mexiletine, lidocaine, tocainide,
abnormal tissue (little effect in normal tissue)
moricizine *
and enhances repolarization
IC
Markedly depresses rapid action potential
upstroke and decreases conduction velocity
Propafenone, encainide, †
(Na+ channel blockade) but exerts little effect
flecainide, moricizine *
on repolarization (little or no K+ channel
blockade)
II
Blocks β-adrenergic receptors
Propranolol, metoprolol,
atenolol, esmolol, labetalol,
nadolol, pindolol, sotalol,
timolol and others
Class
III
Pharmacologic Effect
Antidysrhythmic Drug
Primarily blocks K+ channels and slows
repolarization (little or no Na+ channel
blockade)
Sotalol, amiodarone, bretylium
Verapamil, diltiazem,
nifedipine, and others
From Tan AHL, Hou CJY, Lauer MR, Sung RJ: Electrophysiologic mechanisms of the
long QT interval syndromes and torsades de pointes. Ann Intern Med 1995; 122:701–
714.
IV
Blocks L-type Ca2+ channels
*
Moricizine has been variously classified as a class IB and class IC agent.
†
Encainide was removed from US market in 1991.
Table 41-3 -- Antidysrhythmics: Therapeutic Levels and Elimination
Characteristics
Therapeutic
HalfElimination
Active
Levels
Life
Pathway
Metabolites
Class IA
Quinidine
2–7 μg/mL
6–8 hr
Hepatic
Yes
Procainamide 4–10 μg/mL
3 hr
Hepatic/renal
Yes
Disopyramide 2–5 μg/mL
4–10 hr Renal/some hepatic
No
Class IB
Lidocaine
3–5 μg/mL
1.5–2 hr Hepatic
Yes
Tocainide
3–9 μg/mL
10 hr
Hepatic/renal
No
Mexiletine
1–2 μg/mL
10 hr
Hepatic
No
Encainide
15–100 ng/mL
1–3 hr
Hepatic
Yes
Propafenone
0.2–0.4 μg/mL
6–7 hr
Hepatic
No
Moricizine
0.25–3 μg/mL
2–4 hr
Hepatic
Unknown
Amiodarone
1–2 μg/mL
20–30 d Hepatic
No
Bretylium
Not available
5–10 hr Renal
No
Sotalol
1.4–1.7 mg/L
9–11 hr Renal
No
Class IC
Class III
Pathophysiology
Type IA agents depress the rapid action potential upstroke (phase 0) and decrease
conduction velocity by Na+ channel blockade. They also significantly prolong
repolarization and depress the slope of phase 4 depolarization by K+ channel
blockade.[38][63] At therapeutic doses, patients will commonly manifest a prolonged QTc interval and an increased risk of torsades de pointes (polymorphic ventricular
dysrhythmia). At toxic doses, patients will demonstrate increased Q-Tc and QRS
intervals. Hypotension in type IA intoxication is caused by depressed myocardial
contractility from the Na+ channel blockade and peripheral vasodilation from the K+
channel blockade.
Procainamide is hepatically metabolized to the pharmacologically active N-acetyl
procainamide (NAPA), which is renally excreted. Toxicity of NAPA commonly
occurs in patients on therapeutic doses of procainamide in the setting of decreasing
renal function.[14] Hypotension occurs mainly with intravenous infusions that exceed
20 mg/min.
The Na+ channel blockade of quinidine and probably the other type IA agents has
been demonstrated to increase in acidotic environments and worsen its toxicity.[30]
Clinical Presentation
The most serious manifestations of a type IA intoxication are primarily cardiovascular
( Table 41–4 ).[38] Mild intoxications may only manifest sinus tachycardia with Q-Tc
prolongation and a normal blood pressure. Almost any dysrhythmia can occur in more
serious cases, but the most common ones are QRS and Q-Tc interval prolongation,
bundle branch blocks, ventricular tachycardia (often polymorphic), and ventricular
fibrillation.[3][4][9][16][17][31][35][37][48][50][54][55][56][57][59][60][66][68][70]
Table 41-4 -- Clinical Presentation of Antidysrhythmic Intoxication
Type IA
Mild or early intoxication—tachycardia, normal blood pressure, and Q-Tc
prolongation
Moderate to severe intoxication—QRS widening, hypotension with relative
bradycardia, lethargy, confusion, coma (anticholinergic symptoms, mostly
disopyramide)
Type IB
Confusion, coma, seizures
Hypotension, widened QRS, ventricular dysrhythmias, and asystole in massive
intoxication
Type IC
Q-Tc prolongation
Hypotension
Bradycardia
Coma, respiratory depression, seizures
Type III
Amiodarone—increased PR interval, rare sinus bradycardia
Sotalol—rapid-onset hypotension, bradycardia, Q-Tc prolongation, ventricular
dysrhythmias
Bretylium—profound coma, occasional transient hypertension followed by
hypotension
Hypotension commonly develops in severe intoxications and may be accompanied by
a relative bradycardia. Central nervous system (CNS) symptoms are also commonly
noted in type IA intoxication and can range from lethargy, confusion, coma, and
respiratory depression to seizures. Quinidine has been noted to cause cinchonism, a
syndrome characterized by tinnitus, vertigo, blurred vision, headache, and confusion.
Disopyramide can produce significant anticholinergic effects in overdose and rarely
has produced hypoglycemia during therapeutic use.[16][45] The anticholinergic effects of
disopyramide are mostly mediated through its main metabolite, mono-Ndealkyldisopyramide.
Differential Diagnosis
The differential diagnosis of patients who present with a prolonged QRS interval,
hypotension, relative bradycardia, and CNS symptoms includes a consideration of
other drugs that possess type IA toxicity, other cardiotoxic agents, as well as severe
electrolyte abnormalities ( Table 41–5 ).
Table 41-5 -- Differential Diagnosis of Antidysrhythmic Intoxication
Types IA, IC
Other Agents That Can Prolong Q-Tc and Cause Torsades
Cyclic antidepressants
Phenothiazines
Chloroquine, quinine
Cocaine
Propoxyphene (norpropoxyphene)
Amantadine
Arsenic
Choral hydrate
Organophosphates
Diphenhydramine
Terfenadine
Astemizole
Other Agents with Cardiac Toxicity
β-Blockers
Calcium channel blockers
Electrolyte Abnormality
Hypokalemia
Hypomagnesemia
Hypocalcemia
Type IB
Other causes of seizures (see Chapter 18 )
Severe intoxications
Type IA drugs
Calcium channel blockers
β-Blockers
Type III
Amiodarone, sotalol
Other β-blockers
Calcium channel blockers
Flecainide, encainide
Bretylium
Any sedative/hypnotic
Clonidine
Tetrahydrozoline
Laboratory Studies
The EKG is critical in predicting and following toxicity. An increase in the QRS
complex width of more than 25 per cent over baseline has been used as a reliable
indication of quinidine toxicity and has been commonly seen in both disopyramide
and procainamide toxicity.[11]
Drug levels of quinidine, procainamide, and NAPA are available, but rarely on a
timely basis. Serum K+, Ca2+, and magnesium (Mg2+) levels can help to rule out
significant electrolyte abnormalities.
Treatment
Early cardiac monitoring with intravenous access is important in these patients with a
potential for lethal dysrhythmias ( Table 41–6 ). Aggressive gastrointestinal
decontamination will be most useful early after ingestions. Attention to airway
management in patients with lethargy or coma is important because type IA toxicity
can be worsened by acute respiratory acidosis.
Table 41-6 -- Treatment of Antidysrhythmic Intoxication
All Classes
Airway management, supportive care
Gastrointestinal decontamination—activated charcoal
Electrocardiographic monitoring
Type IA, IC[38][40]
Cardiac Conduction Delays
NaHCO3 1–2 mEq/kg IV boluses. Maintain arterial pH at 7.4 to 7.5.
Hypotension
0.9% NaCl 200–500 mL bolus infusions to correct hypovolemia
NaHCO3 1–2 mEq/kg IV boluses. If still hypotensive, consider a pressor agent.
Dopamine, norepinephrine, or epinephrine. Central hemodynamic monitoring may be
helpful in guiding this therapy.
Consider the use of an intra-arterial balloon pump or temporary cardiopulmonary
bypass for intractable hypotension.
Dysrhythmias
Bradydysrhythmias—isoproterenol or epinephrine infusion. Consider a pacemaker.
Polymorphic ventricular tachycardia (torsades de pointes)
Magnesium, 2 g IV bolus. May repeat in 5–15 minutes.
Isoproterenol or overdrive cardiac pacing
Other
Consider hemodialysis or hemoperfusion in patients with procainamide intoxication
and large ingestions, high plasma concentrations, presence of circulatory collapse, or
renal insufficiency.
Type IB
Seizures
Lorazepam IV
Phenobarbital IV load for persistent seizures
Hypotension
0.9% NaCl 200–500 mL bolus infusions to correct hypovolemia
Dopamine, norepinephrine or epinephrine. Central hemodynamic monitoring may be
helpful in guiding this therapy.
Consider the use of an intra-arterial balloon pump or temporary cardiopulmonary
bypass for intractable hypotension.
Type III
Treat as for types IA and IC.
Amiodarone—cholestyramine may be useful for gastrointestinal decontamination.
Sotalol—glucagon may reverse β-adrenergic receptor antagonist effects (see Chapter
42 ).
Sodium bicarbonate (NaHCO3) has been shown to be an effective therapy in reversing
the EKG and cardiac contractility changes caused by quinidine in both animal models
and in case reports.[4][15][38] It has also been reported effective in procainamide toxicity
and logically should be helpful in disopyramide toxicity.[23]
Several mechanisms may account for the efficacy of NaHCO3 in quinidine toxicity.
Increasing the extracellular Na+ concentration may overcome the inhibition of
conductance through Na+ channels. Alkalinization has been demonstrated to diminish
the relative potency of quinidine at the Na+ channel.[30] There may also be some
beneficial effect of lowering the serum K+. It is generally recommended that the serum
pH be kept between 7.45 and 7.5.
Patients who develop torsades de pointes should be treated with the usual
pharmacologic interventions. Magnesium sulfate, overdrive pacing, and isoproterenol
infusions have been very effective in suppressing this dysrhythmia.[67] Logically,
NaHCO3 should lessen the QTc prolongation and also be helpful in suppressing
torsades de pointes, but this has not been demonstrated clinically.
Ventricular ectopy and ventricular dysrhythmias related to class IA toxicity can be
more difficult to treat. The use of either class IA or IC (flecainide, encainide or
propafenone) antidysrhythmics would be expected to be ineffective or to worsen the
dysrhythmia. There is modest evidence that bretylium may be helpful in this scenario.
NaHCO3 and lidocaine would be logical therapies. Hypotension should initially be
treated by fluid resuscitation and administration of NaHCO3. Hypotensive patients
unresponsive to fluids have been treated successfully with norepinephrine,
isoproterenol, and dopamine. The only animal studies evaluating this question
concluded that isoproterenol was superior to dopamine and glucagon in providing
cardiovascular support.[28][32]
An intra-aortic balloon pump has been used successfully in one patient and should be
considered along with cardiopulmonary bypass for those patients with refractory
hypotension.[60]
Extracorporeal drug removal is useful in procainamide and NAPA toxicity, of little
benefit in quinidine toxicity, and of questionable usefulness in disopyramide toxicity.
Numerous case reports of procainamide poisonings have demonstrated clinically
significant clearance by both hemoperfusion and hemodialysis and should be
considered early in any large procainamide intoxication with hemodynamic
instability, especially in the setting of renal insufficiency or failure.[3][9][17][55][57]
Case reports and studies of disopyramide intoxications demonstrated modest
usefulness of hemodialysis and hemoperfusion.[27][33][35] The role for extracorporeal drug
removal in disopyramide toxicity is not well defined.
Disposition
Because of the rapid absorption of all these drugs, symptoms of toxicity and EKG
changes will be apparent in the first few hours after ingestion. Patients who develop
QRS widening, mental status changes, hypotension, or dysrhythmias need hospital
admission and telemetry monitoring. Patients who are observed for 4 to 6 hours and
do not develop QRS widening or other symptoms can be safely discharged if they are
not suicidal.
Sequelae
The QRS complex may take up to several days to return to baseline even though most
of the significant symptoms occur in the first 12 hours after ingestion. Other longterm sequelae are related to the severity of hypotension and hypoperfusion.
CLASS IB: LIDOCAINE, TOCAINIDE, MEXILETINE
Essentials
•
Confusion, coma, seizures
•
Hypotension, widened QRS complex, ventricular dysrhythmias, and asystole in
massive intoxication
Class IB antidysrhythmics act primarily by inhibiting Na+ channels selectively at
ischemic and rapidly depolarizing myocytes.[5]
Pharmacology/Pathophysiology
Pharmacology
See Tables 41–2 and 41–3 .
Pathophysiology
These Na+ channel blocking agents have little electrophysiologic activity on normal
cells at therapeutic or moderately toxic doses. Because of these properties, there are
no common EKG changes noted in intoxications. Cardiac dysfunction is only noted in
massive intoxications when high concentrations partially block all cardiac sodium
channels similar to type 1A agents.
CNS toxicity is more common and is manifested as confusion or seizures. Ion
transport is disturbed in the brain, and inhibitory neurons are initially blocked, causing
excitatory stimulation and seizures. Higher concentrations will inhibit both excitatory
and inhibitory neurons and induce coma and respiratory depression.
Lidocaine has been shown to develop toxicity when administered orally, mucosally,
and parenterally.[1][26][34][61] Oral lidocaine is well absorbed but undergoes significant
first-pass metabolism. Lidocaine is hepatically metabolized to two active metabolites,
monoethylglycinexylidide (MEGX) and glycine xylidine (GX), that may contribute to
toxicity. The oral bioavailability of tocainide and mexiletine approaches 100 per cent,
and neither compound is metabolized to any active metabolites.
Clinical Presentation
The majority of these intoxications will present as confusion, agitation, or seizures
(see Table 41–4 ). There will likely be no finding other than history to differentiate
this from other causes of seizure activity. Most of these cases will have a normal EKG
and relatively normal vital signs.
Severe intoxications can inhibit the Na+ channel in even normal cardiac tissue and will
be similar to quinidine toxicity with a widened QRS complex and a diminished
cardiac output. Almost any dysrhythmia can be seen in this setting. Mexiletine and
tocainide intoxications are similar in presentation.[13][46][62]
Differential Diagnosis
The differential diagnosis includes any cause of seizures (see Chapter 18 ). The
differential diagnosis of a severe intoxication with hypotension and dysrhythmias
includes other antidysrhythmics and Ca2+ channel blockers (see Table 41–5 ).
Laboratory Studies
Determination of serum electrolyte levels is done to rule out metabolic causes of
seizures. The EKG is monitored for QRS complex widening in cases of severe
intoxication. Lidocaine levels are not readily available, but therapeutic concentrations
are 3 to 5 μg/mL.
Treatment
General supportive care and control of the seizures is done first. Repetitive seizures
should be controlled with escalating intravenous doses of lorazepam. Patients whose
seizures are not controlled with high-dose lorazepam should be given intravenous
phenobarbital. At this point these patients will likely require intubation and
ventilatory support. Phenytoin acts as a class IB antidysrhythmic and should not be
used. After airway management and seizure control, appropriate gastric
decontamination with activated charcoal can be accomplished if necessary.
Bradydysrhythmias may require a temporary pacemaker. Hypotension should be
treated first with a normal saline bolus, then with a vasopressor. A temporary
pacemaker may be helpful in these patients. Theoretically, NaHCO3 should be
efficacious, but it has not been used clinically or studied experimentally.
Extracorporeal cardiac support to maintain blood pressure and improve hepatic
metabolism has proven useful in one experiment and one case report.[21][22]
The experience of treating tocainide and mexiletine intoxications is limited but should
be similar to that of lidocaine.
Disposition
These three agents are quickly and reliably absorbed. All patients should develop
signs of toxicity in the first 1 or 2 hours. Any patient with mental status changes,
seizures, hypotension, or dysrhythmias should be admitted to a monitored bed.
Patients who do not develop symptoms within 4 hours can be safely discharged if they
are not suicidal.
Sequelae
There are no sequelae.
Specific Situations
Special concern should be emphasized about the potential for toxicity with the use of
oral lidocaine. Even though there is extensive first-pass metabolism with oral
ingestion, seizures have been noted to occur with the misuse of oral lidocaine
preparations.[26][34][61]
The maximal doses of subcutaneous lidocaine tolerated are 4.5 mg/kg for plain
lidocaine and 7 mg/kg with lidocaine with epinephrine.
CLASS IC: FLECAINIDE, ENCAINIDE, PROPAFENONE, AND MORICIZINE
Essentials
•
Q-Tc prolongation
•
Hypotension
•
Bradycardia
•
Coma, respiratory depression, seizures
Type IC antidysrhythmics markedly depress the phase 0 rapid action potential
upstroke by blocking the Na+-fast channels. These drugs have little or no effect on the
K+ channels and thus have no effect on repolarization. Moricizine has some features in
common with type IB antidysrhythmics.[20] Propafenone also exhibits minor βblocking and Ca2+-channel blocking activities. Encainide is no longer available in the
United States after being withdrawn because of a prodysrhythmic effect.
Pharmacology/Pathophysiology
Pharmacology
See Tables 41–2 and 41–3 .
Pathophysiology
The agents in this class have much in common with the type IA antidysrhythmics. In
toxicity, the Na+ channel blocking effect will manifest itself as widened QRS and QTc intervals, hypotension, and bradycardia.[2][10][12][29][36][40][42][44][51][52][69] In addition, PR
interval widening has been noted in flecainide intoxications.[42][69]
Clinical Presentation
Flecainide and encainide are both quickly absorbed, very bioavailable, and rapidly
toxic. Most severe cases have demonstrated signs of toxicity within 30 to 120 minutes
of the ingestion.[40] The most prominent signs and symptoms include hypotension,
bradycardia, QRS complex widening, coma, respiratory depression, and seizures (see
Table 41–4 ).
Differential Diagnosis
The differential diagnosis of patients who present with a prolonged QRS interval,
hypotension, relative bradycardia, and CNS symptoms includes other agents that
possess type IA properties and other cardiotoxic agents such as Ca2+ channel blockers
or β-adrenergic blockers (see Table 41–5 ).
Laboratory Studies
The EKG is useful in predicting and following toxicity. In case reports, QRS complex
widening has been consistently useful in predicting the presence and severity of
poisoning.[69]
Treatment
Cardiac monitoring, intravenous access, airway management, and early
gastrointestinal decontamination are important in managing these potentially severe
intoxications. NaHCO3 boluses have been reported useful in treating the cardiotoxic
effects and preventing dysrhythmias and hypotension.[52][58]
There is no clear choice of a vasopressor for those patients who do not respond to
crystalloid infusion and NaHCO3. Rapidly escalating doses of dopamine or
epinephrine should be titrated to a reasonable blood pressure. Pacing has been
successful in improving the hemodynamics in some patients. Extracorporeal cardiac
support, including balloon counterpulsation or cardiac bypass, should be considered in
severe refractory cases.
Efforts at resuscitation should be prolonged because several cases of flecainide and
propafenone poisoning survived extended periods of cardiopulmonary resuscitation
with asystole or pulseless electrical activity and were discharged with normal
neurologic status.[10][36][42][51]
Disposition
Patients with significant ingestions will manifest symptoms in 30 to 60 minutes. All
patients with QRS widening, mental status changes, hypotension, or bradycardia
should be monitored closely in an intensive care unit. These patients should be
monitored for 8 to 12 hours after their symptoms have resolved. There has been one
reported case of late-appearing dysrhythmias in a patient with severe flecainide
intoxication.[29] Patients who have not developed symptoms in 4 to 6 hours can be
safely discharged if they are not suicidal.
Sequelae
There are few or no long-term sequelae. One patient with an acute intoxication of
propafenone had persistent QRS complex widening and diminished cardiac function
at 4 months after ingestion.[36] Most other patients demonstrated complete recovery,
with QRS widening resolving over hours to days.
CLASS III: AMIODARONE, SOTALOL, BRETYLIUM
Essentials
•
Amiodarone—increased PR interval, rare sinus bradycardia
•
Sotalol—rapid onset hypotension, bradycardia, Q-Tc prolongation, confusion;
severe cases— respiratory depression, ventricular dysrhythmias
•
Bretylium—profound coma, occasional transient hypertension followed by
hypotension
Amiodarone, sotalol, and bretylium are type III antidysrhythmics because they
function by blocking K+ channels. This slows the action potential repolarization and
produces Q-Tc prolongation. Despite this one similar function, all of these drugs act
differently in overdose because of their other pharmacologic properties and their
differing pharmacokinetics.[41]
Pharmacology/Pathophysiology
Pharmacology
See Tables 41–2 and 41–3 .
Pathophysiology
The toxicities of this group of antidysrhythmics cannot be predicted or explained by
K+ channel blockade alone. A pure K+ blocker would slow the action potential’s
return to baseline and reset the myocardial cell at a higher level that would make it
more prone to ventricular irritability.
Amiodarone has well-documented chronic toxicities (pulmonary fibrosis, Q-Tc
prolongation, and thyroid abnormalities) but little acute toxicity because of its poor
absorption.[53] The prolonged period of absorption allows the logical use of late
gastrointestinal decontamination and dictates a long observation period.
Sotalol is rapidly and completely absorbed and demonstrates toxicity within an hour
of ingestion. In addition to the K+ channel blockade, it also has a significant βadrenergic receptor antagonist effect that explains most of the hemodynamic changes
in overdose.
Bretylium is only available in intravenous form, and intoxication is usually iatrogenic.
In addition to its type III antidysrhythmic properties, bretylium affects the autonomic
nervous system. An initial release of norepinephrine from sympathetic ganglia results
in a transient increase in blood pressure and heart rate. Later, the drug blocks the
release of norepinephrine by depressing adrenergic nerve excitability, causing
hypotension and bradycardia. The severe coma caused by bretylium remains
unexplained.
Clinical Presentation
Most acute amiodarone intoxications are benign and manifest little or no EKG
changes. Reported EKG abnormalities include prolongation of the PR and Q-Tc
interval, mild bradycardia, and one case of self-limited ventricular tachycardia.[7][8][25]
More severe toxicity can be predicted in the future with the availability of an
intravenous form of amiodarone.
Sotalol intoxications can be expected to develop Q-Tc prolongation, bradycardia, and
hypotension soon after ingestion. More severe intoxications will manifest as coma,
respiratory depression, seizures, and ventricular dysrhythmias.[18][19][43][47][65]
There have only been three reported cases of bretylium overdose.[6][24][64] These patients
developed profound coma lasting 1 to 3 days. One patient developed transient
tachycardia and hypertension, followed by a reduced cardiac output and refractory
hypotension. No specific EKG changes were noted in any of these patients (see Table
41–4 ).
Differential Diagnosis (see Table 41–5 )
The differential diagnosis for the cardiovascular effects caused by amiodarone and
sotalol include other β-adrenergic receptor antagonist drugs, Ca2+ channel blockers,
type 1A and 1C antidysrhythmics, and the other drugs that can cause prolonged Q-Tc
and torsades. Differential considerations for bretylium toxicity include toxicity of any
sedative/hypnotic agent, clonidine, and tetrahydralazine.
Laboratory Studies
The EKG may reveal Q-Tc interval prolongation in significant amiodarone or sotalol
intoxication. Serum K+, Ca2+, and Mg2+ levels will be helpful in gauging the extent of
electrolyte replacement necessary. Serum levels of class III antidysrhythmic drugs are
not readily available.
Treatment
The slow absorption of amiodarone allows for late gastrointestinal decontamination in
cases of significant ingestion. Activated charcoal has been effective in binding
amiodarone and is the therapy of choice.[39] Cholestyramine binds amiodarone in the
gastrointestinal tract as well as reduces the elimination half-life of absorbed drug, but
its role in this ingestion is currently unclear.[49] Intravenous potassium should be given
slowly to increase the serum potassium to greater than 4.5 mmol/L. K+ repletion alone
has been noted to have a protective effect from the dysrhythmias caused by
amiodarone.[53]
Occasionally, torsades de pointes occurs in amiodarone intoxication (usually in
combination with a type IA agent). This should be treated with intravenous
magnesium and an isoproterenol infusion or overdrive pacing to increase the heart
rate.[67]
Sotalol ingestions resemble β-blocker intoxications, with a greater propensity for
ventricular dysrhythmias. The initial treatment includes appropriate gastrointestinal
decontamination, cardiac monitoring, and K+ repletion. Hypotension has been
successfully treated with isoproterenol (to increase myocardial rate), dopamine, and
cardiac pacing. Glucagon, commonly employed in β-adrenergic receptor antagonist
intoxication, is a logical choice in a patient refractory to other pressors. Patients with
recurrent ventricular dysrhythmias have been successfully treated with defibrillation
and lidocaine.
The treatment of bretylium intoxication includes airway management and other
supportive measures. Coma may be prolonged and can resemble brain death. In
addition, hypotension may require vasopressors or extracorporeal cardiac support.
Disposition
Amiodarone’s prolonged absorption, up to 15 hours, dictates a long observation
period and will require the admission of all but the most trivial of ingestions. Clinical
endpoints for amiodarone ingestions are unclear, owing to limited clinical experience.
Sotalol intoxications will demonstrate EKG and vital sign changes within the first few
hours. A patient monitored for 4 to 6 hours without EKG changes, hypotension,
bradycardia, or mental status changes can be safely discharged if the patient is not
suicidal. The Q-Tc prolongation can persist for days and is not a useful endpoint of
observation. Late-presenting torsades has not been reported in these cases. Patients
should be observed for 6 to 8 hours after vital sign abnormalities and dysrhythmias
have resolved.
Bretylium intoxications are usually iatrogenic. These patients require admission and
should be observed for 12 to 24 hours for mental status changes.
Sequelae
Q-Tc interval prolongation can persist for days. There are no other significant
sequelae of these ingestions.