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Calcium Channel and β-Blocker Drug Overdose
Chapter 84 CALCIUM CHANNEL AND b-BLOCKER DRUG OVERDOSE Annie Malouin,
DVM, DACVECC
Lesley G, King,
KEY POINTS Close regulation of intracellular calcium is essential for the body to
accomplish many physiologic processes, including excitationcontraction coupling, impulse formation and conduction, and maintenance of vascular tone. Calcium channel blockers and b-blockers inhibit L-type voltagesensitive calcium channels. The main physiologic derangements caused by overdose of these medications are negative inotropy and chronotropy, leading to decreased cardiac output, hypotension, tissue hypoperfusion, and shock. No single pharmacologic agent has been consistently effective for critically ill patients with these toxicities. A combination of antidotes may be required until the clinical signs have resolved. The prognosis depends on the quantity of drug ingested and the severity of signs. Early aggressive decontamination and good supportive care can prevent serious hemodynamic failure.
INTRODUCTION Drugs classified as calcium channel and b-blockers frequently are prescribed for cardiovascular disease management. In humans, these drugs are effective in patients with hypertension, angina pectoris, cardiac arrhythmias, migraines, tremors, and bipolar disorder.1 In veterinary medicine, calcium channel and b-blockers are used to treat cardiac arrhythmias, hypertrophic cardiomyopathy, and hypertension.2-3 Calcium plays a role in many physiologic processes, including impulse formation and conduction, excitationcontraction coupling, and maintenance of vascular tone. Close regulation of intracellular calcium is essential to accomplish these cardiovascular functions.4 There are several types of calcium channels. Calcium channel blockers inhibit only the voltage-sensitive channels, which open in response to voltage changes across the membrane, for example during depolarization. There are three types of voltage-sensitive calcium channels, designated as neuronal (N-type), transient (T-type), and long lasting (L-type). The L-type channels are the most sensitive to the commercially available calcium channel blockers. b-Blockers inhibit the cardiac adrenergic system, modifying the L-type voltage-sensitive channels via a second messenger system. L-type channels are located in various tissues but are found in highest concentration in the atria, vascular smooth muscle, and skeletal muscle. L-type voltage-sensitive calcium channels are activated as the transmembrane potential of the cell becomes progressively less negative during the upstroke
MVB, MRCVS, DACVECC, DACVIM, DECVIM-CA
of the action potential (phase 0). They have a prolonged opening time and high conductance, therefore allowing large amounts of calcium to pass rapidly into the cell.5 Calcium channel and b-blockers interrupt calcium flux, leading to decreased intracellular calcium, depressing cardiovascular function.5 Although calcium channel and b-blockers have different mechanisms of action, the physiologic effects, clinical signs, and treatment of toxicity are similar.3
METHOD OF ACTION Calcium Channel Blockers Calcium channel blockers exert most of their effects on cardiac myocytes, pacemaker cells, and vascular smooth muscle. They are classified into three major groups based on their structure, including the phenylalkylamines (e.g., verapamil), the benzothiazepines (e.g., diltiazem), and the dihydropyridines (e.g., amlodipine). Structural differences among the classes are associated with distinct binding sites on the calcium channel, resulting in differing potencies and tissue affinities (Table 84-1). Their structural heterogeneity leads to functional heterogeneity with regard to their vasodilator potency and their cardiac inotropic, chronotropic, and dromotropic effects.1-3 Cardiac Effects The calcium ion is essential for impulse conductance through the cardiomyocytes. Pacemaker cells of the sinoatrial (SA) and atrioventricular (AV) nodes rely on the inward calcium flux through L-type and T-type channels to initiate a spontaneous diastolic depolarization (phase 4). Calcium channel blockers inhibit inward flow of calcium through the L-type channel, leading to slow SA activity, decreased conduction of impulses through the AV node, and therefore a decrease in heart rate and prolongation of the refractory period.5 The negative chronotropic effect occurs primarily with the phenylalkylamines and benzothiazepines. With some calcium channel blockers, this effect may be attenuated or even abolished because of reflex stimulation of the sympathetic nervous system.2 Calcium plays an important role during excitationcontraction coupling in cardiac and vascular smooth muscles. Within Purkinje cells and myocytes, opening of the L-type calcium channels in response to membrane depolarization increases calcium conductance (phase 2 of the action potential). This inward flow of calcium triggers the release of additional calcium into the cytoplasm from the sarcoplasmic
357
VIII INTOXICATIONS
Table 84-1 Generic Name
Expected Cardiovascular Effects of Calcium Channel Blocking Agents in Healthy Animals2,3,34 Trade Name
Chronotropic (HR)
Dromotropic (AV Conduction)
Inotropic (Strength)
Systemic Vascular Resistance
Coronary Resistance
0 or þ
þþ
þ
þ
þ
0 or þþ
þþ
0 or þ
þ
þ
0
0
0
þþ
þþ
0
0
0
þþ
þ
Phenylalkylamines Verapamil
Calan, Verelan, Isoptin
Benzothiazepines Diltiazem
Cardizem, Dilacor
Dihydropyridines Nifedipine
Procardia, Adalat
Amlodipine Norvasc
AV, Atrioventricular; HR, heart rate. Key: 0, no change; þ, mild to moderate decrease; þþ, moderate to marked decrease. This effect is rate dependent, being more pronounced at higher heart rates.
reticulum. Intracellular calcium binds to troponin, changing its conformation and allowing interaction between actin and myosin so that contraction can occur. By decreasing the magnitude and rate of rise of the intracellular calcium concentration, the calcium channel blockers decrease calcium release from the sarcoplasmic reticulum, causing a decrease in the force of contraction.2,5 This negative inotropic effect is seen most commonly with the phenylalkylamines and to a lesser extent with the benzothiazepines.2 Most of the calcium channel blockers have a negative inotropic effect at high doses.3 Vascular Effects 358
In vascular smooth muscle cells, opening of calcium channels increases the cytosolic calcium concentration. Calcium interacts with calmodulin, causing phosphorylation of the myosin light-chain and actin-myosin binding, resulting in smooth muscle contraction and vasoconstriction. Calcium channel blockers prevent the rise in intracellular calcium needed for formation of the calcium-calmodulin complex and thus cause dilation of systemic and coronary arteries and arterioles.5 At therapeutic concentrations, they have minimal effect on the venous system. The phenylalkylamines affect both vascular and cardiac tissue, the benzothiazepines have intermediate selectivity, and the dihydropyridines exert a greater effect on vascular tissue.2 Pancreatic Effects The b-cells on the pancreas also contain L-type calcium channels. Calcium influx into pancreatic islet cells via L-type channels is required for insulin release. High doses of calcium channel blockers may therefore cause serum glucose levels to rise while intracellular glucose stores fall. This is another mechanism by which calcium channel blocker overdose may impair cardiovascular function and lead to shock.6-8
b-Blockers There are two types of b-receptors. b1-Receptors are located primarily within the heart and adipose tissue. Stimulation results in increased heart rate, myocardial contractility, AV conduction velocity, and automaticity of subsidiary pacemakers. b2-Receptors are found primarily in bronchial and smooth muscles, where they produce relaxation.4 In human medicine, b-adrenergic blocking agents differ in their ability to block breceptor types.9 In veterinary medicine the primary drugs are propranolol (b1-receptor and b2-receptor blocker), atenolol
(specific b1-receptor blocker), esmolol (specific b1-receptor blocker), and sotalol (b1-receptor and b2-receptor blocker).3 Cardiac Effects Interactions between catecholamines and b-receptors in the cardiac cell membrane stimulate membrane-bound adenyl cyclase, which raises the intracellular concentration of cyclic adenosine monophosphate (cAMP). cAMP activates protein kinases that phosphorylate the L-type calcium channel, increasing myocellular calcium entry and the release of calcium from the sarcoplasmic reticulum. This calcium interacts with the myocardial contractile machinery, producing systole. Protein kinases phosphorylate a protein, phospholamban, that causes the sarcoplasmic reticulum to take up calcium more rapidly, enhancing relaxation (diastole).5 In general, b-adrenergic blockade decreases transmembrane calcium flow by decreasing cAMP synthesis, thereby decreasing atrial and ventricular contractility and decreasing the heart rate by slowing the spread of excitation through the AV node.3 Pulmonary, Pancreatic, Gastrointestinal, Vascular, and Renal Effects In the lung, stimulation of b2-receptors promotes bronchodilation, and their blockade leads to bronchospasm. In the pancreas, b2-receptors mediate insulin release, and their blockade leads to decrease in glycogenolysis, lipolysis, and gluconeogenesis. In the gastrointestinal (GI) tract and vascular smooth muscles, inhibition of b2-receptors results in contraction. b1-Receptors are also present in the kidney, where they mediate renin release.4
PHARMACOKINETICS Calcium Channel Blockers Calcium channel blockers are absorbed rapidly and almost completely from the GI tract but have extensive first-pass metabolism. Times to peak serum concentration are rapid: 20 to 45 minutes for immediate-release forms and 4 to 12 hours for sustained-release formulations and amlodipine besylate (which has a slower absorption rate) in dogs and cats.2 The onset of action varies with the formulation. An animal that bites into and swallows a sustained-release product can show signs within 5 minutes, but one that swallows it whole may not show signs for several hours and may have
Therapeutic Dosages Drugs
Dogs
Cats
0.1 to 5 mg/kg PO q8-12h 0.15 mg/kg IV over 2 minutes
—*
0.5 to 1.5 mg/kg PO q8h 0.25 mg/kg IV over 5 minutes
1.7 to 2.5 mg/kg PO q8h
Amlodipine besylate
0.05 to 0.25 mg/kg PO q24h
0.625 mg/cat PO q24h
Nifedipine
0.5 mg/kg PO q8h
—
Propranolol
If severe cardiac disease: 0.1 to 0.5 mg/kg PO q8h If normal myocardial function: 2 mg/kg PO q8h
2.5 to 10 mg PO q8h
Atenolol
6.25 to 50 mg PO q12h
6.25 mg PO q12h
Esmolol
Loading dose: 0.25 to 0.5 mg/kg IV followed by constant rate infusion: 10 to 200 mg/kg/min IV
Calcium Channel Blockers PHENYLALKYLAMINES
Verapamil hydrochloride BENZOTHIAZEPINES
Diltiazem hydrochloride DIHYDROPYRIDINES
b-Blockers
84 CALCIUM CHANNEL AND b-BLOCKER DRUG OVERDOSE
Table 84-2 Therapeutic Dosage Ranges of Calcium Channel Blockers and b-Blockers Most Commonly Used in Dogs and Cats2,3,12
IV, intravenous; PO, per os. *Verapamil is not recommended for use in cats; the safety of this drug is questionable in this species.
prolonged toxicity because of slower absorption.10 Tissue distribution is extensive in all classes. Calcium channel blockers are approximately 80% protein bound; therefore interaction with other protein-bound drugs may result in competition for binding sites. Additionally, animals with moderate to severe hypoproteinemia may develop higher blood concentrations. In humans, calcium channel blockers are metabolized in the liver by oxidative pathways, predominantly by cytochrome P450 CYP3A. Therefore their clearance will be decreased when hepatic function or blood flow is reduced.1 The phenylalkylamines and benzothiazepines can interact with many drugs because they are strong inhibitors of hepatic microsomal enzymes. Similarly, their elimination can be slowed by drugs that inhibit hepatic enzymes (e.g., cimetidine), potentially increasing their cardiovascular effects and producing toxicity.10,11 Elimination half-lives depend on the formulation (i.e., immediate versus sustained release) and in dogs and cats can vary from 2 to 30 hours. Excretion is primarily through urine and, to a lesser extent, bile and feces.2
b-Blockers The pharmacokinetics of b-blockers, although well established in humans, remain unclear in small animals. The more lipid-soluble compounds (e.g., propranolol) require hepatic biotransformation before secretion and can therefore accumulate if there is decreased hepatic blood flow or hepatic insufficiency. They also have a large volume of distribution and enter the central nervous system (CNS) faster and more easily. In contrast, the water-soluble compounds (atenolol) are excreted by the kidney and can accumulate if there is renal insufficiency. Esmolol is water soluble but does not accumulate in renal failure because it is metabolized by erythrocyte esterases.12
Channel selectivity and concurrent disease should be considered when prescribing these medications. For example, b1-selective agents are safer than nonselective agents for diabetic patients or cats with asthma. In patients with heart failure that are subjected to chronic increases in circulating catecholamine concentrations and increased sympathetic nervous system activity, b-adrenergic receptors are downregulated, and fewer receptors are available for b-blocker binding. However, many patients with compromised myocardial function rely on stimulated b-receptors to maintain a greater degree of myocardial contractility. Thus administration of even medium doses of a b-blocker can result in lethal decreases in contractility and heart rate.3
DIAGNOSIS OF OVERDOSE Clinical signs associated with toxicity due to calcium channel or b-blockers generally reflect an extension of the therapeutic effects of the drugs (Table 84-2).2,3,12 Distinctions among the various drug classes tend to disappear in overdose situations. The primary signs are negative inotropy and chronotropy leading to decreased cardiac output, hypotension, tissue hypoperfusion, and shock. In humans, most calcium channel and b-blocker overdoses are evident within 6 hours of ingestion, but clinical signs may be delayed when sustained-release preparations or sotalol are ingested.9 Although calcium channel and b-blocker overdoses often manifest similarly, subtle differences in the clinical picture may suggest poisoning with one class over another. Following calcium channel blocker toxicity, selectivity for cardiac versus vascular effects is decreased but not eliminated.13,14 Vasodilation, particularly associated with agents that have more pronounced effects on vascular smooth muscle (e.g., dihydropyridines), results in hypotension, decreased systemic
359
VIII INTOXICATIONS
360
vascular resistance, and shock. Distinctions among the various b-blocker classes tend to disappear in overdose situations.15 The most common electrocardiographic findings following significant calcium channel blocker ingestion are sinus bradycardia, AV block, and junctional rhythms.10,16 b-Blocker toxicity also causes bradycardia, but ventricular conduction defects tend to be more common in humans.17 Mild hyperkalemia may be observed with toxic levels of b-blockers, and hypocalcemia is reported occasionally in calcium channel blocker poisoning.9 Electrolyte disturbances may further lower the threshold for serious rhythm abnormalities. Hyperglycemia is a common finding with calcium channel blocker toxicity because insulin release is inhibited.6 Hypoglycemia rarely is encountered in b-blocker overdose in humans, despite decreased gluconeogenesis and glycogenolysis.9 Noncardiogenic pulmonary edema has been reported in association with calcium channel blockers and b-blockers.10,18 This is thought to be secondary to either precapillary vasodilation resulting in increased transcapillary hydrostatic pressure,19 or a secondary effect of massive sympathetic discharge.20 Dyspnea caused by bronchospasm rarely is reported, although it can occur in an asthmatic that has ingested a b2-receptor antagonist. In humans, overdose of highly lipid-soluble b-blockers such as propranolol frequently manifests as CNS depression and seizures.9 Seizures after ingestion of verapamil are rare but have been reported in animals16 and humans.11 Terminal events in both calcium channel and b-blocker toxicity include worsening of shock with multiple organ failure (myocardial infarction, mesenteric ischemia, acute renal failure, coma) and, ultimately, cardiac arrest.
THERAPY Asymptomatic Patients Decontamination GI decontamination should be performed in all asymptomatic animals that have accidentally ingested calcium channel or bblockers (see Chapter 77, Approach to Poisoning and Drug Overdose). If the ingestion occurred within the previous 2 hours and the patient is stable, emesis is recommended. In cases of massive ingestion or in patients with an altered level of consciousness, gastric lavage should be performed. Activated charcoal with a cathartic should be given to absorb and hasten the excretion of any remaining toxicant. The patient should be stable before receiving activated charcoal, and care should be taken to protect the airway and closely monitor hemodynamics.21 Two to four doses of activated charcoal should be administered if a sustained-release product was ingested.10 For the following 24 hours, serial electrocardiograms, blood pressure measurements, and blood glucose concentrations should be monitored. Elimination of calcium channel blockers and lipid-soluble b-blockers (e.g., propranolol) via extracorporeal removal procedures (e.g., hemodialysis, hemoperfusion) is ineffective because these compounds are highly protein bound and have large volumes of distribution. However, hemodialysis may remove water-soluble b-blockers (e.g., atenolol and esmolol).9
Symptomatic Patients Controlling the clinical signs of symptomatic animals is the first priority, emphasizing establishment of an airway and
providing adequate ventilatory and circulatory support. After venous access is obtained, hypotensive animals should receive intravenous fluids such as isotonic crystalloids or synthetic colloids for volume expansion (see Chapter 65, Shock Fluids and Fluid Challenge). Pharmacologic options for hypotensive patients include calcium, atropine, catecholamine pressors, glucagon, regular insulin and dextrose as needed, aminophylline, and digoxin.7,8,11,22-32 All of these drugs have been tested in dogs with cardiogenic shock induced by calcium channel or b-blocker overdose.7,8,23,28-32 No single agent has been consistently effective in critically ill patients with these toxicities; therefore a combination of drugs may be required. Affected patients should be treated and monitored continuously until clinical signs have resolved. Calcium Salts Intravenous administration of calcium is the initial treatment for calcium channel blocker and b-blocker overdose.22 Calcium gluconate is readily available and easily administered through a peripheral or central catheter. Exogenous calcium administration increases the extracellular calcium concentration and thus its availability to the cell, thereby stimulating the sarcoplasmic reticulum to release more calcium into the cytoplasm, which is then available for diverse cellular functions. Calcium administration may improve cardiac conduction, inotropy, and blood pressure.22,23 The optimal dosage of calcium is unclear. In experimental dogs, increasing the serum calcium by 1 to 2 mEq/L resulted in a reversal of the negative inotropic effects of verapamil, and even greater increases in serum calcium resulted in improvement of depressed AV conduction and sinus node function.22 Administration of a continuous calcium infusion titrated to a desirable heart rate and blood pressure has also been suggested.9,24 Calcium gluconate (10%) can be given at a dosage of 0.5 to 1.5 ml/kg slowly intravenously. Excessively rapid injection can cause hypotension, cardiac arrhythmias, and cardiac arrest. Continuous infusions of calcium gluconate are administered at dosages of 10 to 15 mg/kg/hr IV. Calcium chloride can also be used, however care should be taken during its administration because this preparation is more irritating than the other parenteral calcium salts.12 In general, an initial bolus dose of calcium is followed by a continuous infusion, with measurement of serum calcium at least twice daily. Serum calcium concentration should be maintained at normal levels, given the lack of evidence to support supraphysiologic calcium levels. Careful maintenance of patent intravenous access sites is very important to prevent injury secondary to extravasation of calcium solutions. Continuous electrocardiographic monitoring is recommended during administration. Although treatment with intravenous calcium salts is successful in many cases, other therapies should be added if the patient is refractory to calcium infusion. In patients with large overdoses, calcium alone may be ineffective because few if any channels are unblocked and calcium is unable to enter the cell to perform its functions. Parasympatholytic and Sympathomimetic Agents Atropine (0.02 to 0.04 mg/kg IV) is a vagolytic agent normally used to reverse bradycardia and AV blockade,12 but it is inconsistently effective in the treatment of both calcium channel blocker and b-blocker intoxications.11-13,25 Adrenergic agents such as dopamine, dobutamine, norepinephrine, epinephrine, phenylephrine, and isoproterenol may be required either alone or in combination to counter
Glucagon Glucagon is a polypeptide hormone26 that binds to receptor sites that are distinct from L-type calcium channels and adrenergic receptors. It then stimulates adenyl cyclase, which results in the formation of cAMP, promoting calcium influx and stimulating the release of calcium from the sarcoplasmic reticulum. Glucagon’s effects on adenyl cyclase also cause stimulation of the SA and AV nodes. As a result, glucagon has inotropic, chronotropic, and dromotropic properties. Several animal model studies have evaluated the efficacy of glucagon for calcium channel and b-blocker overdoses, and they have shown that it increases heart rate and cardiac output and reverses second-degree and third-degree AV blocks. However, it does not have any effect on mean arterial blood pressure and does not appear to have any effect on survival rate. Glucagon is given as an intravenous bolus of 0.15 mg/kg followed by a constant infusion of 0.05 to 0.1 mg/kg/hr titrated to effect.26 Hyperinsulinemia and Euglycemia In an unstressed state, myocytes oxidize free fatty acids for metabolic energy. However, in a state of shock, such as that associated with overdose of calcium channel blockers and b-blockers, myocytes use glucose for energy. Hypoinsulinemia prevents the uptake of glucose by myocytes, causing a loss of inotropy and shock. Calcium channel blockers inhibit insulin secretion, resulting in hyperglycemia and alterations in myocardial fatty acid oxidation.8 Similarly, blockade of b2-adrenergic receptors due to b-blocker toxicity impairs lipolysis, glycogenolysis, and insulin release.27 Insulin may be effective because it increases lactate oxidation while switching myocardial cell metabolism from fatty acids to carbohydrates during shock, thus restoring calcium fluxes, resulting in a positive inotropic effect.7,28,29 Therefore insulin therapy may improve contractility and increase peripheral vascular resistance by improving the uptake of carbohydrates and accelerating their oxidation by myocytes and smooth muscle cells.29,33 Lactic acidosis from toxicity-induced circulatory shock is partially a manifestation of poor tissue perfusion but is also due to mitochondrial dehydrogenase inhibition. In high concentrations, calcium channel blockers inhibit mitochondrial calcium entry into the sarcolemma and the mitochondrial membrane, which in turn can decrease pyruvate dehydrogenase activity. Pyruvate does not enter the Krebs cycle and
lactate accumulates, producing metabolic acidosis. Insulin can increase myocardial pyruvate dehydrogenase activity, enhancing lactate oxidation and reversing the acidosis.7 Regular insulin is given as an intravenous bolus of 1 IU/kg, followed by an infusion of 1 IU/kg/hr for the first hour, followed by 0.5 IU/kg/hr with concurrent dextrose administration as needed until the toxicity resolves. Depending on the severity of the overdose, resistance to insulin-mediated glucose clearance may be significant.27 Blood glucose should be monitored hourly or more frequently as needed, and dextrose supplemented as required to maintain euglycemia during the insulin infusion. Electrolyte abnormalities such as hypokalemia, hypophosphatemia, and hypomagnesemia may also occur, and their serum levels should be monitored every 12 to 24 hours and supplemented as required. Others The efficacy of many drugs for treating calcium channel blocker and b-blocker toxicity has been evaluated only in laboratory animal models and has not been validated in clinical trials. Nevertheless, some of these drugs are important to consider because they are readily available to most veterinarians. Aminophylline is a phosphodiesterase inhibitor that increases cAMP and therefore intracellular calcium translocation. It is capable of increasing heart rate and systemic arterial blood pressure in dogs with propranolol overdose.30 Digoxin may increase the effectiveness of calcium salt treatment in patients with calcium channel blocker overdose; however, its safety remains unknown in this setting. By inhibiting the sodium-potassium-adenosine triphosphatase pump, digoxin increases intracellular sodium, which is then exchanged for calcium by a process that is not blocked by a calcium channel antagonist.31,32 Mechanical Support Mechanical supportive measures may be necessary if pharmacologic therapy fails. Cardiac pacing, intraaortic balloon counterpulsation, and extracorporeal cardiopulmonary bypass have all been used in humans with calcium channel blocker overdose.9 Although many veterinary centers are able to perform cardiac pacing, more advanced procedures typically are not available.
Supportive Care Supportive care consists of airway protection and management, adequate ventilation, and hemodynamic monitoring. Endotracheal intubation may prevent pulmonary aspiration during vomiting or gastric instillation of charcoal, and may improve cardiac output and survival. A central venous catheter can provide a portal for pulmonary artery catheterization, for monitoring central venous pressure, to adjust fluid and to administer calcium salts (which are irritating to peripheral veins). A urinary catheter should be inserted to monitor urine production, and nutrition should be addressed as soon as possible.
CONCLUSION Flow of calcium across cell membranes is necessary for cardiac automaticity, conduction, and contraction, as well as maintenance of vascular tone and insulin secretion. Calcium channel blockers and b-blockers impede calcium flux
84 CALCIUM CHANNEL AND b-BLOCKER DRUG OVERDOSE
hypotension (see Chapter 176, Vasoactive Catecholamines). These agents act by stimulating a-adrenergic and b-adrenergic receptors. Stimulation of b-adrenergic receptors causes the formation of adenyl cyclase and subsequently cAMP. Direct a-adrenergic receptor agonists promote calcium release from the sarcoplasmic reticulum through receptor-operated calcium channels, bypassing L-channel blockade.5 The choice of agent depends on the hemodynamic picture of the patient and the responses to specific antidotes. b-Adrenergic receptor agonists such as dobutamine or isoproterenol would be logical choices when the toxicity primarily affects cardiac chronotropy and inotropy. Direct a-adrenergic receptor agonists may be a better choice if the toxicity is related primarily to decreased systemic vascular resistance. Combining a-adrenergic and b-adrenergic receptor agonists or using agents with both a-adrenergic and b-adrenergic effects may ameliorate both cardiac dysfunction and decreased systemic vascular resistance.
361
across cell membranes, thereby depressing myocardial contractility, slowing sinus and AV nodal conduction, and causing vasodilation. The prognosis depends on the quantity of drug ingested and the severity of signs at initial evaluation. Early decontamination and good supportive care can prevent serious hemodynamic failure. SUGGESTED FURTHER READING* Cooke KL, Snyder PS: Calcium channel blockers in veterinary medicine, J Vet Intern Med 13:444, 1995.
An excellent review of the pharmacology of calcium channel blockers and their therapeutic uses in veterinary medicine. Holder T: Calcium channel blocker toxicosis, Vet Med 95:912, 2000. Review of calcium channel blocker toxicosis in veterinary medicine using the American Society for the Prevention of Cruelty to Animals National Animal Poison Control database. Pion PD, Brown WA: Calcium blocking agents, Compend Cont Educ 17:691, 1995. An excellent review of the pharmacology of calcium channel blockers and their therapeutic uses in veterinary medicine *See the CD-ROM for a complete list of references.
Chapter 85 DIGOXIN OVERDOSE Meredith L. Daly,
VMD, DACVECC
Deborah C. Silverstein,
KEY POINTS Cardiac glycoside toxicity is not uncommon because of the narrow
362
therapeutic index, variability in patient sensitivities to the medications, and alterations in pharmacodynamics due to comorbid disease. Cardiac glycosides cause positive inotropy through inhibition of membrane-bound sodium and potassium-activated adenosine triphosphatase (Naþ,Kþ-ATPase). Noncardiac manifestations of digoxin overdose include gastrointestinal (GI) disturbances and neurologic abnormalities. Cardiac manifestations of digoxin overdose are extremely variable but classically include arrhythmias characterized by increased automaticity with or without conduction delays. Patients with alterations in serum electrolytes, renal disease, endocrine disease, increased sympathetic nervous system activity, or concurrent drug administration may be more susceptible to digoxin toxicosis. Treatment of digoxin toxicosis involves GI decontamination, recognition and treatment of life-threatening arrhythmias, normalization of serum electrolyte concentrations and, in severe cases, administration of Fab fragments of digoxin-specific antibodies.
INTRODUCTION Cardiac glycosides, the most common of which is digoxin, have an extremely narrow therapeutic index. In addition, there is marked variability in the sensitivity of individual patients to the toxic effects of cardiac glycosides. Therefore it is not uncommon for both human and veterinary patients to exhibit clinical evidence of toxicity. Although information on the incidence of toxicosis in veterinary patients is not available, it has been reported in up to 35% of digitalized human patients.1 Several mechanisms may contribute to toxicosis. Digoxin is excreted primarily by the kidneys. Renal insufficiency may
DVM, DACVECC
therefore increase serum concentrations. Congestive heart failure, renal disease, and hepatic disease may alter the metabolism or volume of distribution of digoxin, as can other medications used for cardiac or other concurrent diseases.2 Serum electrolyte abnormalities, particularly alterations in potassium, calcium, and magnesium, can potentiate cardiac glycoside toxicity.2 Although there is a clinical assay for serum digoxin concentrations, toxicity is still common because serum concentrations do not correlate directly with clinical evidence of toxicity. The most important aspect of digoxin toxicosis treatment is early recognition. Some patients with signs of mild toxicosis may respond to withdrawal of the medication. Therapy of the patient suffering from severe toxicosis includes, but is not limited to, gastrointestinal (GI) decontamination, fluid therapy, correction of serum electrolyte and acid-base abnormalities, treatment of congestive heart failure, antiarrhythmic or pacemaker therapy, and in severely affected animals, the administration of Fab fragments of digoxin-specific antibodies. The incidence and severity of digoxin toxicity has declined since the development of alternative drugs for treating supraventricular arrhythmias, the widespread availability of assays for serum digoxin levels, the identification of interactions between digoxin and other medications, and the increased vigilance of clinicians.1 Although the human literature still suggests a role for digoxin for patients with congestive heart failure,3 it is likely that digoxin use will wane as newer and safer drugs become available.
MECHANISM OF ACTION An understanding of digoxin’s mechanism of action is essential to comprehend the toxicologic features of this medication.
DVM, DACVECC
Lesley G, King,
KEY POINTS Close regulation of intracellular calcium is essential for the body to
accomplish many physiologic processes, including excitationcontraction coupling, impulse formation and conduction, and maintenance of vascular tone. Calcium channel blockers and b-blockers inhibit L-type voltagesensitive calcium channels. The main physiologic derangements caused by overdose of these medications are negative inotropy and chronotropy, leading to decreased cardiac output, hypotension, tissue hypoperfusion, and shock. No single pharmacologic agent has been consistently effective for critically ill patients with these toxicities. A combination of antidotes may be required until the clinical signs have resolved. The prognosis depends on the quantity of drug ingested and the severity of signs. Early aggressive decontamination and good supportive care can prevent serious hemodynamic failure.
INTRODUCTION Drugs classified as calcium channel and b-blockers frequently are prescribed for cardiovascular disease management. In humans, these drugs are effective in patients with hypertension, angina pectoris, cardiac arrhythmias, migraines, tremors, and bipolar disorder.1 In veterinary medicine, calcium channel and b-blockers are used to treat cardiac arrhythmias, hypertrophic cardiomyopathy, and hypertension.2-3 Calcium plays a role in many physiologic processes, including impulse formation and conduction, excitationcontraction coupling, and maintenance of vascular tone. Close regulation of intracellular calcium is essential to accomplish these cardiovascular functions.4 There are several types of calcium channels. Calcium channel blockers inhibit only the voltage-sensitive channels, which open in response to voltage changes across the membrane, for example during depolarization. There are three types of voltage-sensitive calcium channels, designated as neuronal (N-type), transient (T-type), and long lasting (L-type). The L-type channels are the most sensitive to the commercially available calcium channel blockers. b-Blockers inhibit the cardiac adrenergic system, modifying the L-type voltage-sensitive channels via a second messenger system. L-type channels are located in various tissues but are found in highest concentration in the atria, vascular smooth muscle, and skeletal muscle. L-type voltage-sensitive calcium channels are activated as the transmembrane potential of the cell becomes progressively less negative during the upstroke
MVB, MRCVS, DACVECC, DACVIM, DECVIM-CA
of the action potential (phase 0). They have a prolonged opening time and high conductance, therefore allowing large amounts of calcium to pass rapidly into the cell.5 Calcium channel and b-blockers interrupt calcium flux, leading to decreased intracellular calcium, depressing cardiovascular function.5 Although calcium channel and b-blockers have different mechanisms of action, the physiologic effects, clinical signs, and treatment of toxicity are similar.3
METHOD OF ACTION Calcium Channel Blockers Calcium channel blockers exert most of their effects on cardiac myocytes, pacemaker cells, and vascular smooth muscle. They are classified into three major groups based on their structure, including the phenylalkylamines (e.g., verapamil), the benzothiazepines (e.g., diltiazem), and the dihydropyridines (e.g., amlodipine). Structural differences among the classes are associated with distinct binding sites on the calcium channel, resulting in differing potencies and tissue affinities (Table 84-1). Their structural heterogeneity leads to functional heterogeneity with regard to their vasodilator potency and their cardiac inotropic, chronotropic, and dromotropic effects.1-3 Cardiac Effects The calcium ion is essential for impulse conductance through the cardiomyocytes. Pacemaker cells of the sinoatrial (SA) and atrioventricular (AV) nodes rely on the inward calcium flux through L-type and T-type channels to initiate a spontaneous diastolic depolarization (phase 4). Calcium channel blockers inhibit inward flow of calcium through the L-type channel, leading to slow SA activity, decreased conduction of impulses through the AV node, and therefore a decrease in heart rate and prolongation of the refractory period.5 The negative chronotropic effect occurs primarily with the phenylalkylamines and benzothiazepines. With some calcium channel blockers, this effect may be attenuated or even abolished because of reflex stimulation of the sympathetic nervous system.2 Calcium plays an important role during excitationcontraction coupling in cardiac and vascular smooth muscles. Within Purkinje cells and myocytes, opening of the L-type calcium channels in response to membrane depolarization increases calcium conductance (phase 2 of the action potential). This inward flow of calcium triggers the release of additional calcium into the cytoplasm from the sarcoplasmic
357
VIII INTOXICATIONS
Table 84-1 Generic Name
Expected Cardiovascular Effects of Calcium Channel Blocking Agents in Healthy Animals2,3,34 Trade Name
Chronotropic (HR)
Dromotropic (AV Conduction)
Inotropic (Strength)
Systemic Vascular Resistance
Coronary Resistance
0 or þ
þþ
þ
þ
þ
0 or þþ
þþ
0 or þ
þ
þ
0
0
0
þþ
þþ
0
0
0
þþ
þ
Phenylalkylamines Verapamil
Calan, Verelan, Isoptin
Benzothiazepines Diltiazem
Cardizem, Dilacor
Dihydropyridines Nifedipine
Procardia, Adalat
Amlodipine Norvasc
AV, Atrioventricular; HR, heart rate. Key: 0, no change; þ, mild to moderate decrease; þþ, moderate to marked decrease. This effect is rate dependent, being more pronounced at higher heart rates.
reticulum. Intracellular calcium binds to troponin, changing its conformation and allowing interaction between actin and myosin so that contraction can occur. By decreasing the magnitude and rate of rise of the intracellular calcium concentration, the calcium channel blockers decrease calcium release from the sarcoplasmic reticulum, causing a decrease in the force of contraction.2,5 This negative inotropic effect is seen most commonly with the phenylalkylamines and to a lesser extent with the benzothiazepines.2 Most of the calcium channel blockers have a negative inotropic effect at high doses.3 Vascular Effects 358
In vascular smooth muscle cells, opening of calcium channels increases the cytosolic calcium concentration. Calcium interacts with calmodulin, causing phosphorylation of the myosin light-chain and actin-myosin binding, resulting in smooth muscle contraction and vasoconstriction. Calcium channel blockers prevent the rise in intracellular calcium needed for formation of the calcium-calmodulin complex and thus cause dilation of systemic and coronary arteries and arterioles.5 At therapeutic concentrations, they have minimal effect on the venous system. The phenylalkylamines affect both vascular and cardiac tissue, the benzothiazepines have intermediate selectivity, and the dihydropyridines exert a greater effect on vascular tissue.2 Pancreatic Effects The b-cells on the pancreas also contain L-type calcium channels. Calcium influx into pancreatic islet cells via L-type channels is required for insulin release. High doses of calcium channel blockers may therefore cause serum glucose levels to rise while intracellular glucose stores fall. This is another mechanism by which calcium channel blocker overdose may impair cardiovascular function and lead to shock.6-8
b-Blockers There are two types of b-receptors. b1-Receptors are located primarily within the heart and adipose tissue. Stimulation results in increased heart rate, myocardial contractility, AV conduction velocity, and automaticity of subsidiary pacemakers. b2-Receptors are found primarily in bronchial and smooth muscles, where they produce relaxation.4 In human medicine, b-adrenergic blocking agents differ in their ability to block breceptor types.9 In veterinary medicine the primary drugs are propranolol (b1-receptor and b2-receptor blocker), atenolol
(specific b1-receptor blocker), esmolol (specific b1-receptor blocker), and sotalol (b1-receptor and b2-receptor blocker).3 Cardiac Effects Interactions between catecholamines and b-receptors in the cardiac cell membrane stimulate membrane-bound adenyl cyclase, which raises the intracellular concentration of cyclic adenosine monophosphate (cAMP). cAMP activates protein kinases that phosphorylate the L-type calcium channel, increasing myocellular calcium entry and the release of calcium from the sarcoplasmic reticulum. This calcium interacts with the myocardial contractile machinery, producing systole. Protein kinases phosphorylate a protein, phospholamban, that causes the sarcoplasmic reticulum to take up calcium more rapidly, enhancing relaxation (diastole).5 In general, b-adrenergic blockade decreases transmembrane calcium flow by decreasing cAMP synthesis, thereby decreasing atrial and ventricular contractility and decreasing the heart rate by slowing the spread of excitation through the AV node.3 Pulmonary, Pancreatic, Gastrointestinal, Vascular, and Renal Effects In the lung, stimulation of b2-receptors promotes bronchodilation, and their blockade leads to bronchospasm. In the pancreas, b2-receptors mediate insulin release, and their blockade leads to decrease in glycogenolysis, lipolysis, and gluconeogenesis. In the gastrointestinal (GI) tract and vascular smooth muscles, inhibition of b2-receptors results in contraction. b1-Receptors are also present in the kidney, where they mediate renin release.4
PHARMACOKINETICS Calcium Channel Blockers Calcium channel blockers are absorbed rapidly and almost completely from the GI tract but have extensive first-pass metabolism. Times to peak serum concentration are rapid: 20 to 45 minutes for immediate-release forms and 4 to 12 hours for sustained-release formulations and amlodipine besylate (which has a slower absorption rate) in dogs and cats.2 The onset of action varies with the formulation. An animal that bites into and swallows a sustained-release product can show signs within 5 minutes, but one that swallows it whole may not show signs for several hours and may have
Therapeutic Dosages Drugs
Dogs
Cats
0.1 to 5 mg/kg PO q8-12h 0.15 mg/kg IV over 2 minutes
—*
0.5 to 1.5 mg/kg PO q8h 0.25 mg/kg IV over 5 minutes
1.7 to 2.5 mg/kg PO q8h
Amlodipine besylate
0.05 to 0.25 mg/kg PO q24h
0.625 mg/cat PO q24h
Nifedipine
0.5 mg/kg PO q8h
—
Propranolol
If severe cardiac disease: 0.1 to 0.5 mg/kg PO q8h If normal myocardial function: 2 mg/kg PO q8h
2.5 to 10 mg PO q8h
Atenolol
6.25 to 50 mg PO q12h
6.25 mg PO q12h
Esmolol
Loading dose: 0.25 to 0.5 mg/kg IV followed by constant rate infusion: 10 to 200 mg/kg/min IV
Calcium Channel Blockers PHENYLALKYLAMINES
Verapamil hydrochloride BENZOTHIAZEPINES
Diltiazem hydrochloride DIHYDROPYRIDINES
b-Blockers
84 CALCIUM CHANNEL AND b-BLOCKER DRUG OVERDOSE
Table 84-2 Therapeutic Dosage Ranges of Calcium Channel Blockers and b-Blockers Most Commonly Used in Dogs and Cats2,3,12
IV, intravenous; PO, per os. *Verapamil is not recommended for use in cats; the safety of this drug is questionable in this species.
prolonged toxicity because of slower absorption.10 Tissue distribution is extensive in all classes. Calcium channel blockers are approximately 80% protein bound; therefore interaction with other protein-bound drugs may result in competition for binding sites. Additionally, animals with moderate to severe hypoproteinemia may develop higher blood concentrations. In humans, calcium channel blockers are metabolized in the liver by oxidative pathways, predominantly by cytochrome P450 CYP3A. Therefore their clearance will be decreased when hepatic function or blood flow is reduced.1 The phenylalkylamines and benzothiazepines can interact with many drugs because they are strong inhibitors of hepatic microsomal enzymes. Similarly, their elimination can be slowed by drugs that inhibit hepatic enzymes (e.g., cimetidine), potentially increasing their cardiovascular effects and producing toxicity.10,11 Elimination half-lives depend on the formulation (i.e., immediate versus sustained release) and in dogs and cats can vary from 2 to 30 hours. Excretion is primarily through urine and, to a lesser extent, bile and feces.2
b-Blockers The pharmacokinetics of b-blockers, although well established in humans, remain unclear in small animals. The more lipid-soluble compounds (e.g., propranolol) require hepatic biotransformation before secretion and can therefore accumulate if there is decreased hepatic blood flow or hepatic insufficiency. They also have a large volume of distribution and enter the central nervous system (CNS) faster and more easily. In contrast, the water-soluble compounds (atenolol) are excreted by the kidney and can accumulate if there is renal insufficiency. Esmolol is water soluble but does not accumulate in renal failure because it is metabolized by erythrocyte esterases.12
Channel selectivity and concurrent disease should be considered when prescribing these medications. For example, b1-selective agents are safer than nonselective agents for diabetic patients or cats with asthma. In patients with heart failure that are subjected to chronic increases in circulating catecholamine concentrations and increased sympathetic nervous system activity, b-adrenergic receptors are downregulated, and fewer receptors are available for b-blocker binding. However, many patients with compromised myocardial function rely on stimulated b-receptors to maintain a greater degree of myocardial contractility. Thus administration of even medium doses of a b-blocker can result in lethal decreases in contractility and heart rate.3
DIAGNOSIS OF OVERDOSE Clinical signs associated with toxicity due to calcium channel or b-blockers generally reflect an extension of the therapeutic effects of the drugs (Table 84-2).2,3,12 Distinctions among the various drug classes tend to disappear in overdose situations. The primary signs are negative inotropy and chronotropy leading to decreased cardiac output, hypotension, tissue hypoperfusion, and shock. In humans, most calcium channel and b-blocker overdoses are evident within 6 hours of ingestion, but clinical signs may be delayed when sustained-release preparations or sotalol are ingested.9 Although calcium channel and b-blocker overdoses often manifest similarly, subtle differences in the clinical picture may suggest poisoning with one class over another. Following calcium channel blocker toxicity, selectivity for cardiac versus vascular effects is decreased but not eliminated.13,14 Vasodilation, particularly associated with agents that have more pronounced effects on vascular smooth muscle (e.g., dihydropyridines), results in hypotension, decreased systemic
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VIII INTOXICATIONS
360
vascular resistance, and shock. Distinctions among the various b-blocker classes tend to disappear in overdose situations.15 The most common electrocardiographic findings following significant calcium channel blocker ingestion are sinus bradycardia, AV block, and junctional rhythms.10,16 b-Blocker toxicity also causes bradycardia, but ventricular conduction defects tend to be more common in humans.17 Mild hyperkalemia may be observed with toxic levels of b-blockers, and hypocalcemia is reported occasionally in calcium channel blocker poisoning.9 Electrolyte disturbances may further lower the threshold for serious rhythm abnormalities. Hyperglycemia is a common finding with calcium channel blocker toxicity because insulin release is inhibited.6 Hypoglycemia rarely is encountered in b-blocker overdose in humans, despite decreased gluconeogenesis and glycogenolysis.9 Noncardiogenic pulmonary edema has been reported in association with calcium channel blockers and b-blockers.10,18 This is thought to be secondary to either precapillary vasodilation resulting in increased transcapillary hydrostatic pressure,19 or a secondary effect of massive sympathetic discharge.20 Dyspnea caused by bronchospasm rarely is reported, although it can occur in an asthmatic that has ingested a b2-receptor antagonist. In humans, overdose of highly lipid-soluble b-blockers such as propranolol frequently manifests as CNS depression and seizures.9 Seizures after ingestion of verapamil are rare but have been reported in animals16 and humans.11 Terminal events in both calcium channel and b-blocker toxicity include worsening of shock with multiple organ failure (myocardial infarction, mesenteric ischemia, acute renal failure, coma) and, ultimately, cardiac arrest.
THERAPY Asymptomatic Patients Decontamination GI decontamination should be performed in all asymptomatic animals that have accidentally ingested calcium channel or bblockers (see Chapter 77, Approach to Poisoning and Drug Overdose). If the ingestion occurred within the previous 2 hours and the patient is stable, emesis is recommended. In cases of massive ingestion or in patients with an altered level of consciousness, gastric lavage should be performed. Activated charcoal with a cathartic should be given to absorb and hasten the excretion of any remaining toxicant. The patient should be stable before receiving activated charcoal, and care should be taken to protect the airway and closely monitor hemodynamics.21 Two to four doses of activated charcoal should be administered if a sustained-release product was ingested.10 For the following 24 hours, serial electrocardiograms, blood pressure measurements, and blood glucose concentrations should be monitored. Elimination of calcium channel blockers and lipid-soluble b-blockers (e.g., propranolol) via extracorporeal removal procedures (e.g., hemodialysis, hemoperfusion) is ineffective because these compounds are highly protein bound and have large volumes of distribution. However, hemodialysis may remove water-soluble b-blockers (e.g., atenolol and esmolol).9
Symptomatic Patients Controlling the clinical signs of symptomatic animals is the first priority, emphasizing establishment of an airway and
providing adequate ventilatory and circulatory support. After venous access is obtained, hypotensive animals should receive intravenous fluids such as isotonic crystalloids or synthetic colloids for volume expansion (see Chapter 65, Shock Fluids and Fluid Challenge). Pharmacologic options for hypotensive patients include calcium, atropine, catecholamine pressors, glucagon, regular insulin and dextrose as needed, aminophylline, and digoxin.7,8,11,22-32 All of these drugs have been tested in dogs with cardiogenic shock induced by calcium channel or b-blocker overdose.7,8,23,28-32 No single agent has been consistently effective in critically ill patients with these toxicities; therefore a combination of drugs may be required. Affected patients should be treated and monitored continuously until clinical signs have resolved. Calcium Salts Intravenous administration of calcium is the initial treatment for calcium channel blocker and b-blocker overdose.22 Calcium gluconate is readily available and easily administered through a peripheral or central catheter. Exogenous calcium administration increases the extracellular calcium concentration and thus its availability to the cell, thereby stimulating the sarcoplasmic reticulum to release more calcium into the cytoplasm, which is then available for diverse cellular functions. Calcium administration may improve cardiac conduction, inotropy, and blood pressure.22,23 The optimal dosage of calcium is unclear. In experimental dogs, increasing the serum calcium by 1 to 2 mEq/L resulted in a reversal of the negative inotropic effects of verapamil, and even greater increases in serum calcium resulted in improvement of depressed AV conduction and sinus node function.22 Administration of a continuous calcium infusion titrated to a desirable heart rate and blood pressure has also been suggested.9,24 Calcium gluconate (10%) can be given at a dosage of 0.5 to 1.5 ml/kg slowly intravenously. Excessively rapid injection can cause hypotension, cardiac arrhythmias, and cardiac arrest. Continuous infusions of calcium gluconate are administered at dosages of 10 to 15 mg/kg/hr IV. Calcium chloride can also be used, however care should be taken during its administration because this preparation is more irritating than the other parenteral calcium salts.12 In general, an initial bolus dose of calcium is followed by a continuous infusion, with measurement of serum calcium at least twice daily. Serum calcium concentration should be maintained at normal levels, given the lack of evidence to support supraphysiologic calcium levels. Careful maintenance of patent intravenous access sites is very important to prevent injury secondary to extravasation of calcium solutions. Continuous electrocardiographic monitoring is recommended during administration. Although treatment with intravenous calcium salts is successful in many cases, other therapies should be added if the patient is refractory to calcium infusion. In patients with large overdoses, calcium alone may be ineffective because few if any channels are unblocked and calcium is unable to enter the cell to perform its functions. Parasympatholytic and Sympathomimetic Agents Atropine (0.02 to 0.04 mg/kg IV) is a vagolytic agent normally used to reverse bradycardia and AV blockade,12 but it is inconsistently effective in the treatment of both calcium channel blocker and b-blocker intoxications.11-13,25 Adrenergic agents such as dopamine, dobutamine, norepinephrine, epinephrine, phenylephrine, and isoproterenol may be required either alone or in combination to counter
Glucagon Glucagon is a polypeptide hormone26 that binds to receptor sites that are distinct from L-type calcium channels and adrenergic receptors. It then stimulates adenyl cyclase, which results in the formation of cAMP, promoting calcium influx and stimulating the release of calcium from the sarcoplasmic reticulum. Glucagon’s effects on adenyl cyclase also cause stimulation of the SA and AV nodes. As a result, glucagon has inotropic, chronotropic, and dromotropic properties. Several animal model studies have evaluated the efficacy of glucagon for calcium channel and b-blocker overdoses, and they have shown that it increases heart rate and cardiac output and reverses second-degree and third-degree AV blocks. However, it does not have any effect on mean arterial blood pressure and does not appear to have any effect on survival rate. Glucagon is given as an intravenous bolus of 0.15 mg/kg followed by a constant infusion of 0.05 to 0.1 mg/kg/hr titrated to effect.26 Hyperinsulinemia and Euglycemia In an unstressed state, myocytes oxidize free fatty acids for metabolic energy. However, in a state of shock, such as that associated with overdose of calcium channel blockers and b-blockers, myocytes use glucose for energy. Hypoinsulinemia prevents the uptake of glucose by myocytes, causing a loss of inotropy and shock. Calcium channel blockers inhibit insulin secretion, resulting in hyperglycemia and alterations in myocardial fatty acid oxidation.8 Similarly, blockade of b2-adrenergic receptors due to b-blocker toxicity impairs lipolysis, glycogenolysis, and insulin release.27 Insulin may be effective because it increases lactate oxidation while switching myocardial cell metabolism from fatty acids to carbohydrates during shock, thus restoring calcium fluxes, resulting in a positive inotropic effect.7,28,29 Therefore insulin therapy may improve contractility and increase peripheral vascular resistance by improving the uptake of carbohydrates and accelerating their oxidation by myocytes and smooth muscle cells.29,33 Lactic acidosis from toxicity-induced circulatory shock is partially a manifestation of poor tissue perfusion but is also due to mitochondrial dehydrogenase inhibition. In high concentrations, calcium channel blockers inhibit mitochondrial calcium entry into the sarcolemma and the mitochondrial membrane, which in turn can decrease pyruvate dehydrogenase activity. Pyruvate does not enter the Krebs cycle and
lactate accumulates, producing metabolic acidosis. Insulin can increase myocardial pyruvate dehydrogenase activity, enhancing lactate oxidation and reversing the acidosis.7 Regular insulin is given as an intravenous bolus of 1 IU/kg, followed by an infusion of 1 IU/kg/hr for the first hour, followed by 0.5 IU/kg/hr with concurrent dextrose administration as needed until the toxicity resolves. Depending on the severity of the overdose, resistance to insulin-mediated glucose clearance may be significant.27 Blood glucose should be monitored hourly or more frequently as needed, and dextrose supplemented as required to maintain euglycemia during the insulin infusion. Electrolyte abnormalities such as hypokalemia, hypophosphatemia, and hypomagnesemia may also occur, and their serum levels should be monitored every 12 to 24 hours and supplemented as required. Others The efficacy of many drugs for treating calcium channel blocker and b-blocker toxicity has been evaluated only in laboratory animal models and has not been validated in clinical trials. Nevertheless, some of these drugs are important to consider because they are readily available to most veterinarians. Aminophylline is a phosphodiesterase inhibitor that increases cAMP and therefore intracellular calcium translocation. It is capable of increasing heart rate and systemic arterial blood pressure in dogs with propranolol overdose.30 Digoxin may increase the effectiveness of calcium salt treatment in patients with calcium channel blocker overdose; however, its safety remains unknown in this setting. By inhibiting the sodium-potassium-adenosine triphosphatase pump, digoxin increases intracellular sodium, which is then exchanged for calcium by a process that is not blocked by a calcium channel antagonist.31,32 Mechanical Support Mechanical supportive measures may be necessary if pharmacologic therapy fails. Cardiac pacing, intraaortic balloon counterpulsation, and extracorporeal cardiopulmonary bypass have all been used in humans with calcium channel blocker overdose.9 Although many veterinary centers are able to perform cardiac pacing, more advanced procedures typically are not available.
Supportive Care Supportive care consists of airway protection and management, adequate ventilation, and hemodynamic monitoring. Endotracheal intubation may prevent pulmonary aspiration during vomiting or gastric instillation of charcoal, and may improve cardiac output and survival. A central venous catheter can provide a portal for pulmonary artery catheterization, for monitoring central venous pressure, to adjust fluid and to administer calcium salts (which are irritating to peripheral veins). A urinary catheter should be inserted to monitor urine production, and nutrition should be addressed as soon as possible.
CONCLUSION Flow of calcium across cell membranes is necessary for cardiac automaticity, conduction, and contraction, as well as maintenance of vascular tone and insulin secretion. Calcium channel blockers and b-blockers impede calcium flux
84 CALCIUM CHANNEL AND b-BLOCKER DRUG OVERDOSE
hypotension (see Chapter 176, Vasoactive Catecholamines). These agents act by stimulating a-adrenergic and b-adrenergic receptors. Stimulation of b-adrenergic receptors causes the formation of adenyl cyclase and subsequently cAMP. Direct a-adrenergic receptor agonists promote calcium release from the sarcoplasmic reticulum through receptor-operated calcium channels, bypassing L-channel blockade.5 The choice of agent depends on the hemodynamic picture of the patient and the responses to specific antidotes. b-Adrenergic receptor agonists such as dobutamine or isoproterenol would be logical choices when the toxicity primarily affects cardiac chronotropy and inotropy. Direct a-adrenergic receptor agonists may be a better choice if the toxicity is related primarily to decreased systemic vascular resistance. Combining a-adrenergic and b-adrenergic receptor agonists or using agents with both a-adrenergic and b-adrenergic effects may ameliorate both cardiac dysfunction and decreased systemic vascular resistance.
361
across cell membranes, thereby depressing myocardial contractility, slowing sinus and AV nodal conduction, and causing vasodilation. The prognosis depends on the quantity of drug ingested and the severity of signs at initial evaluation. Early decontamination and good supportive care can prevent serious hemodynamic failure. SUGGESTED FURTHER READING* Cooke KL, Snyder PS: Calcium channel blockers in veterinary medicine, J Vet Intern Med 13:444, 1995.
An excellent review of the pharmacology of calcium channel blockers and their therapeutic uses in veterinary medicine. Holder T: Calcium channel blocker toxicosis, Vet Med 95:912, 2000. Review of calcium channel blocker toxicosis in veterinary medicine using the American Society for the Prevention of Cruelty to Animals National Animal Poison Control database. Pion PD, Brown WA: Calcium blocking agents, Compend Cont Educ 17:691, 1995. An excellent review of the pharmacology of calcium channel blockers and their therapeutic uses in veterinary medicine *See the CD-ROM for a complete list of references.
Chapter 85 DIGOXIN OVERDOSE Meredith L. Daly,
VMD, DACVECC
Deborah C. Silverstein,
KEY POINTS Cardiac glycoside toxicity is not uncommon because of the narrow
362
therapeutic index, variability in patient sensitivities to the medications, and alterations in pharmacodynamics due to comorbid disease. Cardiac glycosides cause positive inotropy through inhibition of membrane-bound sodium and potassium-activated adenosine triphosphatase (Naþ,Kþ-ATPase). Noncardiac manifestations of digoxin overdose include gastrointestinal (GI) disturbances and neurologic abnormalities. Cardiac manifestations of digoxin overdose are extremely variable but classically include arrhythmias characterized by increased automaticity with or without conduction delays. Patients with alterations in serum electrolytes, renal disease, endocrine disease, increased sympathetic nervous system activity, or concurrent drug administration may be more susceptible to digoxin toxicosis. Treatment of digoxin toxicosis involves GI decontamination, recognition and treatment of life-threatening arrhythmias, normalization of serum electrolyte concentrations and, in severe cases, administration of Fab fragments of digoxin-specific antibodies.
INTRODUCTION Cardiac glycosides, the most common of which is digoxin, have an extremely narrow therapeutic index. In addition, there is marked variability in the sensitivity of individual patients to the toxic effects of cardiac glycosides. Therefore it is not uncommon for both human and veterinary patients to exhibit clinical evidence of toxicity. Although information on the incidence of toxicosis in veterinary patients is not available, it has been reported in up to 35% of digitalized human patients.1 Several mechanisms may contribute to toxicosis. Digoxin is excreted primarily by the kidneys. Renal insufficiency may
DVM, DACVECC
therefore increase serum concentrations. Congestive heart failure, renal disease, and hepatic disease may alter the metabolism or volume of distribution of digoxin, as can other medications used for cardiac or other concurrent diseases.2 Serum electrolyte abnormalities, particularly alterations in potassium, calcium, and magnesium, can potentiate cardiac glycoside toxicity.2 Although there is a clinical assay for serum digoxin concentrations, toxicity is still common because serum concentrations do not correlate directly with clinical evidence of toxicity. The most important aspect of digoxin toxicosis treatment is early recognition. Some patients with signs of mild toxicosis may respond to withdrawal of the medication. Therapy of the patient suffering from severe toxicosis includes, but is not limited to, gastrointestinal (GI) decontamination, fluid therapy, correction of serum electrolyte and acid-base abnormalities, treatment of congestive heart failure, antiarrhythmic or pacemaker therapy, and in severely affected animals, the administration of Fab fragments of digoxin-specific antibodies. The incidence and severity of digoxin toxicity has declined since the development of alternative drugs for treating supraventricular arrhythmias, the widespread availability of assays for serum digoxin levels, the identification of interactions between digoxin and other medications, and the increased vigilance of clinicians.1 Although the human literature still suggests a role for digoxin for patients with congestive heart failure,3 it is likely that digoxin use will wane as newer and safer drugs become available.
MECHANISM OF ACTION An understanding of digoxin’s mechanism of action is essential to comprehend the toxicologic features of this medication.