Calcium Channel and β-Blocker Drug Overdose

Chapter 84 Calcium Channel and β-Blocker Drug Overdose



Annie Malouin, DVM, DACVECC, Lesley G. King, MVB, MRCVS, DACVECC, DACVIM, DECVIM-CA



KEY POINTS



• Close regulation of intracellular calcium is essential for the body to accomplish many physiologic processes, including excitation-contraction coupling, impulse formation and conduction, and maintenance of vascular tone.

• Calcium channel blockers and β-blockers inhibit L-type voltage-sensitive 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 β-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 β-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, excitation-contraction 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. β-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 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 β-blockers interrupt calcium flux, leading to decreased intracellular calcium, depressing cardiovascular function.5 Although calcium channel and β-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



Table 84-1 Expected Cardiovascular Effects of Calcium Channel Blocking Agents in Healthy Animals2,3,34

image


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 excitation-contraction 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 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


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 β-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



β-Blockers


There are two types of β-receptors. β1-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. β2-Receptors are found primarily in bronchial and smooth muscles, where they produce relaxation.4 In human medicine, β-adrenergic blocking agents differ in their ability to block β-receptor types.9 In veterinary medicine the primary drugs are propranolol (β1-receptor and β2-receptor blocker), atenolol (specific β1-receptor blocker), esmolol (specific β1-receptor blocker), and sotalol (β1-receptor and β2-receptor blocker).3



Cardiac Effects


Interactions between catecholamines and β-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, β-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 β2-receptors promotes bronchodilation, and their blockade leads to bronchospasm. In the pancreas, β2-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 β2-receptors results in contraction. β1-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 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

Related posts:

  1. Deteriorating Mental Status
  2. Hyperthermia and Fever
  3. Ventilator-Associated Lung Injury
  4. Allergic Airway Disease in Dogs and Cats and Feline Bronchopulmonary Disease

Stay updated, free articles. Join our Telegram channel
Tags:
Sep 10, 2016 | Posted by in SMALL ANIMAL | Comments Off on Calcium Channel and β-Blocker Drug Overdose

Full access? Get Clinical Tree
Get Clinical Tree app for offline access