BETA- BLOCKERS & CALCIUM CHANNEL BLOCKER TOXICITY Dr. ASHUTOSH GARG Assoc. consultant Max Super Speciality Hospital Patparganj, New Delhi

2004 Toxic Exposure Surveillance System (TESS) report - 3% (n = 74,145) of the total exposures due to cardiovascular medications. cardiovascular drugs the fifth leading cause of death in the TESS database. CCBs and β-blockers accounted for 37% of these exposures and the majority of cases resulting in death.

Beta-blocker pharmacology β-1 - regulate myocardial tissue and affect the rate of contraction via impulse conduction. β-2 - regulate smooth muscle tone and influence vascular and bronchiolar relaxation. β-3 - primarily affect lypolysis and may have effects on cardiac inotropy.

Some β-blockers may antagonize cardiac sodium channels, producing quinidine-like effects that will increase toxicity in overdose. β – blockers with Membrane stabilizing activity (MSA) (eg, propranolol, acebutolol) inhibit myocardial fast sodium channels, which can result in a widened QRS interval and may potentiate other dysrhythmias β - blockers with Intrinsic sympathomimetic activity (ISA) shows partial agonist effect at the beta receptor site, resulting in less bradycardia and hypotension. The protective effects of ISA do not completely prevent cardiovascular toxicity following overdose. Highly lipid soluble agents such as propranolol cross the BBB and can result in unwanted CNS effects.

CCB pharmacology Voltage-gated calcium channels are found in myocardial cells, smooth muscle cells and β-islet cells of the pancreas. CCBs prevent the opening of these voltage-gated calcium channels and reduce calcium entry into cells during phase 2 of an action potential. CCBs exhibit different selectivity for cardiac vs vascular smooth muscle cell channels.

In myocardial tissue – Negative inotropy (contractility) chronotropy ( rate), and dromotropy (conduction velocity). In vascular smooth muscle – CCBs prevent arterial contraction. Reduced afterload and systemic blood pressure. As DHPs-type CCBs only act peripherally, the vasodilation they cause may induce a compensatory increase in the heart rate. Within the pancreas, calcium channel antagonism results in decreased insulin secretion.

BETA BLOCKER & CCB OVERDOSE In an overdose situation, receptor selectivity is lost, and effects not normally seen at therapeutic doses can occur. In overdose, β-blockers and CCBs often have similar presentation and there is much overlap in treatment. Cardiotoxicity characterized by Hypotension & Bradycardia . It is important to understand the different features of such poisonings by class and specific agents.

Features specific to beta blocker overdose Excessive blockade of the β-receptors - bradycardia and hypotension. G protein responsible for converting ATP to cAMP is disabled, which results in less cytosolic calcium being available As β-selectivity is lost in overdose, even “β1-selective” agents can block β2 & β3-receptors and bring about bronchospasm and a reduction in inotropy. Lipophilicity is a good predictor of CNS depression in β-blocker overdose. Beta-blockers, such as atenolol, that have poor lipid solubility generally will not directly produce sedation.

Features specific to CCB overdose Cardiovascular toxicity hypotension conduction disturbances - sinus bradycardia & varying degrees of AV block. Hyperglycemia is a common finding in cases of CCB poisoning that is not seen with therapeutic dosing. At high doses, CCBs cause a significant decrease in insulin release by blocking calcium influx into pancreatic islet cells. This lack of circulating insulin decreases cardiac carbohydrate metabolism by preventing glucose uptake and use by cardiac muscle.

This results in a lack of fuel for aerobic energy production, causing a shift to fatty acid oxidation within the cells. Impaired energy production coupled with decreased entry of calcium into the cell results in negative inotropy and chronotropy. Poor pumping by cardiac tissue and peripheral vasodilation result in profound shock. Metabolic acidosis then develops systemically because of the resulting decrease in tissue perfusion. Similarly, CNS effects, including drowsiness, confusion, agitation, and seizures, are likely to occur as less oxygen is delivered to the brain.

Calcium enters open voltage-sensitive calcium channels to promote the release of calcium from the sarcoplasmic reticulum. The released calcium combines with troponin to cause muscle contraction via actin and myosin fi bers. EPI binds to β-receptors (β) that are not occupied by a BB. Stimulation of the receptors, which are coupled to a G protein (Gs), brings about the activation of AC. AC catalyzes the conversion of ATP to cAMP, which activates protein kinase A (PKA), which promotes the opening of dormant calcium channels, enhances release of calcium from the sarcoplasmic reticulum, and facilitates release of calcium by troponin during diastole. Therapies that promote cAMP formation generally have transient eff ects in CCB overdose due to the myocyte running out of carbohydrates. Glucagon bypasses β-receptors and acts directly on Gs to stimulate conversion of ATP to cAMP. Amrinone inhibits PDE to prevent the degradation of cAMP. Insulin promotes the uptake and use of carbohydrates as an energy source. It also promotes antiinfl ammatory eff ects that may correct problems caused by ineffi cient energy production. The associated infl ux of potassium may also provide benefi t by prolonging repolarization and allowing calcium channels to remain open longer.

TREATMENT OF COMBINED BETA BLOCKER & CCB POISONING Determining an exact toxic dose for a given individual is difficult because of the variability in patient-specific factors such as age, genetics, health status, and other recently ingested substances. Elapsed time since ingestion Extended-release formulations are common in both classes and have the potential for prolonged toxicity. Also, crushing or chewing these preparations may disrupt the tablet’s release mechanisms and result in a larger amount being available for initial absorption.

ABC’s • Activated charcoal (1 gm/kg) if appropriate – Administer within 60 minutes of ingestion ( Within 2 hours may prevent absorption of SR preparations) – Patient is cooperative with intact airway – No good evidence for repeat doses • Consider gastric lavage – Consider time since ingestion – Benefit outweigh risk? • Consider whole bowel irrigation irrigation with polyethylene glycol in a balanced electrolyte solution for sustained release preparations

EKG Electrolytes BUN/Cr Digoxin level if concomitant toxicity suspected ABG Lactic acid Echocardiogram CXR CT Head w/ altered mental status

I.V. fluids (10–20 mL/kg as a bolus dose) should be used as first-line therapy for patients who develop hypotension. Atropine sulfate 0.5–1 mg i.v.(upto 3 mg) is usually the first-line agent for symptomatic bradycardia. Unfortunately, Surveys have indicated that many hospitals stock a limited variety of antidotes in insufficient quantities. At a minimum, enough stock to treat one patient for 24 hours (50 mg glucagon) should be available.

Antidotes for β-blockers β-agonists, glucagon, and phosphodiesterase inhibitors. Glucagon is generally recognized as first-line therapy. Glucagon is a hormone secreted by the α2 cells of the pancreatic islets of Langerhans. It activate adenylate cyclase in cardiac tissue by directly stimulating a G protein on the β-receptor complex . High-dose glucagon is recommended for cardiotoxicity produced by β-blocker poisoning.

Antidotes for CCBs Calcium, Glucagon, adrenergic drugs (dopamine, norepinephrine, epinephrine), and amrinone. Unfortunately, these agents do not consistently improve hemodynamic parameters or ensure survival in severely intoxicated patients. Vasopressin has been suggested as a potential antidote, but it worsened the cardiac index and failed to improve the MAP in a dog model of verapamil-induced shock. A more promising antidote is high-dose insulin.

Calcium - Theoretically useful – Increases inotropy – Improves BP by increasing stroke volume – Little effect on conduction blocks, heart rate and vascular resistance – Calcium gluconate thought to be safest – CaCl has 3 times more Ca++ than calcium gluconate • 13.6 mEq vs 4.5 mEq in 10% solution – Lam et.al. “Continuous Calcium Chloride Infusion for Massive Nifedipine Overdose”, Chest, 2001 • case report showing CaCl improved BP after calcium gluconate proved ineffective

Bolus 10-20 mL 10% CaCl or 30-60 mL 10% calcium gluconate over 5-10 minutes in adults - Drip 0.2-0.5 mL/kg/hr 10% CaCl or 0.6-1.5 mL/kg/hr calcium gluconate • Do not exceed Ca++ level of 14 mg/dL or twice normal levels of ionized Ca++ • Use central line for CaCl infusion secondary to tissue necrosis • Watch for arrhythmias with rapid infusion Withhold if suspected concomitant digoxin toxicity! – Give Digoxin immune fab before administering calcium

Adrenergic drugs

Epinephrine ( 1-20 μg/kg/min) improves CO and BP – Use with verapamil and diltiazem toxicity • Norepinephrine (2-30 μg/kg/min) and phenylephrine enhance Ca++ influx into Ca++ channels of peripheral vascular smooth muscle – Use with dihydropyridine toxicity • Isoproterenol and dobutamine have β2 effects promoting vasodilation – Add another vasopressor

GLUCAGON Inotropic, chronotropic and dromotropic effects - Stimulates adenyl cyclase, increasing cAMP which causes release of intracellular Ca++ from SR and increases SA and AV nodal activity - Independent of β-adrenergic system - May cause nausea and vomiting – Give 3-10 mg IV • May start with IV boluses of 0.05mg/kg or 3-5 mg over 1-2 min may be repeated every 10 min or may by started infusion @1-5 mg/hr ( dilute in D5).

High Dose Insulin with Dextrose & potassium (HDIDK) THERAPY OR Hyperinsulinemia Euglycemia therapy (HIE) More common over past few years. Reported to improve outcome in both beta blocker as well as CCB poisoning. CCB’s block calcium-mediated insulin release from pancreatic β-islet cells necessary for myocardial cells to use glucose. There are several studies using verapamil in a canine model that indicate that HDIDK is likely to be an effective therapy through enhanced cardiac carbohydrate metabolism and direct inotropic effects.

The initial benefits seen with glucagon and epinephrine are lost after the myocardial cells switch from aerobic to anaerobic metabolism, resulting in acidosis and free radical formation. HDIDK should be considered if there is an inadequate response to fluid resuscitation. It should be administered with calcium and epinephrine.

Before initiation of insulin therapy, check BG & S.K+. If they are <200 mg/dL and <2.5 meq/L, respectively, then dextrose (adults, 50 mL of 50% dextrose injection) and potassium chloride (40 meq orally or i.v.) should be administered. Regular insulin is administered as a 1-unit/ kg bolus dose, followed by 0.5–1.0 unit/kg/hr adjusted to clinical response. Total insulin requirements for 24 hours of therapy for one adult patient are approximately 1500 units of regular insulin.

The goal of therapy in adults is a SBP > 100 mm Hg and a HR > 50 beats/min. Evidence of good organ perfusion (improved mentation or urine output) Adverse effects of insulin infusion - hypoglycemia & hypokalemia. BG monitoring every 20 minutes for the first hour. Then hourly along with S. K+. Infusions of dextrose should be started with the insulin bolus dose to maintain euglycemia. The insulin infusion may be tapered off once signs of cardiotoxicity begin to resolve.

- 7 patients with CCB overdose - 7 patients with CCB overdose. 3/7 received 50 mL D50 followed by a loading dose of 1 U/kg IV short acting insulin – All received insulin maintenance infusion of 0.5-2.0 units/kg/hour and 5- 10% dextrose infusions – All received fluids, calcium and inotropes – Within first hour of HIE therapy pts. who received loading dose insulin had increase of SBP 10-20 mmHg while those who did not receive a loading dose had no increase in SBP – Clinically insignificant cases of hypoglycemia in 1/7 pts and hypokalemia in 2/7 patients, but not within first 24 hours – 6 pts. survived

Databases were searched for the years 1975-2010 . MECHANISMS OF HIGH-DOSE INSULIN BENEFIT - increased inotropy, increased intracellular glucose transport, and vascular dilatation. EFFICACY OF HIGH-DOSE INSULIN. Animal models have shown high-dose insulin to be superior to calcium, glucagon, epinephrine, and vasopressin in terms of survival. Currently, there are no published controlled clinical trials in humans. HIGH-DOSE INSULIN TREATMENT PROTOCOLS. insulin doses were cautiously initiated at 0.5 U/kg bolus followed by a 0.5-1 U/kg/h continuous infusion due to concern for hypoglycemia and electrolyte imbalances. With clinical experience and the publication of animal studies, high-dose insulin dosing increased to 1 U/kg insulin bolus followed by a 1-10 U/kg/h continuous infusion. CONCLUSIONS. High-dose insulin (1-10 U/kg/hour) should be considered initial therapy in these poisonings.

Haemodialysis Hemodialysis - useful in low lipid soluble & low protein binding beta blockers. Atenolol is < 5% protein bound so dialyzable along with nadolol, sotalol & acebutalol. Consider hemodialysis only when glucagon & other pharmacotherapy fails. CCB are highly protein bound so hemodialysis not useful.

Lipid Emulsion Therapy – Theories of effect • Forms a “lipid sink” around lipophilic drug molecules making them ineffective • Fatty acids from the emulsion provide the myocardium with an energy source – May be some benefit with verapamil toxicity • IV bolus 1-1.5 mL/kg of 20% lipid emulsion solution over 1 minute – May be repeated every 3-5 minutes in cases of cardiac arrest with no response • Infusion of 0.25-0.5 mL/kg/minute until hemodynamic recovery

Sodium bicarbonate may be useful for acidemia and wide QRS – Increasing pH may reverse impaired contractility • Rescue therpies - – Transcutaneous or transvenous pacing If HR < 40. Electrical capture is not always successful & if capture does occur BP is not always stored. – IABP – Cardiopulmonary bypass – ECMO – Plasmapharesis

TAKE HOME MESSAGE Poisoning by β-blockers or CCBs usually produces hypotension and bradycardia, which may be refractory to standard resuscitation measures. For cases of β-blocker poisoning where symptomatic bradycardia and hypotension are present, high-dose glucagon is considered the first-line antidote. For cases of CCB poisoning where cardiotoxicity is evident, a combination of calcium and epinephrine should be used initially, reserving HDIDK for refractory cases.

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