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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.
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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
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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.
a) 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.
b) 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.
c) Glucagon bypasses β-receptors and acts directly on Gs to stimulate conversion of
ATP to cAMP.
d) Amrinone inhibits PDE to prevent the degradation of cAMP.
e) 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
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
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– Administer within 60 minutes of ingestion
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( Within 2 hours may prevent absorption of SR preparations)
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– Patient is cooperative with intact airway
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– No good evidence for repeat doses
• Consider gastric lavage
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– Consider time since ingestion
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– 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 βreceptor 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.
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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. 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.
THANKS