BETA-BLOCKERS (TOXICOLOGY) - EXAM-ORIENTED REVIEW FOR EMERGENCY PHYSICIANS

Based on Tintinalli's Emergency Medicine, Chapter 194

KEY FACTS FOR EXAM

Beta-blockers = 8% of all drug-related fatalities reported to US Poison Control (2016); 2% of single-agent fatal exposures

1. PHARMACOLOGY & RECEPTOR SUBTYPES

Beta-Adrenergic Receptor Locations (Table 194-1)

2. PHARMACOLOGIC PROFILES (Table 194-2) - HIGH-YIELD

Key Properties to Remember:

• Most lipophilic (highest CNS penetration, worst CNS effects): Propranolol, Pindolol, Penbutolol, Timolol
• Most β1-selective: Nebivolol (+++) > Bisoprolol (++) > Metoprolol (++)
• Na-channel blockade (like quinidine/TCAs): Propranolol (++), Acebutolol (+), Oxprenolol (+)
• Partial agonist activity (ISA): Pindolol (++), Oxprenolol (++), Acebutolol (+) - less bradycardia at therapeutic use
• Sotalol is UNIQUE: Also a Vaughan-Williams Class III agent (blocks inward rectifier K⁺ channels) → QT prolongation + ventricular dysrhythmias (VT, VF, TdP)
• Carvedilol & Labetalol: Also α1-antagonists → exaggerated hypotension
• Esmolol: Shortest half-life (9 min) - useful for titration

3. CLINICAL FEATURES OF TOXICITY (Table 194-3)

Onset of Symptoms:

• Immediate-release: Peak effects within 1-4 hours (rarely delayed up to 6 hours)
• Sustained-release: Symptoms may be delayed >6 hours after ingestion
• Extended-release with co-ingestants (opioids, anticholinergics): Further delay in absorption

Clinical Manifestations:

• Hypotension
• Bradycardia (sinus node suppression or conduction abnormalities)
• Conduction delays and blocks (1st-degree AV block)
• Ventricular dysrhythmias (especially sotalol)
• Asystole
• Decreased contractility
• Wide-complex bradycardia (Na-channel blockers like propranolol - if QRS >100 ms, can worsen hypotension and shock)

• Depressed mental status
• Coma
• Psychosis
• Seizures
• Respiratory arrest
• More common with high-lipophilicity agents (propranolol)

• Bronchospasm (β2-receptor antagonism; both nonselective and high-dose cardioselective)

• Hypoglycemia (uncommon - euglycemia and hyperglycemia are actually more common)
• Hyperkalemia

• QT prolongation
• Premature ventricular contractions, bigeminy
• Ventricular tachycardia, VF, torsades de pointes

4. DIAGNOSIS

• Clinical diagnosis - based on history + exam + basic labs
• Drug levels: Not useful acutely (don't correlate with toxicity, not available in time)
• ECG is essential - look for: bradycardia, QRS widening (>100-120 ms), QT prolongation (sotalol), Brugada pattern (propranolol)
• Bedside cardiac US - assess contractility
• Labs: BMP (glucose, potassium), ABG (acid-base), renal function

Differentials - Toxicologic Causes of Bradycardia + Hypotension (Table 194-4):

Exam Pearl: Labetalol metabolites are structurally similar to amphetamine → can cause false-positive urine drug screen for amphetamine

5. TREATMENT

Goals of Resuscitation:

• Cardiac EF ≥50%
• QRS <120 ms
• HR >50-60 beats/min
• SBP >90-100 mmHg
• Urine output 1-2 mL/kg/hour
• Improved mentation

GI DECONTAMINATION:

• Activated charcoal: Give if within 1 hour of ingestion, airway intact
• Extended-release formulations: May have a second window for AC
• Gastric lavage: Consider for recent, large ingestions with airway protection
• NOT recommended: Ipecac, cathartic agents
• Whole-bowel irrigation: Can be considered for large extended-release ingestions

PHARMACOLOGIC TREATMENT ALGORITHM

HYPOTENSION
     ↓
Evaluate: ECG, cardiac US, or pulmonary artery catheter
     ↓
┌──────────────┬────────────────────┬──────────────┬─────────────┐
│ QRS >120 ms  │ ↓ Contractility    │ ↓ SVR        │ Bradycardia │
│              │                    │              │             │
│ Sodium       │ Glucagon           │ Vasopressors │ Glucagon    │
│ Bicarbonate  │ High-Dose Insulin  │              │ Adrenergic  │
│              │ Adrenergic agents  │              │ agents      │
│              │ Calcium salts      │              │ Cardiac     │
│              │                    │              │ pacing      │
└──────────────┴────────────────────┴──────────────┴─────────────┘

DRUG-SPECIFIC TREATMENTS:

A. GLUCAGON - First-Line Agent

• Mechanism: Activates myocardial adenylate cyclase independently of β-receptor → ↑ cAMP → positive inotropy + chronotropy
• Dose: IV bolus 3-10 mg (30-150 mcg/kg in children)
• If beneficial response seen → continuous infusion 1-5 mg/hr (20-70 mcg/kg/hr in children)
• Peak effect: 5-7 minutes; Duration: 10-15 minutes
• Adverse effects: Nausea, vomiting (give antiemetics first; check QTc before ondansetron); tachyphylaxis with prolonged use
• Caution: Intubate before glucagon if altered mental status (aspiration risk)
• Limitation: Quantity available at any hospital may be insufficient for a significant overdose

B. HIGH-DOSE INSULIN THERAPY (HDI) - aka Hyperinsulinemia-Euglycemia Therapy

• Mechanism: Acts as inotrope by facilitating myocardial glucose utilization (preferred energy substrate during stress vs. free fatty acids used normally)
• Superior to glucagon, epinephrine, and calcium in animal models for severe overdose
• Protocol (Table 194-5):
  1. Check serum glucose; if <200 mg/dL (<11 mmol/L): give 50 mL of 50% dextrose (children: 1 mL/kg of 25% dextrose)
  2. Administer regular insulin 1 unit/kg IV bolus
  3. Start insulin infusion at 1 unit/kg/hr with 10% dextrose at 200 mL/hr adult (5 mL/kg/hr pediatric)
  4. Titrate up to 10 units/kg/hr to achieve HR >50 + SBP >100 mmHg
  5. Monitor glucose every 15-20 minutes
  6. Maintain glucose 100-200 mg/dL (5.3-10.7 mmol/L)
  7. Monitor potassium; supplement if <2.8 mEq/L
  8. Maintain K⁺ between 2.8-3.2 mEq/L
• Onset: 15-45 minutes; may be delayed by several hours
• Duration of infusion: 9-49 hours reported in case series
• Adverse effects: Hypoglycemia (41% in case series), hypokalemia
• Note: Maximum dose not established; taper gradually when improving

C. ADRENERGIC RECEPTOR AGONISTS

• Norepinephrine, dopamine, epinephrine, isoproterenol
• Results variable even at supra-normal doses
• Best choices: Norepinephrine + epinephrine (chronotropic + vasopressor effects)
• Phenylephrine: vasopressor only (increases HR via reflex)
• Isoproterenol: ↑ HR but causes vasodilation (not ideal)
• Dobutamine: ↑ inotropy but worsens hypotension via vasodilation

D. SODIUM BICARBONATE

• Indication: QRS >120 ms (Na-channel blockade - propranolol, acebutolol)
• Dose: 2-3 mEq/kg rapid IV bolus over 1-2 minutes
• 70-kg adult: 140-210 mEq = 3-4 ampules of 8.4% NaHCO3 (50 mL each)
• Repeat boluses or infusion to maintain QRS <120 ms

E. CALCIUM

• Not routinely recommended; consider in refractory shock unresponsive to other therapies
• Calcium gluconate 10%: 0.6 mL/kg over 5-10 min → infusion 0.6-1.5 mL/kg/hr
• Calcium chloride 10%: 0.2 mL/kg over 5-10 min → infusion 0.2-0.5 mL/kg/hr
• CaCl2 = 3x more elemental calcium than calcium gluconate (give via central line - severe tissue injury with extravasation)
• Monitor ionized calcium every 30 min initially, then q2h; target 2x normal ionized Ca²⁺
• Adverse effects: Hypercalcemia, conduction blocks, worsening bradycardia

F. IV LIPID EMULSION (ILE) - "Fat Emulsion Therapy"

• Mechanism: "Lipid sink" - sequesters lipophilic drug away from target tissue; also supplies myocardium with free fatty acids + phospholipids
• Most effective for lipophilic agents: Propranolol, carvedilol (vs. less effective for metoprolol, atenolol)
• Dose: 20% lipid emulsion - 1.5 mL/kg bolus over 1 minute → infusion at 0.25 mL/kg/min
  • If BP still low: Repeat 1.5 mL/kg bolus → increase infusion to 0.5 mL/kg/min
  • Maximum: 10 mL/kg over first 30 minutes
• Adverse effects: Lipemia (interferes with labs), hypertriglyceridemia, pancreatitis, allergic reaction, ALI, acute renal failure, VTE, fat embolism, infection, cardiac arrest
• Reserve for: Refractory shock after other modalities have failed

G. PHOSPHODIESTERASE INHIBITORS (e.g., Milrinone)

• Mechanism: Inhibit breakdown of cAMP → ↑ intracellular Ca²⁺ → positive inotropy (without increasing myocardial O2 demand), no effect on HR
• No advantage over glucagon; use when glucagon unavailable
• Milrinone dose: Continuous IV infusion starting with 50 mcg/kg bolus → 0.375-0.75 mcg/kg/min infusion

H. ATROPINE

• Unlikely to be effective for beta-blocker-induced bradycardia/hypotension
• Its use is unlikely to cause harm - may be tried briefly but do not rely on it
• May be beneficial for co-ingestants with muscarinic effects

I. CARDIAC PACING (Transvenous/External)

• Consider for bradycardia refractory to medications
• Caveat: Electrical capture may not restore blood pressure (lack of intracellular Ca²⁺ for contraction)
• Most beneficial for sotalol-induced TdP

J. SOTALOL-SPECIFIC MANAGEMENT (in addition to above):

• Magnesium supplementation
• Lidocaine
• Cardiac overdrive pacing (for TdP/QT prolongation)

K. EXTRACORPOREAL OPTIONS:

• Hemodialysis: Useful for Acebutolol, Atenolol, Nadolol, Sotalol (low protein binding, water-soluble, small Vd)
• ECMO / Intra-aortic balloon pump: For cardiogenic shock refractory to pharmacologic therapy

6. DISPOSITION

EXAM HIGH-YIELD MEMORY POINTS

1. Glucagon = First-line for bradycardia/hypotension. Bypasses β-receptor. Start antiemetics first.
2. High-Dose Insulin = Most consistent inotrope. Use early, especially in severe overdose. Monitor glucose q15-20 min.
3. Propranolol = Worst actor: High lipophilicity (seizures, coma) + Na-channel blockade (wide QRS) + nonselective.
4. Sotalol = Unique: K-channel blocker → QT prolongation + TdP → needs magnesium + overdrive pacing.
5. QRS >120 ms → Sodium bicarbonate (treat Na-channel blockade).
6. Atenolol, Sotalol, Nadolol are dialyzable (water-soluble, low protein binding).
7. ILE is reserved for refractory lipophilic agent (propranolol, carvedilol) toxicity.
8. Labetalol → false-positive urine amphetamine screen.
9. Hypoglycemia is uncommon in beta-blocker toxicity; euglycemia/hyperglycemia are more common.
10. Immediate-release: safe to discharge if asymptomatic at 6 hours with normal vitals.
11. Pindolol, acebutolol (ISA) may present with tachycardia/hypertension, not bradycardia, at therapeutic doses.
12. Activated charcoal: only within 1 hour of ingestion, with intact airway.