1. Epidemiology and Incidence

Cardiovascular agent overdoses account for a significant proportion of poisonings requiring intensive care unit admission. While prescribing patterns have shifted, β-blockers (BB), calcium-channel blockers (CCB), and tricyclic antidepressants (TCA) remain major sources of morbidity and mortality, with distinct demographic and regional trends.

1.1 Global and Regional Overdose Data

• β-Blockers: Account for approximately 5% of cardiovascular drug exposures, with propranolol being the most commonly implicated agent due to its high lipophilicity and membrane-stabilizing effects.
• Calcium-Channel Blockers: Exposures are rising, with over 6,000 single-agent reports annually in the United States. Clusters of severe poisonings are increasingly noted in Europe and Australasia.
• Tricyclic Antidepressants: While outpatient use has declined in high-income countries, TCAs remain a common and highly lethal agent in self-harm attempts, particularly in low- and middle-income regions.

1.2 Critical Care Demographics and Trends

Patient demographics and intent are key predictors of severity. Intentional ingestions, especially with CCBs, carry the highest fatality risk. Co-ingestion of multiple cardiotoxic agents, such as a BB and a CCB, can double the risk of refractory shock and life-threatening arrhythmias.

2. Mechanisms of Toxicity

The pathophysiology of overdose is a direct extension of each drug’s therapeutic mechanism. Blockade of key receptors and ion channels leads to predictable, yet often severe, hemodynamic collapse and arrhythmogenesis.

2.1 β-Blockers

• Mechanism: Competitive β1/β2 receptor antagonism decreases intracellular cyclic AMP (cAMP), leading to negative inotropy and chronotropy.
• Lipophilic Agents (e.g., propranolol): Also cause membrane stabilization (sodium channel blockade), which can widen the QRS complex and precipitate seizures.

2.2 Calcium-Channel Blockers

• Mechanism: Inhibition of L-type calcium channels in cardiac and smooth muscle cells reduces intracellular calcium influx, causing profound negative inotropy, chronotropy, and vasodilation.
• Metabolic Effect: Blockade of calcium channels on pancreatic β-cells impairs insulin release, leading to hyperglycemia. This starves the myocardium of its preferred energy substrate (glucose), creating a vicious cycle of energy failure and cardiac depression.

2.3 Tricyclic Antidepressants

• Mechanism: The primary driver of mortality is fast sodium channel blockade, which slows phase 0 of the cardiac action potential, prolonging the QRS duration and predisposing to ventricular arrhythmias.
• Other Effects: α1-adrenergic blockade causes vasodilation and hypotension, while anticholinergic effects contribute to tachycardia and delirium.

3. Impact of Chronic Comorbidities

Pre-existing cardiovascular and metabolic diseases significantly lower the patient’s ability to compensate for an overdose, intensifying toxicity and complicating management.

3.1 Cardiovascular Disease States

• Heart Failure: Reduced cardiac reserve magnifies the negative inotropic effects of BBs and CCBs, leading to earlier and more profound shock.
• Conduction System Disease: Patients with baseline bundle branch block or AV block are at high risk for developing high-degree or complete heart block. Transvenous pacing may be required at lower-than-usual toxicity thresholds.
• Ischemic Heart Disease: Coronary perfusion is highly dependent on diastolic blood pressure. The hypotension caused by these overdoses can precipitate myocardial ischemia, further worsening cardiac function.

3.2 Metabolic and Pharmacokinetic Factors

• Diabetes: An impaired autonomic response can mask early signs of toxicity. In CCB overdose, baseline insulin resistance is exacerbated.
• Renal Impairment: Clearance of hydrophilic β-blockers (e.g., atenolol, nadolol) is significantly prolonged, leading to a longer duration of toxicity.
• Hypoalbuminemia: Increases the free, active fraction of highly protein-bound drugs like verapamil and TCAs, leading to greater effect at a given total drug level.

4. Social Determinants of Health (SDOH)

Socioeconomic factors, medication access, and health literacy are critical, often overlooked, contributors to both the risk of overdose and the severity of outcomes.

4.1 Medication Access and Literacy

High co-pays or lack of insurance can lead to inconsistent medication use, creating a risk for iatrogenic overdose when a patient takes a “catch-up” dose. Limited health literacy can delay recognition of early signs of toxicity, causing patients to present later in their clinical course when they are more critically ill.

4.2 Socioeconomic Factors and Mitigation

Housing instability and lack of social support are well-established risk factors for nonadherence and intentional self-harm. Proactive mitigation strategies are crucial for prevention:

• Pharmacy-Led Outreach: Pharmacists can play a key role in medication reconciliation, adherence counseling, and identifying patients struggling with cost.
• Community Health Workers: Engaging community health workers can bridge gaps in care for vulnerable populations, reinforcing education and ensuring early detection of problems.
• Universal Screening: There is an ongoing debate about universal vs. targeted screening for SDOH-related risks in clinical settings. Proponents of universal screening argue it reduces stigma and captures at-risk individuals who might otherwise be missed.

5. Key Concepts and Clinical Decision Points

Effective management requires integrating epidemiologic risk factors with pathophysiologic principles to guide initial triage and intervention.

5.1 Integrating Epidemiology into Risk Assessment

• Combine agent class, estimated dose, intent (intentional vs. unintentional), patient age, and comorbidities to create a comprehensive risk profile.
• Rule of Thumb: Any intentional CCB ingestion warrants early consideration for ICU admission due to the high risk of delayed, profound, and difficult-to-treat shock.

5.2 Applying Pathophysiology to Initial Interventions

• QRS Widening Present? → Administer sodium bicarbonate immediately.
• Bradycardia from a β-Blocker? → Provide glucagon and prepare for pacing.
• Shock from a CCB? → Give IV calcium and start high-dose insulin euglycemia therapy (HIET).
• Persistent Hypotension Despite First-Line Therapy? → Escalate to vasopressors and consider lipid emulsion therapy for refractory cases, especially with lipophilic agents.