Toxicity of Cardiovascular Agents

Myocardial Cells
Smooth Muscle Cells
$\beta$-islet cells of the pancreas

Selectivity may be lost at supratherapeutic doses

Inhibition of L-type Ca channels results in:
• Decreased inotropy
• Decreased chronotropy/dromotropy
• Peripheral vasodilation
• Hyperglycemia

Hallmark symptoms: hypotension & bradycardia

Severe symptoms of conduction blockade
• Idioventricular rhythms
• AV conduction abnormalities & complete heart block

Cardiogenic shock may occur in patients even after asymptomatic presentation

Overdose with dihydropyridine agents often leads to reflex (baroreceptor) tachycardia if selectivity is not lost

CNS symptoms: fatigue, dizziness, lightheadedness

Respiratory symptoms: ARDS (severe poisoning)

Most of the toxicity of beta blocker overdose is at cardiac beta-adrenergic receptors
($\beta_1$>>$\beta_2$ ,
-In overdose, cardioselectivity is largely lost
-Peripheral vascular effects are less prominent in overdose

Beta blockers competitively antagonize beta-adrenergic receptors leading to
*conduction delays, decreased inotropy and chronotropy

Sotalol overdose cases have documented QT prolongation (K channel blockade)

• Hallmark symptoms: hypotension & bradycardia
-Some patients may be asymptomatic
• Reduced cardiac output
-Decreased inotropy, decreased chronotropy
• Depressed SA node function
-Decreased inotropy, decreased chronotropy
• Impaired AV conduction
-Prolonged PR, QRS, or QT intervals

• BB/CCB overdose are leading causes of poisoning fatalities, attempts to prevent absorption from the GI tract are recommended unless contraindicated

• Always important to evaluate airway!
• GI decontamination may cause nausea/vomiting
• Aspiration may be fatal with unprotected airway

• Activated charcoal, whole bowel irrigation recommended for BB/CCB overdose, OG lavage rarely performed

• IV crystalloids if hypotensive
• 10-20 mL/kg (repeat as needed)
• Dose with caution given risk for cardiogenic shock, limit in patients with CHF, ARDS, CKD

• Atropine if bradycardic (symptomatic)
• Increases HR and CO through blocking Ach effect from vagus
• Generally ineffective for severe poisonings
• 0.5-1mg IV q2-3 minutes, max 3mg
• Monitor GI motility in patients receiving GI decontamination

These measures are generally ineffective in severe poisonings

• Increases extracellular calcium concentration and transmembrane concentration gradient
• Reverses negative inotropy, impaired conduction, and hypotension
• Effect on BP is greater than effect on HR
• Effect often short-lived
• Potential concern if coingestion with digoxin (“Stone Heart Syndrome”)

• Ionized calcium levels q30min
• S/S of calcium toxicity (confusion & lethargy), hypercalcemia, hypophosphatemia

Endogenous hormone secreted by pancreatic $\alpha$ cells in response to hypoglycemia and catecholamines

• Produces positive inotropic and chronotropic effects

• Stimulates production of cAMP via Gs protein
• Independent of beta receptor stimulation

• Recommended for beta-blocker overdose (limited evidence), not recommended for calcium channel blocker overdose

• Hyperglycemia
• Hypokalemia
• Nausea and vomiting
• Tachyphylaxis

• Often administered once first-line therapies fail
• Indicated if patient progresses to cardiogenic shock despite initial therapies

• Can increase SVR and HR (therefore CO and BP)
• Increase myocardial oxygen demand

• Variable success in CCB and BB poisoning
• No single agent shown to be consistently effective/superior

Multiple Proposed Mechanisms
1. Increased intracellular glucose transport
• Stressed myocardium primarily uses glucose a preferred energy substrate
• Insulin increases rate of intracellular glucose transport increasing carbohydrate metabolism
2. Vascular dilatation
• Vasodilation of systemic, coronary, and pulmonary vasculature -> increased cardiac output
3. Increase inotropy
• Result of increased glucose transport, vascular dilation as well as possible improved calcium handling and increased coronary blood flow.

Treatment of choice for patients with significant poisoning
• Likely greater benefit for CCB rather than BB poisoning but recommended for significant cases of each.

Beneficial when myocardial dysfunction is present

Improves myocardial glucose utilization and consequent hemodynamic function

Electrolytes
• K, Mg, PO4 abnormalities are expected and should be monitored and corrected
• *Lower levels/replacement thresholds may be appropriate given intracellular shifts

Blood Glucose
• Monitoring q15-30 minutes until stable then q1-2h
• Titrate dextrose infusion to maintain BG between 100-250 mg/dL

• BP and contractility typically improve within 15-60 minutes

• Goals of HDIET
• Maintain organ perfusion
• MAP > 65 mmHg
• SBP >100 mmHg
• HR > 50 bpm

• Monitor clinical parameters
• Mental status, skin warmth, urine output, vital signs, lactate, pH, echocardiography

• Proposed mechanisms:
• Activation of ion channels
• Enhancement of intracellular metabolism
• Acting as a lipid sink to sequester lipid-soluble drugs

• May theoretically benefit highly lipophilic CCB and BB

• Concern that increasing lipid content of blood may increase absorption of oral lipophilic drugs

• Limited data with significant publication bias, considered last resort

The most severely poisoned patients may not respond to any pharmacologic treatment
Additional options: levosimendan, methylene blue

Cardiac pacing
Intra-aortic balloon counterpulsation
Extracorporeal membrane oxygenation (ECMO)
Cardiopulmonary bypass machines
Major adsorbent recirculating system (MARS)

• Direct effect:
• Increased inotropy (force)
• Increased automaticity (ease of contracting)

• Indirect effects:
• Decreased chronotropy (rate)
• Decreased dromotropy (rhythm)
• Decreased circulating norepinephrine and renin

• Congestive heart failure
• Improves contractility and slows ventricular rate to allow for maximal ventricular filling
• Improves cardiac output (CO = HR x SV)

• Atrial fibrillation
• Decreased chronotropy for rate control

Narrow therapeutic index 0.5-2 ng/mL
• Afib: 0.8-1.2 ng/mL
• CHF: 0.5-0.9 ng/mL

Excessive inhibition of Na-K ATPase pump increases intracellular Na which causes increased intracellular Ca
Increased Na and Ca in the cell results in an increase in resting membrane potential (phase 4)
This sensitizes cardiac myocytes, making it easier to initiate an action potential (phase 0)
Results in possibility for tachydysrhythmias & extrasystoles

• Reduced conduction through AV node (vagomimetic effect –increased vagal tone)
• AV nodal block (action potential does not pass from atria to ventricles)
• Increased PR interval on EKG (time from initiation of P wave to the beginning of the QRS complex)

Hyperkalemia
• Results from inhibition of Na-K-ATPase pump (less K going into
myocardium)
• More common in acute poisoning, but can occur in chronic
• Important prognostic implications in acute poisoning (K >5)

Hypokalemia
• Can occur in chronic toxicity (where serum K is often variable)

Hypomagnesemia, hypercalcemia, and hypo/hyperkalemia can augment toxicity of digoxin

Commonly involves PK and DDI
Absorption
• Can be increased with concomitant use of antibiotics (macrolides, tetracyclines)
• Gut bacteria can inactivate up to 40% of digoxin before it is absorbed

Elimination
• Can be reduced by drugs competing for the same elimination
mechanism (70% renal elimination)
• P-gp inhibitors also decrease elimination in the kidney
(amiodarone, quinidine, verapamil, diltiazem)

Renally compromised patients (AKI)
• Decrease in renal blood flow due to acute decompensated HF, shock
• Drug-induced: NSAIDs, ACE-I, ARBs, aminoglycosides

Hypothyroidism
• Decreased volume of distribution and renal clearance

Dosing errors
• Especially in pediatrics and unintentional ingestions in younger children

Properly obtain a digoxin and potassium level
• Interpret levels in conjunction with clinical condition of the patient

Digoxin level considerations
• Digoxin has biphasic distribution
• Takes ~8-12 hours to distribute from serum into tissues (70x higher concentration in tissues)
• Levels drawn within 6 hours of an oral dose or 4 hours of an IV dose may be falsely elevated.

Even appropriately timed digoxin levels do not always correlate well
with toxicity

• Supportive care (airway, breathing, circulation)
• Discontinue digoxin therapy
• Obtain and monitor vitals & EKG
• Obtain relevant lab values
• Decontamination
• Antidotal therapy

Digoxin is rapidly absorbed in the GI tract, however undergoes enterohepatic recirculation.

Activated charcoal may be used in acute poisoning (not chronic)
• Binds drug that is recirculated enterohepatically
• Prevents reabsorption from GI tract and reduces serum half-life
• Consider if antidotal therapy not available or renal impairment

Multidose activated charcoal is recommended to reduce enterohepatic recirculation

Dosing: 1 g/kg PO or NGT every 2-4 hours for up to 4 doses

Potassium
• Potassium abnormalities worsen digoxin toxicity and should be corrected.
• Correction of life-threatening/severe potassium deficiencies should precede antidotal therapy

Calcium
• Calcium has traditionally been considered contraindicated in digoxin
toxicity given concern for “stone heart syndrome”
• Increasing intracellular calcium may produce irreversible non-contractile
state due to increased calcium-troponin C binding.
• Case reports of harm have been published but larger studies have not
observed

Bradycardia
• Atropine antagonizes cardiac glycoside vagal activation, increasing heart rate
• May initially respond to atropine (0.5-1 mg q 5 minutes)
• Dopamine may be considered, monitor closely for rhythm disturbances

Hypotension
• Hydration with IV fluids

Digoxin-specific antibody fragments for life-threatening toxicity.

Digibind® (38 mg vial) and Digifab (40 mg vial)
• Interchangeable, derived from immunized sheep

Mechanism of action
• Digoxin has a higher binding affinity for DSFab than for Na-K ATPase
• Creates a concentration gradient which causes digoxin to diffuse out of cells which can then be bound and excreted

• Digoxin-related life-threatening dysrhythmias
• VT, VF, 2nd/3rd degree AV block, bradycardia resistant to atropine

• Serum potassium > 5 mEq/L in acute digoxin poisoning

• Elevation of digoxin level associated with dysrhythmias, significant GI symptoms, or altered mental status

• Digoxin level ≥ 15 ng/mL at any time

• Digoxin level ≥ 10 ng/mL at 6 hours post-ingestion

• Acute ingestion of 10 mg of digoxin (4 mg in child)

• Poisoning with non-digoxin cardioactive steroid