Cardiovascular Drug Toxicity

• Cardiovascular drug toxic effects can arise from overdose, drug interactions, or patient susceptibility.
• Cardiovascular drug toxicity can be life-threatening, requiring prompt detection and management.
• Understanding toxicokinetics, toxicodynamics, and antidotes is essential for effective cardiovascular drug toxicity management.

General Mechanisms of Cardiovascular Drug Toxicity

• Direct cardiac toxicity can manifest as bradycardia and AV block, which can be induced by beta-blockers, calcium channel blockers (CCBs), and digoxin.
• Digoxin can cause ventricular arrhythmias.
• Beta-blockers and CCBs can cause negative inotropy.
• Vascular toxicity and hypotension can manifest as severe hypotension and shock, which can be induced by nitrates, alpha-blockers, ACEIs/ARBs, and CCBs.
• Nitrates, alpha-blockers, and CCBs can cause reflex tachycardia.
• Electrolyte disturbances, such as hyperkalemia, can be caused by digoxin (acute toxicity) and potassium-sparing diuretics like spironolactone.
• Hypokalemia increases the risk of digoxin toxicity and may occur with loop and thiazide diuretics.
• CNS toxicity can manifest as seizures and hallucinations, seen with lipophilic beta-blockers like propranolol and lidocaine (Class Ib Antiarrhythmic).
• Clonidine can cause sedation and respiratory depression.

Toxicology of Antihypertensive Drugs: Methyldopa

• Methyldopa affects centrally acting agents and may cause hemolytic anemia, hepatitis, pancreatitis, or myocarditis.
• May cause headache, drowsiness, depression, edema, nasal stuffiness, nightmares, sexual dysfunction, gynecomastia, or galactorrhea.
• Can lead to hypothermia, dry mouth, nausea, vomiting, hypotension, dizziness, weakness, lethargy, coma, bradycardia, paresthesias, and headache.
• Treatment includes ICU admission, monitoring for cardiovascular complications, isotonic fluid infusion, and Trendelenburg positioning for hypotension.
• Dopamine or noradrenaline for persistant hypotension.
• Atropine can treat bradycardia
• Hemodialysis is a potential treatment for methyldopa overdose.

Toxicology of Antihypertensive Drugs: Alpha Adrenergic Antagonists

• Adverse effects of Doxazocin, parazocin, and terazocin, include the first-dose phenomenon, dizziness, tachycardia, and palpitations.
• Clinical toxic features include hypotension and reflex tachycardia as common manifestations.
• Treatment includes administration of IV fluid boluses and vasopressors like dopamine.

Toxicology of Antihypertensive Drugs: Vasodilators

• Adverse effects of hydralazine include headache, dizziness, lacrimation, blurred vision, edema of the eyelids, nausea, flushing, hypotension, palpitations, and tachycardia.
• Hydralazine can induce Lupus-like syndrome, glomerulonephritis, and peripheral neuropathy.
• Treatment consists of IV fluid boluses, peripherally acting vasopressors like noradrenaline.
• Calcium channel blockers or beta blockers may be considered for persistent tachycardia.
• Peripheral neuropathies can be corrected with pyridoxine.

Toxicology of Antihypertensive Drugs: Angiotensin Converting Enzyme Inhibitors (ACEIs)

• ACE Inhibitors cause skin rash, chronic cough, bronchospasm, neutropenia, hyperkalemia, hypotension, proteinuria, renal insufficiency, and angioneurotic edema.
• Pancreatitis is linked to lisinopril and enalapril, while hepatotoxicity is associated with captopril.
• ACE inhibitors are teratogenic and cause fetal anomalies and should not be used during pregnancy.
• In ACEI toxicity, angioneurotic edema occurs in about 0.1% of patients.
• Dermatitis incidence ranges from 6.1 to 10.9% and depends on the dose.
• Dyspnea, chest pain, and airway compromise may occur due to elevated bradykinin levels.
• Treatment includes airway maintenance and antiallergic drugs.
• Cough from ACEI toxicity responds to sodium cromoglycate.
• Drug interactions with ACE Inhibitors:
  • Hypoglycemia can occur with simultaneous use of ACE inhibitors and insulin or oral hypoglycemics.
  • Hyperkalemia may result from combining ACE inhibitors with potassium-sparing diuretics.
  • Renal insufficiency can occur when ACE inhibitors are combined with NSAIDs.

Clinical Toxic Features: ACE Inhibitors

• Patients often remain asymptomatic in ACE inhibitor overdoses.
• Hypotension, hyperkalemia, and renal failure may occur.
• Fatalities are rare.
• Treatment involves monitoring serum creatinine for hypotension or renal issues.
• Administer activated charcoal.
• Isotonic fluid infusions in Trendelenburg position for hypotension.
• Administer dopamine or noradrenaline if hypotension persists.
• Angiotensin II infusion reverses hypotension unresponsive to volume and pressor infusions.
• Hemodialysis may be beneficial.

Angiotensin II Receptor Antagonists

• Adverse effects include dizziness, insomnia, headache, muscle cramps, and leg pain.
• May also cause hyperkalemia, oliguria, and azotaemia in severe CHF or renal artery stenosis.
• Reversible hepatotoxicity and angioedema are also possible.
• Angiotensin II receptor antagonists should be stopped with detection of pregnancy
• Clinical toxic features include hypotension and hyperkalemia.
• Treatment includes symptomatic and supportive measures, monitoring renal and liver function, and frequent monitoring of blood pressure and heart rate.
• Hemodialysis is ineffective due to protein binding.

Beta Adrenergic Antagonists

• Adverse effects include bradycardia, dizziness, fatigue, diarrhea, sleepiness, confusion, depression, and headache.
• CNS effects are more common with lipid-soluble agents like propranolol and metoprolol in therapeutic doses, while all agents cause CNS depression in overdose.
• Therapeutic doses may cause bronchospasm, AV blocks, ventricular arrhythmias, and cardiac arrest.
• Abruptly stopping beta-blockers after chronic use can cause rebound hypertension, tachycardia, palpitations, tremor, headache, and sweating.
• Treatment consists of Glucagon, which has antidotal action and produces positive chronotropic and inotropic cardiac effects despite beta blockage.
• May increase myocardial contractility in isoproterenol-refractory patients.
• Glucagon activates the adenylate cyclase system at a different site than isoproterenol.
• Monitor a patient's electrolytes and renal function and monitor blood glucose and blood pressure.
• Obtain a chest X-ray to inspect for pulmonary edema.
• Hypotension usually responds to glucagon, atropine, or isoproterenol.
• Treat hypoglycemia with intravenous dextrose.
• Treat bronchospasm with salbutamol.

Toxicology of Digoxin

• Digoxin and digitoxin are digitalis glycosides are found in Digitalis purpurea (foxglove).
• Digoxin and digitoxin are absorbed orally, with 25% and 97% protein binding, respectively.
• Peak serum concentrations of digoxin occur within 1.5 to 6 hours, while digitoxin and digitalis leaf peaks occur in 4 to 12 hours.
• Digoxin is metabolized a minor extent and metabolism does not depend on the cytochrome P450 system.
• Digoxin is excreted in the urine. 60-80% is unchanged, the terminal half-life is about 36 hours.
• Digitoxin's elimination half-life is about 100 hours.
• Acute cardiac glycoside toxicity differs from chronic toxicity.
• Acute overdose poisons Na/K ATPase, causing intracellular potassium decrease and extracellular potassium increase.
• A reduction in normal membrane resting potential can slow electrical conduction, eventually leading to myocardial electrical function loss.
• Clinically, can result in high-grade heart block and asystole, which may not respond to electrical pacing.
• Adverse effects of Digoxin include arrhythmias, AV block, anorexia, nausea, vomiting, weakness, confusion, disorientation, headache, hallucinations (digitalis delirium), transient amblyopia, blurred vision, photophobia, gynecomastia, and restlessness.
• Drug interactions that increase toxicity involves diuretics and corticosteroids, because of hypokalaemia,
• Drugs that reduce elimination of cardiac glycosides and result in digitalis intoxication include amiodarone, propafenone, quinidine, and verapamil.
• Metoclopramide interferes with absorption of Digoxin.
• Absorption of Digoxin is increased by erythromycin, tetracycline, and omeprazole.
• Blood levels of Digoxin increased by calcium channel blockers, spironolactone, and quinidine.
• Clinical toxic features of Digoxin include
• Cardiotoxicity with nausea and vomitting.
• Nonspecific symptoms like malaise and weakness in chronic poisoning.
• Additionally, the patient can experience drowsiness, paraesthesias, headache, hallucinations, agitation, confusion, and delirium.
• Can induce cardiac arrhythmia.
• Hypotension and cardiac arrest.
• Common profound hyperkalaemia in acute ingestion.
• Can cause photophobia, amblyopia, miosis.
• The fatal dose of digoxin is under 10mg/adult, and 4mg/child while for Digitoxin: ~3mg
• Acute digoxin ingestion of greater than 10 mg in adult or 4 mg in a child may produce serious toxicity, including cardiac arrest.
• Digoxin Initial Treatment includes Emesis, lavage, and activated charcoal.
• Digoxin immune Fab fragments are the preferred treatment for severe or life-threatening intoxication.
• Forced diuresis, hemodialysis and hemoperfusion are generally ineffective.
• Monitor serum glycoside and potassium levels frequently.
• Digoxin advanced treatment:
• Using Digoxin specific antibody fragments (Fab) is useful in digitalis overdose cases.
• Administer Fab fragments intravenously. Digoxin and potassium levels should be followed, continuous ECG monitoring is also indicated.
• Indications for antidotal treatment of Digoxin include:
• Ingestion of greater than 10 mg
• Potassium concentration exceeding 5 mEq/L
• Serum digoxin level of more than 15 ng/ml
• Progressive bradyarrhythmia or severe ventricular arrhythmias.
• Alternatives when Fab fragments are unavailable:
• Phenytoin or lignocaine can be used to treat ventricular irritability.
• Atropine can be used to manage bradycardia and heart block.
• Magnesium is another treatment that is shown to reverse arrhythmias caused by Digoxin.
• Pacing is also a viable alternative
• Hemodialysis is ineffective in ridding cardiac glycosides.
• Treatment of hypo- or hyperkalemia includes:
  • Magnesium sulfate intravenously for hypomagnesaemia.
  • IV potassium chloride for hypokalaemia.
  • IV insulin, dextrose, and sodium bicarbonate for hyperkalemia.
• Digoxin immune Fab is the first line treatment.
• Fab fragments, bicarbonate, insulin, and glucose should not be combined.

Toxicology of Antiarrhythmic Drugs and Amiodarone

• Unfortunately, antiarrhythmic drugs are known to control arrhythmias but can also cause them.
• Thus, prescribing antiarrhythmic drugs requires that precipitating factors be excluded or minimized.
• Amiodarone is a Class III antiarrhythmic agent known for prolonging cardiac action potential duration.
• Each 200 mg of Amiodarone contains 75 mg of iodine.
• Adverse effects and clinical toxic features include respiratory distress syndrome (dyspnoea, cough, fever, chest pain, malaise, weakness, anorexia, weight loss), proarrhythmias, ventricular arrhythmias, bradycardia, heart block, hypotension and metallic/salty taste.
• Can also cause Hypo or hyperthyroidism.
• Acute pancreatitis can occur
• Causes Blue-green discoloration of skin and nails and alopecia.
• Can induce Hepatotoxicity: Transient liver enzyme elevations and signs and symptoms including hepatomegaly, ascites, abdominal pain, nausea, vomiting, anorexia and weight loss.
• Malaise. Fatigue, tremors, a lack of coordination, ataxia, dizziness, and paresthesia
• Peripheral neuropathy
• Corneal microdeposits can occur
• Treatment for Amiodarone induced toxicity involves continuous ECG, and decontamination.
• Oral cholestyramine can reduce halflife
• Use Corticosteroid for pulmonary toxicity.
• Bradycardia can be treated with beta adrenergic agonists.
• Intravenous magnesium sulfate has been used to treat non sustained ventricular tachycardia.