Toxicology of Cardiovascular Drugs PDF

‫بسم هللا الرحمن الرحيم‬ TOXICOLOGY OF CARDIOVASCULAR DRUGS Ahmed Altayeb Ali Omer  Objectives ❖ Toxicology of some Antihypertensive Drugs ❖ Toxicology of Digoxin ❖ Toxicology of Amiodarone  Overview Cardiovascular drugs are widely used to treat CVD; however, toxic...

‫بسم هللا الرحمن الرحيم‬ TOXICOLOGY OF CARDIOVASCULAR DRUGS Ahmed Altayeb Ali Omer  Objectives ❖ Toxicology of some Antihypertensive Drugs ❖ Toxicology of Digoxin ❖ Toxicology of Amiodarone  Overview Cardiovascular drugs are widely used to treat CVD; however, toxic effects can occur due to overdose, drug interactions, or individual patient susceptibility. Cardiovascular drug toxicity can be life-threatening, requiring rapid recognition and intervention. Understanding their toxicokinetic, toxicodynamic, and antidotes is crucial for effective management. General Mechanisms of Cardiovascular Drug Toxicity 1. Direct Cardiac Toxicity Bradycardia & AV Block: Beta-blockers, Calcium Channel Blockers (CCBs), Digoxin Ventricular Arrhythmias: Digoxin, Class I Antiarrhythmics, QT-prolonging drugs Negative Inotropy: Beta-blockers, CCBs 2. Vascular Toxicity & Hypotension Severe Hypotension & Shock: Nitrates, Alpha-blockers, ACEIs/ARBs, CCBs. Reflex Tachycardia: Nitrates, Alpha-blockers, CCBs 3. Electrolyte Disturbances Hyperkalemia: Digoxin (acute toxicity), Potassium- sparing diuretics (Spironolactone) Hypokalemia (↑ Digoxin Toxicity Risk): Loop & Thiazide Diuretics 4. CNS Toxicity Seizures, Hallucinations: Lipophilic Beta-blockers (Propranolol), Lidocaine (Class Ib Antiarrhythmic) Sedation & Respiratory Depression: Clonidine Toxicology of Antihypertensive Drugs ❑ Sympatholytic Drugs Centrally Acting Agents: Methyldopa: Adverse Effects and Toxic Features: 1. Haemolytic anaemia, hepatitis, pancreatitis, and myocarditis. 2. Headache, drowsiness, depression, oedema, nasal stuffiness, nightmares, sexual dysfunction, gynaecomastia, galactorrhoea. 3. Hypothermia, dry mouth, nausea, vomiting, hypotension, dizziness, weakness, lethargy, coma and bradycardia. Paraesthesias, headache, weakness.  Treatment: 1. Patient should be admitted to the ICU and monitored for cardiovascular complications. 2. For hypotension, infuse isotonic fluid and place in Trendelenburg position. ▪ If hypotension persists, administer dopamine or noradrenaline. 3. Atropine can be used to treat bradycardia. 4. Haemodialysis following methyldopa overdoses, may be of value. Alpha Adrenergic Antagonists Doxazocin, parazocin, terazocin  Adverse effects: First dose phenomenon. Dizziness. Tachycardia. Palpitations.  Clinical toxic features: Hypotension and reflex tachycardia are the most common manifestations.  Treatment: Administration of IV fluid boluses, and vasopressors such as dopamine.  Vasodilators Hydralazine Adverse Effects: Headache, dizziness, lacrimation, blurred vision, oedema of the eyelids, nausea, flushing, hypotension, palpitations and tachycardia. Lupus like syndrome. Glomerulonephritis. Peripheral neuropathy.  Treatment: IV fluid boluses, and peripherally acting vasopressors such as noradrenaline. Calcium channel blockers or beta blockers may be considered in patients with persistent tachycardia. Peripheral neuropathies may be corrected with pyridoxine. Angiotensin Converting Enzyme Inhibitors (ACEIs)  Adverse Effects Skin rash, chronic cough, bronchospasm, neutropenia, hyperkalaemia, hypotension, proteinuria, renal insufficiency, and occasionally angioneurotic oedema. Pancreatitis has only been reported with lisinopril and enalapril. Hepatotoxicity has been associated with captopril. ACE inhibitors must not be used in pregnancy since they are teratogenic and cause fetal anomalies.  Angioneurotic oedema occurs in about 0.1% of patients receiving ACE inhibitors. Dermatitis, the overall incidence of rashes ranges from 6.1 to 10.9% and is dose dependant. Dyspnoea, chest pain, and airway compromise may develop. Elevation of bradykinin levels is said to be the cause. Treatment involves maintenance of airway and antiallergic drug therapy. Cough responds well to sodium cromoglycate.  Drug interaction: Hypoglycaemia, with simultaneous use of ACE inhibitors and insulin or oral hypoglycaemic. The combination of ACE inhibitors and potassium sparing diuretics may cause hyperkalaemia. The combination of NSAIDs and ACE inhibitors may cause renal insufficiency.  Clinical Toxic Features 1. In many cases of overdose, patients remain asymptomatic. 2. Hypotension, hyperkalaemia, and renal failure. 3. Fatalities are rare.  Treatment: 1. Monitor serum creatinine if there is significant hypotension or renal disease. 2. Administration of activated charcoal in the usual manner. 3. For hypotension, Infuse isotonic fluid and place in Trendelenburg position, if hypotension persists, administer dopamine or noradrenaline. 4. Angiotensin II infusion has been successful in reversing hypotension in patients who did not respond to volume and pressor infusions. 5. Haemodialysis may be beneficial.  Angiotensin II receptor antagonists  Adverse Effects: Dizziness, insomnia, headache, muscle cramps, and leg pain. Hyperkalaemia. Oliguria and azotaemia in patients with severe CHF or renal artery stenosis. Reversible hepatotoxicity. Angioedema.  Angiotensin II receptor antagonists should be discontinued when pregnancy is detected, Because it cause severe fetal deformity.  Clinical Toxic Features: Hypotension Hyperkalemia  Treatment: 1. Symptomatic and supportive measures. 2. Monitor renal and liver function tests in symptomatic patients or following significant overdose. 3. Monitor blood pressure and heart rate frequently following a significant ingestion. 4. Based on the high protein binding of most of these agents, hemodialysis would not be effective. Beta Adrenergic Antagonists  Adverse Effects: 1. Bradycardia, dizziness, fatigue, diarrhoea, sleepiness, confusion, depression, and headache. ▪ CNS effects at therapeutic doses are more often associated with more lipid soluble agents (propranolol, metoprolol), but in overdose all agents may cause significant CNS depression. 2. Therapeutic doses of beta blockers may cause bronchospasm. Other cardiovascular effects may include AV blocks, ventricular arrhythmias and cardiac arrest. Abrupt stoppage of beta blockers after chronic use may result in rebound hypertension, tachycardia, palpitations, tremor, headache, and sweating. Treatment: 1. Glucagon have antidotal action. It produces a positive chronotropic and inotropic cardiac effect, which occurs despite beta blockage. The drug increase myocardial contractility in patients refractive to isoproterenol. Glucagon is thought to activate the adenylate cyclase system at a different site than isoproterenol. 2. Monitor electrolytes and renal function in patients with hypotension. 3. Monitor blood glucose in symptomatic children and diabetics. 4. ECG monitoring, monitor blood pressure. 5. Obtain a chest X ray in patients with respiratory depression, significant hypotension or evidence of pulmonary oedema. 6. Hypotension usually responds to intravenous glucagon, atropine, isoproterenol. 7. Hypoglycaemia should be managed with intravenous dextrose. 8. Bronchospasm responds to salbutamol.  Toxicology of Digoxin CARDIAC GLYCOSIDES:  Digitalis purpurea, the common name of this plant is foxglove.  The digitalis glycosides digoxin and digitoxin which are the most widely used cardiac glycosides.  Toxicokinetic: Both digoxin and digitoxin are well absorbed orally, their protein binding is 25%, 97% respectively. Peak serum concentrations of digoxin occur within 1.5 to 6 hours after an oral dose. For digitoxin and digitalis leaf, the peak of cardiac toxicity is 4 to 12 hours.  Digoxin is metabolized to a very minor extent (about 16%) via hydrolysis, oxidation, and conjugation. Metabolism is not dependant on the cytochrome P450 system. After a single dose, digoxin is the major serum and urine metabolite of digitoxin. 60 to 80% of digoxin is excreted unchanged in the urine and the terminal half life is about 36 hours. Digitoxin has a much longer elimination half life (about 100 hours). ❖ Massive acute cardiac glycoside differ significantly from chronic toxicity. In acute overdose, Na/K ATPase is poisoned, producing a fall in intracellular potassium and a rise in extracellular potassium, which may be marked. The normal membrane resting potential is reduced, and electrical conduction is slowed, with eventual complete loss of myocardial electrical function. Clinically this results in high grade heart block, and eventually in asystole, which may not respond to electrical pacing.  Adverse Effects: CVS: Arrhythmias, All grades of AV block. GIT: Anorexia, nausea, vomiting, weakness. CNS: Confusion, disorientation, headache, and hallucinations (digitalis delirium). Eye: Transient amblyopia, blurred vision and photophobia. Miscellaneous: Gynaecomastia, restlessness.  Drug Interactions Toxicity is increased by diuretics (except potassium sparing) and corticosteroids, because of hypokalaemia. Common drugs that may reduce the elimination of cardiac glycosides and result in digitalis intoxication include: amiodarone, propafenone, quinidine and verapamil.  Metoclopramide interferes with absorption. Erythromycin, tetracycline, and omeprazole increase absorption. Blood levels increased by calcium channel blockers, spironolactone, quinidine.  Clinical Toxic Features  Poisoning may be acute or chronic. In an acute ingestion, nausea and vomiting are prominent as well as evidence of cardiotoxicity. In chronic poisoning, non specific symptoms, such as malaise and weakness. Drowsiness, paraesthesias and headache. Hallucinations, agitation, confusion, and delirium. Cardiac arrhythmia. Hypotension and cardiac arrest may occur. Profound hyperkalaemia after acute ingestion is common. Photophobia, amblyopia, miosis. ❑ Usual Fatal Dose: Digitalis leaf: 2 grams Gitalin: 15 mg Digoxin: 10 mg Digitoxin: 3 mg ❑ Acute digoxin ingestion of greater than 10 mg in adult or 4 mg in a child may produce serious toxicity, including cardiac arrest. Treatment 1. Initial Treatment A. Decontamination: Emesis, lavage, activated charcoal. While digoxin immune Fab fragments are the preferred treatment for severe or life-threatening intoxication, multiple dose activated charcoal may be useful in situations in which Fab fragments are not available. B. Forced diuresis, hemodialysis and hemoperfusion are generally ineffective. C. Monitor serum glycoside and potassium levels frequently. 2. Advanced Treatment: 2.1Antidote: Digoxin specific antibody fragments (Fab) Fab therapy is of proven efficacy in digitalis overdose. Fab fragments are administered intravenously, they bind intravascular free digoxin and then diffuse into the interstitial space and bind free digoxin there. Digoxin and potassium levels should be followed, continuous ECG monitoring is also indicated.  Indications for antidotal treatment include: 1. Ingestion of greater than 10 mg digoxin by an adult or 4 mg by a child. 2. Potassium concentration exceeding 5 mEq/L. 3. Serum digoxin level of more than 15 ng/ml. 4. Progressive bradyarrhythmia or severe ventricular arrhythmias. 2.2 phenytoin or lignocaine: in the absence of Fab fragments, can be used to treat ventricular irritability. 2.3 Atropine: is useful in the management of bradycardia, and varying degrees of heart block. 2.4 Magnesium: has been reported to reverse digoxin induced arrhythmias. 2.5 External pacemaker: should be considered in severe bradycardia and slow ventricular rate due to second- or high-degree AV block that not respond to atropine and phenytoin when digoxin Fab are not available. 2.6 Hemodialysis: is ineffective in removing cardiac glycosides but may assist in restoring serum potassium to normal levels. 2.7 Treatment of hypo or hyperkalemia and hypomagnesaemia as follows: ❖ Hypomagnesaemia: 2 grams magnesium sulfate (10%) IV over 20 minutes. ❖ Hypokalaemia: IV potassium chloride in 0.9 or 0.45 % sodium chloride. ❖ Hyperkalemia: IV insulin, dextrose, sodium bicarbonate. Digoxin immune Fab is first line treatment. Fab fragments and bicarbonate/ insulin/glucose should not be used simultaneously because severe hypokalemia may result.  Toxicology of antiarrhythmic drugs Unfortunately, antiarrhythmic drugs not only help to control arrhythmias but also can cause them. Thus, prescribing antiarrhythmic drugs requires that precipitating factors be excluded or minimized.  Amiodarone: Amiodarone is a class III antiarrhythmic agent that primarily prolongs cardiac action potential duration. Each 200 mg contains 75 mg of iodine.  Adverse Effects and Clinical Toxic Features: Respiratory distress syndrome, manifest as dyspnoea, cough, fever, chest pain, malaise, weakness, anorexia, weight loss. Proarrhythmias, ventricular arrhythmias, bradycardia, heart block. Hypotension has been reported with rapid IV infusion. A metallic or salty taste occur with chronic therapy. Hypo or hyperthyroidism.  Acute pancreatitis occur following therapeutic use of amiodarone. Blue green discoloration of skin and nails, alopecia. Hepatotoxicity: Transient liver enzyme elevations. Signs and symptoms may include hepatomegaly, ascites, abdominal pain, nausea, vomiting, anorexia and weight loss. Malaise, fatigue, tremors, lack of co-ordination, ataxia, dizziness, and paresthesia. Peripheral neuropathy. Corneal microdeposits: occur in 76 to 100% of patients  Treatment 1. Monitoring of ECG and may need to be continued for days post ingestion. 2. Decontamination may be effective up to several hours post ingestion. 3. Oral Cholestyramine (4 grams every hour for 4 hours) may reduce half life of amiodarone. 4. Pulmonary toxicity responds to corticosteroids. 5. Bradycardia responds to beta adrenergic agonists or pacemaker. 6. Intravenous magnesium sulfate has been successfully used to treat non sustained ventricular tachycardia. THANKS