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- 1. Antiarrhythmic Drugs Dr SeebatMasrur D-card Student Cardiology Department SZMCH
- 2. Arrhythmia Arrhythmias are abnormalbeats which may be too slow, too rapid, too irregular, or too early. The term arrhythmia refers to any change from the normal sequence of electrical impulses, causing abnormal heart rhythms.
- 3. Sites of Arrhythmias •Sinus Node • Atrial cells • AV Node • Ventricular Cells Mechanism of Arrhythmia • Automaticity • Reentry • After depolarization • Enhanced/Ectopic pacemaker activity
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- 6. Types of Arrhythmias •Sinus Origin-Sinus Tachycardia, Sinus Bradycardia, Sinus Arrhythmias • Atrial Origin-SVT, Atrial Fibrillation, Atrial Flutter • Av Nodal or Junctional origin- Junctional rhythm, Junctional tachycardia • Ventricular origin-Ventricular Tachycardia, ventricular fibrillation
- 7. Ionic Basis ofMembrane Electrical Activity • The transmembrane potential of cardiac cells is determined by the concentrations of several ions. -Sodium -Potassium -Calcium -Chloride On either side of the membrane and the permability of the membrane to each ion • These ions move across cell membranes in response to their gradients only at specific times during the cardiac cycle when these ion channels are open.
- 9. Vaughan-Williams Classification of Antiarrhythmic Drugs Somedrugs such as digoxin, ivabradine and adenosine have no place in this classification, while others such as amiodarone have properties in more than one class Class Action Example I Sodium channel blockade Ia Block Na+ channel and prolong action potential Quinidine, disopyramide Ib Block Na+ channel and shorten action potential Lidocaine, mexiletine Ic Block Na+ channel with no effect on action potential Flecainide, propafenone II β-Adrenergic receptor blockade Atenolol, bisoprolol, metoprolol III Potassium channel blockade and/or inward current enhancer. Amiodarone, dronedarone, sotalol IV Calcium channel blockade. Verapamil, diltiazem
- 10. An Updated Classificationof Current Antiarrhythmic Pharmacological Drugs Circulation. 2018;138:1879–1896. DOI: 10.1161/CIRCULATIONAHA.118.035455 Class Pharmacological Target Example 0 HCN channel– mediated pacemaker current (I f ) block Ivabradin Ia Voltage-gated Na+ channel blockers Quinidine, ajmaline, disopyramide Ib Voltage-gated Na+ channel blockers Lidocaine, mexiletine Ic Voltage-gated Na+ channel blockers Propafenone, flecainide Id Voltage-gated Na+ channel blockers Ranolazine
- 11. An Updated Classificationof Current Antiarrhythmic Pharmacological Drugs Circulation. 2018;138:1879–1896. DOI: 10.1161/CIRCULATIONAHA.118.035455 Class Pharmacological Target (Autonomic inhibitors and activators) Examples IIa Nonselective β- and selective β1-adrenergic receptor inhibitors Atenolol, Bisoprolol, Betaxolol, Celiprolol, Esmolol, Metoprolol IIb Nonselective β-adrenergic receptor activators Isoproterenol IIc Muscarinic M2 receptor inhibitors Atropine, Anisodamine, Hyoscine, Scopolamine IId Muscarinic M2 receptor activators Carbachol, Pilocarpine, Methacholine, Digoxin IIe Adenosine A1 receptor activators Adenosine, Aminophylline
- 12. An Updated Classificationof Current Antiarrhythmic Pharmacological Drugs Circulation. 2018;138:1879–1896. DOI: 10.1161/CIRCULATIONAHA.118.035455 Class Pharmacological Targets Examples IIIa Voltage dependent K+ channel blockers Amiodarone, Dronedarone, Ibutilide, Sotalol IIIb Metabolically dependent K+ channel openers Nicorandil, pinacidil IIIc Transmitter dependent K+ channel blockers Blocker under regulatory review for management of atrial fibrillation:
- 13. An Updated Classificationof Current Antiarrhythmic Pharmacological Drugs Circulation. 2018;138:1879–1896. DOI: 10.1161/CIRCULATIONAHA.118.035455 Class Pharmacological targets Examples IVa Nonselective surface membrane Ca2+ channel blockers Bepridil, Verapamil, Diltiazem IVb Intracellular Ca2+ channel blockers Flecainide, propafenone IVc Sarcoplasmic reticular Ca2+-ATPase activators No clinically approved drugs in use IVd Surface membrane ion exchange inhibitors No clinically approved drugs in use IVe Phosphokinase and phosphorylase inhibitors No clinically approved drugs in use
- 14. An Updated Classificationof Current Antiarrhythmic Pharmacological Drugs Circulation. 2018;138:1879–1896. DOI: 10.1161/CIRCULATIONAHA.118.035455 Class Pharmacological Targets Examples V Mechanosensitive channel blockers No clinically approved drugs in use VI Gap junction channel blockers Carbenoxolone VII Upstream target modulators ACEI, ARBs, Omega 3 fatty acids, Statins
- 15. Ivabradine Ref Drugs forheart; Circulation. 2018;138:1879–1896. DOI: 10.1161/CIRCULATIONAHA.118.035455 • Ivabradine is a blocker of the pacemaker current If, It likely acts through hyperpolarization activated cyclic nucleotide-gated channel block. • There is no negative inotropic effect nor BP reduction as with b-blockers, nor any rebound on cessation of therapy. • The downside is that the current If is also found in the retina, so that there may be disturbance of nocturnal vision with flashing lights (phosphenes) that could impair driving at night and is often transient. • Ivabradine, is used to reduce heart rates in situations of inappropriate sinus tachycardia or when sinus tachycardia accompanies cardiac failure.
- 16. Ivabradine Ref Drugs forheart; Circulation. 2018;138:1879–1896. DOI: 10.1161/CIRCULATIONAHA.118.035455 • The treatment of chronic heart failure New York Heart Association level II to IV with systolic dysfunction in patients in sinus rhythm and whose heart rate is 75 bpm or more, in combination with standard therapy including b-blocker therapy or when b-blocker therapy is contraindicated or not tolerated. • Ivabradine can cause Sinus bradycardia by depressing sinus node automaticity by blocking of If.
- 17. Lidocaine • Lidocaine actspreferentially on the ischemic myocardium and is more effective in the presence of a high external potassium concentration. • Lidocaine can be used when tachyarrhythmias or very frequent premature ventricular contractions seriously interfere with hemodynamic status in patients with AMI. • Lidocaine should not be used prophylactically or when there is bradycardia or bradycardia plus ventricular tachyarrhythmias. • Dose-IV 75-200 mg; then 2-4 mg/min for 24-30 h. (No oral use). T1 ⁄2 approximately 2 h. • Side effects- drowsiness, numbness, speech disturbances and dizziness, bradycardia, hypotension.
- 18. Beta- Adrenoceptor Antagonist • Noncardioselective-Propranolol, Sotalol • Cardioselective-Metoprolol, Bisoprolol •Vasodilatory b-Blockers, Nonselective-Labetalol, Carvedilol • Vasodilatory b-Blockers, Selective-Nebivolol
- 19. Beta-Blocking Agents Ref DrugsFor Heart Indications for b-Blockade FDA-Approved Drugs Ischemic Heart Disease Atenolol, metoprolol, Carvedilol, Bisoprolol Hypertension Labetalol, Bisoprolol, Nebivolol, Atenolol, Esmolol Arrhythmias Metoprolol, Esmolol, Propranolol, Acebutalol Congestive Heart failure Carvedilol, metoprolol, bisoprolol, Nebivolol Hypertrophic obstructive cardiomyopathy Propranolol POTS Propranolol low dose Anxiety Essential tremor Migraine prophylaxis Alcohol withdrawal Propranolol, nadolol, timolol Endocrine Thyrotoxicosis (arrhythmias) Propranolol Gastrointestinal Esophageal varices Propranolol Glaucoma (local use) Timolol
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- 23. Side Effects ofBeta-Blockers Ref-Drugs for heart 1. Smooth muscle spasm (bronchospasm and cold extremities) 2. Exaggeration of the cardiac therapeutic actions (bradycardia, heart block, excess negative inotropic effect) 3. Central nervous system penetration (insomnia, depression), and 4. Adverse metabolic side effects(B-blockers to increase new diabetes) 5. In a large group with mean age 48 years, erectile problems took place in 11% given a b-blocker, compared with 26% with a diuretic and 3% with placebo.
- 24. Beta-Blockade: Contraindications and CautionsRef-Drugs for heart Cardiac Absolute: Severe bradycardia, high-degree heart block, cardiogenic shock, overt untreated left ventricular failure (versus major use in early or stabilized heart failure). Relative: Prinzmetal’s angina (unopposed a-spasm), high doses of other agents depressing SA or AV nodes (verapamil, diltiazem, digoxin, antiarrhythmic agents); in angina, avoid sudden withdrawal.
- 25. Pulmonary Ref-Drugs for heart Absolute:Severe asthma or bronchospasm. Must question for past or present asthma. Risk of fatalities. Relative: Mild asthma or bronchospasm or chronic airways disease. Use agents with cardioselectivity plus b2-stimulants (by inhalation).
- 26. Central Nervous Ref-Drugs forheart • Absolute: Severe depression (especially avoid propranolol). • Relative: Vivid dreams, Visual hallucinations, Fatigue, Erectile dysfunction, Psychotropic drugs (with adrenergic augmentation) may adversely interact.
- 27. Peripheral Vascular, RaynaudPhenomenon Ref-Drugs for heart Absolute: Active disease: gangrene, skin necrosis, severe or worsening claudication, rest pain. Relative: Cold extremities, absent pulses, Raynaud phenomenon. Avoid nonselective agents (propranolol, sotalol, nadolol); prefer vasodilatory agents.
- 28. Diabetes Mellitus Ref-Drugs forheart Relative: Insulin-requiring diabetes: nonselective agents decrease reaction to hypoglycemia; use selective agents. Note successful use of atenolol in type 2 diabetes in prolonged UK trial at cost of weight gain and more antidiabetic drug usage.
- 29. Metabolic Syndrome orPrediabetes Ref-Drugs for heart Beta-blockers may increase blood sugar by 1-1.5 mmol/L and impair insulin sensitivity especially with diuretic co-therapy; consider use of carvedilol or nebivolol.
- 30. Renal Failure Ref-Drugs forheart • Relative: As renal blood flow falls, reduce doses of agents eliminated by kidney.
- 31. Liver Disease Ref-Drugs forheart • Relative: Avoid agents with high hepatic clearance (propranolol, carvedilol, timolol, acebutolol, metoprolol). Use agents with low clearance (atenolol, nadolol, sotalol).
- 32. Pregnancy Hypertension Ref-Drugs forheart Beta-blockade increasingly used but may depress vital signs in neonate and cause uterine vasoconstriction. Labetalol and atenolol best tested.
- 33. Others Ref-Drugs for heart SurgicalOperations-may be maintained throughout, provided indication is not trivial; otherwise stop 24 to 48 hours beforehand. May protect against anesthetic arrhythmias and perioperative ischemia. Preferred intravenous drug: esmolol. Use atropine for bradycardia, b-agonist for severe hypotension. Age-Helps to reduce BP, but lacks positive outcome data. Watch pharmacokinetics and side effects in all older adult patients. Smoking- Is less effective Hyperlipidemia-Triglycerides increase and HDL-cholesterol falls
- 34. Amiodarone Ref-Drugs for heart •Amiodarone is a complex antiarrhythmic agent, predominantly class III, that shares at least some of the properties of each of the other three EP classes of antiarrhythmics. • Amiodarone has a very long tissue half-life (25–110 days) • Indication- Recurrent VF or hemodynamically unstable VT -Atrial Fibrillation(acute conversion of chronic AF) -Preventing recurrences of paroxysmal atrial fibrillation or flutter • Amiodarone has been regarded as one of the most effective agents available, yet is now being replaced by ICDs
- 35. Ref-Drugs for heart •Amiodarone also has a cytotoxic effect on thyroid follicular cells and inhibits conversion of T4 to T3 (increasing the ratio of T4 :T3). Most patients receiving amiodarone have normal thyroid function but up to 20% develop hypothyroidism or thyrotoxicosis, and so thyroid function should be monitored regularly. TSH provides the best indicator of thyroid function. • The pathophysiology of amiodarone-induced hypothyroidism (AIH) is thought to be due to the high iodine content of amiodarone causing a Wolff-Chaikoff effect. • AIT Type 1-Excess iodine-induced thyroid hormone synthesis. • AIT Type 2-Amiodarone-related destructive thyroiditis
- 36. Adverse Effects of Amiodarone •Thyroid Dysfunction-Both Hypothyroidism and Hyperthytroidism • Corneal Deposits • Pulmonary Fibrosis/Pneumonitis • Liver Fibrosis/Hepatitis • Peripheral Neuropathy • Photosentivity • Slate grey appearance • Thrombophlebitis • LQTS, Bradycardia
- 37. Nondihydropyridine . Ref-Drugs forheart Examples-Diltiazem, Verapamil Indications • Angina • Hypertension • Verapamil for SVT
- 38. Verapamil- non-DHP agent Ref-Drugsfor heart Electrophysiology-Verapamil inhibits the action potential of the upper and middle regions of the AV node where depolarization is calcium mediated. Pharmacokinetics and interactions- Oral verapamil takes 2 hours to act and peaks at 3 hours. Therapeutic blood levels (80 to 400 ng/mL) are seldom measured. The elimination half-life is usually 3 to 7 hours. Verapamil doses-The usual total oral daily dose is 180-360 mg daily, no more than 480 mg given once or twice daily (long-acting formulations) or three times daily for standard short-acting preparations
- 39. Side effects-Verapamil Ref-Drugs forheart • Headaches • Facial flushing • Dizziness • Constipation • Rare side effects may include pain in the gums, facial pain, epigastric pain, hepatotoxicity, and transient mental confusion
- 40. Diltiazem Ref-Drugs for heart Pharmacokinetics-Theonset of action of short-acting diltiazem is within 15 to 30 minutes , with a peak at 1 to 2 hours. The elimination half-life is 4 to 7 hours; hence, dosage every 6 to 8 hours of the short- acting preparation is required for sustained therapeutic effect. The therapeutic plasma concentration range is 50 to 300 ng/mL. Diltiazem doses- The dose of diltiazem is 120 to 360 mg, given in four daily doses of the short-acting formulation or once or twice a day with slow-release preparations. Cardizem SR permits twice-daily doses
- 41. Side effects-Diltiazem Ref-Drugs forheart • Headache • Dizziness • Ankle Oedema • Constipation Contraindications-Contraindications resemble those of verapamil
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- 43. Digoxin Ref-Drugs for heart •It has weak positive inotropic effect, it slows the ventricular rate, which allows better ventricular filling in CHF, especially with atrial fibrillation. • Sodium pump inhibitionDirect calcium uptake • Renin release from the kidney is inhibited because digoxin decreases the activity of the renal sodium pump with a natriuretic effect. • Blood half-life approximately 36 hr
- 44. Digoxin use Ref-Drugs forheart 1. Chronic atrial fibrillation without overt CHF. 2. In chronic atrial fibrillation with heart failure. 3. In CHF with sinus rhythm the limited benefits found in the large DIG trial. Contraindications include hypertrophic obstructive cardiomyopathy, some cases of Wolff-Parkinson-White syndrome with atrial fibrillation , significant AV nodal heart block, and diastolic dysfunction. Relative contraindications are renal failure and older age (reduce doses).
- 45. Digoxin Toxicity https://www.passmedicine.com/v7/textbook/textbook.php# The BNFadvises that the likelihood of toxicity increases progressively from 1.5 to 3 mcg/l. Features- • Lethargy, nausea & vomiting, anorexia, confusion, yellow-green vision • Arrhythmias (e.g. AV block, bradycardia) • Gynecomastia Precipitating factor Hypokalemia, renal failure, elderly, myocardial ischemia etc Drugs-Amiodarone, verapamil, diltiazem, Thiazide and loop diuretics.
- 46. ECG Feature • Down-slopingST depression ('reverse tick', 'scooped out’) • Flattened/inverted T waves • Short QT interval • Arrhythmias e.g. AV block, bradycardia Management •Digibind •Correct arrhythmias •Monitor potassium https://www.passmedicine.com/v7/textbook/textbook.php#
- 47. Adenosine • It hasmultiple cellular effects mediated by opening of the adenosine- sensitive inward rectifier potassium channel, with inhibition of the sinus and especially the AV node. • Adenosine is most commonly used to terminate supraventricular tachycardias. • It should be avoided in asthmatics due to possible bronchospasm. • Other side effects-Chest discomfort, Flushing, Nausea. • Adenosine's half-life is 10-30 seconds
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