L5 Pharmacology Oct 2024 PDF

Pharmacology L5 Oct. 20th. 2024 Ass. Prof. Dr. Al-Abbassi Fawzia Antiarrhythmic Drugs Introduction: Antiarrhythmic drugs are medications used to treat abnormal heart rhythms (arrhythmias), which arise from irreg...

Pharmacology L5 Oct. 20th. 2024 Ass. Prof. Dr. Al-Abbassi Fawzia Antiarrhythmic Drugs Introduction: Antiarrhythmic drugs are medications used to treat abnormal heart rhythms (arrhythmias), which arise from irregular electrical activity in the heart. Arrhythmias can manifest as:- 1. Tachycardia (fast heart rate), 2. Bradycardia (slow heart rate), 3. Irregular rhythms, like atrial fibrillation. The goal of antiarrhythmic therapy is to: - 1. Restore normal heart rhythm 2. Slow excessively fast heart rates 3. Manage symptoms Mechanism of Cardiac Action Potential: The heart’s electrical activity is regulated by ion channels controlling the flow of sodium (Na⁺), calcium (Ca²⁺), and potassium (K⁺). The cardiac action potential consists of five phases: Phase 0 (Depolarization): Rapid influx of Na⁺, causing rapid depolarization. Phase 1 (Initial repolarization): Outward flow of K⁺. Phase 2 (Plateau): Influx of Ca²⁺ balances K⁺ efflux. Phase 3 (Repolarization): Continued outward flow of K⁺, restoring resting membrane potential. Phase 4 (Resting Phase): Stable membrane potential until the next stimulus. Different classes of antiarrhythmic drugs target specific ion channels or phases of the cardiac action potential to correct abnormal rhythms. Vaughan-Williams Classification: Antiarrhythmic drugs are categorized into four classes based on their mechanism of action. Class I: Sodium Channel Blockers These drugs slow the influx of sodium during Phase 0, reducing the rate of depolarization and slowing conduction. They are subdivided into three categories based on the extent of Na⁺ channel blockade and effects on repolarization: Class IA: Moderate Na⁺ channel blockade and prolongs repolarization (prolonged QT). Drugs: Quinidine, Procainamide, Disopyramide. Clinical use: Atrial and ventricular arrhythmias. Class IB: Mild Na⁺ channel blockade and shortens repolarization. Drugs: Lidocaine, Mexiletine. Clinical use: Ventricular arrhythmias (especially post-myocardial infarction). Class IC: Strong Na⁺ channel blockade with little effect on repolarization. Drugs: Flecainide, Propafenone. Clinical use: Supraventricular arrhythmias (such as atrial fibrillation), but caution in structural heart disease due to proarrhythmic potential. Class II: Beta-Adrenergic Blockers These drugs inhibit sympathetic stimulation of the heart by blocking beta- adrenergic receptors, reducing heart rate and contractility, especially during times of stress or exercise. They primarily work on the SA and AV nodes (affecting Phase 4). Drugs: Metoprolol, Atenolol, Propranolol, Esmolol. Clinical use: 1.Supraventricular tachycardia (SVT), 2.rate control in atrial fibrillation, and 3.ventricular rate control in other arrhythmias. Adverse effects: Bradycardia, hypotension, bronchospasm (especially in non- selective beta-blockers). Class III: Potassium Channel Blockers These drugs prolong repolarization (Phase 3) by inhibiting the efflux of K⁺. This lengthens the action potential duration and increases the refractory period, reducing the likelihood of reentrant arrhythmias. Drugs: Amiodarone, Sotalol, Dofetilide, Ibutilide. Clinical use: 1.Atrial fibrillation, 2.atrial flutter, 3.ventricular tachycardia. Adverse effects: QT prolongation, potentially fatal ventricular arrhythmia, organ toxicity (especially with amiodarone – pulmonary, thyroid, liver, etc.). Class IV: Calcium Channel Blockers These drugs block L-type calcium channels, primarily affecting the SA and AV nodes (slow conduction through the AV node). They are especially useful for rate control in supraventricular arrhythmias. Drugs: Verapamil, Diltiazem. Clinical use: 1.Atrial fibrillation, 2.atrial flutter, 3.PSVT (Paroxysmal Supraventricular Tachycardia). Adverse effects: Bradycardia, hypotension, worsening heart failure (due to negative inotropic effect). Class V: Miscellaneous Antiarrhythmics These drugs don't fit into the traditional Vaughan-Williams classification but are frequently used in clinical practice. 1.Adenosine: Short-acting agent used to terminate supraventricular tachycardia (SVT). It works by hyperpolarizing the AV node and briefly blocking conduction. Use: Acute termination of paroxysmal supraventricular tachycardia. Adverse effects: Chest pain, flushing, transient asystole. 2.Digoxin: Enhances vagal tone, leading to slowed conduction through the AV node. Use: Atrial fibrillation with rapid ventricular response, heart failure. Adverse effects: Digoxin toxicity (nausea, vomiting, arrhythmias). 3.Magnesium sulfate: Primarily used to treat a specific type of ventricular tachycardia associated with QT prolongation. Clinical Considerations: Selection of Antiarrhythmic Drug: depends on 1.the type of arrhythmia (supraventricular or ventricular), 2.the presence of structural heart disease, and 3.individual patient factors (age, comorbidities). Proarrhythmic Risk: Many antiarrhythmic drugs carry a risk of inducing arrhythmias (proarrhythmia), particularly in patients with underlying structural heart disease or electrolyte imbalances (e.g., hypokalemia, hypomagnesemia). Monitoring: Electrocardiogram (ECG) monitoring is essential when starting or adjusting antiarrhythmic drugs due to the potential for QT prolongation and other arrhythmic complications. Summary: Class I drugs primarily act on sodium channels and are divided into: - 1.IA (moderate Na⁺ block, prolonged QT), 2.IB (mild Na⁺ block, shortened QT), and 3.IC (strong Na⁺ block, minimal QT effect). Class II drugs (beta-blockers) slow heart rate and are used for rate control. Class III drugs (potassium channel blockers) 1.prolong repolarization and 2.are effective for both atrial and ventricular arrhythmias. Class IV drugs (calcium channel blockers) slow AV nodal conduction, used primarily in supraventricular arrhythmias. Class V drugs include agents like adenosine and digoxin, used for specific arrhythmias. Clinical Judgment: Selecting antiarrhythmic drugs requires careful balancing of efficacy, safety, and the patient's overall cardiovascular health. Regular monitoring and dose adjustments are necessary to minimize adverse effects and ensure the best therapeutic outcome. Antianginal Drugs Overview of Angina Angina pectoris is chest pain resulting from myocardial ischemia (insufficient oxygen supply to the heart muscle). Angina occurs when there is an imbalance between myocardial oxygen supply and demand, usually due to narrowed coronary arteries. The primary goal in managing angina is to reduce symptoms and prevent complications like myocardial infarction. Types of Angina Stable Angina: Occurs predictably with exertion or stress and is relieved by rest or nitroglycerin. Unstable Angina: Occurs unpredictably, often at rest, and is more severe. It's a medical emergency as it can precede myocardial infarction. Variant (Prinzmetal’s) Angina: Caused by coronary artery spasm, leading to transient ischemia, often occurring at rest. Mechanisms of Antianginal Therapy Antianginal drugs aim to: Decrease myocardial oxygen demand by 1.reducing heart rate, 2.contractility, or 3.afterload. 4.Increase myocardial oxygen supply by improving coronary blood flow. Classes of Antianginal Drugs 1.Nitrates Examples: Nitroglycerin, Isosorbide dinitrate, Isosorbide mononitrate. Mechanism of Action: Nitrates are converted to nitric oxide (NO) in vascular smooth muscle cells. NO stimulates the production of cyclic GMP, leading to vasodilation. Venodilation reduces preload (venous return), decreasing myocardial oxygen demand. Arterial dilation reduces afterload (resistance against which the heart must pump), decreasing oxygen demand. Coronary artery dilation improves oxygen supply, particularly useful in variant angina due to coronary spasm. Clinical Use: 1.Stable Angina: Reduces symptoms by decreasing myocardial oxygen demand. 2.Unstable Angina: Can be used but requires additional therapy (e.g., antiplatelets, beta-blockers). 3.Variant Angina: Effective in relieving vasospasm. Adverse Effects: Headache, hypotension, reflex tachycardia, tolerance with continuous use. 2.Beta-Adrenergic Blockers (Beta-Blockers) Examples: Metoprolol, Atenolol, Propranolol. Mechanism of Action: Beta-blockers block β1-adrenergic receptors in the heart, leading to 1.decreased heart rate (negative chronotropy), 2.decreased contractility (negative inotropy), and 3.decreased blood pressure. All of which reduce myocardial oxygen demand. Clinical Use: 1. First-line therapy for stable angina to reduce frequency and severity of angina attacks. 2. Not used in variant angina, as they may worsen coronary vasospasm. Adverse Effects: Bradycardia, hypotension, fatigue, bronchospasm (in non- selective agents), exacerbation of heart failure in some patients. 3.Calcium Channel Blockers (CCBs) Examples: Amlodipine, Diltiazem, Verapamil, Nifedipine. Mechanism of Action: Dihydropyridines (e.g., Amlodipine): Primarily cause vasodilation by inhibiting L-type calcium channels in vascular smooth muscle, leading to reduced afterload. Non-Dihydropyridines (Verapamil, Diltiazem): Also reduce heart rate and myocardial contractility, decreasing oxygen demand. Clinical Use: 1.Stable Angina: Both classes reduce symptoms. 2.Variant Angina: Dihydropyridines are especially effective for vasospastic angina. Adverse Effects: I-Dihydropyridines: 1.Reflex tachycardia, 2.peripheral edema, 3.headache. II-Non-Dihydropyridines: 1.Bradycardia, 2.heart block, 3.constipation (verapamil). 4.Ranolazine Mechanism of Action: Ranolazine inhibits the late phase of the sodium current in myocardial cells, reducing calcium overload. This leads to decreased myocardial contractility and oxygen consumption without significantly affecting heart rate or blood pressure. Clinical Use: Used as an add-on therapy in patients with chronic stable angina who are inadequately controlled with other antianginal drugs. Adverse Effects: Dizziness, constipation, nausea, prolonged QT interval (risk of arrhythmias). 5.Ivabradine Mechanism of Action: Ivabradine selectively inhibits the current in the sinoatrial node, reducing heart rate without affecting myocardial contractility or blood pressure, thus lowering myocardial oxygen demand. Clinical Use: Approved for use in patients with stable angina who cannot tolerate beta-blockers or have contraindications to their use. Adverse Effects: Bradycardia, visual disturbances. 6.Antiplatelet Agents Examples: Aspirin, Clopidogrel. Mechanism of Action: Inhibit platelet aggregation, reducing the risk of thrombus formation on atherosclerotic plaques. Clinical Use: Used in unstable angina and stable angina to prevent progression to myocardial infarction. Adverse Effects: Bleeding, gastrointestinal ulceration (aspirin). 7.Statins Examples: Atorvastatin, Rosuvastatin. Mechanism of Action: Inhibit HMG-CoA reductase, the enzyme responsible for cholesterol synthesis, leading to a decrease in LDL cholesterol levels and stabilization of atherosclerotic plaques. Clinical Use: Used in all forms of angina to reduce cardiovascular risk. Adverse Effects: Myopathy, liver enzyme elevation. Combination Therapy in Angina 1.Nitrates + Beta-Blockers: Effective in stable angina as beta-blockers prevent reflex tachycardia induced by nitrates. 2.Nitrates + Calcium Channel Blockers: Useful in cases where beta-blockers are contraindicated. 3.Beta-Blockers + Calcium Channel Blockers: Non- dihydropyridines (like verapamil) should be used cautiously with beta- blockers due to the risk of excessive bradycardia. Guidelines for Antianginal Drug Use 1.Stable Angina: First-line: Beta-blockers or calcium channel blockers. Add-on: Nitrates, Ranolazine, or Ivabradine if needed. 2.Unstable Angina: Aspirin and antiplatelet agents (Clopidogrel), with early use of nitrates and beta-blockers. Consider anticoagulation and coronary intervention. 3. Variant Angina: Nitrates and calcium channel blockers (dihydropyridines) are the primary treatments. Emerging Therapies and Future Directions Gene Therapy: Focused on improving myocardial blood flow by inducing angiogenesis. New Molecular Targets: Research continues into drugs that target different ion channels and metabolic pathways involved in myocardial ischemia. Key Points to Remember Antianginal drugs work either by decreasing myocardial oxygen demand or increasing oxygen supply. Nitrates are the most effective agents for acute symptom relief. Beta-blockers are the first-line agents for long-term management of stable angina. Calcium channel blockers are useful for both stable and variant angina. Newer agents like Ranolazine and Ivabradine offer additional options for patients inadequately controlled with conventional therapy. These are the foundational principles of antianginal pharmacotherapy, ensuring the management of angina in a multifaceted approach to meet individual patient needs.