CVS Lecture 20 PDF

Pharmacology of CVS Assoc. Prof. Mohamed Mostafa Elbadr L20 (Pharmacology) Assoc. Prof. Mohamed Mostafa Elbadr Overview of Drugs Used to Treat Arrhythmias CLASSIFICATION OF ANTIARRHYTHMIC DRUGS: CLASS I (Na+ channel blockers)...

Pharmacology of CVS Assoc. Prof. Mohamed Mostafa Elbadr L20 (Pharmacology) Assoc. Prof. Mohamed Mostafa Elbadr Overview of Drugs Used to Treat Arrhythmias CLASSIFICATION OF ANTIARRHYTHMIC DRUGS: CLASS I (Na+ channel blockers) IA Quinidine, procainamide, disopyramide Antiarrhythmic: block fast Na+ channels (↓ INa) Preferentially in the open or activated state—“state-dependent” blockade Also blocks K+channel (prolongs repolarization), ↑ action potential duration and effective refractory period Drugs: – Quinidine º In addition to the above, causes muscarinic receptor blockade, which can ↑ HR and AV conduction. º May also cause vasodilation via alpha block with possible reflex tachycardia. º Orally effective; in atrial fibrillation need initial digitalization to slow AV conduction. º Adverse effects: Cinchonism (GI, tinnitus, ocular dysfunction, CNS excitation), hypotension, prolongation of QRS and ↑ QT interval associated with syncope (torsade). º Drug interactions: hyperkalemia enhances effects and vice versa; displaces digoxin from tissue binding sites, enhancing toxicity. º Quinidine is a weak base, and antacids increase its absorption, thus greatly increasing its toxicity – Procainamide º Less muscarinic receptor block º Metabolized via N-acetyltransferase (genotypic variation) to N-acetyl procainamide (NAPA), an active metabolite º Adverse effects: systemic lupus erythematosus (SLE)–like syndrome (30% incidence) more likely with slow acetylators; hematotoxicity (thrombocytopenia, agranulocytosis); CV effects (torsade) CLINICAL USE Atrial and ventricular arrhythmias Class 1B Antiarrhythmic: block fast Na+ channels (↓ INa) Block inactivated channels—preference for tissues partly depolarized (slow conduction in hypoxic and ischemic tissues). This results in an 1 Pharmacology of CVS Assoc. Prof. Mohamed Mostafa Elbadr increased threshold for excitation and less excitability of hypoxic heart muscle. ↓ APD—due to block of the slow Na+ “window” currents, but this increases diastole and extends the time for recovery. Drugs and uses: – Lidocaine º Post-MI, open-heart surgery, digoxin toxicity–ventricular arrhythmias only º Side effects: CNS toxicity (seizures); least cardiotoxic of conventional anti-arrhythmics º IV use because of first-pass metabolism – Mexiletine º Same uses as lidocaine º Oral formulations Phenytoin (antiepileptic) Used mainly in the treatment of atrial and ventricular arrhythmia caused by digoxin toxicity Side effects: 1-Gingival hyperplasia is the main side effect 2-Cerebellar-vestibular dysfunction: nystagmus, vertigo, diplopia, ataxia and drowsiness Class 1C Block fast Na+ channels (↓ INa), especially His-Purkinje tissue No effect on APD No ANS effects Drug: – Flecainide, propafenone º Limited use because of proarrhythmogenic effects, leading to ↑ in sudden death post-MI and when used prophylactically in VT CLASS II (β-Blockers) Prevent β-receptor activation, which would normally ↑ cAMP ↓ SA and AV nodal activity ↓ Slope of phase 4 (diastolic currents) of AP in pacemakers Drugs: – Propranolol (nonselective) and the cardioselective drugs: acebutolol and esmolol – Uses: º Prophylaxis post-MI and in supraventricular tachyarrhythmias (SVTs) º Esmolol (IV) is used in acute SVTs CLINICAL USE: 2 Pharmacology of CVS Assoc. Prof. Mohamed Mostafa Elbadr Ventricular and supraventricular arrhythmias As atrial tachycardia, flutter and fibrillation (correct only tachycardia but in flutter and fibrillation used to protect ventricle by decreasing A-V nodal conduction) SIDE EFFECTS: Bradycardia, AV block and other side effects of beta-blockers With non-selective group as propranolol -Bronchospasm -Mask symptoms of hypoglycemia -Cold extremities CLASS III (K+ channel blockers) Decrease IK (delayed rectifier current) slowing phase 3 (repolarization) of AP Increase APD and ERP, especially in Purkinje and ventricular fibers Amiodarone, Dronedarone Mimics classes I, II, III, and IV Increase APD and ERP in all cardiac tissues Uses: any arrhythmia Amiodarone blocks also alpha, beta receptors and calcium channels It has the longest t ½ (>80 days), so it is used in high loading dose for 2 weeks, followed by low maintenance dose once/day. Binds extensively to tissues (large Vd and multiple effects) Side effects: interstitial pneumonitis and pulmonary fibrosis, phototoxicity, corneal deposits, hepatic necrosis, iodine-related side effects including blue skin pigmentation and thyroid dysfunction (amiodarone) Dofetilide (pure potassium channel blocker) Sotalol Decreases IK, slowing phase III Non-selective beta blocker: β1 blockade, leading to ↓ HR, ↓ AV conduction Use: life-threatening ventricular arrhythmia Side effects: Torsade CLINICAL USE Treatment and prevention of ventricular arrhythmias Maintain sinus rhythm after correction of AF by cardioversion CLASS IV (Ca2+ channel blockers) Block slow cardiac Ca2+ channels Decrease phase 0, ↓ phase 4 3 Pharmacology of CVS Assoc. Prof. Mohamed Mostafa Elbadr Decrease SA, ↓ AV nodal activity Verapamil and Diltiazem Prototype Ca2+-channel blockers (see Antianginal Drugs chapters in this section) Uses: supraventricular tachycardias Side effects: constipation (verapamil), dizziness, flushing, hypotension, AV block Drug interaction: – Additive AV block with β-blockers, digoxin – Verapamil displaces digoxin from tissue-binding sites CLASS V (UNCLASSIFIED) Adenosine Activates adenosine receptors: causes Gi -coupled decrease in cAMP Decreases SA and AV nodal activity Uses: DOC for paroxysmal supraventricular tachycardias and AV nodal arrhythmias Administered by bolus IV: t½ less than 10 seconds Side effects: flushing, sedation, dyspnea Adenosine is antagonized by methylxanthines (theophylline and caffeine) Magnesium sulphate, used I.V. Mechanism of action: Unknown Clinical use Torsades de pointes Side effects Respiratory depression Digoxin Mechanism of action: Decrease AV nodal conduction and decrease normal automaticity Clinical use Supraventricular arrhythmias Side effects Nausea, vomiting, blurred vision, gynecomastia, bradycardia and heart block Clinical Correlate Long QT Syndrome 4 Pharmacology of CVS Assoc. Prof. Mohamed Mostafa Elbadr -A familial condition associated with increased risk of ventricular arrhythmias may result from a mutation in the gene encoding cardiac potassium channels. In such patients, class IA and class III antiarrhythmic drugs may increase the risk of torsades. Drugs which cause torsades include: Potassium-channel blockers (class 1A and class III) Antipsychotics (thioridazine) Tricyclic antidepressants To treat the torsades, correct the hypokalemia, correct the hypomagnesemia using magnesium sulphate, and discontinue drugs that prolong the QT interval. Clinical Correlate Atrial fibrillation is the most common arrhythmia in the United States. There are 2 primary goals: Ventricular rate control with beta blocker, CCB, or digoxin Anticoagulation Treatment of atrial fibrillation: 1-Before treatment of atrial fibrillation we need to: 1-Blocking of A-V nodal conduction by B-blockers, Ca++ channel blockers (as verapamil) or digoxin to decrease the A-V nodal conduction, so reducing the ventricular rate. 2-The use of anticoagulant 3 weeks before and 4 weeks after the use of these drugs as atrial fibrillation is usually associated with stagnation of blood with thrombosis in the atrium. 2-Treatment of atrial fibrillation: -Better by cardioversion 3-Prevention of recurrence of atrial fibrillation: -After correction of atrial fibrillation, the sinus rhythm is maintained using quinidine, amiodarone or dofetilide. Clinical Correlate Potassium Both hyperkalemia and hypokalemia are arrhythmogenic. Summary of the uses of beta blockers, Ca++ channel blockers & digoxin in arrhythmia: - Ca++ channel blockers, beta blockers and digoxin are effective only in atrial arrhythmia (tachycardia, flutter and fibrillation) 5 Pharmacology of CVS Assoc. Prof. Mohamed Mostafa Elbadr -All these drugs can correct only the tachycardia but not correct flutter and fibrillation but they are used in such cases for protection of the ventricles by decreasing the A-V nodal conduction -Beta-blockers are exception because they are also effective in ventricular arrhythmia due to excessive sympathetic stimulation Wolff-Parkinson-White Syndrome There is accessory pathways (fast muscle fibers) for transmission of impulse between atrium and ventricle in addition to the A-V node (Slow conduction) Do block accessory pathway with I A or III Do not slow AV conduction (avoid digoxin, β-blocker, Ca2+-channel blocker, adenosine) 6