Overview Class I - Na+ Channel Blockers General principles slow or block Na+ conduction preferentially in depolarized cells selective for abnormal cardiac tissue that is frequently depolarized use and state dependence phase 4 depolarization in SA node (automaticity current) is dependent on Na+ channel opening blockage results in ↓ slope of phase 4 depolarization and ↓ SA node rate hyperkalemia causes ↑ toxicity for all class I drugs Class IA Examples quinidine, procainamide, disopyramide remember: quin + the amides Effects acts on atrial and ventricular arrhythmias especially reentrant and ectopic supraventricular and ventricular tachycardia ↓ rate of phase 0 depolarizating resulting in ↑ QT interval ↑ AP duration ↑ effective refractory period (ERP) Toxicity quinidine cinchonism headache, tinnitus, vertigo thrombocytopenia ↑ QT interval can result in torsades de pointes can enchance digoxin toxicity procainamide reversible SLE-like syndrome remember: procAiNAmide (antinuclear antibody in SLE) Class IB Examples lidocaine, mexiletine, tocainide phenytoin can also fall into class IB Effects acts on ischemic or depolarized Purkinje and ventricular tissue does not act on healthy or atrial tissue effective in treating structurally abnormal tissue (especially post-MI) useful in acute ventricular arrhythmias and in digitalis-induced arrhythmias ↓ rate of phase 3 repolarization resulting in ↓ AP duration Toxicity local anesthetic CNS stimulation/depression Class IC Examples flecainide, encainide, propafenone Effects acts on His-Purkinje system in cardiac tissue WITHOUT structural abnormalities useful in V-tachs progressing to VF and refractory SVT drugs of last resort no effect on AP duration Toxicity proarrhythmic contraindicted with structural abnormalities e.g., post-MI significantly prolongs refractory period in AV node Use Dependence Higer rates of depolarization = increased Na+ channel blockade due to channels spending less time in the resting state type 1C antiarrythmics bind Na+ channels the strongest have the highest likelihood of use dependence type 1B antiarrythmics bind the least avidly to Na+ channels minimal cumulative effect over multiple cardiac cycles more selective for ischemic myocardium lowest likelihood of use dependence Na+ channel binding strength: 1C > 1A > 1B Class II - β-blockers Examples propranolol, esmolol, metoprolol, atenolol, timolol esmolol very short acting Mechanism ↓ slope of phase 4 resulting in ↓ automaticity due to ↓ cAMP, ↓ Ca2+ currents results in ↑ PR interval, ↓ conduction in AV node Clinical use ventricular tachycardia, SVT slowing ventricular rate during atrial fibrillation and atrial flutter post-MI arrhythmia prophylaxis (cardioprotective) Toxicity cardiovascular effects bradycardia, AV block, CHF CNS effects sedation, sleep alterations, depression may mask the signs of hypoglycemia impotence exacerbation of asthma only for non-selective (non-beta1 specific) metoprolol can cause dyslipidemia treat overdose with glucagon ↑ cAMP via a mechanism independent of beta receptors Class III - K+ Channel Blockers Examples sotalol, ibutilide, bretylium, dofetilide, amiodarone Mechanism ↑ phase 3 due to ↓ K+ current results in ↑ AP duration, ↑ ERP, ↑ QT interval effective for antrial and ventricular arrhythmias antiarrhythmics of last resort amiodarone has class I, II, III, and IV effects due to alterations lipid membrane Toxicity torsades de pointes due to ↑ QT interval amiodarone is the only example of a drug that lengthens QT but does not have risk of torsades de pointes sinus bradycardia sotalol excessive β blockade bretylium new arrhythmias ↓ BP amiodarone pulmonary fibrosis hepatotoxicity hypothyroidism/hyperthyroidism amiodarone is 40% iodine by weight (amIODarone) must watch LFTs, TFTs, PFTs corneal deposits photosensitivity skin color changes (blue/gray) neurologic effects constipation cardiovascular effects bradycardia, heart block, CHF Class IV - Ca2+ Channel Blockers Examples verapamil, diltiazem note: other Ca2+ channel blockers (nifedipine, amlodipine) have little action on the heart Mechanism ↓ L-type Ca2+ channels current primarily in AV nodal cells L-type Ca2+ channels responsible for the plateau phase results in ↓ conduction velocity, ↑ ERP, ↑ PR interval used in prevention of nodal arrhythmias, AV nodal reentry Toxicity antimuscarinic effects constipation, diziness, flushing edema CV effects negative ionotropy, AV block, sinus node depression