Cardiac Action Potentials & EKGs PDF

# Chapter 19 ## Before discussing arrhythmias, let's revise the action potentials of the heart and EKGs. ### Phases of cardiac action potentials: - Phase 0: Fast upstroke ($[Na^+$ influx] - Phase 1: Partial repolarization ($[K^+$ efflux] - Phase 2: Plateau ($[Ca^{2+}$ influx, $K^+$ efflux] - Phas...

# Chapter 19 ## Before discussing arrhythmias, let's revise the action potentials of the heart and EKGs. ### Phases of cardiac action potentials: - Phase 0: Fast upstroke ($[Na^+$ influx] - Phase 1: Partial repolarization ($[K^+$ efflux] - Phase 2: Plateau ($[Ca^{2+}$ influx, $K^+$ efflux] - Phase 3: Repolarization ($[K^+$ efflux] - Phase 4: Increasing depolarization ($[↑Na^+$ Permeability] ## EKGs consist of P,Q,R,S,T waves: - P wave: Atrial depolarization - Q wave: Interventricular septum depolarization - R wave: Main ventricular mass depolarization - S wave: Remaining parts depolarize - T wave: Ventricular repolarization ### EKG Diagram Description The EKG diagram depicts an electrical impulse traveling through the heart. The following measurements are labeled on the diagram: - RR interval (distance between R waves) - PP interval (distance between P waves) - PR segment - P-Wave Duration - PR interval (0.12-0.22s) - QRS duration (<0.12s) - ST-T segment - TP interval - QT duration - Corrected QT duration (men: ≤ 0.45s, women: ≤ 0.47s) **Note:** The reference level for measuring ST-segment deviation (depression or elevation) is not the TP interval. The correct reference level is the PR segment. This level is also called baseline level or isoelectric level. ## By origin, arrhythmias can be: - Atrial: Atrial flutter, Atrial fibrillation - AV node: AV nodal reentry, Supraventricular TC - Ventricular: Ventricular TC, Ventricular fibrillation ## Arrhythmias are caused by: - **Abnormal automacity:** This happens when instead of the SA node being the dominant focus of impulses generated, ectopic foci are having enhanced automacity. This can be managed by blocking $Na^+$ and $Ca^{2+}$ channels. - **Conduction abnormality:** When a portion of the myocardium is injured or has a longer refractory period, it can cause unidirectional blocks that lead to short circuits in the other direction and thus an a abnormal rhythm. This is called reentry and is the most common cause of arrhythmias. ## There are 5 classes of Antiarrhythmic drugs but some of them are pro-arrhythmic as well, prolonging QT intervals leading to torsades de pointes. ## Classification of Drugs: | Classification of Drug | Mechanism of Action | Comment | |---|---|---| | IA | $Na^+$ channel blocker | Slows Phase 0 depolarization in ventricular muscle fibers | | IB | $Na^+$ channel blocker | Shortens Phase 3 repolarization in ventricular muscle fibers | | IC | $Na^+$ channel blocker | Markedly slows Phase 0 depolarization in ventricular muscle fibers | | II | β-Adrenoreceptor blocker | Inhibits Phase 4 depolarization in SA and AV nodes | | III | $K^+$ channel blocker | Prolongs Phase 3 repolarization in ventricular muscle fibers | | IV | $Ca^{2+}$ channel blocker | Inhibits action potential in SA and AV nodes | # Class I Class I are $Na^+$ channels blockers, they exhibit a property called *state dependence* (greater affinity to channels frequently depolarizing) and thus they interfere with regular heartbeat. They can be pro-arrhythmic in patients with ventricular issues and CAD. ## Class IA: Quinidine, Procainamide, Disopyramide - Quinidine slows Phase 0, decreases the slope of Phase 4, inhibits $K^+$ and $Ca^{2+}$ channels, it is also α-, M-blocker. - Disopyramide's M blocking is greater, while Procainamide is less. - Disopyramide causes peripheral vasoconstriction and shows greater negative inotropic effect. - They can be used for atrial, AV and ventricular arrhythmias. - Quinidine is metabolized by CYP3A4 to active metabolites. - Procainamide is acetylated into a class III drug. - Disopyramide is metabolized by CYP3A4 into inactive metabolites. - Quinidine at high doses causes cinchonism, it also is an inhibitor of P-gp and CYP2D6. - Procainamide can cause hypotension and Disopyramide anti-M symptoms. ## Class IB: Lidocaine, Mexiletine - These agents rapidly bind and dissociate to $Na^+$ channels, they also shorten Phase 3. - They are used to treat ventricular arrhythmias. - Lidocaine is dealkylated by CYP1A2 and CYP3A4. - Mexiletine is metabolized by CYP2D6. - Adverse effects of lidocaine include nystagmus, drowsiness, paresthesia, slurred speech, confusion but it has a wide TI. - Mexiletine has a narrow TI but causes nausea, vomiting and dyspepsia. ## Class IC: Flecainide, Propafenone - These drugs slowly dissociate from resting $Na^+$ channels, are negative inotropic and Proarrhythmic. - Flecainide suppresses Phase 0 in Purkinjee fibers, increases threshold potential, blocks $K^+$ channels while Propafenone doesn't block $K^+$ but β-receptors (weakly). - Flecainide is used for atrial and refractory ventricular arrhythmias, while Propafenone is for atrial and Prophylaxis of PSVT. - Both are metabolized by CYP2D6. - Flecainide is well-tolerated but causes blurred vision, dizziness and nausea. - Propafenone can also cause bronchospasm and is P-gp inhibitor. # Class II Class II drugs are β-blockers. By acting on β receptors they diminish Phase 4, prolong AV conduction, reduce heart rate and contractility. They are used for atrial and AV arrhythmias, and prevent ventricular life-threatening arrhythmias that follow (MI). Metoprolol is the most used, and Esmolol which is fast-acting. # Class III Class III agents are $K^+$ blockers, meaning that they prolong action potentials. They all are proarrhythmic. ## Amiodarone: - Amiodarone has mixed class I, II, III, IV actions and α-blocking. It contains iodine and is similar to T4. - Its T1/2 is several weeks. It's used for all 3 types of arrhythmias and its adverse effects include Pulmonary fibrosis, comeal deposits, neuropathies, hepatotoxicity, skin discoloration, thyroidosis but is the least proarrhythmic out of classes I and III. - Metabolized by CYP3A4 but inhibits other CYPs and P-gp. ## Dronedarone: - An amiodarone derivative but lacks I moieties and is less lipophilic. - It has classes I, II, III, IV actions, better side effects but can cause hepatic failure. - It's used for atrial arrhythmias but less effective. ## Sotalol: - L-Sotalol is β-blocker but D- is $K^+$ blocker. - It can be used for the 3 types of arrhythmias. ## Dofetilide: - Pure $K^+$ blocker, it is 1st-line for persistent atrial-fib and heart failure. - T1/2 is 10h and it's not metabolized. ## Ibutilide: - $K^+$ blocker that has mixed class IA and III actions. - Used for atrial-flutter. - It gets extensive metabolism. # Class IV ## Verapamil and Diltiazem: - Bind to open depolarized $Ca^{2+}$ channels, shortening Phase 2 and decreasing Phase 4 rate. - They slow conduction in SA, AV nodes and are more effective for atrial arrhythmias. - Metabolized by CYP3A4 and adverse effects are bradycardia, BP↓, pulmonary edema. # Other Drugs ## Digoxin: - Inhibiting ATPase shortens refractory period in the myocardium and slows AV node conduction. It's used to control the response of ventricles in atrial arrhythmias. - At toxicity it can result in ectopic ventricular beats and V-fib. ## Adenosine: - At high doses, adenosine slows conduction, prolongs the refractory period and decreases AV node automacity. - Its T1/2 is 10-15s. - IV adenosine is the drug of choice for acute SVT. ## Mg Sulfate: - Mg is necessary for Na, K, Ca transport. It slows SA node impulse generation and myocardial conduction - It treats torsades de pointes and digoxin-induced arrhythmias. ## Ranolazine: - Antianginal with properties similar to amiodarone. - It shortens repolarization and action potential duration like mexiletine. - Metabolized by CYP3A, CYP2D6. - Treats refractory arrhythmias.