Week 4 Pharm May 20 part 2 Antiarrhythmics and Antianginals

Arrhythmias and Medications

Learning Objectives

• Understanding of maintenance, actions, contraindications, and interactions of medications for arrhythmias and angina.

Overview of Arrhythmias

• Arrhythmias are abnormal heartbeats or heart rhythms.
• Tachyarrhythmia:
  • Heart rate of $100$ beats per minute or faster.
• Bradyarrhythmia:
  • Heart rate less than $60$ beats per minute.
• Antiarrhythmics are used less frequently due to interventions like ICDs (Implantable Cardioverter-Defibrillators) or ablation.
• Non-pharmacological interventions are increasingly common.

Impulse Generation and Action Potential

• Action potential: a cell goes from negative to positive.
• Important phases to consider regarding antiarrhythmics:
  • Sodium ([Na^+]) influx into the cell.
  • Potassium ([K^+]) efflux from the cell.
  • Calcium ([Ca^{2+}]) influx into the cell.
• Conduction velocity: Regulation of action potential.
• Refractory period:
  • Absolute: A cardiac cell cannot propagate an action potential.
  • Relative: A cardiac cell may propagate another action potential, but requires a strong electrical stimulus.

Chemical Level of Action Potential

• Phase 0: Dramatic increase in cell potential from negative to positive due to sodium ions ([Na^+]) rushing into the cell.
• Calcium ([Ca^{2+}]) also rushes in during phase 0.
• Potassium ([K^+]) exits and sodium ([Na^+]) leaves the cell as the action potential decreases, leading to repolarization (becoming more negative).

Vaughan Williams Classification of Antiarrhythmic Drugs

• Four main classes of antiarrhythmics:
  • Class 1: Sodium channel blockers.
  • Class 2: Beta-adrenergic antagonists (beta blockers).
  • Class 3: Medications that prolong the action potential by blocking potassium channels.
  • Class 4: Calcium channel antagonists.
• Other antiarrhythmics not in these classes:
  • Digoxin.
  • Adenosine (sometimes referred to as Class 5).

Class 1: Sodium Channel Blockers

• Decrease the action potential by preventing sodium influx.
• Subdivided into Class 1a, 1b, and 1c.
• Affect cardiac conduction velocity, refractory period, and automaticity.
• Generally decrease conduction velocity and automaticity.

Class 1 Subclasses

• Class 1a:
  • Drugs include disopyramide, procainamide, quinidine (not commonly used anymore).
  • Mnemonic: "Pretty Darn Quick".
  • Used for supraventricular or ventricular arrhythmias, including autonomic and reentry arrhythmias.
  • Slow conduction velocity, increase refractory period.
• Class 1b:
  • Drugs include lidocaine, mexiletine.
  • Lidocaine given IV for ischemic tissue, ventricular tachycardia, and fibrillation.
  • Mexiletine given PO for life-threatening ventricular arrhythmias, but has significant side effects.
• Class 1c:
  • Drugs include flecainide and propafenone.
  • Strongest effect on action potential with strong sodium blockade.
  • Used for supraventricular and life-threatening ventricular arrhythmias.
  • Can cause ventricular arrhythmias; propafenone may cause metallic taste.

Cardiac Conduction Velocity, Refractory Period, and Automaticity

• Cardiac Conduction Velocity:
  • Speed at which signals travel through the heart's muscle tissue (SA node to AV node).
  • Class 1 drugs generally slow conduction velocity.
• Refractory Period:
  • Time frame in which cardiac muscles respond to electrical stimuli.
  • Some Class 1 drugs increase, some decrease refractory period.
• Automaticity:
  • Ability of heart cells to spontaneously generate electrical impulses.
  • Class 1 drugs generally decrease automaticity.

Class 1a Drugs - Specifics

• Procainamide and Disopyramide:
  • Used for supraventricular and ventricular arrhythmias.
  • Procainamide side effects: lupus-like syndrome, hypotension, Torsades de pointes.
  • Disopyramide: rarely indicated; has negative inotropic and anticholinergic side effects; caution in heart failure and elderly.
• Anticholinergic Side Effects Reminder:
  • Can't see, can't pee

Class 1b Drugs - Specifics

• Lidocaine:
  • Given IV, more effective for ischemic than normal tissue; used for ventricular tachycardia and fibrillation.
  • Side effects: nervousness, tremors.
• Mexiletine:
  • Given PO for life-threatening ventricular arrhythmias
  • Side effects: seizures, blood dyscrasias, hepatic effects

Class 1c Drugs - Specifics

• Flecainide and Propafenone:
  • Strongest sodium blockade.
  • Used for supraventricular and life-threatening ventricular arrhythmias.
  • Important Note: Antiarrhythmics can sometimes cause arrhythmias.
  • Propafenone: Metallic taste as distinguishing side effect; can cause heart block, bradycardia.

Class 2: Beta-Adrenergic Antagonists (Beta Blockers)

• Includes metoprolol, propranolol, esmolol.
• Esmolol (Breviblock) is given IV primarily for supraventricular arrhythmias.
• Slow heart rate by blocking beta-1 receptors.
• Decrease AV node conduction velocity and increase AV node refractory period.
  *SA node is the sinoatrial node (natural pacemaker)
  *AV node controls the ventricles*

Class 3: Potassium Channel Blockers

• Amiodarone is the most utilized.
• Prolong action potential by affecting potassium efflux.
• Drugs include amiodarone, ibutilide, dofetilide, sotalol, dronedarone.
• Mnemonic: "I Done Studied Antiarrhythmics" (Ibutilide, Dofetilide, Sotalol, Dronedarone, Amiodarone).
• Amiodarone increases refractory period in atrial and ventricular tissues by blocking potassium channels (delayed potassium rectifier current).

Amiodarone

• Blocks calcium and sodium channels, with some beta-blockade effects.
• Used for supraventricular and ventricular arrhythmias (A-fib, A-flutter, SVT, V-tach).
• Maintenance dose: $100-200$ mg daily.
• IV use for rapid ventricular rate control.
• Significant side effects include:
  • Bradycardia
  • Torsades de pointes
  • Blue-gray skin discoloration (Smurf look)
  • Photosensitivity
  • Pulmonary fibrosis
  • Thyroid dysfunction (hypo- or hyperthyroidism).
• Drug interactions: increases concentration of warfarin; can cause seizures with phenytoin.
• Monitoring: LFTs, chest X-ray, eye exam.

Other Class 3 drugs

• Dofetilide:
  • Selectively blocks potassium channels.
  • Used IV or orally for chemical cardioversion of A-fib or flutter.
  • Can cause Torsades de pointes and QT prolongation.
• Sotalol:
  • Has beta-adrenergic agonist properties too (beta-blocker).
  • Prolongs cardiac action potential by blocking potassium.
  • Non-selective beta-blocker properties, can cause bronchospasm (contraindicated in patients with asthma).
  • Can cause QT prolongation.

Class 4: Calcium Channel Blockers

• Diltiazem and verapamil are non-dihydropyridine calcium channel blockers.
• Decrease conduction velocity, increase refractory period, and decrease automaticity.
• Block L-type calcium channels.
• Decrease AV node conduction velocity and increase AV node refractory period.

Specifics

• Adverse events: hypotension, bradycardia, constipation.
• Dihydropyridine calcium channel blockers (amlodipine, nicardipine, nifedipine) affect arteries and veins, however these are rarely used for antiarrythmic indications.

Other Antiarrhythmics (Not in Vaughan Williams Classification)

• Adenosine, atropine, and digoxin.

Adenosine

• Administered IV only for SVTs, including Wolff-Parkinson-White syndrome.
• Activates potassium current in atria, SA node, and AV nodes.
• Opens potassium channels, causing potassium to leak out of the cell and making the AV node more negative.
• Inhibits action potential propagation.
• Can cause bronchospasm and cardiovascular events.
• Short half-life, given in bolus doses.

Digoxin

• Inhibits sodium-potassium ATPase, increases intracellular calcium.
• Slows conduction through the AV node, increases refractory period, decreases conduction velocity.
• Used for ventricular rate control in A-fib and for heart failure.
• Positive inotropic effect, increases cardiac efficiency.
• Requires monitoring because can become toxic; CNS and cardiac side effects.

Drugs That Can Cause QT Interval Prolongation

• Can lead to fatal arrhythmias such as Torsades de pointes.
• Psychotropics, antidepressants, antibiotics (macrolides, fluoroquinolones).
• SSRIs, tricyclic antidepressants, anti-infectives.
• Additive effects need to be considered, especially with dual psychotropics and antidepressants.

Torsades de Pointes

• Ventricular tachycardia.
• Discontinue causative medication.
• Correct low potassium and magnesium levels with IV magnesium.
• Cardioversion if hemodynamically compromised.

Patient Case: Amiodarone and Thyroid Issues

• 58-year-old woman treated for chronic suppression of ventricular arrhythmias. After two months, she feels she claims about feeling tired all the time. Examination reveals a resting heart rate of ten weeks per minute lower than her previous rate. Her skin is cool and cramming. Lab results indicate low methionine is significantly elevated TSH, which is why antiarrhythmias is likely to cause these signs and symptoms.
  Examination reveals a resting heart rate of ten weeks per minute lower than her previous rate. Her skin is cool cool and cramming. Lab results indicate low methionine is significantly elevated TSH, which is why antiarrhythmias is likely to cause these signs and symptoms.
  *Examination reveals a resting heart rate of ten weeks per minute lower than her previous rate. Her skin is cool and cramming. Lab results indicate low methionine is significantly elevated TSH, which is why antiarrhythmias is likely to cause these signs and symptoms.
• Amiodarone is the likely cause due to thyroid dysfunction (hypothyroidism).

Antiarrhythmic Drugs - Summary Chart

• Summary of drug actions, indications, and drugs in each category, including adenosine.

Recap of Antiarrhythmic Classes

• Class 1a: block sodium channels (procainamide, disopyramide).
• Class 1b: block sodium channels (lidocaine, mexiletine).
• Class 2: beta blockers (esmolol IV, propranolol, metoprolol).
• Class 3: prolong action potential (amiodarone, sotalol, ibutilide).
• Class 4: calcium channel blockers (verapamil, diltiazem).
• Other: adenosine.

Antianginal Drugs

• Some antiarrhythmics can also be used to treat angina.
• Additional drug classes:
  • Nitrates.
  • Metabolic modifiers.

Antianginal Drug Classes:

• Nitrates: Nitroglycerin, isosorbide mononitrate, isosorbide dinitrate
• Calcium Channel Blockers and Beta Blockers from anti-arrhythmics
• Metabolic Modifiers: Ranexa (ranolazine) as a last-line drug for angina

Understanding Angina and Treatment Goals

• Angina occurs due to lack of oxygen ((O_2)).
• Goal: reduce the heart's workload by decreasing oxygen demand.
• Reduce heart rate and myocardial contractility.
• Also reduce systolic pressure and left ventricular volume (preload).
• Drugs affect these parameters differently:
  • Beta blockers: heart rate.
  • Nitrates: left ventricular volume.
  • Calcium channel blockers: systolic pressure and heart rate.

Nitrates

• Used for acute anginal attacks and stable angina.
• Can be used long-term, but often used short-term or for acute attacks.
• Not for unstable angina.
• Available in various forms:
  • IV, oral, sublingual, buccal spray, transdermal, ointment.
• Limitations:
  • Poor oral bioavailability due to first-pass effect.

Nitrates - Usage and Mechanism

• Sublingual:bypass first pass effect; absorbed quickly.
• Dosages: $0.3-0.4$ mg sublingually every $5$ minutes before activity.
• Chronic prophylaxis w/ long-acting forms: patches but tolerance develops over time. Remove after $10-12$ hours.
• Mechanism: Release of nitric oxide ((NO)) causes vasodilation in vascular smooth muscle. Venous pooling of blood decreases return to heart and decreases ventricular volume, pressure, and (O_2) demand (reduces cardiac output and preload).

Nitrates - Side Effects and Drug Interactions

• Most common: Headache (vasodilation in brain).
• Postural hypotension.
• Flushing (vasodilation).
• Tachycardia (reflex).
• Elevated intracranial pressure.
• Drug Interaction: Dangerous hypotension when taking with sildenafil (Viagra) or other phosphodiesterase inhibitors.
  So it's been a film that that could cause this dangerous hypotension.
  But you're basically taking two vasodilators there.

Nitrates - Formulations

• Variety of short-acting and long-acting forms.
• Oral medications: isosorbide mononitrate or isosorbide dinitrate (for long-term use).

Calcium Channel Blockers for Angina

• Effective in monotherapy.
• Often used when patients are intolerant to beta blockers, or in combination with beta blockers.
• Improve blood flow through coronary arteries via vasodilation.
• Improve skeletal muscle perfusion (vs. beta blockers), decreasing fatigue and improving exercise tolerance.
• Dihydropyridines (amlodipine, nicardipine, nifedipine) do not affect heart rate and contractility as much as diltiazem or verapamil (non-dihydropyridines).

Calcium Channel Blockers for Angina - Best Candidates

• Those who can't use beta blockers.
• Prinzmetal angina (vasospastic angina). Calcium channel blockers vasodilate the coronary arteries in this case.
• Peripheral vascular disease or severe ventricular dysfunction.
• Concurrent hypertension.

Beta Blockers vs Calcium Channel Blockers for Angina

• Beta blockers used in typical angina, acute MI, not for vasospastic angina (Prinzmetal's). Also not for acute anginal attacks.

• Nitroglycerin used for acute attacks, not beta blockers.

• Nitrates can cause tachycardia. Dihydropyridine calcium channel blockers vasodilation can give reflex tachycardia.

• Post MI, beta blockers can decrease risk of recurrence of MI.

• Drugs Used: atenolol, propranolol, metoprolol. (Cardio-selective beta-blockers such as atenolol or metoprolol are preferred over non-selective such as propranolol)

• Caution: Patients with Asthma

Ranolazine (Ranexa) - Metabolic Modifier

• Last-line therapy.
• Reduces calcium overload in the heart muscle through inhibition of sodium channels.
• Does not affect heart rate or inotropic state.
• May improve oxygen supply to the heart.
• Indicated for chronic angina treatment.
• May prolong the QT interval.
• Contraindications: co-administration w/ drugs also causing QT interval