Cardiovascular Drugs #4: Anti-Arrhythmics

Why does the heart contract?

Specialized cells in the Sinoatrial (SA) node in the RA and the Atrioventricular (AV) node generate spontaneous action potentials that result in the stimulation and contraction of cardiac muscle cells

Which node generates impulses faster? Why is this important?

• The SA node generates impulses faster than the AV node

• This is important because the atria need to contract before the ventricles, which allows for that to happen

The SA node has an inherent rate that is modified by sympathetic (__) and parasympathetic (__). What effect do each of these receptors have on the rate of the SA node?

• Sympathetic (Beta-1)

  • β1 activation stimulates Na+ and Ca++ influx enhancing signal generation and increasing the rate of depolarization and impulse generation

  • Sympathetic = Faster HR

• Parasympathetic (M2 (Muscarinic))

  • M2 stimulation increases the K + efflux and decreases the Na+ influx which decreases the rate of signal generation.

  • Parasympathetic = Slower HR

When the signal travels from the atrium to the ventricle, it passes through the AV node, what is something important that happens here that facilitates the proper function of the heart?

It pauses briefly (fraction of a second), this allows for the atria to contract and fill the ventricle before the ventricle contracts

What are Arrhythmias?

Disruptions of the normal HR or Rhythm

What causes Arrhythmias?

Abnormal impulse formation, conduction, or both

Describe the difference between Bradycardia and Tachycardia, how is C.O affected during each of these scenarios?

• Tachycardia

  • HR is increased

  • The C.O is decreased because there is less time for the ventricle to fill between the beats

• Bradycardia

  • HR is slowed/blocked

  • Decreased C.O due to a decreased number of BPM

Why are anti-arrhythmic drugs only used seriously?

They can cause arrhythmias and potentially may increase the chance of death

What are the 4 classes of Anti-Arrhythmic drugs?

1. Class I: Na channel blockers

2. Class 2: Beta-blockers

3. Class 3: K channel blockers

4. Class 4: Ca channel blockers

Which class of anti-arrhythmic drug acts at each point of the graph?

1. Class 1: Na Channel Blockers

2. Class 4: Ca2+ channel blockers

3. Class 3: Potassium channel blockers

4. Class 4: Beta blockers

Class 1 chemicals are similar to _____ _______

Local Anesthetics

How do class 1 anti-arrhythmics work?

• They are Na+ channel blockers

• They decrease rapid Na influx → slows rate of depolarization in phase 0

Class 1 Anti-Arrhythmics have how many subclasses? What are they?

• 3

  • 1a

  • 1b

  • 1c

A major benefit of Class 1 Anti-Arrhythmics is that they only target what?

Block excitable cells discharging at abnormally high rates in the heart

What does “Use-Dependence“ mean in terms of Class I Anti-Arrhythmics?

Anti-Arrhythmics that bind more strongly to sodium channels at faster heart rates (They bind to open Na channels not resting ones)

What specific type of Arrhythmias are Class 1 Anti-Arrhythmics used to treat?

• Ventricular Arrhythmias

• Supraventricular Arrhythmias

How does Class 1 Anti-Arrhythmics affect the heart (what effect does their decreasing the influx of Na have)?

• Decreases HR

• Decreases conduction velocity through the atria, ventricles, and HIS purkinje fibers

What is the best drug for ventricular Arrhythmias?

Lidocaine (1B)

T/F: Lidocaine is effective in treating atrial arrhythmias

False, it is a class 1 Anti-Arrhythmic, it is effective on the ventricles

_______ is commonly used to revert ventricular arrhythmias that develop during surgery or anesthetisia

Lidocaine (In a normal heart rate, it dissociates before the next beat (safe), but in tachycardia, it stays bound to block the channel.)

What are the adverse effects associated with Lidocaine? What should be done if these signs show up?

• Nausea, vomiting, skeletal muscle fasciculation, CNS (excitement, seizures)

• Stop the CRI, Lidocaine has a very short half-life, by stopping administration you will end the adverse effects

What is known as the “Oral Lidocaine“? Why is it regarded this way?

• Mexiletine (1B)

  • It works very similar to lidocaine and they are both Class 1 Anti-Arrhythmics

Unlike lidocaine, _______ can be used as a long-term oral treatment for ventricular arrhythmias

Mexiletine

Procainamide (1A) is in the same class as Lidocaine/Mexiletine but functions differently than them, what is its function/MOA?

1. Inhibits Na (primary), K, and Alpha-1 receptors

2. Vagolytic

   1. a substance that blocks the action of the vagus nerve, which slows the heart rate

T/F: Procainamide is a good first option for treating ventricular arrhythmias

False, it is a backup to Lidocaine

How is Procainamide normally administered?

Oral (long-term)

Class II Anti-Arryhthmics are ____-Blockers

Beta-Blockers (Antagonists at Beta-1/Beta-2)

By what 3 mechanisms do Beta-Blockers (Class II) act as Anti-Arrhythmics?

• Decrease Na and Ca influx

• Depresses SA node

• Slows AV conduction

  • Decreases the ventricular response to atria

  • Increases the refractory period in conducting tissues (4)

Beta Blockers (Class II) treat arrhythmias by decreasing ________ input

Sympathetic

What are the clinical uses of Beta-Blockers?

• Arrhythmias caused by excess sympathetic stimulation

• Decreasing the ventricular rate in supraventricular or ventricular arrhythmias

• Decrease Tachycardia in hyperthyroid cats

• Feline hypertrophic cardiomyopathy

T/F: Class I and Class II Anti-Arrhythmics cannot be combined for any reason

False, they can be combined if single drug therapy is ineffective

What are the adverse effects of Beta-Blockers?

• Bradycardia

• Decreased contractility and CO

• Extracardiac effects

  • Beta-2 Bronchoconstriction

Which of these isn’t a Class II Beta Blocker?

Sotolol

What is Sotolol?

A class III Anti-Arrhythmic

Which Class II beta blocker does this describe?

• Original Non-selective product

• Short half-life (TID dosing)

• Hepatic metabolism

Propanolol

Which Class II beta blocker does this describe?

• Relatively Beta-1 selective

• Excreted unchanged by the kidneys (good for liver patients)

• Dosed q12-24h

Atenolol

Which Class II beta blocker does this describe?

• Beta-1 specific

• Liver metabolized

• High first pass effect → High inter-patient variability

• Can cause cardiovascular depression or and AV-block

Metoprolol

How do III Anti-Arrhythmics work?

• They are K+ channel blockers

• They function during phase 3

• They inhibit K+ efflux (leaving)

What is the MOA of Class II Anti-Arrhythmics?

Inhibit K+ efflux → delays repolarization → prolongs the AP → delays conduction → Increase effective refractory period → decreases ectopic activity of ventricular arrhythmias

What does ectopic activity mean?

Ectopic activity refers to premature, extra heartbeats (ectopic beats)

What type of Anti-Arrhythmic is Amiodarone? Why is it known as a “dirty drug“?

• Class III (K)

• It also has Class I (Na), Class II (Beta), and Class IV (Ca) effects

What are the dangers of Amiodarone use?

Long half-life (3.2 days) + serious Adverse effects (hepatopathy, keratopathy, dermatopathy) make for a bad combination

What are the clinical indications of Amiodarone?

• Refractory ventricular tachycardia (Amiodarone is the main treatment for)

  • a persistent, life-threatening rapid heart rhythm that resists standard treatments

• Prevent recurrence of atrial fibrillation

Which of these is a Class III Anti-Arrhythmic?

Sotolol

What is the MOA of Sotolol?

• It is a combination of

  • Class II (Beta-blocker)

  • Class III (K)

Answer the following about Sotolol

• _____ blocker at low concentrations and _______ blocker at high concentrations

• ____ administration

• ____ bioavailability

• _____ excretion

• Short-term/Long-term?

• Beta-1/2 blocker at low conditions and K channel blocker at high concentrations

• Oral

• High bioavailability

• Renal Excretion

• Can be used long-term

What are the clinical indications of Sotolol?

• Longterm for refractory ventricular tachyarrhythmias (eg boxer)

• Refractory atrial fibrillation

What are the adverse effects of Sotolol?

• Bradycardia

• Hypotension

• Arrhythmias

• GI irritation

Class IV Anti-Arrhythmics are _____ channel blockers

Calcium

What is the MOA of Class IV Anti-Arrhythmics?

Block slow Ca influx in cardiac myocytes and vascular smooth muscle

T/F: Class IV Anti-Arrhythmics are +ve Inotropes

False, they are -ve inotropes (they reduce the contractility of the heart)

What are the clinical indications of Class IV Anti-Arrhythmics?

• Supraventricular tachycardia

• Vasodilation

Class IV Anti-Arrhythmics should be avoided in patients that have what condition? Why?

• CHF

  • Because Class IV Anti-Arrhythmics reduce contractility (-ve inotrope)

Decreasing the influx of Ca into the cell by Class IV Anti-Arrhythmics has what effect on the heart?

• Slows SA firing

• Slows AV conduction

• Causes peripheral vasodilation

You should avoid using Class IV Anti-Arrhythmics with __________ in order to avoid causing bradycardia

Beta-Blockers

Diltiazem and Verapamil are both class __ Anti-Arrhytmics

IV

What is the major differences between Diltiazem and Verapamil?

• Both are Class IV (Ca) Anti-Arrhythmics

• Diltiazem

  • More Popular, less myocardial depression

  • Indications

    • Used for canine A-fib and feline HCM

• Verapamil

  • More potent -ve inotrope, -ve chronotrope (agents that decrease heart rate by affecting the electrical conduction system (specifically the SA node)), and vasodilator.

  • Higher risk of hypotension, cardiac depression, and bradycardia

  • Not a first choice

What type of Anti-Arrhythmic drug is Digoxin?

• Mechanism: Increases parasympathetic (vagal) tone to the heart.

• Use: Atrial arrhythmias (slows AV conduction).

What type of Anti-Arrhythmic drug is Isoproterenol?

• Mechanism: Non-specific beta-agonist (sympathomimetic).

• Use: Medical treatment for AV block or bradycardia that doesn't respond to atropine.

• ADR: Hypotension (Beta-2)

Anticholinergic drugs antagonize _____ receptors, what effect does this have on the heart? What is this conditional on?

• Muscarinic

• Effects of Anticholinergic drugs of heart

  • Inc sinus rate and AV conduction

• ANTICHOLINERGIC DRUG CAN’T TREAT ARRHYTHMIAS UNLESS THEY ARE CAUSED BY EXCESSIVE VAGAL TONE

What are the clinical indications of Anticholinergic drugs?

• Sinus bradycardia

• AV blocks during anesthesia

What type of Anti-Arrhythmic is Atropine Sulphate?

Antimuscarinic

What type of Anti-Arrhythmic is Glycopyrolate?

Antimuscarinic

Compare and Contrast the main functions of Glycopyrrolate and Atropine Sulphate

• Atropine Sulphate

  • Crosses the BBB

  • Mechanism: Affects the SA node and increases conduction through the AV node.

  • Indications: Good for treating bradycardia, specifically when there is a vagal component.

  • Vascular Effect: Has no significant effect on vasculature.

    • Adverse Effects (ADR):

      • CNS excitation.

      • Decreased GI contractions and urinary bladder tone.

      • Bronchodilation, mydriasis (pupil dilation), and cycloplegia (paralysis of the ciliary muscle).

      • Dry mouth.

• Glycopyrrolate

  • Doesn’t cross the BBB

  • Indications: Often used as a preanesthetic to treat sinus bradycardia, SA arrest, or incomplete AV block.

  • Adverse Effects (ADR):

    • Dry mouth.

    • Decreased bronchial secretions.

Which Anti-Arrhythmics affect Impulse generation (Phase 0 and Phase 4)?

• Class II (Beta-Blockers)

• Class IV (Ca Blockers)

What drugs are effective at treating ventricular arrhythmias short and long term?

• Short

  • Lidocain

• Long

  • Procainamide

  • Mexiletine

  • Sotalol

What drugs are effective at treating Atrial Tachycardias?

• Calcium channel blockers (Type IV)

• Beta-Blockers (Type II)

• Digoxin

Decreasing sympathetic input to the heart may be the key to prolonged survivability, what type of drugs do this?

• Beta-Blockers

• ACE inhibitors

• Spironolactone