Exam 1: Lecture 14/15, Anti-arrhythmic 1 & 2 Flashcards by Patryk Lasiuk

Class 1A drugs are…

fast Nav Channel blockers that prolong AP, little effect on phase 0 initiation

increase ERP

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Examples of Class 1A drugs…

Quinidine and procainamide

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Class 1B drugs are…

Nav channel blockers that shorten AP, limited effect on phase 0 initiation…state dependent block

decrease ERP

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Examples of Class 1B drugs….

Lidocaine, mexiletine, ranolazine

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Class 1C drugs are…

Nav channel blockers with no effect on AP length, act on initiation of phase 0….. state dependent block

No effect ERP

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Examples of Class 1C drugs….

Flecainide, propafenone

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Class 1A drugs work by…

reducing the rate and magnitude of depolarization, which decreases conduction velocity through non-nodal tissues

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Class with intermediate association/dissociation Kinetics?

Class 1A

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Class with Fast association/dissociation Kinetics?

Class 1B

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Class with slow association/dissociation kinetics?

Class 1C

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Procainamide

Class 1A, anti-arrhythmic but also local anesthetic

Voltage dependent blocker of Cardiac Ina and ikr (hERG)

Uses: Ventricular tacharrhythmias, supra ventricular tachycardia and A.fib

Can be given tablet, IM or IV

Side effects: Ventricular arrhythmia, LQT3, Bradycardia, hypotension, Drug-induced lupus

Narrow therapeutic window, any changes in weight/activity/etc can have effect

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Lidocaine

Class 1B

Indicated for IV use in ventricular arrhythmia and carioversion (= getting normal heart beat)

Potential side effects: Hypotension, bradycardia, arrhythmias

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Mexilatine (Mexitil)

Class 1B, anti-arrhythmic..oral analogue of lidocaine

uses: ventricular tachyarrhythmias (especially confirmed cases of LQT3), some types of chronic pain

state dependent blocker

Side effects: Ventricular arrhythmia, bradycardia and hypotension

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Flecainide (Tambocor)

Class 1C anti-arrhythmic

** Suitable for children **

Uses: superventricualr tachycardia, Wolff-Parkinson White Syndrome, Brugada Syndrome

Side effects: Hypotension, bradycardia, arrhythmias

Avoid in pt with left ventricular hypertrophy, other form of HF, atherosclerosis….reduces ejection fraction + CO

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Sotalol

Class 2 = beta blockers but also Class 3 = K+ channel blocker (increase AP duration)

B1/B2 antagonist,

Suitable for ventricular tachycardia and A.fib

Side effects: Dizziness, Headache, Shortness of breath, Bradycardia, Arrhythmia

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Amiodarone

Class 3 = K+ channel blocker

** Blocks hERG and CaV channels ***

Uses: V-tachycardia, V-fib, A-fib, and supra ventricular tachycardia

Side effect: can cause anti-thyroid acton due to similar structure to thyroxine, Hypotension, Bradycardia, arrhythmias

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Dronedarone

Multaq

non-ionidated version that lacks the thyroxine complication but has worse outcomes in patients with HF

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Verapamil

Class 4 = Calcium channel blocker (reduce AP duration)

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Adenosine

Class 5 = other

Commonly used IV for terminating Superventricualr tachycardia

can cause temporary cardiac systole

Acts at Adensoinde A1-receptors (Gai coupled…reduce cAMP/activate Girk) in the AV node leading to hyperpolarization

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What is an arrhythmia?

change in velocity and/or route of AP conduction through the tissue

caused by disruption to the conduction system of the heart

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congenital arrhythmias:

Mutations, polymorphisms or structural changes that you’re born with

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Acquired arrhythmias:

primary or secondary disease process; can also be structural.

ie. left ventricular hypertrophy, adverse effects of a drug or signaling molecule in the conduction pathway.

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Heart rate is controlled autonomously by….

Parasympathetic and sympathetic activity

intrinsic and integrated feedback from chemoreceptors

changes in either increase or decreasing heart rate

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Cardiac conduction pathway

Starts at SA node “pacemaker cells”

Then goes to AV node, then Purkinje fibers conduct AP through and into ventricular muscle

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Multiphase cardiac depolarization

1. Depolarize atria 2. Depolarize septum from left to right 3. Depolarize anteroseptal region of myocardium toward the apex 4. Depolarize bulk of ventricular myocardium, from endocardium to epicardium 5. Depolarize posterior portion of base of the left ventricle 6. The ventricles are now depolarized

Multiphase cardiac depolarization

Negative chronotropes will...

decrease heart rate

positive chronotropes will...

increase heart rate

Negative Chronotrope drugs

``` B blockers M2 receptor agonist (acetylcholine) Digoxin Non-dihydropyridine CaV blockers (diltiazem and verapamil) Adenosine (at A1-receptors) ```

Positive chronotrope drugs

``` Most B-receptor agonist M2 receptor antagonists (atropine) Milrinone Theophylline Caffeine (a1 antagonist) ```

Dromotropic drug will...

affet AV node conduction ``` + = increase conduction - = decrease conduction ```

Phase 0

upstroke of the AP (Ica is slower than Ica+Ina)

Phase 1

Rapid depolarization, inactivation of Ica/Ina and activation of outward K+ current (Ito)

** Phase 2 **

plateau phase in ventricle. duration depends on cintuned entry of Ca or Na, with NA/Ca exchanger NCX1

Phase 3

depolarization due to multiple K+ channel currents

Phase 4

Electrical diastole Negative Vm, In SA/AV nodal cells, If depolarized Vm leading to regenerative action potentials

Most Prominent cardiac membrane protein channel

K+, hERG

How does action potential pass from cell to cell?

via connexions One cell will depolarize, and cause next cell to depolarize but slightly less, and so on and so on. signal is fo about 6 cells, but must effect lost after 3

Connexins and A.Fib

A.Fib can be associated with a change in number of connexions between cells or Change in connexion distribution, particularly lateralization

Current definition of Bradycardia

HR <60 BPM

Current definition of tachycardia

HR > 100 BPM

Supraventricualr tachycardia

> 150 BPM, decreases CO....really dangerous

Fibrillation

irregular heart rhythm in the atria or ventricles (A-Fib, V-Fib

Atrial Fibrillation (A-Fib)

most common random impulse cause atrial muscle to fibrillate create local circuits, electricity travels in atria in chaotic fashion causing upper chambers to quiver prevalence increase with age and following general anesthesia

Atrial Flutter

Originate across larger areas of the atrium heart contracts rapidly but with a regular rhythm

Supraventricular tachycardias (SVT)

hard to control with med, usually requires ablation (using paddles to "reset" heart.

Wolfe Parkinson White Syndrome

alternative pathway exists between the atria and ventricles known as "Bundle of Kent" also known as Atrioventricular reciprocating tachycardia

Tachycardia

rapid ventricular contractions may limit CO and reduce blood flow to the body

Ventricular Fibrillation (V-Fib)

Most serious random/chaotic impulse in ventricular walls ventricle "quivers" instead of beats = no blood to aorta requires immediate medical attention

Bradycardia

slow HR Can be due to slowing or failure of the SA node to initiate an impulse (too little SNS or too much PNS activity, physical damage to heart) also can be due to blockage of signal from SA node (due to damage or dysfunctional AV node)

Causes of arrhythmia

Structural changes to the myocardium Dysregulation of intrinsic, integrated,autonomic responses Ion channel issues

Gene: SCN5A

Protein: Nav1.5a subunit Channel: Nav1.5 (contains B subunit) Current: Ina

SCN5A mutation gain of function:

LQT3

Gene:KCNQ1

Protein:Kv7.1 a subunit Channel: IKs (contains KCNE1 subunit) Current: iks

KCNQ1 mutation loss of function:

LQT1

Gene:KCNH2

Protein:Kv11.1a subunit Channel:hERG CurrentL Ikr

KCNH2 mutation loss of function:

LQT2

Long QT3 due to....

gain of Nav1.5 channel function increasing the late current of Nav1.5 channels opposes depolarization of cardiomyocytes

Drug-induced arrhythmia

Hydroxychloroquine found to increase that's why drugs are tested to see if they interact with hERG mostly issue for aging population, not young adults

Long QT2 due to...

loss of function or drug interactions with hERG channels

Long QT syndrome....

reduced K+ current, slowing repolarization (phase 3)

Short QT syndrome...

increased K+ current, repolarization (phase 3) is speed up

Long QT1 due to...

mutations in the KCNQ1 subunit of the IKs K+ channel Most common

Jervell and Lange-nielsen syndrome

Long QT syndrome that manifests with sever, bilateral hearing loss caused by specific mutations in Kv7.1 505 mortality by 15 yrs old if untreated most serious form of LQTS