Exam 1: Lecture 14/15, Anti-arrhythmic 1 & 2 Flashcards
Class 1A drugs are…
fast Nav Channel blockers that prolong AP, little effect on phase 0 initiation
increase ERP
Examples of Class 1A drugs…
Quinidine and procainamide
Class 1B drugs are…
Nav channel blockers that shorten AP, limited effect on phase 0 initiation…state dependent block
decrease ERP
Examples of Class 1B drugs….
Lidocaine, mexiletine, ranolazine
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
Examples of Class 1C drugs….
Flecainide, propafenone
Class 1A drugs work by…
reducing the rate and magnitude of depolarization, which decreases conduction velocity through non-nodal tissues
Class with intermediate association/dissociation Kinetics?
Class 1A
Class with Fast association/dissociation Kinetics?
Class 1B
Class with slow association/dissociation kinetics?
Class 1C
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
Lidocaine
Class 1B
Indicated for IV use in ventricular arrhythmia and carioversion (= getting normal heart beat)
Potential side effects: Hypotension, bradycardia, arrhythmias
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
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
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
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
Dronedarone
Multaq
non-ionidated version that lacks the thyroxine complication but has worse outcomes in patients with HF
Verapamil
Class 4 = Calcium channel blocker (reduce AP duration)
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
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
congenital arrhythmias:
Mutations, polymorphisms or structural changes that you’re born with
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.
Heart rate is controlled autonomously by….
Parasympathetic and sympathetic activity
intrinsic and integrated feedback from chemoreceptors
changes in either increase or decreasing heart rate
Cardiac conduction pathway
Starts at SA node “pacemaker cells”
Then goes to AV node, then Purkinje fibers conduct AP through and into ventricular muscle
Multiphase cardiac depolarization
- Depolarize atria
- Depolarize septum from left to right
- Depolarize anteroseptal region of myocardium toward the apex
- Depolarize bulk of ventricular myocardium, from endocardium to epicardium
- Depolarize posterior portion of base of the left ventricle
- The ventricles are now depolarized
Multiphase cardiac depolarization
- Depolarize atria
- Depolarize septum from left to right
- Depolarize anteroseptal region of myocardium toward the apex
- Depolarize bulk of ventricular myocardium, from endocardium to epicardium
- Depolarize posterior portion of base of the left ventricle
- The ventricles are now depolarized
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
