Arrhythmias and Pharmacology Flashcards Preview

CVPR Exam 1 > Arrhythmias and Pharmacology > Flashcards

Flashcards in Arrhythmias and Pharmacology Deck (77):
1

The vast majority of the time arrhythmias are due to what phenominae?

• Myocardial infarction
• Ischemia
• Acidosis
• Alkalosis
• Electrolyte abnormalities
• Excessive catecholamine exposure
• Drug toxicity

2

What were the named drugs that can lead to arrhythmias?

• Cardiac glycosides
○ digoxin
• Antihistamines
○ Astemizole
○ terfenadine
• Antibiotics
○ sulfamethoxazole

3

What are the primary targets of antiarrhythmic drugs?

• Cardiac channels
○ Sodium channel
○ Calcium channels
○ Potassium channels
• Beta Adrenergic receptors (GPCRs)
○ These modulate (often) the actions of the cardiac channels

4

What channels are INDIRECT targets of Beta blockers?

• I-f
• I-Ca-L
• I-K-s
○ They end up slowing heart rate by slowing conduction velocity and elongating relative refractory periods

5

What is the definition of familial long QT syndrome?


• Prolongation of the duration of the cardiac action potential
• Predisposition to ventricular arrhythmia and sudden death
• Prolongation of phase 2

6

What is the treatment of long QT syndrome and why?

• Beta blockers. They lower sympathetic tone
• They also reduce heart rate by slowing conduction velocity and elongating the refractory period. This decreases the chances of reentry and arrhythmia
• Sympathetic innervation triggers the problems associated with long QT syndrome

7

What channel, when blocked, leads to prolongation of phase 2?


• Phase 2 is the plateau phase
• Blocking I-K-r is the best way to prolong 2
• I-k-r is the rapid delayed rectifyer, responsible for initial repolarization phase

8

What is the visual difference between Torsades de pointes and V-fib?

• In the EKG, torsades de points has big amplitude, an area of skinny amplitude, then big amplitude again
• V-fib is an indeterminate squiggly line

9

What genes are most commonlly mutated in Long QT syndrome?

• LQT1
○ I-k-s
• LQT2
○ I-k-r
• LQT3
○ I-Na

10

What are the three important polarizing channels?

• I-Na
• I-Ca-L
• I-NCX

11

What are the 4 important repolarizing channels?

• I-k-1
• I-to
• I-k-r
• I-k-s

12

Can you draw the current diagrams for the following REPOLARIZING channels?

• I-k-1
• I-to
• I-k-r
• I-k-s

13

What does I-NCx mean?

• The electrogenic Na/Ca exchanger in cardiac myocytes

14

What is the potassium current that ends the plateau phase of the action potential?

• I-k-r + I-k-s
○ The delayed rectifier currents both play important roles in phase 3
• Long QT mutations often result in a loss of fxn in these channels

15

How can alteration of a Na channel lead to prolonged plateau?

• If you remove inactivation (like in a Long QT syndrome mutation) the sodium influx is too long

16

What should be done 1st before deciding on a treatment regimen for a long QT syndrome patient?

• Molecular characterization of the mutation
• You don't want to use the wrong drug which may just compound the problem, not fix it

17

What type of drug should be used for LQT1,2,3 mutations?

• LQT1 and 2
○ Potassium channel OPENER (non currently exist)
○ So NOT potassium channel blocker
• LQT3
○ Sodium channel blocker, since this mutation leaves the sodium channel open longer by messing with the inactivation gate

18

What's up with Brugada syndrome?


• Easily triggered V-fib because of many different sodium channel mutations

19

How might changing a PKA binding site on a potassium channel lead to problems?

• Problems here are afterdepolarizations and arrhythmias
• Phase 2 is prolonged
• PKA is the effector kinase of beta-adrenergic receptors, normally increased calcium and potassium channel sensitivity
• Without the increased potassium permeability, but still the increased calcium permeability by PKA phosphorylation, you could have membrane potential problems

20

What are the two fundamental problems with arrhythmias?

• Inappropriate impulse initiation (SA or ectopic)
• Disturbed impulse conduction (anywhere)
○ Allows for the possibility of re-entry if there is a unidirectional block

21

What are the two general causes of inappropriate impulse initiation?

• Ectopic foci (out of the SA or AV node)
• Triggered afterdepolarizations
○ EADs (early afterdepolarizations)
○ DADs (delayed afterdepolarizations)

22

What might lead to a DAD?

• Increased concentration of calcium in the cell
• I-NCX is in overdrive and that brings the membrane closer to threshold (and over it)

23

Why does the presence of a previous infarct lead to membrane depolarization?

• Na/k ATPase has failed there since the cell is dead
• This alters the postassium concentration in the cell and keeps it closer to threshold
• Depolarization is the result

24

What might lead to an EAD?

• Increased intracellular calcium will lead to increased activation of Calcium channels
• This will drive the cell to threshold

25

Can you draw what might happen if I-NCX is working overtime?

• Start with normal action potential curve
○ Phase 0,1,2,3,4
• During phase 4, I-NCX is moving the membrane potential towards threshold pumping Calcium out and sodium in, which is net current IN

26

What are the 2 general causes of disturbed impulse conduction?

• Conduction block
• Re-entry
○ Requries a unidirectional block in a functional circuit and also requires that conduction time around that circuit is greater than refractory period
○ Thus the treatment of re-entry by prolonging refractory period

27

In many cases, what initiates the arrhythmia and what MAINTAINS the arrhythmia?

• Initiated by afterdepolarization
• Maintained by re-entry

28

Increasing inward current does the same thing as decresing outward current during the cardiac action potential…what is it?

• Prolongs phase 2, or the plateau phase
• This can be dangerous as hovering closer to threshold can trigger after depolarizations which can result in arrhythmias

29

What does the Vaughn williams drug classification scheme actually tell us?


• The effects of drugs, not really classifying the drugs themselves
• Drugs can have several effects, but the classification scheme says it's DOMINANT one
• So, if a drug is Class1a, that's the dominant effect but it can have other effects

30

What's the difference between class 1 drugs?

• 1a, 1b,1c drugs - all have a little bit of activity against potassium channels
• A - moderate sodium channel block
○ Slows phase 0 and prolongs repolarization
• B - mild sodium channel block
○ Mostly lengthens repolarization
○ Little bit of phase 0 slope change
• C - Really blocks those sodium channels
○ Very slow phase 0 and not much else

31

What is the primary action of all Class 1 drugs?

• Blocking voltage gated Na channels
• To a lesser extent, L-type Calcium channel blockage
• This lowers the conduction rate, and increases the refractory period
• If one of these mechanisms works to decrease re-entry, it works!

32

What does the Vaughn williams drug classification scheme actually tell us?


• The effects of drugs, not really classifying the drugs themselves
• Drugs can have several effects, but the classification scheme says it's DOMINANT one
• So, if a drug is Class1a, that's the dominant effect but it can have other effects

33

What's the difference between class 1 drugs?

• 1a, 1b,1c drugs - all have a little bit of activity against potassium channels
• A - moderate sodium channel block
○ Slows phase 0 and prolongs repolarization
• B - mild sodium channel block
○ Mostly lengthens repolarization
○ Little bit of phase 0 slope change
• C - Really blocks those sodium channels
○ Very slow phase 0 and not much else

34

What is the primary action of all Class 1 drugs?

• Blocking voltage gated Na channels
• To a lesser extent, L-type Calcium channel blockage
• This lowers the conduction rate, and increases the refractory period
• If one of these mechanisms works to decrease re-entry, it works!

35

Class 1a and 1c drugs have one extra secondary action that 1b drugs do not…?


• Potassium channel blockage
• Results in lengthening phase 2

36

What is one possible SCARY side effect of Quinidine?

• Quinidine causes a dose-related QT interval prolongation, which may lead to increased ventricular automaticity and polymorphic ventricular tachycardias 

37

What does quinidine do?

• class 1A anti-arrhythmic.
• Within cardiac muscle and Purkinje fibers, quinidine depresses the inward depolarizing sodium current, thereby resulting in slowed conduction and reduced automaticity while increasing effective refractory period in the atria, ventricles, and Purkinje fibers.
• Quinidine can prevent or interrupt reentrant arrhythmias and arrhythmias caused by increased automaticity, including atrial flutter, atrial fibrillation, and paroxysmal supraventricular tachycardia by slowing cardiac conduction and prolonging the effective refractory period.
• Quinidine causes a dose-related QT interval prolongation, which may lead to increased ventricular automaticity and polymorphic ventricular tachycardias 
• Quinidine also displays anticholinergic, alpha-adrenergic antagonist and negative inotropic activity
What conditions are treated with quinidine?
• Quinidine can prevent or interrupt reentrant arrhythmias and arrhythmias caused by increased automaticity,
• including atrial flutter, atrial fibrillation, and paroxysmal supraventricular tachycardia by slowing cardiac conduction and prolonging the effective refractory period.

38

What are the three drugs we talked about as Class 1a Sodium channel blockers?

• Quinidine
• Procainamide
• Disopyramide

39

What does Procainamide do?

* IV class 1a antiarrhythmal drug
* Procainamide, a class 1a antiarrhythmic, increases effective refractory period and reduces impulse conduction velocity and excitability in the atria, His-Purkinje fibers and ventricular muscle of the heart.
*This is caused by an increase in excitability threshold combined with inhibition of ectopic pacemaker activity. Therapeutic levels of procainamide exert weak vagal activity and do not usually affect cardiac contractility

40

What does Disopyramide do?

* Ventricular arrhythmia, Life-threatening -
rapid control, immediate-release, patients greater than 50 kg, 300 mg ORALLY followed by appropriate maintenance dose
* Disopyramide phosphate is a type 1 anti-arrhythmic drug that decreases rate of diastolic depolarization (phase 4) in cells with augmented automaticity,
* also decreases all myocyte upstroke velocity (phase 0), and the disparity in refractoriness between adjacent normally perfused and infarcted myocardium.
*increases the action potential duration of normal cardiac cells and has no effect on alpha- or beta-adrenergic receptors

41

Class 1a drugs can be expected to do what?




• Slow phase 0 (upstroke) because of sodium channel block
○ All class one drugs block sodium channels
• Also, to a lesser extent they delay repolarization because of potassium channel block
○ All 1a drugs have a class 3 effect

42

What are the 3 class 1b sodium channel blockers we discussed?

• Lidocaine
• Mexiletine
• phenytoin

43

What are the effects of Quinidine NOT sodium channel related?

• Potassium blockage to a fair degree (prolongs AP duration)
• Vagal inhibition
• Alpha-adrenergic receptor antagonist

44

By what 2 processes do Class 1a drugs increase refractory period?

• Classic, use-dependent mechanism (open channels are now inactivated by drug)
• Deploarization potential is prolonged (phase 2 prolonged)

45

All Class 1a drugs have a [blank] effect?

• All 1a drugs have a class 3 effect

46

What is lidocaine and what does it do?

Class 1b antiarrhythmal drug
* Lidocaine blocks both initiation and conduction of nerve impulses by decreasing ionic flux through the neuronal membrane by blocking sodium channels, which results in local anesthesia [10]. The mechanism by which lidocaine depresses arrhythmias may be its ability to depress conduction in ischemic myocardium rather than to improve conduction or to suppress the normal or abnormal automaticity
* FDA approved for ventricular arrhythmia and fibrillation

47

What is mexiletine and what does it do?

Class 1b antiarrhythmal drug
* Ventricular arrhythmia, Life-threatening-
rapid control, loading dose, 400 mg ORALLY then 200 mg ORALLY in 8 hours
* Mexiletine hydrochloride is a local anesthetic and Class 1B antiarrhythmic agent that has structural and pharmacological similarities to lidocaine. Mexiletine hydrochloride reduces the rate of rise of the action potential, Phase 0, by inhibiting the inward sodium current. The drug lowers the effective refractory period (ERP) in Purkinje fibers to a lesser degree than the reduction in action potential duration (APD), resulting in an increase in the ERP/APD ratio

48

What is phenytoin and what does it do?

* primarily an anti-seizure med
also a Class 1b antiarrhythmal drug, sodium channel blocker
* Phenytoin is an antiepileptic drug that possibly enhances sodium efflux from neurons of the motor cortex. This cellular event tends to stabilize the threshold against hyperexcitability that results from excessive stimulation or environmental changes capable of reducing membrane sodium gradient. Posttetanic potentiation at synapses is then reduced preventing cortical seizure foci from detonating adjacent cortical areas

49

What do class 1a drugs do that class 1b drugs do NOT?



• 1a prolongs phase 2, 1b does not
• 1b are "purest" of class 1 drugs on 1st response
○ Pure sodium channel blockage
• 1b are still able to increase refractory period by slowing repolarization

50

What do Class 1c drugs do?

• Use dependent blockers of sodium channels
• Greatest effect on phase 0 slowing, mild phase 2 prolongation
• The net effect is powerful increase in refractory period

51

What 3 important Class 1c drugs did we discuss?

• These are class 1 so they are sodium channel blockers
• Use dependent blockers of sodium channels
• Greatest effect on phase 0 slowing, mild phase 2 prolongation
• The net effect is powerful increase in refractory period
• Propafenone
• Flecainide
• Encainide

52

What Class 1b drug is most clinically important in treating antiarrhythmias?

• Lidocaine

53

What is propafenone and what does it do?

* Class 1c antiarrhythmal drug
* Atrial fibrillation - Chemical cardioversion
(pill-in-the-pocket) a single dose of propafenone 600 mg (body weight 70 kg or more), and propafenone 450 mg (body weight less than 70 kg) [3]; prior to antiarrhythmic initiation, a beta-blocker or nondihydropyridine calcium channel antagonist should be administered to prevent rapid atrioventricular conduction if atrial flutter occurs
* Propafenone hydrochloride is a Class1C antiarrhythmic agent which has local anesthetic effects and stabilizing action on myocardial membranes. It reduces the upstroke velocity (Phase 0) of the monophasic action potential, spontaneous automaticity, and the fast inward current carried by sodium ions in Purkinje fibers. It also prolongs effective refractory period and increases the diastolic excitability threshold

54

What is Flecainide and what does it do?

* Class 1c antiarrhythmal drug
* Paroxysmal supraventricular tachycardia; Prophylaxis
initial, 50 mg ORALLY every 12 hours [2]
titration, increase by 50 mg ORALLY twice daily at intervals of at least 4 days to a MAX daily dose of 300 mg
* Flecainide acetate is a class I C antiarrhythmic drug that possesses local anesthetic and electrophysiologic activity indicated for paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation/flutter (PAF), and ventricular arrhythmias

55

What is Encainide and what does it do?

* Class 1c antiarrhythmal drug
* used in Supraventricular arrhythmia
* Like flecainide, encainide has been classified as a type IC antiarrhythmic agent and demonstrates potent sodium channel blockade [187]. It has minimal effects on cardiac action potential duration and produces a marked decrease in the maximum upstroke velocity of phase 0 of the action potential

56

What conformation does a class 1 drug force a sodium channel into?

• Inactivation. It stabilizes the inactivated conformation, slowing recovery from inactivation
• This prolongs the refractory period and helps with the arrhythmia

57

How do Class 1 drugs achieve their goal of supressing re-entry?

• Making unidirectional block bi-directional
○ Slowing phase 0 and lowering force of AP
• Increasing refractory period so that conduction time through the block is now shorter than refractory period

58

Why does decreasing the slope of phase 0 lead to a slower conduction velocity?

• Lower upstroke means lower potential change and lower ACTIVE CURRENT
• The current drives neighboring channels to open and propogate AP
• You are making it harder for one channel to lead to the activation of its neighbors

59

How does slowed conduction velocity lead to the creation of a bi-directional block from a uni-directional block?

• In the depressed region, retrograde or circus reentry is more likely to fail
• It slows the already slow retrograde flow and increases the chances it won't propogate through the problem area

60

What is the other name for class II antiarrhythmic drugs?



• Beta-blockers

61

What is the net result of Beta blocker action?

• They reduce I-f, I-Ca-L, I-K(r+s)
• Reduce rate of diastolic depolariazation in pacemaker cells
○ Functionally reduce heart rate
• Reduce upstroke rate
• Slow repolarization in AV node
• Pacing rate reduced, refractory period prolonged

62

What are the 3 beta blocker drugs we discussed?

• Propanolol
• Metoprolol
• Esmolol

63

What are the 5 class III drugs we discussed?



• Ibutilide
• Defetilide
• Amiodarone
• Sotald
• Bretylium

64

Sotalol has what unique property?

• It's a class III drug that is structurally related to a class II drug and thus has the added Beta-blocker activity

65

Amiodarone is a bit unique as a class III drug…why?

• Reduces conduction velocity AND increases refractory period by blocking sodium channels
• Also decreases diastolic depolarization (phase 4) in SA and AV nodal cells

66

What is the mechanism of action for class III drugs?

• Primarily, to increase refractory period
• Prolong phase 2 by blocking potassium channels
• Prolonging phase 2 will lead to a greater percentage of depolarizing channels being rendered inactive

67

What do class IV drugs target?


• Calcium channels. Usually L-type calcium channels

68

How do class IV drugs work?

• Slow upstroke in nodal cells
• Decrease the rate of firing and thereby decrease heart rate
• Slow conduction velocity (AV node)
Indirectly inhibit potassium channel activation, increasing refractory period

69

What are the 2 class IV drugs we discussed?

• Verapamil, diltiazem

70

What is the all important classless antiarrhythmic drug?


• ADENOSINE

71

Acetylcholine and adenosine both act on what channel?

• I-K-Ach

72

What does adenosine do?

• Similar in function to Beta blocker but it doesn't block the beta-adrenergic receptor
• Increases potassium current
• Decreased I-Ca-L
• Decreased I-f
• Binds to Gi-coupled receptor
○ Antagonizes the beta-adrenergic receptor's Gs stimulation

73

What is the only disease condition that warrants primary use of antiarrhythmic drugs?

• Atrial fribrillation
• Ablation or ICD is currently thought to be equal in efficacy

74

How do you treat atrial fibrillation?

• Acute
○ AV nodal blockers
○ Electrical cardioversion (shock)
• Chronic
○ AV nodal blockers and anticoagulation (warfarin)
○ Cardioversion (electrical, ibutilide) and mainanence of sinus rhythm by drugs
○ Class III and Class 1c drugs

75

How do you treat PSVT?

• PSVT = paroxysmal supraventricular tachycardia (re-entry disease)
• Acute
○ Adenosine (super short 1/2 life)
• Chronic
○ Class II
○ Class IV
○ Class III (amiodarone, sotalol)
○ Digoxin
• Catheter ablation of ectopic focus

76

How do you treat Ventricular Tachycardia/fibrillation?

• This is an afterdepolarization and re-entry disease
• Acute
○ Amiodarone, lidocaine, procainamide (class III and II)
• Prevent sudden cardiac death
• Beta blockers and ACEI WILL help (with pressure lowering drugs like aspirin, statins)
• DON'T USE class 1 and 4 drugs

77

What is digoxin and what does it do?

Digoxin inhibits sodium-potassium ATPase, which increases intracellular sodium concentration leading to increased intracellular calcium concentration. Autonomic effects of this include vagomimetic action and baroreceptor sensitization which lead to positive inotropic action, reduced sympathetic response and decreased renin-angiotensin system output (neurohormonal deactivation)
* used for atrial fibrillation and heart failure mostly (micromedex)