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Pharmacology > Antiarrhythmic Drugs - part 2 > Flashcards

Antiarrhythmic Drugs - part 2 Flashcards

1
Q

What currents can be/are modulated by beta AR activity?

A

the two key currents of pacemaker APs

  1. L-type Ca+ for upstroke (0)
  2. “funny” currents (4) that spontaneously depolarize

these are important for setting HR

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2
Q

Explain the way in which B-adrengeric receptors accomplish their signaling to HCN in pacemaker cells

What does this mean for the cell and the ability to conduct?

A

bAR stimulation resulints in increased cAMP formation, which directly increases the activity of hyper polarized activated cyclic-nucleotide gated cation channels (HCN)
–> this results in increased depolarizating currents during phase 4 of the AP and helps return the cell to firing threshold sooner

HCM modulated by

  • cAMP –> more cAMP, more easily it will conduct
  • membrane potential –> more depolarized channel opens better
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3
Q

Explain the relationship between Ca2+ channels and the bAR

A

bAR stimulation and cAMP formation also increased protein kinase A activity, which increases phosphorylation of L-type voltage gated calcium channels
–>this increases the ant of current these channels can pass and also allows them to open are more negative membrane potentials

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4
Q

Blockade of Beta adrengeric receptor signaling in pacemaker cells results in …

A
  1. Decreased Ca activity –> slows 0 upstroke phase
  2. L-type voltage gated Ca channels now have to depolarize more in order to open –> AP will fire less frequently
  3. Decreased diastolic pacemaker current due to dec HCN channel activity –> slope of 4 flattens –> longer to return to threshold
  4. AP slightly wider, so increased ERP
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5
Q

What do cardioselective b-blockers preferentially inhibit?

A

beta 1 adrenergic receptors in the heart

and not B2 or alpha receptors

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6
Q

Which B-blockers are often used as anti-arrhythmics

A 
Esmolol
Acebutolol
Propanolol
(Sotolol)
others can be used too
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7
Q

Esmolol

A

Cardioselective (B1)
Short half life (due to plasma esterase hydrolysis)
Given IV

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8
Q

Acebutolol

A

Cardioselective
Weak partial agonist at B1AR (sympathomomimetic)
Weak Na+ channel blockade

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9
Q

Propanolol

A

Non-selective

Weak Na+ channel blockade

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10
Q

Clinically, when are B-blockers used?

A

Arrhythmias involving catecholamines
Atrial arrhythmias (protect ventricular rate)
Post MI prevention of ventricular arrhythmias
Prophylaxis in long QT syndrome

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11
Q

Recall, in the pacemaker cells, which current in responsible for the upstroke?
What is the implication of this?

A

Calcium channels - iCaL - phase 0

Blocking L-type voltage gated Calcium channels should therefore provide some specificity for controlling the upstroke of pacemaker cells but should do little to manipulate the excitability of myocytes

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12
Q

What effects does a calcium channel blockade have?

A

Slows the pacemaker AP upstroke
Makes the firing threshold a more depolarized voltage

AP amplitude may be diminished
AP width is increased
–> ERP is increased

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13
Q

Which calcium channel blockers are used as anti-arrhythmics?

A

Verapamil

Diltiazem

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14
Q

MOA of verapamil, diltiazem

A

Frequency dependent block of Cav1.2 channels
Selective block for channels opening more frequently
Accumulation of blockade in rapidly depolarizing tissue
– i.e. heart in tachycardia

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15
Q

Clinically, when are Ca channel blockers used?

A

Block re-entrant arrhythmias involving AV node

CHIEFLY used to protect ventricular rate in a flutter and a fib

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16
Q

What effect on the ECG do both B blockers and Ca channel blockers have?

A

Increase PR interval

  • increase AV refractoriness
  • slow phase 0 (ca+ current)
  • slow phase 4 (HCN current)

See summary slide in notes for more

17
Q

Class I drugs have different binding affinities for the different states of the ion channel. Differentiate between them.

A

Ia - O > I

Ib - I&raquo_space; O

Ic - O

18
Q

Important points about class IA

A 
Mixed blockade: Na+ and K+
Preferentially blocks open state
Moderate, incomplete dissociation (seconds)
Widens QRS
Prolongs QT
19
Q

Important points about class IB

A 
Na+ channel block
Blocks open and inactivated state
Rapid, complete dissociation (milliseconds)
Slight narrowing of AP
No clinically significant effect on ECG
20
Q

Important points about class IC

A

Strong Na+ channel block
Blocks open state
Very slow, incomplete dissociation (> 10 seconds)
Widens QRS

21
Q

Class I drugs are helpful in controlling arrhythmias by doing one or more of the following

A
  1. Suppress ectopic pacemaker activity
  2. Suppress aberrant activity arising from damaged tissue such as ischemic tissue
  3. Abolish re-entry circuits
22
Q

How can class I drugs suppress the ectopic focus?

A
  1. blocking HCN channels that produce phase 4 pacemaker current
  2. blocking sodium channels to slow conduction in the ectopic focus –> increases firing threshold
  3. increasing refractoriness via K+ channel block properties of class IA
23
Q

How can class I drugs suppress activity of damaged tissue in which there is rapid heart rates?

A

Frequency dependent blocks

Normally, class I drugs dissociated from channels between beats, but in cells firing rapidly, there is no time to dissociate
Therefore each AP results in more and more channels being blocked --> eventually this silences activity from these cells

Note: these drugs spare normal electrical activity while controlling inappropriately high rates of depolarization

24
Q

How can class I drugs suppress activity of damaged tissue in which there is a depolarized membrane potential?

A

Voltage dependent block

Depolarized membrane potentials significantly increased the number of channels that are constitutively in the inactivated state –> this increases the number of channels that are blocked by class I drugs, which slows electrical activity selectively in this depolarized tissue

25
Q

How can class I drugs abolish re-entry arrhythmias?

A

Class 1 drugs will increase the amount of time it takes for sodium channels to recover from inactivation, which can prolong the ERP of the cell

If conduction is slowed enough, retrograde impulses will encounter refractory tissue

26
Q

Class IA drugs

A

Quinidine
Procainamide
Disopyramide

27
Q

Quinidine

A

2-8% risk of Torsades de Pointes

Anti-muscarinic activity

28
Q

Procainamide

A

Lupus-like syndrome

Ganglionic blocker

29
Q

Disopyramide

A

Anti-muscarinic activity

30
Q

Class IB drugs

A

Lidocaine

Mexiletine

31
Q

Lidocaine

A

IV only; not effective orally

Among top choices for rapid control of ventricular arrhythmias

Only ventricular, not atrial

32
Q

Mexiletine

A

Orally available, similar to lidocaine in efficacy

33
Q

Class IC drugs

A

Flecainide

Propafenone

34
Q

Flecainide

A

Ventricular and supra ventricular

Orally available

35
Q

Propafenone

A

Ventricular and supra ventricular
B-AR blocking activity
Orally available

Pharmacology (45 decks)

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