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Drug Action I > Block 3 - Antiarrhythmics Med Chem > Flashcards

Block 3 - Antiarrhythmics Med Chem Flashcards

1
Q

What are pharmacology properties of having a more lipophilic drug?

A
  1. Bind to plasma proteins
  2. High volumes of distribution
  3. Longer duration
  4. Long half life
  5. Rapidly absorbed
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2
Q

What are pharmacology properties of having a more basic drug?

A
  1. Amines with pKa of 8-10 is charged at physiological pH
  2. Low bioavailability
  3. Charged can’t cross membranes easily
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3
Q

What are arrhythmias?

A

Alteration in normal sequence of electrical impulse rhythm that leads to contraction of myocardium

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4
Q

What abnormalities does arrhythmias affect?

A
  1. Rate
  2. Impulse origination site
  3. Conduction through myocardium
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5
Q

What are the Antiarrhythmic drug classes?

A
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6
Q

Compare the 3 Class I?

A
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7
Q

What is the APD and Kinetics of Class IA? Drug class?

A

Prolonged APD; intermediate dissociation kinetics

Slow phase 0 depolarization

Na+ channel blockers

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8
Q

What are Class IA?

A
  1. Quinidine
  2. Procainamide
  3. Disopyramide
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9
Q

What is the physiological properties of quinidine?

A
  1. Basic nitrogens (pKa 11)
  2. Water soluble salt (sulfate or gluconate)
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10
Q

Which has better IV and PO/IM capabilities?

A

Gluconate more water soluble → better for emergenies (injectable), sulfate usually oral or IM

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11
Q

What are DDIs of quinidines?

A
  1. P-gp substrate -> inhibits renal tubular secretion of digoxin
  2. Increases plasma levels of digoxin
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12
Q

What is the contaminate that contributes to quinidine’s effectiveness?

A

Dihydroquinidine

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13
Q

How does Dihydroquinidine contribute to quinidines activity?

A
  1. Reduction of vinyl group to an ethyl
  2. More potent as an anti arrhythmic, but more toxic
  3. Commercial preps can vary based on levels of contaminant
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14
Q

How was procain modified for better efficacy? What was the new drug called?

A

Procainamide replaces an ester with an amide which is more resistant to esterase hydrolysis

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15
Q

How is procainamide metabolisized and why is this significant?

A

N-acetyltrasferase has genetic variations

Slow acetylators → elevated levels → drug induced lupus syndrome

Metabolite also implicated in torsades de pointes

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16
Q

How does disopyramide differ from procainamide?

A

Has anti-cholinergic effects due to its struccutral similarities

Receptors prefer a tertiary amine with a 2-4 carbon distance from 2 different rings

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17
Q

What is the APD and kinetics of Class IB?

A

Shortens (or no effect) APD; rapid dissociation from sodium channels

Shortens Phase 3 repolarization

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18
Q

What are the drugs in IB?

A
  1. Lidocaine
  2. Tocainide
  3. Mexiletine
  4. Phenytoin
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19
Q

How is lidocaine dosed? What happens if its given PO?

A
  1. Given as an IV
  2. Emergency treatment of ventricular arrhythmia → rapid on set
  3. Rapid first-pass metabolism (hydrolysis) by CYP3A4 and 2D6
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20
Q

ADRS of lidocaine?

A
  1. CNS (DZ, paresthesia, seizures)
  2. GI
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21
Q

In order to have a longer half-life, how does tocainide differ from lidocaine? ADRs?

A

a-methyl → slows metabolism, increased half-life

GI and CNS

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22
Q

How is mexiletine more effective than lidocaine and tocainide? Do the ADRs differ?

A

Amide → ether

Drug can be PO due to slow metabolism and longer half-life

No

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23
Q

What is unique about phenytoin metabolism?

A

Induces CYP3A4/UGT including its own therefore its half-life is quite high

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24
Q

What is route for phenytoin?

A

IV dissolved in a pH of 12 (weakly acidic)

Can’t do IM → tissue necrosis and erratic absorption

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25
Q

In addition to arrhythmias, what is another indication for phenytoin?

A

Seizures

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26
Q

What is the APD and kinetics of Class IC?

A

No effect to APD; slow dissociation from sodium

Slow Phase 0 depolarization

Slows conduction

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27
Q

What are the drugs of IC?

A
  1. Flecainide
  2. Encainide
  3. Propafenone
  4. Moricizine
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28
Q

What is important to note about flecainides metabolism? ADRs?

A

Metabolized by the genetic variable CYP2D6

Cna aggravate existing arrhythmias or induce new ones

29
Q

How does encainide differ from flecainide?

A

Less negative inotropic effect

30
Q

What is unique about propafenone structure?

A
  1. Related to b receptor blockers
  2. S enantiomer produce b blocking
  3. Both enantiomers are anti arrhythmic
31
Q

Describe the PK properties of propafenone? How is it significant?

A

Good absorption, but low bioavailability due to metabolism by CYP2D6 (genetic variability) → PD effect variation

32
Q

How is Moricizine metabolized?

A

Short half-life due to CYP1A2 metabolism but duration of action for many hours

33
Q

What class of drug is considered b-receptor blockers?

A

Class 2

34
Q

What are the rate control classes?

A

II and IV

35
Q

What is the MOA of Class II?

A

Depress enhanced calcium influx, work best on SA and AV nodes

36
Q

What the kinetics of Class II?

A
  1. Slow Phase 4 depolarization
  2. Prolong repolarization
37
Q

Describe how Class II has anesthetic properties at high doses?

A

1.. Decreased excitability
2. Decreased conduction velocity
3. Prolonged effective refractory period

38
Q

What drugs are considered Class II?

A
  1. Propanalol
  2. Sotalol
39
Q

What kind of b-blocker is propranolol?

A

Nonselective

40
Q

What is unique about sotalol?

A

Class II/III
Given as an enantiomer mixture
Nonselective

41
Q

Describe the activity of sotalol enantiomers?

A

Both block potassium channels but ultimately produce different effects on the heart

L(-) enantiomer has β-blocking activity

42
Q

Why is sotalol considered a good drug?

A
  1. Good F
  2. Not metabolized by the liver
  3. Not bound to plasma proteins
  4. Excreted unchanged in kidneys
  5. Very few DDIS
43
Q

What is the APD and kinetics of Class III? Drug class?

A

Prolong APD → prolongs refractory period

Rhythm control

Prolong Phase 3 repolarization

K+ channel blockade

44
Q

Describe how Class III affect action potential Figure

A
45
Q

Drugs in Class III?

A
  1. Bretylium Tosylate
  2. Ibutilide
  3. Amiodarone (Cordarone, Pacerone)
  4. Dronedarone
46
Q

How is bretylium tosylate used?

A

Quaternary ammonium (Nitrogen) salt for HTN but can cause hypotension

Erratic PO absorption due to permanent charge

47
Q

Describe the activity of ibutilide? Dosage forms?

A

Affinity for Na+ channels

IV fumarate salt

PO is dofetilide

48
Q

What is the unique MOA of amiodarone?

A
  1. Alters lipid membrane where ion channels and receptors are located
  2. Acts as an all class drug
  3. Very toxic → agent of last choice
49
Q

How does the PK properties of amiodarone contribute to its toxicity?

A
  1. Half life is 58 day (lipophilic from iodines and rings)
  2. Slow onset (several days)
  3. Large Vd

Thyroid hormones accounting for some of its adverse effects

50
Q

What was the improved solution to decrease amiodarone toxicity?

A

Dronedarone contains:
1. Methysulfonamido group (Decrease lipophilicity and neurotoxicity)
2. Dibutyl substitution on Nitrogen
3. Removal of Iodines
4. Increased F with high fat foods, heavy protein binding

51
Q

How is dronedarone metabolized?

A

It is a substrate and inhibitor of CYP3A4

52
Q

What is Class IV?

A

CCB that blocks inward current carried by Ca2+ → Best for Ca2+ dependent cells → rate control

Slows phase 4 depolarization

53
Q

What are the Class IV drugs?

A
  1. Verapamil
  2. Diltiazem
54
Q

Describe the PK of Verapamil? Any DDIs?

A

Long onset (2hr)

AUC increase in digoxin

55
Q

What are the forms of Diltiazem? How is it metabolized?

A

PO and IV for A fib

Fast onset

CYP3A4 metabolite → mechanism based inhibition of CYP3A4

56
Q

What is mechanism based inhibition?

A

Drug generates a metabolite that inhibits metabolizing enzyme

57
Q

Identify the class and activity?

A

Class IA
Increase ERP
Increased AP duration

58
Q

Identify the class and activity?

A

Class II
Increased PR interval

59
Q

Identify the class and activity?

A

Class IV
Increased PR interval
Increased ERP

60
Q

Identify the class and activity?

A

Class IB
Decreased ERP
Decreased AP duration

61
Q

Identify the class and activity?

A

Class III
Increased ERP
Increased AP duration

62
Q

Identify the class and activity?

A

Class IC
Normal ERP
Normal AP duration

63
Q

What is the MOA of adenosine?

A

1.Endogenous nucleoside
2. Slows conduction time through AV node
3. Can restore normal sinus rhythm in patients with paroxysmal supraventricular tachycardia

64
Q

DDIs of Adenosine?

A

Antagonized by caffeine/theophylline (adenosine receptor blockers)

65
Q

PK and ADRs of adenosine?

A

Half-life in blood less than 10 seconds -> Given as rapid intravenous bolus (6 mg administered over a 1 – 2 second period)

  1. Facial flushing
  2. SOB
  3. Sweating
  4. Nausea
66
Q

Why does adenosine have such a short half-life?

A

Endogenous compounds get metabolized very fast → short half-lives/duration of action IF they even absorb

67
Q

Match

A
68
Q
A

Drug Action I (32 decks)

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