Block 3 - Antiarrhythmics Med Chem Flashcards
What are pharmacology properties of having a more lipophilic drug?
- Bind to plasma proteins
- High volumes of distribution
- Longer duration
- Long half life
- Rapidly absorbed
What are pharmacology properties of having a more basic drug?
- Amines with pKa of 8-10 is charged at physiological pH
- Low bioavailability
- Charged can’t cross membranes easily
What are arrhythmias?
Alteration in normal sequence of electrical impulse rhythm that leads to contraction of myocardium
What abnormalities does arrhythmias affect?
- Rate
- Impulse origination site
- Conduction through myocardium
What are the Antiarrhythmic drug classes?
Compare the 3 Class I?
What is the APD and Kinetics of Class IA? Drug class?
Prolonged APD; intermediate dissociation kinetics
Slow phase 0 depolarization
Na+ channel blockers
What are Class IA?
- Quinidine
- Procainamide
- Disopyramide
What is the physiological properties of quinidine?
- Basic nitrogens (pKa 11)
- Water soluble salt (sulfate or gluconate)
Which has better IV and PO/IM capabilities?
Gluconate more water soluble → better for emergenies (injectable), sulfate usually oral or IM
What are DDIs of quinidines?
- P-gp substrate -> inhibits renal tubular secretion of digoxin
- Increases plasma levels of digoxin
What is the contaminate that contributes to quinidine’s effectiveness?
Dihydroquinidine
How does Dihydroquinidine contribute to quinidines activity?
- Reduction of vinyl group to an ethyl
- More potent as an anti arrhythmic, but more toxic
- Commercial preps can vary based on levels of contaminant
How was procain modified for better efficacy? What was the new drug called?
Procainamide replaces an ester with an amide which is more resistant to esterase hydrolysis
How is procainamide metabolisized and why is this significant?
N-acetyltrasferase has genetic variations
Slow acetylators → elevated levels → drug induced lupus syndrome
Metabolite also implicated in torsades de pointes
How does disopyramide differ from procainamide?
Has anti-cholinergic effects due to its struccutral similarities
Receptors prefer a tertiary amine with a 2-4 carbon distance from 2 different rings
What is the APD and kinetics of Class IB?
Shortens (or no effect) APD; rapid dissociation from sodium channels
Shortens Phase 3 repolarization
What are the drugs in IB?
- Lidocaine
- Tocainide
- Mexiletine
- Phenytoin
How is lidocaine dosed? What happens if its given PO?
- Given as an IV
- Emergency treatment of ventricular arrhythmia → rapid on set
- Rapid first-pass metabolism (hydrolysis) by CYP3A4 and 2D6
ADRS of lidocaine?
- CNS (DZ, paresthesia, seizures)
- GI
In order to have a longer half-life, how does tocainide differ from lidocaine? ADRs?
a-methyl → slows metabolism, increased half-life
GI and CNS
How is mexiletine more effective than lidocaine and tocainide? Do the ADRs differ?
Amide → ether
Drug can be PO due to slow metabolism and longer half-life
No
What is unique about phenytoin metabolism?
Induces CYP3A4/UGT including its own therefore its half-life is quite high
What is route for phenytoin?
IV dissolved in a pH of 12 (weakly acidic)
Can’t do IM → tissue necrosis and erratic absorption
In addition to arrhythmias, what is another indication for phenytoin?
Seizures
What is the APD and kinetics of Class IC?
No effect to APD; slow dissociation from sodium
Slow Phase 0 depolarization
Slows conduction
What are the drugs of IC?
- Flecainide
- Encainide
- Propafenone
- Moricizine
What is important to note about flecainides metabolism? ADRs?
Metabolized by the genetic variable CYP2D6
Cna aggravate existing arrhythmias or induce new ones
How does encainide differ from flecainide?
Less negative inotropic effect
What is unique about propafenone structure?
- Related to b receptor blockers
- S enantiomer produce b blocking
- Both enantiomers are anti arrhythmic
Describe the PK properties of propafenone? How is it significant?
Good absorption, but low bioavailability due to metabolism by CYP2D6 (genetic variability) → PD effect variation
How is Moricizine metabolized?
Short half-life due to CYP1A2 metabolism but duration of action for many hours
What class of drug is considered b-receptor blockers?
Class 2
What are the rate control classes?
II and IV
What is the MOA of Class II?
Depress enhanced calcium influx, work best on SA and AV nodes
What the kinetics of Class II?
- Slow Phase 4 depolarization
- Prolong repolarization
Describe how Class II has anesthetic properties at high doses?
1.. Decreased excitability
2. Decreased conduction velocity
3. Prolonged effective refractory period
What drugs are considered Class II?
- Propanalol
- Sotalol
What kind of b-blocker is propranolol?
Nonselective
What is unique about sotalol?
Class II/III
Given as an enantiomer mixture
Nonselective
Describe the activity of sotalol enantiomers?
Both block potassium channels but ultimately produce different effects on the heart
L(-) enantiomer has β-blocking activity
Why is sotalol considered a good drug?
- Good F
- Not metabolized by the liver
- Not bound to plasma proteins
- Excreted unchanged in kidneys
- Very few DDIS
What is the APD and kinetics of Class III? Drug class?
Prolong APD → prolongs refractory period
Rhythm control
Prolong Phase 3 repolarization
K+ channel blockade
Describe how Class III affect action potential Figure
Drugs in Class III?
- Bretylium Tosylate
- Ibutilide
- Amiodarone (Cordarone, Pacerone)
- Dronedarone
How is bretylium tosylate used?
Quaternary ammonium (Nitrogen) salt for HTN but can cause hypotension
Erratic PO absorption due to permanent charge
Describe the activity of ibutilide? Dosage forms?
Affinity for Na+ channels
IV fumarate salt
PO is dofetilide
What is the unique MOA of amiodarone?
- Alters lipid membrane where ion channels and receptors are located
- Acts as an all class drug
- Very toxic → agent of last choice
How does the PK properties of amiodarone contribute to its toxicity?
- Half life is 58 day (lipophilic from iodines and rings)
- Slow onset (several days)
- Large Vd
Thyroid hormones accounting for some of its adverse effects
What was the improved solution to decrease amiodarone toxicity?
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
How is dronedarone metabolized?
It is a substrate and inhibitor of CYP3A4
What is Class IV?
CCB that blocks inward current carried by Ca2+ → Best for Ca2+ dependent cells → rate control
Slows phase 4 depolarization
What are the Class IV drugs?
- Verapamil
- Diltiazem
Describe the PK of Verapamil? Any DDIs?
Long onset (2hr)
AUC increase in digoxin
What are the forms of Diltiazem? How is it metabolized?
PO and IV for A fib
Fast onset
CYP3A4 metabolite → mechanism based inhibition of CYP3A4
What is mechanism based inhibition?
Drug generates a metabolite that inhibits metabolizing enzyme
Identify the class and activity?
Class IA
Increase ERP
Increased AP duration
Identify the class and activity?
Class II
Increased PR interval
Identify the class and activity?
Class IV
Increased PR interval
Increased ERP
Identify the class and activity?
Class IB
Decreased ERP
Decreased AP duration
Identify the class and activity?
Class III
Increased ERP
Increased AP duration
Identify the class and activity?
Class IC
Normal ERP
Normal AP duration
What is the MOA of adenosine?
1.Endogenous nucleoside
2. Slows conduction time through AV node
3. Can restore normal sinus rhythm in patients with paroxysmal supraventricular tachycardia
DDIs of Adenosine?
Antagonized by caffeine/theophylline (adenosine receptor blockers)
PK and ADRs of adenosine?
Half-life in blood less than 10 seconds -> Given as rapid intravenous bolus (6 mg administered over a 1 – 2 second period)
- Facial flushing
- SOB
- Sweating
- Nausea
Why does adenosine have such a short half-life?
Endogenous compounds get metabolized very fast → short half-lives/duration of action IF they even absorb
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