Cardo Test 4 Gupta

Front 1

What may affect the Activity of Na+ channel blockers?

Back 1

Activity may be influenced by pH variations
- Difference in onset of action is affected by the acidic pH in the myocardial cells.
- Drugs exist in ionized and non-ionized form in biological pH

Front 2

Quinidine (IA)
What does solubility depend on?
What is it a substrate/inhibitor of?
Which form is given IV?
What enzyme is it metabolized by?
What is it a potent inhibitor of?

Back 2

Solubility depends on the salt forms (Gluconate and Sulfate salts) Gluconate is water soluble so always given IV. Sulfate can be given orally due to low water solubility

Substrate/Inhibitor of P-gp
(ex: DDI with Digoxin in Kidney)

Undergoes first- pass metabolism (LIVER)

~ 85% plasma protein bound

Metabolized by CYP3A4

Potent inhibitor of 2D6

Front 3

What are the 2 DDI between Quinidine and Digoxin?

Back 3

1. Quinidine can inhibit Digoxin via PGP

2. It can displace Digoxin from it's binding site

Front 4

Procainamide (1A)

dosage form
duration of action
metabolism
enzymes metabolized by

Back 4

Not orally active (only active as a sustained release XR)

Short duration of action

Undergoes extensive first- pass metabolism (LIVER)

Metabolized by NAT (N-acetyl transferase)
-Polymorphism seen due to NAT enzyme
- metabolized into NAPA (n-acetyl procainamide 25% active)
- NAPA has some class III action (k+ channel blocker)

Front 5

Disopyramide (1A)

Where is is metabolized?

Back 5

More than 50% of the dose is renally eliminated (KIDNEY metabolized and LIVER)

Front 6

Lidocaine (1B)

Dosage form
half life
metabolism

Back 6

Effective only by IV
-because 90% degraded in GI (due to the N-alkyl group)

Short plasma half-life (15-30 min)

Fast Metabolism into active and inactive metabolites

Contains an amide bond and N-alkyl group (both of which are metabolized)

Active metabolite is 80% as active as parent Lidocaine. It then futher metabolizes into non active metabolite via MICROSOMAL AMIDASE (in liver but NOT a cyp enzyme)

Front 7

What is the differences between Mexiletine (1B) and Lidocaine (1B)?
***TEST QUESTION***

Back 7

Mexiletine
1. contains either bond -o- (it CANNOT be hydrolyzed by microsomal amidases)
2. Metabolism is much SLOWER
3. Half life is longer at 12-16 hours
4. Taken orally (*because of ether bond -o- is metabolically stable in GI)
5. Don't have to worry about dealkylation because it's just an -NH2 group at end( not a N-alkyl group like lidocaine)

Lidocaine
1. has amide bond, N-alkyl
2. Fast metabolism
3. Given IV
4. Short t1/2 of 15-30 min

Front 8

Flecainide (1C)

properties
metabolism

Back 8

-Very lipophilic due to 2 FFF groups

- max CNS permeability. Crosses BBB.

-Metabolized by O-Dealkylation
-Metabolized by 2D6
- Has 2D6 polymorphism (ultrarapid, slow, or normal)
- If rapid metabolizer of 2D6 = increase dose, if slow = lower dose
*remember Quinidine is an inhibitor of 2D6 = DDI)

Front 9

Propafenone (1C)

properties
metabolite
metabolism

Back 9

S and R isomers

S isomer also produce β- blocking activity (non-selective)
(because parent contains an aryloxypropanolamine structure)

Potent 5-Hydroxy metabolite
(does NOT have b-blocking activity)

Metabolized by CYP2D6
(polymorphism with 2D6: slow and rapid)

Polymorphic metabolism
(if slow 2D6 metabolizer then still have b-blocking activity cuz it's in the parent)
(if fast 2D6 metabolizer then b-bblocking activity is lost cuz nnone in the metabolite

Front 10

What are the 6 b-blockers?
What is the main functional group that gives it's property?

Back 10

(b1/b2)
propanolol, nadolol, sotalol
(b1)
atenolol, metoprolol, esmolol

**aryloxypropanolamine**

Front 11

Sotalol

unique dual properties

Back 11

Both Class II and Class III effects

Enantiomers produce different magnitude of effects on heart

l (-) enantiomer has both Class II and Class III activity

d (+) enantiomer has much LOWER Class II activity but similar Class III activity as l (-) isomer

**So L enantiomer is equal b-blocking and K+ channel blocking.
D enantiomer is equal K+ channel blocking and LOWER b-blocking activity***

Not metabolized (no CYP interactions)

Front 12

Amiodarone (Class III)

properties

Back 12

- contains 2 Iodines (most lipophilic halogen)

-strong effect on the Thyroid

-Slow onset of action

-Long half-life (50-60 days)

-High volume of distribution
**(LIVER and LUNG toxicity because both are lipophilic fatty tissues)(toxicity even when drug is discontinued due to long t1/2)

-Bound to plasma proteins (96%)

-Metabolized into active metabolite

-Strong inhibitor of PgP

-Strong inhibitor of CYP isozymes (3A4, 2D6, 1A1, 1A2, 2C9)

-has photosensitivity reactions to sun (need to wear sunscreen)

Front 13

Amiodarone

metabolism
- what enzymes metabolize it?
- what are the metabolites?
- inhibitor of what?

Back 13

metabolized by
1. CYP3A4 and CYP2C8

2. Metabolite is Desethylamiodarone which is EQUALLY active as Amiodarone

3. Desethylamiodarone (missing one ethyl) is a much more POTENT inhibitor of CYP (3A4, 2D6, 1A1, 1A2, 2C9) than Amiodarone (moderate inhibitor)

Front 14

Dronedarone (class III)

properties

Back 14

Shorter half-life than Amiodarone (less than 24 hrs)

Less lipophilic than amiodarone (**less distribution to LIVER and LUNGS = less toxicity) (does NOT contain Iodine)

Bound to plasma proteins (98%)

Metabolized into a LESS active metabolite called Desbutyldronedarone(20% less active than parent)(it is lacking a butyl group off the N)

Strong inhibitor of PgP

Metabolized by CYP3A4

Front 15

What are the differences between Amiodarone and Dronedarone? (class III)
***Exam Question***

Back 15

Dronedarone is better because
1. no iodine in structure
2. no direct thyroid effect due to iodine
3. less toxicity to liver/lungs
4. liss distribution to liver/lungs b/c its not as lipophilic
5. has no significant photosensitivity reactions