Exam 2 - Medchem 753, Stevens Inotropics

Question 1

What effects are seen during cardiac failure?

Answer 1

Inability of heart to pump blood effectively
- Force of contraction of Cardiac Muscle
 - dec CO; dec BP; Dec Renal Q
Edema in legs/Lungs
Renal failure

Question 2

What is the action of all positive Inotropes?

Answer 2

They affect the availability of intracellular Ca or inc sensitivity of contractile proteins

Question 3

What is the basic action of cardiac steroids?

Answer 3

inhibit the Na/K ATPase

Question 4

What is the basic action of Phospodiesterase inhibitors?

Answer 4

Block cAMP degradation

• inc [cAMP]; activating cAMP dependent protein kinases
• stimulate Ca influx through VG channels,
• inc release and reaccumulation of CA in SR

Question 5

What is the basic action of Ca2+ sensitivity stimulants

Answer 5

Inc the effect of existing Ca2+ levels

Question 6

What is the basic action of B-adrenergic agonists?

Answer 6

Leads to inc cAMP production, more forceful contractions due to inc calcium presence

Question 7

How are cardiac steroids different from other average steroids?

Answer 7

They are characterized by their 5B, 14B stereochemistry, which results in a curved, or convexely shaped molecule

Question 8

What are the 2 different groups of cardiac steroids?

Answer 8

1. Cardenolides

2. Bufadienolides

Question 9

Cardenolides

1. Origin
2. Chemical structure

Answer 9

1. Plant Origin

2. C-17R group is an alpha-B-unsaturated butyrolactone

Question 10

Bufadienolides

1. Origin
2. Chemical structure

Answer 10

1. Found in Toad Skin

2. C-17R group is a Pyrrone Ring

Question 11

Most cardiac sterols naturally occur as ______ and have approximately ______ sugars attached where?

Answer 11

Glycosides
1-4 sugars
3B-OH of steroid

Question 12

Digitalis Purpurea

Answer 12

Flox Glove (purple), it is the commercial source of digitoxin

Question 13

Digitalis lanata

Answer 13

Woolly foxglove (white) commercial source of digoxin

Question 14

in 1785, Digitalis leaves were used to treat several things including swelling. What were some remarkable side effects of the drug?

Answer 14

Yellow Vision

Nausea

Question 15

What kept most physicians from using digitalis preparations until the 1900s?

Answer 15

Narrow therapeutic index

Question 16

What site difference between digitoxigenin, Digoxigenin and Gitoxigenin makes the large pharmacological difference in their chemistry?

Answer 16

12-OH (Digoxin)
12-H (Digitoxin)
16-OH (gitoxigenin); pharmaceutically irrevelevant

Question 17

What is the main cardiac glycoside found in Digitalis Lanata leaves?

Answer 17

Lanatoside C

Question 18

How is Digoxin extracted from Digitalis leaves?

Answer 18

Lantoside C is treated w/ Bglucosidase, to form acetyldigoxin, which is then treated with NaOH and neutrialized with Ch3COOH to become digoxin

Question 19

Inhibition of Na/K-ATPase has what effect on calcium levels?

Answer 19

Increased intracellular Na levels –> increased release of Ca from intracellular stores

Question 20

Why is simultaneous treatment of Lasix and Digoxin dangerous?

Answer 20

Lasix lowers extracellular K levels, which increases phosphorylation and eventually the binding affinity of Digoxin

Question 21

What is the result of coadministration of Digoxin and Erythromycin?

Answer 21

Erythromycin kills microbes that would otherwise help metabolize orally available digoxin, increasing the amount of Digoxin available.

Question 22

What neuro-hormonal effect does Digoxin have in CHF patients?

Answer 22

Inc Parasympathetic (vagal activation)
and decreased sympathetic activity

Question 23

What is the preferred cardiac glycoside for CHF?

Answer 23

Digoxin

Question 24

What is the metabolism for Digoxin?

Answer 24

minimal (80% unchanged) Hepatic Metabolism by:

• Hydrolysis
• Sulfation
• Glucuronidation

Question 25

What result would be seen from Quinidine coadminstration with Digoxin?

Answer 25

Increased plasma levels of Digoxin

Question 26

What result would be seen with coadminstration of Verapamil and Digoxin

Answer 26

Increased absorption of Digoxin | Verapamil inhibits intestinal pgp efflux of digoxin

Question 27

What result would be seen with coadministration of Rifampin and Digoxin

Answer 27

Decreased absorption of Digoxin | Rifampin induces intestinal pgp efflux expression

Question 28

What would the results of coadministration of Bile Acid binding resins such as Cholestryamine and Digoxin be?

Answer 28

Decreased Digoxin Absorption

Question 29

What is the plasma protein binding, onset, and 1/2 life for Digoxin?

Answer 29

PPB - 30% Onset - 15-30min T1/2 - 1-2 days

Question 30

What is the plasma protein binding, onset and 1/2 life for digitoxin?

Answer 30

PPB - ~95% onset - 05-2hrs T1/2 - 4-7 days

Question 31

What are the primary problems and side effects of Cardiac Glycosides?

Answer 31

Narrow Therapeutic WIndow | SE: Loss of appetite, blurred vision, GI distress, potentially proarrhythmmic (Afib, Vtach, MI)

Question 32

How would you treat acute toxicity of Digoxin?

Answer 32

Digibind (digoxin immune Fab)

Question 33

What are the disappointing results of most PDE inhibitors?

Answer 33

Inc Mortality rates Inc Incidence of arrhythmias Causes tachycardia Loss of positive inotropic effect w/ chronic use

Question 34

When are PDE3 inhibitors used for CHF?

Answer 34

Acute CHF

Question 35

Why was amrinone renamed in the year 2000?

Answer 35

Was confused with Amiodarone, which led to some fatal medication errors

Question 36

What is the difference in naming between PDE3 inhibitors and PDE5 inhibitors?

Answer 36

PDE3 - ends in 'one' | PDE5 - ends in 'fil'

Question 37

Inamrinone 1. Class, indication 2. Metabolism/T1/2 3. SE 4. Formulations

Answer 37

1. PDE3 inhibitor, Acute CHF 2. 3-4hrs, mainly excreted unchanged in urine 3. Thrombocytopenia (10%) 4. Short term IV

Question 38

Milrinone 1. Class, Indication 2. Metabolism/T1/2 3. SE 4. Formulation

Answer 38

1. PDE3 inhibitor, Acute CHF 2. 30-60min, Mainly excreted unchanged in urine 3. Fewer side effects than Inamrinone 4. Lactate for IV

Question 39

MoA for Ca sensitizing agents

Answer 39

Increase contractility by binding the N-terminus of troponin C and stabilizing the Ca-bound conformation. Activation of ATP-regulated K channels and cause vasodilation in vascular smooth muscle.

Question 40

Levosimendan 1. Class/Indication 2. Formulations

Answer 40

1. Calcium sensitizing agent, CHF | 2. IV formulation for Acute CHF

Question 41

B-adrenergic agent for treatment of CHF

Answer 41

Dobutamine

Question 42

Dobutamine Racemate actions results in what overall effect?

Answer 42

In vasculature, A1 agonist negated by A1-antagonist (no vasodilation) Overall: B1 effect: increased stroke volume and little increase in HR.

Question 43

Dobutamine Administration and Availbility

Answer 43

T1/2 ~2min Only active Rapid first pass COMT (Wrap IV bags in aluminum to prevent oxidation to ortho-quinone)