Block 2 - CHF Med Chem

Question 1

Describe what MAO metabolism is?

Answer 1

Primary amine → aldehyde

Question 2

Describe what COMT metabolism is?

Answer 2

Metabolism of meta OH of catechol adding a methyl group

Question 3

What receptors are found in arterioles? Response?

Answer 3

a1 and 2: Constriction

Question 4

What receptors are found in the heart? Response?

Answer 4

b1: Increased rate and force

Question 5

What is glycosides?

Answer 5

Molecules in which a sugar molecule is bound to another functional group (eg: steroid) by a glycosidic bond

Question 6

The sugar portion of glycosides is called ___ while the non sugar is known as ___

Answer 6

Glycone; aglycone or genin

Question 7

If they act on the heart they are referred to as _____

Answer 7

Cardiac glycosides

Question 8

T or F: Aglycone is considered a steroid.

Answer 8

True: it has a steroid nucleus

Question 9

How does digoxin differ from digitoxin? And how do it affect the PK properties?

Answer 9

Digoxigenin has an extra OH → More hydrophilic → lower absorption → Shorter half-life → Lower protein binding

Question 10

What gives aglycone its U shape?

Answer 10

A-B and C-D are cis-fused, whereas B-C are trans-fused

Question 11

Describe the SAR of aglycone?

Answer 11

1. 2 methyl group at C-10 and 13
2. Hydroxyl groups are present at C-3 and C-14
3. • C-14 unsubstituted hydroxyl is necessary for cardiotonic activity
4. Lactone ring at C-17 required and varies with source (usually 5-membered if from plants, 6-membered if from animals)

Question 12

OH increases ______ and _____ half-life for algycones

Answer 12

Hypophilicity; shorter

Lowers absorption

Question 13

Describe the SAR of glycone?

Answer 13

1. C-3 of steroid linked to monosaccharide or polysaccharide
2. O-acetyl groups on sugars affect PK/lipophilicity

Question 14

What is the dual effect of glycosides?

Answer 14

Directly (on cardiac muscle and SA node, AV node and His-Purkinje system)

Indirectly (through autonomic nervous reflexes)

Dose-dependent

Question 15

What electrophysiologic properties does glycosides change?

Answer 15

1. Contractility
2. HR
3. Excitability
4. Conductivity
5. Refractory period
6. Automaticity of atrium, ventricle, Purkinje fibers, AV node, and SA node

Question 16

What is the MOA of cardioglycosides

Answer 16

Inhibits Na/K-ATPase pump:
→ Restores membrane potential to normal
→ Inhibit Na+ exchange with K+ → Increased intracellular Na+ → increased intracellular Ca2+
→ Increased Ca2+ → increase in contraction (positive inotropic)

Question 17

What are examples of cardioglycosides?

Answer 17

Digoxin (Lanoxin)

Question 18

What are the DDIs with digoxin? and why?

Answer 18

Digoxin is a substrate for P-gp therefore interacts with drugs that are substrates, inhibitors, and inducers of P-gp

Question 19

Digoxin is considered toxic due to its ____ therapeutic window

Answer 19

Narrow

Question 20

What are the toxic ADRs associated with digoxin?

Answer 20

1. High intracellular Ca levels
2. Hypokalemia
3. GI effects ventricular tachycardia, AV block → ventricular fibrillation → Give K+ salts

Question 21

What are the MOA of PDE3i? Common ADR?

Answer 21

Gs protein activation → formation of intracellular cAMP → increases Ca2+ → cardiac muscle contraction → relaxation is when cAMP is hydrolyzed by PDE3 → Inhibitor of PDE3 → increased cAMP

Ventricular arrhythmias

Question 22

____ is the suffix for PDE3is while ___ is the suffix for PDE5is

Answer 22

-ones; -fils

Question 23

Example of PDE3i?

Answer 23

1. Inamrinone
2. Milrinone

Question 24

What are ADRS associated with Inamrinone? Dosage form?

Answer 24

1. Thrombocytopenia
2. GI and liver impairments

Question 25

What are warnings associated with milrinone?

Answer 25

1. Incompatible with Lassie → precipitation with milrinone lactate salts

Question 26

How does Ivabradine differ from other PDE3i?

Answer 26

Blocks the "funny" (If) current/channel from the SA node 1. NA-K inward current 2. Reduces cardiac pacemaker activity, slows heart rate 3. Decrease rate without reducing contractility

Question 27

Compare the PK properties of the 2?

Question 28

How does structure affect the PK property? How does it impact its counseling points

Answer 28

Complete oral absorption due to lipophilicity → food may slow absorption and increase plasma exposure

Question 29

What is shock?

Answer 29

Inadequate tissue perfusion associated with hypotension

Question 30

What do you treat shock with?

Answer 30

Want both a and b activity

Question 31

Why do we need both alpha and beta agonistism?

Answer 31

Only β agonist → increased blood flow but risk of myocardial ischemia Only α agonist → increased blood pressure and vascular tone but can decrease cardiac output and impair tissue blood flow

Question 32

Differentiate NE from E?

Answer 32

NE: predominantly α but modest β effects → increased BP E: all receptors but more β1 effects → Increased heart rate

Question 33

What is dopamine MOA?

Answer 33

B1 agonist: G protein signal transduction process → increases intracellular cAMP levels → increase in intracellular calcium

Question 34

Why do you rarely use dopamine for shock?

Answer 34

Acts on too many receptors including dopamine receptors → too many ADRS including arrhythmias

Question 35

How are catecholamines metabolized and how does it affect its availability in the body?

Answer 35

COMT and MAO → short DOA with no oral activity

Question 36

How does dobutamine differ from dopamine?

Answer 36

Metabolized only by COMT → IV push to avoid rapid first-pass metabolism Catecholamine increases air oxidation → sodium bisulfate it used for stabilization

Question 37

Describe the activity of dobutamine mixtures?

Answer 37

S-(-) enantiomer = β1 agonist, α1-agonist R-(-) enantiomer = Non-selective β agonist, α1-antagonist Overall just β1 agonist

Question 38

What is the structure and MOA of nediritide? ADRs?

Answer 38

Synthetic BNP Increase cGMP in smooth muscle cells, reduces venous and arteriolar tone Excessive hypotension

Question 39

Why does nesiritide have a short half-life despite its size?

Answer 39

1. Peptides is easily metabolized → low oral bioavailability 2. BNP is already in the body → body recognize it and metabolize Short half-life and should not be PO

Question 40

Describe the structure and activity of sacubitril?

Answer 40

Prodrug activated by by carboxyl esterase 1 (CES1) in the liver to sacubritrilat

Question 41

What is the MOA of sacubitril?

Answer 41

Inhibits the enzyme neprilysin

Question 42

What degrades BNP and ANP?

Answer 42

Endopeptidase

Question 42

What degrades BNP and ANP?

Answer 42

Endopeptidase

Question 43

What is Entresto?

Answer 43

Combination of sacubitril, the first-in-class neprilysin inhibitor, and the angiotensin II receptor blocker valsartan

Question 44

What is the MOA of SGLT2 inhibitors?

Answer 44

1. No SGLT2 in heart 2. Inhibition of glucose reuptake in kidney tubules -> improved diuresis and preload reduction 3. May also inhibit sodium hydrogen exchanger or later sodium influx