Block 2 - CHF Med Chem Flashcards
Describe what MAO metabolism is?
Primary amine → aldehyde
Describe what COMT metabolism is?
Metabolism of meta OH of catechol adding a methyl group
What receptors are found in arterioles? Response?
a1 and 2: Constriction
What receptors are found in the heart? Response?
b1: Increased rate and force
What is glycosides?
Molecules in which a sugar molecule is bound to another functional group (eg: steroid) by a glycosidic bond
The sugar portion of glycosides is called ___ while the non sugar is known as ___
Glycone; aglycone or genin
If they act on the heart they are referred to as _____
Cardiac glycosides
T or F: Aglycone is considered a steroid.
True: it has a steroid nucleus
How does digoxin differ from digitoxin? And how do it affect the PK properties?
Digoxigenin has an extra OH → More hydrophilic → lower absorption → Shorter half-life → Lower protein binding
What gives aglycone its U shape?
A-B and C-D are cis-fused, whereas B-C are trans-fused
Describe the SAR of aglycone?
- 2 methyl group at C-10 and 13
- Hydroxyl groups are present at C-3 and C-14
- C-14 unsubstituted hydroxyl is necessary for cardiotonic activity
- Lactone ring at C-17 required and varies with source (usually 5-membered if from plants, 6-membered if from animals)
OH increases ______ and _____ half-life for algycones
Hypophilicity; shorter
Lowers absorption
Describe the SAR of glycone?
- C-3 of steroid linked to monosaccharide or polysaccharide
- O-acetyl groups on sugars affect PK/lipophilicity
What is the dual effect of glycosides?
Directly (on cardiac muscle and SA node, AV node and His-Purkinje system)
Indirectly (through autonomic nervous reflexes)
Dose-dependent
What electrophysiologic properties does glycosides change?
- Contractility
- HR
- Excitability
- Conductivity
- Refractory period
- Automaticity of atrium, ventricle, Purkinje fibers, AV node, and SA node
What is the MOA of cardioglycosides
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)
What are examples of cardioglycosides?
Digoxin (Lanoxin)
What are the DDIs with digoxin? and why?
Digoxin is a substrate for P-gp therefore interacts with drugs that are substrates, inhibitors, and inducers of P-gp
Digoxin is considered toxic due to its ____ therapeutic window
Narrow
What are the toxic ADRs associated with digoxin?
- High intracellular Ca levels
- Hypokalemia
- GI effects ventricular tachycardia, AV block → ventricular fibrillation → Give K+ salts
What are the MOA of PDE3i? Common ADR?
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
____ is the suffix for PDE3is while ___ is the suffix for PDE5is
-ones; -fils
Example of PDE3i?
- Inamrinone
- Milrinone
What are ADRS associated with Inamrinone? Dosage form?
- Thrombocytopenia
- GI and liver impairments
What are warnings associated with milrinone?
- Incompatible with Lassie → precipitation with milrinone lactate salts
How does Ivabradine differ from other PDE3i?
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
Compare the PK properties of the 2?
How does structure affect the PK property? How does it impact its counseling points
Complete oral absorption due to lipophilicity → food may slow absorption and increase plasma exposure
What is shock?
Inadequate tissue perfusion associated with hypotension
What do you treat shock with?
Want both a and b activity
Why do we need both alpha and beta agonistism?
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
Differentiate NE from E?
NE: predominantly α but modest β effects → increased BP
E: all receptors but more β1 effects → Increased heart rate
What is dopamine MOA?
B1 agonist: G protein signal transduction process → increases intracellular cAMP levels → increase in intracellular calcium
Why do you rarely use dopamine for shock?
Acts on too many receptors including dopamine receptors → too many ADRS including arrhythmias
How are catecholamines metabolized and how does it affect its availability in the body?
COMT and MAO → short DOA with no oral activity
How does dobutamine differ from dopamine?
Metabolized only by COMT → IV push to avoid rapid first-pass metabolism
Catecholamine increases air oxidation → sodium bisulfate it used for stabilization
Describe the activity of dobutamine mixtures?
S-(-) enantiomer = β1 agonist, α1-agonist
R-(-) enantiomer = Non-selective β agonist, α1-antagonist
Overall just β1 agonist
What is the structure and MOA of nediritide? ADRs?
Synthetic BNP
Increase cGMP in smooth muscle cells, reduces venous and arteriolar tone
Excessive hypotension
Why does nesiritide have a short half-life despite its size?
- Peptides is easily metabolized → low oral bioavailability
- BNP is already in the body → body recognize it and metabolize
Short half-life and should not be PO
Describe the structure and activity of sacubitril?
Prodrug activated by by carboxyl esterase 1 (CES1) in the liver to sacubritrilat
What is the MOA of sacubitril?
Inhibits the enzymeneprilysin
What degrades BNP and ANP?
Endopeptidase
What degrades BNP and ANP?
Endopeptidase
What is Entresto?
Combination of sacubitril, the first-in-class neprilysin inhibitor, and the angiotensin II receptor blocker valsartan
What is the MOA of SGLT2 inhibitors?
- No SGLT2 in heart
- Inhibition of glucose reuptake in kidney tubules -> improved diuresis and preload reduction
- May also inhibit sodium hydrogen exchanger or later sodium influx
