Angiotensin Converting Enzyme Inhibitors Flashcards
(23 cards)
The key component of this process is—————— which is a peptide hormone with potent——————- properties.
angiotensin II, vasoconstrictive
Angiotensin II also promotes the release of another hormone called———— from the adrenal cortex.
aldosterone: Aldosterone promotes increased fluid retention in the kidneys—another factor that increases blood pressure because of increased blood volume.
Problems of hypertension occur when the RAAS cascade becomes too active, and so a number of antihypertensive agents have been designed which block the cascade at various points:
Angiotensin-converting enzyme (ACE) Inhibitors
• Angiotensin II receptor antagonists (ARB)
• Aldosterone inhibitors
• Renin inhibitors
————— is a key component of the biosynthetic pathway that generates the hormone————.
Angiotensin-converting enzyme (ACE) , angiotensin II.
The pathway involves the conversion of——- to ———catalysed by the enzyme ——— , followed by the conversion of——- to — -, catalysed by ——.
angiotensinogen, angiotensin I , renin
angiotensin I to angiotensin II, ACE
Angiotensin II : drugs that block the synthesis or actions of this hormone can act as ——-.
1-potent vasoconstrictor
2-increases blood pressure
antihypertensives
Why is the peptidase renin released?
1-As a result of the decreased blood perfusion to the juxtaglomerulus
2- Sympathetic Stimulation
3- decreased levels of salt
ACE
1-membrane-bound enzyme which has been difficult to isolate and study.
2-t is a member of a group of enzymes called the zinc metalloproteinases and catalyses the hydrolysis of a dipeptide fragment from the end of a decapeptide called angiotensin I to give the octapeptide angiotensin II.
Although the enzyme ACE could not be isolated, the design of ACE inhibitors was helped by studying the structure and mechanism of another zinc metalloproteinase that could—an enzyme called (carboxypeptidase).
1- Is cytosolic and easier to isolate
2- This enzyme splits the terminal amino acid from a peptide chain and is inhibited by L-benzylsuccinic acid .
What is the structure of L-Benzylsuccinic acid?
- 4 carbons + 2 carboxylic acids on the terminal end + benzene ring.
- Design is based on hydrolysis of products arising from enzymatic reaction.
- Benzyl group occupies the S1 pocket, carboxylate ion is present to form an ionic interaction with Arg-145
- 2nd carboxylate acts as a ligand to the zinc ion, mimicking the carboxylate ion of the other hydrolysis product.
-CANT BE HYDROLYSED AS THERE IS NO PEPTIDE BOND PRESENT SO THE ENZYME IS INHIBITED FOR AS LONG AS THE COMPOUND STAYS ATTACHED
What makes thiol (-SH) a better substituent than carboxylic acid CA?
1- non ionizable
2- more hydrophobic
3- can make stronger coordinate interactions with zinc making it better in oral absorption and giving it a high affinity
What does the active site of carboxypeptidase include that’s crucial for its binding?
Charged arginine unit and a zinc ion.
Carboxylic acid is bound ionically to the arginine unit while the carbonyl group of terminal peptide is bound to zinc ion
How does the S1 hydrophobic pocket affect binding?
It accepts the side chain of amino acid.
Aromatic rings bind strongly to the pocket raising specificity of enzyme towards a peptide substrate containing an aromatic amino acid at the C-terminus
How is hydrolysis of the terminal peptide bond affected by zinc ion?
-plays a role in the mechanism by polarizing the carbonyl group and making the amide group more susceptible to hydrolysis.
Teprotide (ACE inhibitors)
1-nonapeptide was isolated from venom of viper
2- Amino acid proline at C-terminal
3- A reasonably potent inhibitor but susceptible to digestive enzymes and is orally inactive
4- succinyl proline was the end result
5-SP was found to be weak but specific inhibitor of ACE and it was proposed that both carboxylate groups were ionized, one interacting with the arginine group and one with zinc ion
All ACE inhibitors are prodrugs except?
Captopril (non peptide ACE inhibitors)
-It is more absorbable and lipophilic
-CA is masked by ester that ionizes to gain an extra carbon
-a pocket must be available to accommodate AA side chains on either side (methyl group increases activity)
-addition of thiol group increases activity but causes rash and metallic taste
-a good ACE inhibitor must lack thiol
-2nd carboxylic acid increases polarity and causes poor oral absorption so drug is administered as enalapril.
Lisinopril (ACE inhibitor)
-similar to enalaprilate but where the methyl substituent has been extended to an aminobutyl substituent side chain is lysine.
Supposedly arginine but actually has lysine
Replacing proline ring with a variety of bicyclic ring gives better hydrophobic interactions as in:
Moexipril, quinapril,perindopril ,trandolapril,ramipril, and benzazepril
Why is a single ester harder to hydrolyze?
Steric hindrance; once external hydrolyzes internal also follows creating an extended ester prodrug.
Phosphonate-containing inhibitors
-lack sulfhydryl group
- interaction of zinc atom with phosphonic acid (bioistere) is similar to that seen with thiole and carboxylate groups.
-
Bradykinin hydrolysis
-caused by ACE inhibitors
- results in vasodilation causing dry cough/angioedema (fluid accumulation in face/larynx were there’s vasoconstriction)
- inhibiting ACE enzyme accumulates bradykinin causes vasodilation
First line treatment of hypertension
-enalapril and lisinopril
-used for patients with high coronary disease risk, history of diabetes, stroke,HF,MI, or chronic kidney disease
-ACE inhibitors lower blood pressure by reducing peripheral vascular resistance without increasing CO, HR, or contractility.
ACE and Bradykinin
- ACE is responsible for bradykinin (product that increases nitric oxide and prostacyclin (potent vasodilators) production) breakdown by BVs
-ACE inhibitors decrease angiotensin 2and increase bradykinin levels - Vasodilation occurs as a result of decreased vasoconstriction (from diminished levels of angiotensin 2) and enhanced vasodilation (from increased bradykinin)
-reducing Angiotensin 2 decreases aldosterone secretion and so decreasing sodium and water retention.
-ACE inhibitors reduce both cardiac preload and afterload thereby decreasing cardiac work
