Block 2 - HTN Med Chem Flashcards
Describe the RAAS and where its components come from?
Angiotensinogen (Liver) → Renin (Kidney) → Angiotensin I → ACE (Zinc protease, kidney and lung) → Angiotensin II
What are the different controls of angiotensinogen?
GC, thyroid hormones, angiotensin II
What controls renin release?
Aspartyl protease
JG cells sense stretching of arteries and increase in NaCl flux in kidneys → BP increases → Decrease in renin release
Describe how zinc protease converts angiotensin I to II?
R-A system need Leu-His-Phe
ACE cleaves His-Phe stopping at Pro due to its penultimate position
Decapeptide → octapeptide
What are the outcomes of angiotensin II formation?
- Increased PVR (rapid pressor response)
- Regulation of renal function (slow pressor response)
What are the classes of ACEIs?
- Sulfhydryl
- Dicarboxylate
- Phosphate
What falls under the sulfhydryl ACEI?
Captopril
What attributes to ACEIs poor oral bioavailability?
Peptides get metabolized into amino acids therefore IV prevents first pass metabolism
What is the SAR of ACE inhibitors?
- O= for chelation with Zn2+
- O= for H-bonding
- R1 and R2 (hydrophobic pocket) and R3
- COO- for hydrophilic binding
Why is captopril considered the most effective sulfhydryl ACEIs?
-SH brings more chelation with zinc, COO- for ion-ion binding
What are the major ADRs of Captopril?
Capoten has sulfur
1. Smell
2. Metallic taste
3. Skin rashes
4. Loss in taste, drug can bind to taste buds → taste fatigue
What are the metabolites of Capoten?
Captopril metabolizes into disulfide dimer and captopril-cysteine disulfide which are both inactive
In what ways did decarboxylate ACEs differ from Captopil?
- w/o Sulfur, instead was replaced with dicarboxylate
- Although, COO- didn’t chelate zinc as well, manufactures added a transition group that mimicked Ang I
What is the purpose of R1 and R2 side chains on ACEI?
Binding to Lys and His respectively
Why did Enalapril have terrible bioavailability? How was it fixed?
Vaster was too poor, dicarboxy ionized and didn’t absorb well
Transformed into a prodrug to increases is F
Describe the SAR of dicarboxyl ACEI?
R1: CH3 except for Lisinopril
R2: CH2CH3 attached to COO that get cleaved (prodrug)
R3: Lipophilic ring
Ring: contains COOH
How does phosphate ACEI differ from its predecessor?
- Phosphate chelates just as well as sulfhydryl
- Transition state mimics better than decarboxylates
What is the phosphate ACEI? Why is it a good drug?
Fosinopril has a stable phosphate ester, prodrug gives it great bioavailability
What is the most important ADR of ACEI?
Persistant cough due to build up of BK in lungs
Hypotension
Hyperkalemia
What is the ARB site of action?
AT1
What are the actions of AT2?
Anti-AT1: Vasodilation and hypotension
Apoptosis, cell differentiation, tissue repair
What are the actions of AT4?
Release plasminogen activator inhibitor I
Can increase BP by cooperating with ANG II on AT1
How did ARBs development start?
Mimicking ANG II
Saralasin had a ILe to Val substitution, however, since it was a peptide it had poor PO F due to peptide metabolism
What are the important SAR for ARB binding?
- COOH for ion-ion binding
- Hydrophilic rich for H-bonding can be lipophilic some
- Lipophilic group for hydrophobic pocket
What was the significance of the first ARB?
Losartan (Cozaar) was one of the first drug to be developed by computer-aid and experimentation
How is Losartan effective for AT1 binding?
- Biphenyl tetratrazole (lipophilic and negative charge)
- E- rich ring ring
- Lipophilic for pocket
- Phenylalanine (hydrophobic pocket)
Tetrazole has better binding than COO-
How does Eprosartan differ from other ARBs?
- Greater potency than others
- Mimics COOH binding
- Additional carboxylate
- Not as balanced or have a biphenyl tetrazole
What is the only renin inhibitor? When is it used?
Aliskerin (Tekturna)
Used for patients who can’t take ACEI or ARBs
Great for diabetics b/c its renal protective → helps albuminemia
What are the indication of DHP and non-DHPs?
DHP: HTN
Non: CHF
Describe the SAR components of DHPs?
- Phenyl ring @C4 increases activity (small nonplanar alkyl decreases)
- Ortho- and meta- substitutions is optimal EWG (para- decreases)
- Perpendicular is a blocker and planar is an activator
- 1,4-DHP ring is essential for good activity
- Esters @ C3 and C5 optimize activity
What is the MOA of CCB?
Bind to receptor sites within the the central a1 subunits of L-type potential-dependent channels
What are the 3 conformations of Ca2+ channels?
- A resting state which can be stimulated by membrane depolarization
- An open state which allows calcium to enter
- An inactive state which is refractory to further depolarization
What are MOA of vasodilators?
Relax smooth muscle in BV → reduction in arterial BP
What are the drawbacks of vasodilators?
- Induce baroreceptor mediated reflex stimulation of the heart (HTN)
- Impair baroreceptors-mediated reflex vasoconstriction → orthostatic hypotension
- Increase renal retention of Na+ and H2O
What is another name for vasodilators?
Direct acting or K+ channel openers
What is the MOA of direct-acting VD? Drug?
- K+ channel opener
- Inhibit IP3-induced release of calcium from SM
- Stimulate NO release from vascular endothelium
Specific for arterial vessels
Hydralazine
Describe mechanism behind VD K+ channel opener activity
Describe how VD can inhibit Ca2+?
Describe how VD stimulates NO?
What are the types of VDs that can be used for HTN?
- Hydralazine (Apresoline)
- Minoxidil ( Loniten, Rogaine)
How is Minoxidil used for HTN?
How is Rogaine metabolized?
O-glucoronide: drug becomes more hydrophilic and inactive
