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Drug Action I > Block 2 - HTN Med Chem > Flashcards

Block 2 - HTN Med Chem Flashcards

1
Q

Describe the RAAS and where its components come from?

A

Angiotensinogen (Liver) → Renin (Kidney) → Angiotensin I → ACE (Zinc protease, kidney and lung) → Angiotensin II

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2
Q

What are the different controls of angiotensinogen?

A

GC, thyroid hormones, angiotensin II

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3
Q

What controls renin release?

A

Aspartyl protease

JG cells sense stretching of arteries and increase in NaCl flux in kidneys → BP increases → Decrease in renin release

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4
Q

Describe how zinc protease converts angiotensin I to II?

A

R-A system need Leu-His-Phe

ACE cleaves His-Phe stopping at Pro due to its penultimate position

Decapeptide → octapeptide

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5
Q

What are the outcomes of angiotensin II formation?

A
  1. Increased PVR (rapid pressor response)
  2. Regulation of renal function (slow pressor response)
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6
Q

What are the classes of ACEIs?

A
  1. Sulfhydryl
  2. Dicarboxylate
  3. Phosphate
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7
Q

What falls under the sulfhydryl ACEI?

A

Captopril

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8
Q

What attributes to ACEIs poor oral bioavailability?

A

Peptides get metabolized into amino acids therefore IV prevents first pass metabolism

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9
Q

What is the SAR of ACE inhibitors?

A
  1. O= for chelation with Zn2+
  2. O= for H-bonding
  3. R1 and R2 (hydrophobic pocket) and R3
  4. COO- for hydrophilic binding
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10
Q

Why is captopril considered the most effective sulfhydryl ACEIs?

A

-SH brings more chelation with zinc, COO- for ion-ion binding

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11
Q

What are the major ADRs of Captopril?

A

Capoten has sulfur
1. Smell
2. Metallic taste
3. Skin rashes
4. Loss in taste, drug can bind to taste buds → taste fatigue

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12
Q

What are the metabolites of Capoten?

A

Captopril metabolizes into disulfide dimer and captopril-cysteine disulfide which are both inactive

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13
Q

In what ways did decarboxylate ACEs differ from Captopil?

A
  1. w/o Sulfur, instead was replaced with dicarboxylate
  2. Although, COO- didn’t chelate zinc as well, manufactures added a transition group that mimicked Ang I
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14
Q

What is the purpose of R1 and R2 side chains on ACEI?

A

Binding to Lys and His respectively

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15
Q

Why did Enalapril have terrible bioavailability? How was it fixed?

A

Vaster was too poor, dicarboxy ionized and didn’t absorb well

Transformed into a prodrug to increases is F

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16
Q

Describe the SAR of dicarboxyl ACEI?

A

R1: CH3 except for Lisinopril
R2: CH2CH3 attached to COO that get cleaved (prodrug)
R3: Lipophilic ring
Ring: contains COOH

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17
Q

How does phosphate ACEI differ from its predecessor?

A
  1. Phosphate chelates just as well as sulfhydryl
  2. Transition state mimics better than decarboxylates
18
Q

What is the phosphate ACEI? Why is it a good drug?

A

Fosinopril has a stable phosphate ester, prodrug gives it great bioavailability

19
Q

What is the most important ADR of ACEI?

A

Persistant cough due to build up of BK in lungs
Hypotension
Hyperkalemia

20
Q

What is the ARB site of action?

A

AT1

21
Q

What are the actions of AT2?

A

Anti-AT1: Vasodilation and hypotension

Apoptosis, cell differentiation, tissue repair

22
Q

What are the actions of AT4?

A

Release plasminogen activator inhibitor I
Can increase BP by cooperating with ANG II on AT1

23
Q

How did ARBs development start?

A

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

24
Q

What are the important SAR for ARB binding?

A
  1. COOH for ion-ion binding
  2. Hydrophilic rich for H-bonding can be lipophilic some
  3. Lipophilic group for hydrophobic pocket
25
Q

What was the significance of the first ARB?

A

Losartan (Cozaar) was one of the first drug to be developed by computer-aid and experimentation

26
Q

How is Losartan effective for AT1 binding?

A
  1. Biphenyl tetratrazole (lipophilic and negative charge)
  2. E- rich ring ring
  3. Lipophilic for pocket
  4. Phenylalanine (hydrophobic pocket)

Tetrazole has better binding than COO-

27
Q

How does Eprosartan differ from other ARBs?

A
  1. Greater potency than others
  2. Mimics COOH binding
  3. Additional carboxylate
  4. Not as balanced or have a biphenyl tetrazole
28
Q

What is the only renin inhibitor? When is it used?

A

Aliskerin (Tekturna)

Used for patients who can’t take ACEI or ARBs
Great for diabetics b/c its renal protective → helps albuminemia

29
Q

What are the indication of DHP and non-DHPs?

A

DHP: HTN
Non: CHF

30
Q

Describe the SAR components of DHPs?

A
  1. Phenyl ring @C4 increases activity (small nonplanar alkyl decreases)
  2. Ortho- and meta- substitutions is optimal EWG (para- decreases)
  3. Perpendicular is a blocker and planar is an activator
  4. 1,4-DHP ring is essential for good activity
  5. Esters @ C3 and C5 optimize activity
31
Q

What is the MOA of CCB?

A

Bind to receptor sites within the the central a1 subunits of L-type potential-dependent channels

32
Q

What are the 3 conformations of Ca2+ channels?

A
  1. A resting state which can be stimulated by membrane depolarization
  2. An open state which allows calcium to enter
  3. An inactive state which is refractory to further depolarization
33
Q

What are MOA of vasodilators?

A

Relax smooth muscle in BV → reduction in arterial BP

34
Q

What are the drawbacks of vasodilators?

A
  1. Induce baroreceptor mediated reflex stimulation of the heart (HTN)
  2. Impair baroreceptors-mediated reflex vasoconstriction → orthostatic hypotension
  3. Increase renal retention of Na+ and H2O
35
Q

What is another name for vasodilators?

A

Direct acting or K+ channel openers

36
Q

What is the MOA of direct-acting VD? Drug?

A
  1. K+ channel opener
  2. Inhibit IP3-induced release of calcium from SM
  3. Stimulate NO release from vascular endothelium
    Specific for arterial vessels

Hydralazine

37
Q

Describe mechanism behind VD K+ channel opener activity

A
38
Q

Describe how VD can inhibit Ca2+?

A
39
Q

Describe how VD stimulates NO?

A
40
Q

What are the types of VDs that can be used for HTN?

A
  1. Hydralazine (Apresoline)
  2. Minoxidil ( Loniten, Rogaine)
41
Q

How is Minoxidil used for HTN?

A
42
Q

How is Rogaine metabolized?

A

O-glucoronide: drug becomes more hydrophilic and inactive

Drug Action I (32 decks)

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