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PHCY 310 > L 18 Medicinal Chemistry of Hypertension > Flashcards

L 18 Medicinal Chemistry of Hypertension Flashcards

1
Q

What Hypertension causes?

A

decreased vascular tone.

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2
Q

Hypertension can be risk factors for many other disease?

A

Stroke, Myocardial infarction (IHD)
Heart Failure(HF)
Atrial fibrillation (AF)
Chronic Kidney Disease(CKD)

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3
Q

What target drug in RAA (Renin angiotensin aldosterone) system?

A

Angiotensinogen is a 452 protein, which hydrolyzed by renin and produces angiotensin I,

then it further converted by angiotensin-converting enzyme and form angiotensin ii than it makes the signals to GPCR.

(Remember if Angiotensin ii is high in our blood cause hypertension, so drug target is Angiotensin ii)

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4
Q

Why we can’t just use peptides?

A

Because they hydrolyzed easily. Not good.

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5
Q

What are the types of angiotensin II receptor subtypes?

A

AT1 receptor and AT2 receptor

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6
Q

Angiotensin II is an … at both … and …

A

Angiotensin II is an endogenous agonist at both AT1R and AT2R

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7
Q

Drugs that are angiotensin II ‘blockers’ are thought to be … …

A

AT1R antagonists

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8
Q

What are the 3 different drug targets for hypertension?

A
  1. Renin
  2. ACE (angiotensin-converting enzyme)
  3. AT2R (Angiotensin 2 Receptor)
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9
Q

What are the Adv and Dis of peptide drugs:

A

Adv: highly specific and high affinity for target
Disadv: hydrolysed quickly = poor stability & low oral bioavailability.

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10
Q

ACE inhibitors + examples (x6)

A

e.g captopril, enalapril, cilazapril, perindopril, quinapril, lisinopril.

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11
Q

Is lisinopril a prodrug?

A

Not

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12
Q

Which ACEI are administered in their active form?

A

Lisinopril and captopril

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13
Q

Is losartan a prodrug? What class of drug is losartan?

A

No, because technically both losartan and its metabolite have biological activity.
Drug class = Angiotensin II Receptor Blocker (ARB)

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14
Q

Is the candesartan cilexetil a prodrug?

A

Yes

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15
Q

Ester hydrolysis of Candesartan occurs during…?

A

Absorption from the GIT

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16
Q

What are the Examples of Angiotensin II Receptor Blockers?

A

Losartan, candesartan, irbesartan

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17
Q

Which part of the losartan bind to the target and with which help?

A

Carboxylic acid moiety binds with the target. With the hlep of CYP 2C9 & 3A4 enzyme.

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18
Q

Is losartan a prodrug?

A

No

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19
Q

Which receptors do angiotensin II blockers act at?

A

AT1 receptors

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20
Q

Calcium Channel Blockers act at… by binding to the …

A

CCBs act at L-type voltage-gated calcium channels by binding to the alpha i subunit of the membrane spanning protein.

21
Q

Examples of DHP calcium channel blockers in NZ. Which of these are racemic mixtures?

A

Amlodipine, felodipine, isradipine, nifedipine, nimodipine. (the core is 1,4, DHP)
All are racemic except nifedipine.

22
Q

The structure of Dihydropyridines (DHP) of Calcium channel blockers has?

A

Esters at C3 and C5 and Phenyl ring at C4 of 1,4 Di Hydro Pyridine.

23
Q

Non DHP Calcium Channel Blockers examples:

A

Verapamil, diltiazem

24
Q

Stimulation of B1 in the heart causes.?

A

Increased heart rate, contractility, AV node conduction and cardiac output.

25
Q

What will B2AR agonists cause… therefore B2AR antagonists will cause….?

A

B2AReceptor agonists cause bronchodilation therefore B2AR antagonists will cause bronchoconstriction

26
Q

What if A1AR antagonists will cause…

A

Vasodilation of blood vessels (therefore decrease in resistance and blood pressure).

27
Q

Examples of B1AR blockers

A

Prazosin, terazosin, doxazosin

28
Q

Does AR bind with both B1 and B2?

A

Yes but they do not elicit a receptor signal or do not work as antagonists.
Remember that the First generation is non selective but 2nd generation is selective

29
Q

Does AR bind with both B1 and B2?

A

Yes but they do not elicit a receptor signal or do not work as antagonists.
Remember that the First generation is nonselective but 2nd generation is selective

30
Q

BAR and XAR are … to each other

A

Beta and alpha adrenoreceptors are structurally different to each other.

31
Q

Which one is more lipophilic and can more cross BBB?

A

Propranolol or Nadolol or Pindolol

Propranolol as its clogp is higher than other its 2.58 and can cross BBB.

32
Q

First generation BAR blockers are selective for … but are not selective for ….

A

First generation BAR blockers are selective for bAR over xAR but are not selective for b1AR over b2AR

33
Q

B blockers are a ……

A

B blockers are a racemic mixture.

34
Q

Examples of Non-selective B blockers

A

Propanolol, nadolol, pindolol

35
Q

Which of the following are the most lipophilic?

A 
ClogP: 2.58
ClogP: 0.87
ClogP: 1.69
Highest clogP = more lipophilic
Therefore 2.58 is the most lipophilic
36
Q

A more lipophilic drug is …. likely to diffuse across the BBB

A

More lipophilic = more likely to diffuse across membrane

37
Q

Lipophilic B blockers can cause…

A

Nightmares, sleep disturbances, hallucinations

38
Q

Second generation B blockers are selective for …

A

Selective for BAR over alpha AR and selective for B1AR over B2AR

39
Q

Why is B1 selectivity desirable?

A

B1 selectivity can target the heart without getting unwanted side effects in the lungs, therefore can be used in asthmatics.

40
Q

How do you make a B1 selective blocker? What functional group do you add?

A

Changing the drug structure to favour B1 means that it no longer will bind well in the other subtypes.
Add a functional group off the phenyl ring that is capable of hydrogen bonding.

41
Q

How do we design a drug with a short duration of action?

A

Make it as ester to be rapidly cleaved in the body.Ex esmolol

42
Q

Examples of selective 2nd generation B blockers

A

Metoprolol, atenolol

43
Q

Examples of drugs that bind to both x1, B1 and B2 ARs. What structural difference do they have?

A

Labetalol, carvedilol

Have an extended chain with an aromatic group.

44
Q

What do diuretics do?

A

They increase the rate of urine formation

45
Q

Examples of different diuretic classes + examples within these classes

A 
Thiazides (e.g bendroflumethiazide)
Loop diuretics (e.g furosemide)
46
Q

How do thiazide diuretics work?

A

Blocks Na+Cl- symporter, causing less Na+ reabsorption (and therefore less water reabsorption).
Lower Na+ also causes vasodilation

47
Q

Structural requirements of thiazides

A

Electron withdrawing group, sulfonamide, lipophilic group

48
Q

How do loop diuretics work?

A

Inhibiting Na/K/2Cl co-transporter (aka NKCC2) therefore more excretion of Na+ and water.
They treat edema and can help hypertension

PHCY 310 (65 decks)

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