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PHRM3041 > Hypertensives > Flashcards

Hypertensives Flashcards

1
Q

ACE is what kind of peptidase?

A

Non selective

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2
Q

Where does ACE cleave?

A

On the last two amino acids from many peptides

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3
Q

Where does ACE not cleave?

A

On peptide in which the second last amino acid is PROLINE

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4
Q

How many amino acid does angiotensin 1 have?

A

10 amino acids

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5
Q

How many amino acids does Angiotensin 2 have?

A

8 amino acids, the second last amino acid is proline

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6
Q

what is the name of the snake where the scientists got the venom from?

A

Bothrops Jararaca

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7
Q

What does the venom do.?

A

Decrease BP, Can cause death

It inhibits ACE

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8
Q

What is the name of the peptide isolated from the venom?

A

Teprotide

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9
Q

Why is teprotide not good?

A

Because it is not orally active

Second amino acid is proline

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10
Q

How is ACE and carboxypeptidase similar?

A

They both need Zn2+ for activity, both are peptides

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11
Q

What is the inhibitor of carboxypeptidase A?

A

D-2-benzylsuccinic acid

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12
Q

How to make D-2-methylsuccinic proline

from D-2-benzylsuccinic acid?

A

Add proline group to make ACE recognise it
👉 succinyl-proline
increase the chain length by adding a methyl like the dipeptides
👉 D-2-methylsuccinic proline

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13
Q

How to make captopril

A

add THIOL GROUP to D-2-methyl succinic proline

Change COOH to -SH which can act as Zn2+ ligand,
Interacting with positive

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14
Q

CAPTOPRIL SARs

A

Methyl : increased potency 20x

Thiol: increase potency x1000

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15
Q

Any possible modification to captopril

A

Addition of S in 5-ring 👉 thioproline

Addition of benzene to the 5-ring (benzofusion) 👉 increase potency 3-7x

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16
Q

When can captopril be inactive?

A

When benzene ring is added too close to the COOH

👉 steric hindrance

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17
Q

Some limitation of captopril caused by SH (thiol)

A

Rash, change/loss of taste

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18
Q

What is the ACEI without the thiol group

A

Enalapril

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19
Q

How to make enalaprilat from D-2-methylsuccinyl pro?

A 
Add amine (NH) to make it more like a peptide
Add silicon/ benzene to make it more lipophilic
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20
Q

Is enalaprilat a good ACEI?

A

No, it is very polar due to too many charges (too much ionisation by 2 x COOH and NH)

👉👉add an ester to the top COOH. And make it enalapril (prodrug)

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21
Q

Enalapril and enalaprilat ionisation difference

A

Enalapril - pKa (NH) ~5.5
Less ionised at physiological pH, non polar, orally active

Enalaprilat - pKa (NH) ~7.6
More ionised, very polar, orally inactive

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22
Q

Enalapril SARS

A

S1- amine ring and COOH (needed for activity)
S2 - methyl group
S3 - benzene ring

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23
Q

When does enalapril lose activity?

A 
S1
When proline is removed 
When COOH is converted to amide
S3
When branching on a-carbon (2 carbons away from benzene)
When addition of acidic side chain
S2
When any carbon branching (steric hindrance)
When addition of acidic side chain
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24
Q

How to make indolapril?

A

From enalapril, on s1, add 6-ring onto the amine ring (retained activity)

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25
Q

Any fine modification on captopril

A

On s3- modification of aliphatic and aromatic rings
On s2- many side chains

All retain activity

26
Q

How to make Lisinopril

A

S2= (CH2)4 NH2
Do not need to convert to ester
Because lisinopril is a Di-zwitterion in the duodenum pH
It forms ion pairs and can cross membrane together
👉 orally active

27
Q

What is the first ARB made from?

A

Takes a lead

based on “imidazole-­‐5-­‐acetic acid analogues” – patent filed

28
Q

What did DuPont Merck do to make a different ARB?

A

Tried to make a new one based on peptide inhibitor but failed
Looked at what the takeda lead contained to mimic ang2
and what the takeda lead was missing
DEVELOPED LOSARTAN

29
Q

What does takeda lead have that mimic the ang 2?

A

1)   C-­‐terminus carboxylate ion (on the right end)
2)   Imidazole ring (between carboxylate ion and butyl group, at the bottom)
3)   n-­‐butyl group of S-­‐8038 similar to isoleucine side chain of Ang II (in the middle on top)

30
Q

What was takeda lead missing?

A

Acidic side chain on the N terminus

Good interaction on the C terminus but barely any interaction on the N

31
Q

Big breakthrough in developing ARB from takeda lead

A

Addition of acidic group (COOH) on the benzene ring

32
Q

How to make losartan?

A

Through further modification to takeda lead including addition of acidic group
👉👉 tetrazole group on the benzene ring (mimicking the COOH group, the negative charge)

33
Q

One example of losartan analogues

And what does it need?

A

Valsartan

It needs ester groups (pro drugs need to be hydrolysed to become active)

34
Q

Other improvements on takeda lead

A

Instead of focusing on the missing acidic group on n terminus,
Focus on mimicking the c terminus as much as possible

👉Eprosartan

35
Q

Activation of beta-1 adrenergic receptor leads to…

A

Increase rate and force of cardiac contractions

Increase blood pressure

36
Q

Activation of beta-2 adrenergic receptors leads to…

A

Bronchodilation

37
Q

What are the two types of non-selective beta adrenergic receptor blockers?

A

Arylethanolamine type e.g. Sotalol

Aryloxypropanolamine type e.g. Propranolol

38
Q

What is the general rule of selective beta-1 adrenergic receptor blocker?

A

4-(para) substituted phenoxypropanolamines

If 3-substituted, it is non-selective

39
Q

What stops the alpha-activity of other beta-blockers?

What is lacked in the mixed alpha/beta adrenergic blockers?

A

N substituents

40
Q

What are the examples of mixed alpha and beta blockers

A

Carvedilol and labetalol

41
Q

What are the examples of selective beta 1 receptor blockers?

A

Atenolol, metoprolol

42
Q

What are the examples of non selective betablockers

A

Sotalol, propranolol

43
Q

What happens if you activate alpha receptor

A

Vasoconstriction

44
Q

What is the non selective AGENT of alpha blocker?

A

Phenoxybenzamine

45
Q

What is the stable salt form of phenoxybenzamine?

A 
Aziridinium ion (high reactive in water)
It reacts with nucleophile group (S,N,O) of an amino acid on an alpha receptor.
46
Q

What is the name of the receptor when the drug is covalently bonded to the alpha receptor?

A

Alkylated receptor

47
Q

What is the duration of action of phenoxybenzamine?

A

Very long acting
Because the drug is stuck to the receptor and the only way to get rid of this effect is to make a new receptor (as the receptor is alkylated)

48
Q

What is phenoxybenzamine used for?

A

To relieve symptoms of some adrenal tumours that secrete large amounts of A and NA

49
Q

What is the classic a1 selective antagonist?

And what aromatic ring does it contain?

A

Prazosin

Quinozoline (two 6-rings together), aliphatic 6-ring, furan ring (5-ring with oxygen)

50
Q

How do you increase duration of action in a1 selective antagonist?

A

Reduce the furan ring (From double bond to single bond)

51
Q

Centrally acting agents are what type of receptor agonist?

A

A2 adrenergic receptor

52
Q

What happens if you activate A2 receptor?

A

Decrease in BP –> antihypertensive

53
Q

Where else can a1 agonist be used for?

A

Nasal decongestant

54
Q

What are examples of centrally acting agent? - a2 agonist

A

Clonidine (classic), guanabenz, a-methyl norepinephrine (prodrug is methyldopa)

55
Q

What is important in a way clonidine acts?

A

Conformation and ring orientation

56
Q

Does methyldopa cross BBB

A

Yes

57
Q

What do CCB target in the cells?

A

L- type calcium channels

58
Q

What are the chemical classes in CCB?

A

Dihydropyridine eg. Amlodipine
Phenylalkyamines eg. Verapamil (OFTEN SYMMETRICAL)
Benzothiazipines eg. Diltiazem (Sulfur in the ring)
Diaminopropanol eg. Bepridil (rare)

59
Q

What is special about dihydropyridines?

A

Subtle changes in structure can change properties
You can make it a calcium channel activator
(Swapping CO2CH3 in isradipine to NO2)

60
Q

Dihydropyridines SARS

A

Substituted phenyl ring at the C4 position optimises activity
Ortho or meta substituents increase activity
PARA or None substituents decrease activity

PHRM3041 (9 decks)

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