ppt

1. Duane C. Hombrebueno
Min Gyun Lee

2. Chapter Overview
 Describes the role renin-angiotensin
system plays in regulating the
cardiovascular system
 Critical role in the mechanism of
hypertension and congestive heart failure
 Development of therapeutic agents that act
on the various enzymes and receptors
associated with the renin-angiotensin
system

3. Chapter Overview
 Renin-angiotensin system influences
normal physiological function
 Components of the system such as renin,
angiotensin I and II, and angiotensin-
converting enzyme

4. Renin-Angiotensin System
and Hypertension
Renin-Angiotensin system – is a hormonal
system that plays a central role in the
control of sodium excretion and body fluid
volume. Interacts closely with the
sympathetic nervous system and
aldosterone secretion in the regulation of
blood pressure.

5. Renin-Angiotensin System
and Hypertension
Renin – a kidney extract produced a potent
vasopressor response.
- An aspartyl protease (MW 35,000 –
40,000).
- Primary source is kidney.
- Cleaves the Leu-Val bond from the
aspartic acid end of the angiotensinogen
polypeptide molecule to release the
decapeptide angiotensin I

6. Renin-Angiotensin System
and Hypertension
Angiotensin – hypertensive substance
isolated and identified as decapeptide
- is a glycoprotein (MW 58,000 – 61,000).
- synthesized primarily in the liver and
brought into the circulatory system

7. Biochemical Conversion
 The Cleavage of a dipeptide (His-Leu)
from the carboxyl terminal of angiotensin
converting enzyme to form octapeptide
which is angiotensin II (a potent
vasoconstrictor)
 Angiotensin III is formed by removal of
the N-terminal aspartate residue of
angiotensin II a reaction catalyzed by
glutamyl aminopeptidase

8. Biochemical Conversion
 In contrast to angiotensin II, angiotensin
III has a less potent but significant
regulatory effect on sodium excretion by
the renal tubules
 This is primarily resulting from the effect
angiotensin III has in stimulating
aldosterone secretion, a potent
mineralcorticoid.

9. Vasoconstrictive effects
of angiotensin II
Angiotensin II – stimulates the release of
vasopressin from the hypothalamus.
Vasopressin – also known as antidiuretic
hormone (ADH)
- This peptidic hormone is typically
released to conserve water when body is
dehydrated.

10. Vasoconstrictive effects
of angiotensin II
Endothelin – a 21 amino acid peptide that
is produced in the vascular endothelium
and plays a role in the regulation of
smooth muscle contraction and contributes
to blood pressure regulation.
Aldosterone – secreted by adrenal cortex
and elicits its effects at various sites.
Responsible for the absorption of sodium
in the bloodstream

11. Regulatory action of the
renin-angiotensin system,
- In controlling sodium and potassium
balance and arterial blood pressure is
modified by vasodilators called kinins.
Kallikrein – is activated in plasma by
noxious influences to act on a kinin,
callidin, which is converted to bradykinin
by tissue enzymes.

12. Regulatory action of the
renin-angiotensin system,
Bradykinin – enhances release of the
prostaglandins PGE2 and PGI2 within
certain tissues to produce a vasodilatory
effect.
- Converted to inactive products by ACE
and other carboxypeptidases.

13. ACE – a membrane bound enzyme
anchored to the cell membrane through a
single transmembrane domain.
- Zinc containing glycoprotein (MW
130,000)
- A non specific peptidyldipeptide
hydrolase, widely distributed in mamalian
tissues.
- Is a tripeptide with a free carboxylate
group.

14. Active sites of ACE
 Important binding points
- Cationic site to attract a carboxylate ion
- Zinc ion that can polarize a carbonyl
group of an amide function to make it
more susceptible to hydrolysis.
In the active site, there is a nucleophilic
attack of the amide carbonyl by the y-
carbonyl group of a glutamic acid
residue to cause hydrolysis of peptide.

15. Important role of renin
angiotensin system
 Regulating kidney function
 Aldosterone release
 Electrolyte balance
 Blood volume

16. Renin-Angiotensin system
inhibitors
Captopril – 1-[(2S)-3-mercapto-2-methyl-
1-oxopropionyl]proline (Capoten)
- Blocks the conversion of angiotensin I to
angiotensin II by inhibiting the
converting enzyme.
- Was designed with a carboxyl group on a
proline and a thiol group was introduced
to enhance binding to zinc ion of ACE.

18. Lisinopril – 1-[N2-[S-1-carboxy-3-phenylpropyl]-
L-lysyl]-L-proline dihydrate (Privinil, Zestril)
- A lysine derivative of enalaprilat, active
metabolite of enalapril.
- Like all ACE inhibitors, it is an active site-
directed inhibitor of the enzyme, with the zinc
ion used in an effective binding interaction at a
stoichiometric ratio of 1:1
- Pharmacological effect are similar to those of
captopril and enalapril.

20. ACE-Inhibitors ProDrugs
- Available for the treatment of
hypertension following the clinical
effectiveness of enalapril
- These drugs, like the prototypical drug
captopril, are used in the treatment of
mild to moderate hypertension, either
alone or in conjunction with diuretics or
calcium channel blockers

21. Enalapril Maleate - 1-[N[(S)-1-carboxy-3-
phenylpropyl]-L-alanyl]-L-proline 1-ethyl
ester maleate (Vasotec)
- Is a long-acting ACE inhibitor.
- Is devoid of the side effects of rash and loss
of taste seen with captopril
- The absence of the thiol group in enalapril
maleate may free it from these side effects.
- The half-life is 11 hours.

23. Benazepril Hydrochloride - (3S)-3-[[(1S)-1-
carbethoxy-3-phenylpropyl]amino]-2,3,4,5-
tetrahydro-2-oxo-1H-1-benzazepine-1-acetic
acid 3-ethylester hydrochloride (Lotensin)
- Metabolized rapidly to the active diacid
benazaprilat.
- No mutagenicity has been found, even
though these drugs cross the placenta.

25. Quinapril Hydrochloride - (S)-[(S)-N-[(S)21-
carboxy3-phenylpropyl]alanyl]-1,2,3,4-
tetrahydro-3-isoquinolinecarboxylic acid 1-
ethyl ester hydrochloride (Acuretic)
- forms the diacid quinaprilate in the body. It is
more potent than captopril and equipotent to
the active form of enalapril.

27. Ramipril - (2S, 3aS, 6aS)-1-[(S)-N-[(S)-1-
carboxy-3phenylpropyl]alanyl]
octahydrocyclopenta[b]-pyrrole-2-carboxylic
acid 1-ethyl ester (Altace)
- Is hydrolyzed to ramiprilat, its active diacid form,
faster than enalapril is hydrolyzed to its active
diacid form.
- Peak serum concentrations from a single oral
dose are achieved between 1.5 and 3 hours.
- ramiprilate formed completely suppresses ACE
activity for up to 12 hours, with 80% inhibition
of the enzyme still observed after 24 hours.

29. Fosinopril Sodium - (4S)-4-cyclohexyl-1-
[[[(RS)-1-hydroxy-2-methylpropoxy](4-
phenylbutyl) phosphinyl]acetyl]-L-proline
sodium salt (Monopril)
- Phosphorus-containing ACE inhibitor.
- It is inactive but serves as a prodrug, being
completely hydrolyzed by intestinal and liver
enzymes to the active diacid fosinoprilat

31. Trandolapril - 1-[2-(1-ethoxycarbonyl-3-
phenylpropylamino)propionyl]octahydroindole-
2-carboxylicacid (Mavik)
- an indole-containing ACE inhibitor that is
structurally related to most of the preceding
agents
- Very similar to Enalapril with the primary
difference occurring in the heterocyclic
systems
- must be hydrolyzed to tranolaprilate, which is
the bioactive species

33. The End