Duane C. Hombrebueno

DRUGS ACTING ON THE RENAL SYSTEM

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

Renin-angiotensin system influences normal physiological function

Components of the system such as renin, angiotensin I and II, and angiotensin-converting enzyme

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.

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

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

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

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.

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.

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

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.

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.

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.

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.

Important role of renin angiotensin system

-Regulating kidney function

-Aldosterone release

-Electrolyte balance

-Blood volume

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.

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.

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

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.

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.

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.

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.

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

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