ARBs (ACE/Renin Blockers) PDF

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Summary

ARBs are a lecture topic for Exam II. This summary covers all of the Objectives for this topic. ...

Description

Learning Objectives— ARBs and Renin Inhibitors 1.

Know the characteristics and function of the four angiotensin II receptors

Type 1 (AT1)

Four types of receptors for angiotensin II Type 2 (AT1) Involved in vascular growth G-protein coupled receptor

o o o o o

G-protein coupled receptor Causes vasoconstriction Increases renal sodium reabsorption Enhances cardiac contractility Displayed on the heart, blood vessels, kidneys, and adrenal cortex

2.

Understand the nomenclature of angiotensin II receptor type 1 blockers (ARBs) ARBs as Drugs • Angiotensin II Receptor Type 1 Blockers • Angiotensin II Receptor Blockers • Angiotensin Receptor Blockers (ARBs) • Also described by suffix, sartans • Some are antagonists • Some are inverse agonists

o o

Types 3 (AT3) o

not well tolerant

Development of ARBs • Similar to ACE inhibitors… • Peptide identified with promising activity but poor PK and low oral bioavailability • Peptide converted to small molecule • Small molecule optimized 3.

Be able to describe the development of the ARBs from saralasin Delvelopment of ARBs from Saralasin

Types 4 (AT4) o

not well tolerated

4.

Know the mechanism of action, pharmacology, teratogenicity, and metabolism of losartan, candesartan, olmesartan, and azilsartan Losartan Candesartan Olmesartan Azilsartan

MOA Competitive antagonist of angiotensin II receptor

MOA Competitive antagonist of angiotensin II receptor Ester prodrug

MOA Inverse agonist of angiotensin II receptor Ester prodrug

MOA Inverse agonist of angiotensin II receptor Ester prodrug Oxadiazolone

Pharmacology Dosed once per day Also used in diabetic nephropathy

Pharmacology Similar to active metabolite of losartan Used in hypertension and heart failure

Pharmacology Similar to active metabolite of losartan Used in hypertension

Pharmacology Similar to active metabolite of losartan Used in hypertension

Similar teratogenicity of ACE inhibitors— Teratogenic agent ***Metabolism CYP2C9 and CYP3A4

Teratogenic agent

Teratogenic agent

Teratogenic agent

Metabolism Ester Hydrolysis

Metabolism Ester Hydrolysis

Metabolism Ester Hydrolysis

Losartan Metabolism—CYP3A4 & CYP26D

5.

Be able to identify the ARBs that are prodrugs: 3 Prodrugs

6.

Know the mechanism of action, pharmacology, and teratogenicity of valsartan, irbesartan, telmisartan, and eprosartan Valsartan Irbesartan Telmisartan Eprosartan

MOA Inverse agonist of angiotensin II receptor

MOA Competitive antagonist of angiotensin II receptor

MOA Inverse agonist of angiotensin II receptor

MOA Competitive antagonist of angiotensin II receptor

Pharmacology Amide instead of imidazole Displays carboxylic acid Used in hypertension and heart failure

Pharmacology Displays imidazolone and butyl chain Used in hypertension and diabetic nephropathy

Pharmacology Displays benzimidazole and propyl chain No tetrazole Used in hypertension

Pharmacology Imidazole carboxylic acid Distinct structure Used in hypertension

Teratogenic agent

Teratogenic agent

Teratogenic agent

Teratogenic agent

Metabolism No CYP metabolism

Metabolism No metabolism

Metabolism Inactivated by glucuronidation

Metabolism Excreted unchanged

7.

Be able to identify a tetrazole, imidazole, benzimidazole, imidazoline, and oxadiazolone

TETRAZOLE

IMIDAZOLE

BENZIMIDAZOLE

OXADIAZOLONE

8.

IMIDAZOLINE

Know the structure–activity relationships of the ARBs SAR Relationships of ARBs • • • • •

9.

Imidazole carboxylic acid scaffold Carboxylic acid group, tetrazole, or oxadiazolone is required Imidazole, benzimidazole, imidazolone, or amide is required Alkyl chain necessary for potency – Pentyl chain is site of CYP metabolism A second carboxylic acid (or ester) may be displayed

Be able to distinguish the competitive antagonists and inverse agonists in the ARBs class of drugs

Competitive antagonist

Inverse agonist

10. Understand the role and function of renin Role of Renin • Aspartic protease • Cleaves angiotensinogen into angiotensin I • Also called angiotensinogenase • Secreted by kidneys • Regulates arterial blood pressure 11. Know the mechanism of action, pharmacology, teratogenicity, and metabolism of aliskiren Aliskiren (Tekturna®)

MOA •

Discovered by structure–based drug design

Pharmacology • Approved in 2006 for hypertension • Highly potent and orally bioavailable

Teratogenic agent Metabolism

Mechanisms of ARBs • Some are inverse agonists – Losartan metabolite, valsartan, telmisartan, olmesartan, and azilsartan • Some are competitive antagonists – Losartan, erposartan, irbesartan, candesartan • Three are prodrugs • All are dosed once per day • All are teratogens • Only losartan has CYP-interactions

Summary • Angiotensin II effects are also blocked by ARBs and renin inhibitors • ARBs are designed from imidazole carboxylic acid • Affect the renin-angiotensin-aldosterone system • Useful in hypertension and other cardiovascular disorders • Risks of teratogenicity • We will learn about aldosterone inhibitors in diuretics...