AT1 Receptor Antagonists

What are AT1 receptor antagonists also known as?

ARBs

How does the renin-angiotensin system work?

Renin is secreted into the kidneys and cleaves angiotensinogen to give angiotensin 1. ACE cleaves angiotensin 1 to give angiotensin 2 during passage through the lungs

What is renin?

Proteolytic enzyme that is secreted into the kidneys

How is renin secreted in the kidneys?

Juxtaglomerular apparatus if there is a fall in sodium levels or in renal perfusion pressure

What is angiotensinogen?

High molecular weight protein produced by the liver

What does angiotensin 2 do in the body?

• Constricts efferent arteriole greater than afferent and increases/maintains glomerular filtration pressure

• Increases sympathetic activity

• Tubular Na+ and Cl- reabsorption and K+ excretion, water also retained

• Aldosterone secreted and the retention of Na+ and H2O increases blood volume

• Arteriolar vasoconstriction which increases blood pressure

• ADH secretion.

What is a diagram showing the renin angiotensin system?

Where do AT1 receptor antagonists act?

Antagonist angiotensin II receptor and inhibits vascular growth

Where is the AT1 receptor found?

Throughout the body but found mostly in vasculature and angiotensin 2 is usually ligand

What type of receptor is the AT1 receptor?

GPCR

How does the AT1 receptor usually get activated?

• Signal transduction by G protein

• Activates phospholipase C to generate diacylglycerol and inositol triphosphate

• Release of inositol triphosphate causes release of Ca from intracellular stores

• Ca2+ and diacylglycerol activate protein kinases to phosphorylate proteins and effect cell function

What is a diagram showing how AT1 acts as a GPCR?

How do AT1 receptor antagonists work?

Block AT1 receptors and prevent angiotensin 2 to bind - allow angiotensin 2 to be produced but binding, therefore inhibit vasoconstriction and aldosterone secretion

What side effects are not observed as frequently as in ACE inhibitors as a result of AT1 receptor antagonists not effecting bradykinins?

Reduced cough and angioedema

What are some examples of angiotensin 2 receptor antagonists?

Losartan, irbesartan, valsartan, candesartan

What are the physiochemical values of the Sartan at1 receptor antagonists?

Around 4.68-5.39 in range for log P, PKa of 3.44 for candesartan in acids to 5.85, basic PKa of 1.51 for candesartan to 4.12 in irbesartan

What structural properties do the sartans have in common?

All have a tetrazole ring for lipophilicity and two benzene rings

What functional group is tetrazole a bioisostere for?

Carboxylic acids

What are the advantages of telmisartan as an at1 receptor antagonists?

Interacts with the tyrosine receptor using the benzydimidazole group and has strong TT-TT interactions

What is a way to remember telmisartan?

Tell me something else