PR2153 Chui IC4

Pharmacology and medicinal chemistry

Identify the druggable targets in the renin-angiotensin system (RAS) suitable for blood pressure lowering effect.

These targets include angiotensin-converting enzyme (ACE), angiotensin II type 1 receptor (AT1R), and renin itself.

Describe the mode of action of the antihypertentive agents on the targets of the ACE inhibitors, Angiotensin II receptor blocker (ARB), and Calcium Channel Blocker (CCB).

ACE inhibitors block the conversion of angiotensin I to angiotensin II, reducing vasoconstriction. Also reduces bradykinin degradation which is a potent vasodilator, resulting in further vasoconstriction.

ARBs block the action of angiotensin II at the AT1 and AT2 receptors (a LOT more selective for AT1), inhibiting the effects of angiotensin II which includes vasoconstriction, aldosterone secretion which increases the amount of fluid and NaOH retention which increases the peripheral resistance. Blocking AT1 also reduces Ca release from intracellular stores (hence relaxed smooth muscles) and decrease sympathetic activity.

CCBs bind to different allosteric sites on the Calcium channel and inhibit calcium influx through them in vascular smooth muscle, leading to vasodilation.

What are the side effects and contraindications of ACE inhibitors?

Adverse effects: dry cough, severe hypotension, lightheadedness, acute renal failure, hyperkalemia, angioedema

Contraindication: Pregnancy

What are the side effects and contraindications of Angiotensin II receptor blockers?

Adverse effects: hypotension, lightheadedness, less angioedema, NO dry cough

Contraindication: Pregnancy

What are the side effects and contraindications of DHP Calcium Channel Blockers?

Adverse effects: Dizziness, peripheral oedema (to monitor), Hypotension

Contraindication: resultant severe hypotension

What are the side effects and contraindications of non-DHP Calcium Channel Blockers?

Adverse effects: dizziness, peripheral oedema (less than DHP ones), constipation (verapamil), Digoxin interaction

What are the lead compounds used for the development of ACE inhibitors and ARB (Angiotensin II receptor blockers)?

ACEi: Teprotide

ARB: Angiotensin II

How to classify CCBs by their structures? What is this?

1,4-dihydropyridine (DHP) namely Nifedipine

How to classify CCBs by their structures? What is this?

Phenylalkylamine namely Verapamil

How to classify CCBs by their structures? What is this?

Benzothiazepine namely diltiazem