Lecture 8: Drugs Used to Manage High Blood Pressure (Part 2)

Question 1

What are the characteristics of alpha1 adrenergic receptors?

Answer 1

agonist effects: vasoconstriction

antagonist effects: vasodilation

Question 1

What are the characteristics of beta1 adrenergic receptors?

Answer 1

agonist effects: increased cardiac contractility, rate

antagonist effects: decreased cardiac contractility, rate

Question 2

What are the characteristics of beta2 adrenergic receptors?

Answer 2

agonist: relaxation of airway, vascular smooth muscle

antagonist: constriction of airway, vascular smooth muscle

Question 3

What are Ca2+ channel blockers (CCBs)?

Answer 3

increased intracellular Ca2+ is the main signal for smooth muscle contraction; this can arise from plasma membrane Ca2+ channels, or activation of a Gq-coupled cascade (such as alpha1)

contraction can be diminished by blockers of voltage-gated Ca2+ channels - a common drug in this class is amlodipine

Question 4

What is the RAAS system?

Answer 4

renin angiotensin aldosterone system

this is a powerful regulatory system that controls blood volume, salt balance, and blood pressure

RAAS is targeted by several classes of drugs: angiotensin receptor blockers (ARBs), angiotensin converting enzyme inhibitors (ACEis)

Question 5

What is renin in the RAAS system?

Answer 5

enzyme secreted by the kidney that processes angiotensinogen to ATI

release is stimulated by beta1 activation

Question 6

What is ACE in the RAAS system?

Answer 6

enzyme (angiotensin converting enzyme) that processes ATI to ATII

exists primarily as a membrane bound protein in the pulmonary capillary endothelium

Question 7

What is ATII in the RAAS system?

Answer 7

powerful vasoactive peptide that causes vascular smooth muscle control, and aldosterone release

angiotensin II effects are primarily mediated by the ATII receptor (Type 1) - usually called the AT1 receptor

AT1 receptors are GPCRs, coupled to the Gq signaling cascade

Question 8

What is aldosterone in the RAAS system?

Answer 8

steroid hormone that promotes reabsorption of Na+ and H2O in the kidney (preserves blood volume and increases blood pressure)

key transcriptional targets are in the nephron, including the distal convoluted tubule: Na+/K+ pump, epithelial Na+ channel (ENaC), NCC (Na+/Cl- symporter)

net effect is to promote Na+ (and therefore water reabsorption)

Question 9

How does ATII act in the adrenal cortex?

Answer 9

Ca2+ signals trigger synthesis/release of aldosterone

aldosterone is a steroid hormone so it cannot be “pre-packaged” for exocytosis like many hormones/neurotransmitters you have learned about

Question 10

How does ATII act in the vascular smooth muscle?

Answer 10

AT1-receptors mediate vasoconstriction

Question 11

What are the key players in RAAS system modulation?

Answer 11

ACE inhibitors

AT1 blockers (“ARBs”)

Question 12

What are ACE inhibitors in RAAS system modulation?

Answer 12

drug to remember: Captopril

enzyme inhibitor (prevents cleavage of Angiotensin 1)… therefore it reduces generation of all downstream RAAS signals (ATII, aldosterone)

most common side effect is dry cough due to bradykinin-mediated bronchoconstriction

Question 13

What are AT1 blockers in RAAS system modulation?

Answer 13

drug to remember: Losartan

Losartan and other ARBs have a vasodilatory effect

inhibits powerful vasoconstrictive effects of ATII

widely used drug class, often better tolerated than ACE inhibitors

Question 14

What are aldosterone antagonists in RAAS system modulation?

Answer 14

drug to remember: spironolactone

competitive antagonist of the aldosterone receptor

has diuretic actions by inhibiting aldosterone effects

Question 15

How effective are these drugs?

Answer 15

some appear to be more effective than others for certain outcomes, but differences are not enormous

it is common to use anti-hypertensive drugs in combination therapy, because they can have ~additive effects on blood pressure