Pharmacology I - 11/18

Front 1

Where is angiotensinogen produced?

Back 1

The liver

Front 2

What converts Angiotensinogen to Angiotensin I? Angiotensin II?

Back 2

Renin
ACE

Front 3

What are the effects of angiotensin II?

Back 3

1) Augmented Sympathetic Activity
2) Increased Na reabsorption K excretion
3) Increased secretion of aldosterone leading to Increased Na retention and K excretion
4) Vasoconstriction
5) ADH secretion leading to increased water retention

Front 4

What mechanism will essentially turn RAAS off?

Back 4

Increased blood pressure inhibits the secretion of renin from the kidneys.

Front 5

What 3 things trigger renin release?

Back 5

1) Local pressure sensing in the kidney
2) Sympathetic input to the kidney
3) Local [Na+] sensing (low Na)

Front 6

Where in the kidney is renin released from?

Back 6

Juxtaglomerular cells in response to low tension in the afferent arterioles.

Front 7

Via stimulation of what receptor is renin secretion increase?

Back 7

Beta 1

Front 8

What is tubuloglomerular feedback?
Where is it located?

Back 8

The Na sensing mechanism in the thick ascending loop of henle
Decreased tubular Na = Increased renin

Front 9

Describe the intracellular response of juxtaglomerular cells to B1 receptor stimulation.

Back 9

Norepinephrine binding induces Gs protein activation leading to cAMP production. Increased cAMP leads to renin secretion.

Front 10

Describe the intracellular process associated with tubuloglomerular feedback.

Back 10

- Increased tubular Na means increased levels in the TAL cells. Increased Na leads to adenosine release and adenosine receptor activation on the JG cell. Adenosine activation inhibits cAMP formation and therefore renin release.
- Decreased tubular Na activates COX-2 in the TAL cells which increases prostaglandin production, release and activation of the PG receptor on JG cells. Via a Gs coupled receptor again, cAMP is produced and therefore renin released

Front 11

What is AT1R?

Back 11

The receptor that Angiotensin II binds to.
It is a G-protein coupled receptor

Front 12

Name the 4 parts of the body that angiotensin II works on via the AT1R.

Back 12

Adrenal Cortex (aldosterone release)
PCT/TAL (Na reabsorption)
Renal Efferent Arterioles (Increased GFR)
Hypothalamus (Increased thirst. ADH secretion)

Front 13

Specifically, how does angiotensin II effect the PCT intracellarly to increase Na absorption?

Back 13

It can activate 3 different Na channels:
a) NHE3 channel (Na into cell)
b) NBC1 channel (Na/Bicarb into body)
c) Na/K ATPase (Na into body/K into cell from body)

Front 14

What channel does angiotensin II activate in the TAL?

Back 14

NKCC2 Na/K/Cl transporter which brings these 3 ions into the cell.

Front 15

How does angiotensin II stimulate Na reabsorption in the CD?

Back 15

Via aldosterone release
Aldosterone activates the Mineralocorticoid receptor in the CD which increases ENac expression bringing Na into the cell.

Front 16

In a normal healthy individual, which portion of the renal arteriole is more constricted?

Back 16

Afferent - associated with decreased GFR

Front 17

In renal hypotension, which portion is more constricted?

Back 17

Efferent arteriole - increased GFR due to increased filtration through the glomerulus

Front 18

Angiotensin II will tend to decrease renal blood flow. Why?
What are the 3 mechanisms by which it accomplishes this?

Back 18

To minimize Na excretion
1) Constricts the afferent more than efferent arteriole (Ca-mediated contraction)
2) sympathetic stimulation - Alpha 1 stimulation and vasoconstriction of renal arteries
3) Facilitation of renal adrenergic transmission by inhibiting Norepi uptake into the pre-synaptic nerve terminals

Front 19

What is the mechanism by which angiotensin II induces Smooth Muscle Contraction?

Back 19

Stimulation of a G-protein coupled receptor that induces Ca efflux from the SR into the cytosol.

Front 20

This stimulation leads to increased CO and afterload in the short term. What occurs in the long term?

Back 20

Muscle cell hypertrophy

Front 21

Describe the effect of ACE inhibitors on stimulation of the ATR2 receptors.

Back 21

ACE inhibitors inhibit ACE which breaks down bradykinin into inactive peptides. Bradykinin normally stimulates BKR and induces Vasodilation via NO.

Front 22

Name 3 ACE inhibitors

Back 22

Enalapril
Captopril
Lisinopril

Front 23

What 5 disease states are ACE inhibitors indicated for?

Back 23

Hypertension
Coronary artery disease
Congestive Heart Failure
Diabetes
Stroke

Front 24

Describe the pharmacogenetic aspect of RAAS inhibitors.

Back 24

AA's respond less to RAAS inhibitors in general

Front 25

ACE inhibitors are far more efficacious when used in combination with this drug class.

Back 25

Diuretics
30-40 vs 75-85

Front 26

What are the adverse effects of ACE inhibitors?

Back 26

Bradykinin related - Angioedemia, cough
Patients with renal artery stenosis - Hypotension and Acute Renal Failure
They are also teratogenic - use another antihypertensive

Front 27

What is an important DDI of ACE inhibitors?

Back 27

K-sparing diuretics - Hyperkalemia

Front 28

Describe why there is a compensatory increase in renin associated with ACE inhibitors.

Back 28

ACE inhibitors decrease the amount of angiotensin II synthesized. Angiotensin II inhibits the TAL NKCC2 Na/Cl/K co-transporter leading to decreased Na reabsorption. This decreased intracellular Na activates COX-2 and increases prostaglandin production and therefore PG receptor stimulation, cAMP production and renin release. This mechanism will eventually supersede the effect of an ACE inhibitor.