ACE inhibitors

Question 1

RAAs system regulates?

Answer 1

Blood pressure
Intravascular volume/NA+/K+
Fetal development

Junta-glomerular cells
- reduce circulating renin
Locally produced - RAA
- myocardium, vascular endothelium, adrenal

Question 2

Pathophysiological effects of RAAS

Answer 2

increased activation in CCF (congestive heart failure) and in hypertension
Adverse cardiovascular effects
- cardiac hypertrophy
- atherosclerosis development and plaque rupture
- pro inflammatory / pro-oxidant
Close relationship with sympathetic nervous system

Question 3

The AT1 vs AT2 receptor

Answer 3

angiotensin II acts on the AT1 receptor to mediate adverse properties e.g. aldosterone secretion, vasoconstriction and classic angiotensin actions (increase synthetic tone, oxygen stress, hypertrophy)
Whereas binding to the AT2 receptor seems to have antagonistic effects to the AT1 receptor = anti proliferation, tissue repair, apoptosis, vasodilation, kidney development

Question 4

ACE inhibitors

Answer 4

stop conversion of AT1-2 but they also prevent breakdown of bradykinin and substance P and therefore ACE inhibitors will increase their plasma levels, also by blocking ACE you shunt angiotensin down another synthetic pathway mediated by a different enzyme which can also have beneficial effects e.g. lowering BP, anticoagulants

Question 5

Angiotensin II antagonists inhibit?

Answer 5

angiotensin II antagonists type I receptors

Question 6

Why do renin levels increase when you take ACE inhibitors?

Answer 6

Because with lack of negative feedback from ACE inhibitors you get pressure to keep synthesising angiotensin I

Question 7

Angiotensin II effects on cardiac myocytes

Answer 7

Hypertrophy 
apoptosis 
cell sliding 
increased wall stress 
Increased O2 consumption 
Impaired relaxation

Question 8

angiotensin II effects on fibroblasts

Answer 8

hyperplasia
collagen synthesis
fibrosis

Question 9

angiotensin II effects on peripheral artery

Answer 9

vasoconstriction
endothelial dysfunction
hypertrophy
decreased compliance

Question 10

angiotensin II effects on coronary artery

Answer 10

Vasoconstriction 
Endothelial dysfunction 
Atherosclerosis 
Restenosis 
Thrombosis

Question 11

Where are type I angiotensin receptors found

Answer 11

kindly, heart, vascular smooth muscle, brain, adrenal glands, adipocytes, placenta

Question 12

where are type II angiotensin receptors found?

Answer 12

heart, adrenal, CNS, kidney

Question 13

Effects of aldosterone on cardiac myocytes

Answer 13

hypertrophy, NE release

Question 14

Effects of aldosterone on fibroblasts

Answer 14

hyperplasia, collagen synthesis, fibrosis

Question 15

Effects of aldosterone on peripheral artery

Answer 15

vasoconstriction
endothelial dysfunction
hypertrophy
decreased compliance

Question 16

Effects of aldosterone on the kidney

Answer 16

potassium loss

sodium retention

Question 17

ACEi benefits short and long term

Answer 17

plasma effects in the first few weeks 
- dec AII conc 
- dec Aldosterone conc 
But later 
- return to normal AII and aldosterone 
- due to chemise activity 
- what about local tissue levels 
But bradykinin levels increase (vasorelaxation, endothelial function increase)

Question 18

ACE drug types NZ

Answer 18

Cilazapril 0.5-5mg od

Question 19

AIIA drug types NZ

Answer 19

candesartan 4-32mg od

Question 20

candesertan and losartan excretion

Answer 20

renal 60%

Bile 40%

Question 21

ACE indications

Answer 21

hypertension

congestive heart failure

Question 22

AIIA indications

Answer 22

ACEi intolerant patients
hypertension
heart failure

Question 23

why should you never combine ACEi and AIIA

Answer 23

so significant improvement and you argument adverse side effects
esp. hyperkalemia

Question 24

ACEi side effects

Answer 24

side effects can take a while to manifest so you have to keep monitoring patients
If they develop cough (probably due to inc Brady kinin and substance P) on ACE inhibitor then swap them to angiotensin II antagonist where chance of cough is much lower
- hyperkalemia
- Renal Fx deterioration
- Hypotesion
- Angio-edema
- Contra indicated pregnancy

Question 25

common treatment regime for hypertension

Answer 25

Diuretic + ACE inhibitor + vasodilator

Question 26

Common treatment regime for heart failure?

Answer 26

Diuretic + ACE inhibitor + beta-blocker + spironolactone +/- AII antagonist

Question 27

AII antagonists

Answer 27

Dry cough 
Hyperkalemia 
Renal Fx deterioration 
Hypotension 
Angio-edema 
contra-indicated pregnancy

Question 28

Absolute contraindications to use of ACEi or AIIA

Answer 28

• pregnancy: 2nd and 3rd trimester, renal defects, oligohydroaminos, fatal death.
• Bilateral renal artery stenosis: this you cant test for so have to monitor patient really closely when you start them on the drug. Efferent arteriole tone is very high so to maintain glomerular filtration pressure when renal artery narrow. but giving said drugs will cause relaxation of efferent arteriole = rapid deterioration in renal function

Question 29

ACEi and AIIA possible non-BP lowering effects?

Answer 29

Reduce incidence of developing new diabetes

Question 30

How can angiotensin II lead to the development of diabetes?

Answer 30

Oxidant stress 
Pro-inflammation 
Increase sympathetic activity 
Impaired insulin signalling 
Impair pancreatic function 
Reduced insulin sensitivity

Question 31

A renin inhibitor?

Answer 31

Aliskiren available in US + EU is a renin inhibitor