ACE inhibitors Flashcards
RAAs system regulates?
Blood pressure
Intravascular volume/NA+/K+
Fetal development
Junta-glomerular cells
- reduce circulating renin
Locally produced - RAA
- myocardium, vascular endothelium, adrenal
Pathophysiological effects of RAAS
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
The AT1 vs AT2 receptor
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
ACE inhibitors
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
Angiotensin II antagonists inhibit?
angiotensin II antagonists type I receptors
Why do renin levels increase when you take ACE inhibitors?
Because with lack of negative feedback from ACE inhibitors you get pressure to keep synthesising angiotensin I
Angiotensin II effects on cardiac myocytes
Hypertrophy apoptosis cell sliding increased wall stress Increased O2 consumption Impaired relaxation
angiotensin II effects on fibroblasts
hyperplasia
collagen synthesis
fibrosis
angiotensin II effects on peripheral artery
vasoconstriction
endothelial dysfunction
hypertrophy
decreased compliance
angiotensin II effects on coronary artery
Vasoconstriction Endothelial dysfunction Atherosclerosis Restenosis Thrombosis
Where are type I angiotensin receptors found
kindly, heart, vascular smooth muscle, brain, adrenal glands, adipocytes, placenta
where are type II angiotensin receptors found?
heart, adrenal, CNS, kidney
Effects of aldosterone on cardiac myocytes
hypertrophy, NE release
Effects of aldosterone on fibroblasts
hyperplasia, collagen synthesis, fibrosis
Effects of aldosterone on peripheral artery
vasoconstriction
endothelial dysfunction
hypertrophy
decreased compliance
Effects of aldosterone on the kidney
potassium loss
sodium retention
ACEi benefits short and long term
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)
ACE drug types NZ
Cilazapril 0.5-5mg od
AIIA drug types NZ
candesartan 4-32mg od
candesertan and losartan excretion
renal 60%
Bile 40%
ACE indications
hypertension
congestive heart failure
AIIA indications
ACEi intolerant patients
hypertension
heart failure
why should you never combine ACEi and AIIA
so significant improvement and you argument adverse side effects
esp. hyperkalemia
ACEi side effects
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
common treatment regime for hypertension
Diuretic + ACE inhibitor + vasodilator
Common treatment regime for heart failure?
Diuretic + ACE inhibitor + beta-blocker + spironolactone +/- AII antagonist
AII antagonists
Dry cough Hyperkalemia Renal Fx deterioration Hypotension Angio-edema contra-indicated pregnancy
Absolute contraindications to use of ACEi or AIIA
- 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
ACEi and AIIA possible non-BP lowering effects?
Reduce incidence of developing new diabetes
How can angiotensin II lead to the development of diabetes?
Oxidant stress Pro-inflammation Increase sympathetic activity Impaired insulin signalling Impair pancreatic function Reduced insulin sensitivity
A renin inhibitor?
Aliskiren available in US + EU is a renin inhibitor
