ACE inhibitors Flashcards
Adverse pathophysiological effects of RAAS
- Increase in hypertension and advancement of congestive heart failure
- Cardiac hypertrophy and atherosclerotic plaque development
- Pro-inflammatory^
- close relationship with sympathetic nervous system (VC etc)
RAAS pathway again (AT1 and 2 receptors)
ACE blockage causes? (diagram)
Renin converts angiotensinogen to angiotensin 1
Angiotensin 1 to angiotensin 2 by ACE
AT1 receptors: aldosterone, VC.
AT2: anti proliferative effects/ VD?
Increased bradykinin, as this is broken down by ACE also.
Also shunt A1 to be broken down by ACE2, producing Angiotensin 1-9, which is broken down by ACE NEP to Angiotensin 1-7 which has anti-hypertensive effects
ACE inhibitors and AT2 antagonists mechanisms
ACE inhibitors: inhibit ACE thus decreasing A2 levels, decreasing other vasoactive peptides and increase bradykinin
A2 antagonists: Inhibit AT1 receptors only
How else can Angiotenisn 1 be broken down?
What else stimulates aldosterone production?
Aldosterone has what effect on renin?
- Chymase, trypsin or cathepsin
- K+
- negative, thus drugs increase renin levels
Angiotenin receptor locations, is a GPCR
AT1: kidney, heart, vascular smooth msucle, brian, adrenals, adipocytes, placenta
AT2: heart, adrenal, CNS, kidney, counter balance AT1 effects
Angiotensin 2 effects on: cardiac myocyte; fibroblast; peripheral artery; coronary artery
Cardiac myocyte: Hypertrophy, wall stress, increased O2 consumption
Fibroblast (Vascular tree): collagen synthesis, fibrosis
Peripheral artery: VC, endothelial dysfunction
Coronary: VC, atherosclerosis formation
ACEi and A2A block these effects!
Aldosterone effects
myocytes; fibroblast; arteries; kidney
Myocytes: hypertrophy, NE release
Fibroblast: collagen synthesis, fibrosis
Peripheral artery: VC, endothelial dysfunction
Kidney: K+ loss and Na+ retention
ACEi and A2A block these!
Time course of ACEi
First few weeks, decrease in A2 and aldosterone
Later: A2 and aldosterone return to normal, potentially due to increased chymase activity, but increased bradykinin induces VD and endothelial function promotion (increased NO and PG’s)
Drug types and examples of ACEi’s and AT2A’s
ACEi: Cilazapril, others ramipril
A2A: Losartan, candesartan
ACEi and A2A systemic effects
Vasodilation: decreasing arterial and venous pressure, thus decreasing after load and preload
Decrease in blood volume: natriuresis, diuresis
Decrease sympathetic activity
Decrease in cardiac and vascular hypertrophy
ACEi indications
First line hypertension: ACEi + diuretic to synergise.Can use alone
Congestive heart failure: As part of multiple treatments: ACEi (or A2A), diuretics, BB, Aldosterone antagonist
A2A indications
When patients are intolerant to ACEi in
Hypertension and heart failure
Never combine with ACEi
ACEi and A2A side effects
differences?
- Dry cough(increased bradyknin, cantake months). Less with A2A
- Hyperkalaemia: notably those with chronic kidney disease or using aldosterone agent
- Renal Fx deterioration*
- Angio-oedema (less than ACEi)
- Hypotension
- Contra-indicated in pregnancy (due to important A2 in renal development)
ACEi and A2A contraindications
2nd and 3rd trimester pregnancy
Bilateral renal artery stenosis
Why is there contraindication in bilateral renal artery stenosis
- A2 acts on efferent arteriole, VC to give pressure gradient between afferent and efferent
- With stenosis, AA pressure very low, thus more A2 produced to VC efferent arteriole more to maintain pressure gradient
- ACEi or A2A will result in EA vasodilation, and a reduction in renal function due to less/no pressure gradient
