Drugs of the Cardiovascular System – The Vasculature Flashcards
Name three drug classes that interfere with the renin-angiotensin system.
Renin inhibitors
ACE inhibitors
Angiotensin receptor blockers
Describe the action of aldosterone in collecting duct tubule cells.
Aldosterone passes through the plasma membrane and binds to mineralocorticoid receptors intracellularly and increases the synthesis of Na+ channels and Na+/K+ pumps
This causes an increase in sodium reabsorption and potassium excretion. (increased intracellular K+ due to Na+/K+ pump, the K+ then diffuses out passively on the tubular fluid side via K+ channels)
What are the uses of ACE inhibitors?
Hypertension Heart Failure Diabetic Nephropathy Post-MI Progressive Renal Insufficiency Patients at high risk of cerebrovascular disease
Give an example of an ACE inhibitor.
Enalapril
Ramipril
drugs that end in ‘-pril’ are normally ACE inhibitors
What are the main actions of angiotensin II?
How do ACEi treat hypertension and heart failure?
A2 actions:
- intrinsic salt retention ability
- Salt retention via aldosterone
- Vasoconstriction
- SNS activation
Hypertension:
Reduce TPR, less fluid retention and hence less venous return
Heart failure:
reduced TPR=lower afterload
reduced venous return= less preload
What law links venous return to contractility?
Starling’s Law
What is diabetic nephropathy caused by?
It is due to significant damage to the kidney glomerulus because of toxic products building up at the glomerulus
NOTE: hyperglycaemia increases the risk of exposure to oxygen free radicals
Why are ACE inhibitors used in diabetic nephropathy?
ACE inhibitors reduce the angiotensin II-mediated vasoconstriction of the efferent arteriole
This reduces the blood pressure at the glomerulus and hence reduces the accumulation of toxic products at the glomerulus
Give an example of an angiotensin receptor blocker.
Losartan
ARBs end in ‘sartan’
What is the most common side effect of ACE inhibitors?
COUGH
due to bradykinin build up
Which 2 group of patients do you have to be careful of when thinking of prescribing ARBs or ACEi ? Think of its potential side effects
- Hyperkalaemia (aldosterone causes increased potassium excretion). So NOT given to patients on K supplement or K sparing diuretics
- Patients with renal failure as a result of renal artery stenosis (stenosis reduces blood flowing into glomerulus, so low pressure and low GFR. A2 normally constricts efferent arteriole. If you stop this then the pressure is reduced further in the glomerulus)
Describe the excitation-contraction coupling of vascular smooth muscle cells.
Deplarisation causes the opening of voltage-gated calcium channels (VGCC)
This leads to calcium influx
The calcium then binds to calmodulin forming a Ca2+-CaM complex
This complex activates Myosin Light Chain Kinase (MLCK), and the MLCK-mediated phosphorylation leads to smooth muscle contraction
What type of calcium channel blocker is more selective for blood vessels? Give an example.
Dihydropyridines – nicardipine
(non rate limiting CCB)
dipine = dihyropyridines
Give 4 examples of non-rate slowing CCBs.
Nicardipine
Nitrendipine
Amlodipine
Nisoldipine
Which part of the calcium channel do the different CCBs bind to?
Dihydropyridines bind to the extracellularly component of the calcium channel
Diltiazem and verapamil binds to the intracellular component so for a CCB to have an effect on the heart it needs to be able to penetrate the membrane and act on the receptor inside the cell
Why are non-rate slowing CCBs preferred to rate-slowing CCBs in the treatment of hypertension and heart failure?
They have a more powerful effect on vascular smooth muscle. Targeting the TPR is more effective for treating HT.
nb non rate slowing CCBs (dihydropyridines) can cause reflex tachycardia and increased inotropy (contraction force)
What type of receptor is a beta adrenoceptor?
G-protein coupled receptor (Gs protein linked)
What are the effects of noradrenaline that cause an increase in blood pressure?
Increase in heart rate and cardiac contractility (leads to increase in CO) via beta-1 receptors in the heart
Stimulation of beta-1 receptors in the kidneys promotes renin release –> increase in angiotensin II
What is hypertension in younger patients normally caused by?
Increased sympathetic drive
Give an example of a cardio-selective beta-blocker.
Atenolol
What are mixed beta-alpha blockers? Give an example.
They are beta-1, beta-2 and alpha-1 blockers
Carvedilol
You get extra vasodilation due to alpha-1 blockade
Give an example of an alpha-1 blocker.
Prazosin
Give an example of a non-selective alpha blocker.
Phentolamine
Why is it important for alpha-1 blockers to be selective?
Alpha-2 receptors are the negative feedback receptors of the SNS
Blocking them will result in enhancement of sympathetic activity
What is step 1 in the NICE guidelines for treatment of hypertension?
< 55 years = ACEi + ARB
>55 years or Afro-Caribbean of any age = CCBs + thiazide-type diuretics
What is step 2?
ACEi or ARB
AND CCB or thiazide diuretic
What is step 3?
ACEi/ARB
CCB
Thiazide diuretic
What is step 4?
Further diuretic therapy (low-dose spironolactone)
Alpha or beta-blocker
What is spironolactone?
It is an aldosterone receptor antagonist
What is chronic heart failure?
Impaired cardiac function due to ischaemic heart disease, hypertension or cardiomyopathy that results in fluid retention, oedema and fatigue
Which drugs are normally used on patients with chronic heart failure?
ACEi
ARB
Beta-blockers
Spironolactone
