Drugs for the vasculature Flashcards
What is the main factor determining BP
Peripheral resistance mostly is the target for HTN
to reduce arteriolar contraction
Which vessels contribute to BP
What can sympathetic nerves release onto VSMC
Arterioles
Sympathetic nerves release noradrenaline, neuropeptide Y and ATP
What is the effect of contracting and relaxing vessels on BP
Contract reduces radius, increasing resistance, reducing flow…
What is vascular tone
Arteriolar S.M. normally displays a state of partial constriction
Why is HTN important
Single most important risk factor for stroke, causing about 50% of ischaemic strokes
What percentage of HF cases does HTN acount for
Accounts for ~25% of heart failure (HF) cases, this increases to ~70% in the elderly
What is HTN a risk factor for
myocardial infarction (MI) & chronic kidney disease (CKD)
What is the treatment for HTN
Combinations of
ACEi/ARB; CCB and thiazide like diurectic
Last stage is spironolactone or b/blocker or a blocker
note that ARB is angiotensin II receptor blocker WHEREAS
spironolactone (a K+ sparing diuretic) blocks the aldosterone receptor
What increases renin secretin
↓renal Na+ reabsorption (i.e. if sodium in the filtrate reaching the DCT is low)
↓ renal perfusion pressure
↑ sympathetic NS
Outline RAAS
Angiotensinogen –> Angiotensin 1 by renin
Angiotensin 1 –> angiotensin 2 by ACE
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What is the effect of Angiotentin 2
Vasoconstriction via AT1 receptor
Stimulates aldosterone release promotong sodium reabsorption
angiotensin II can also promote sodium reabsorption
acts on the brain to increase thirst
MAO of ACEi
Inhibit the somatic form of angiotensin converting enzyme (ACE)
Prevent the conversion of angiotensin I to angiotensin II by ACE
Use of ACEi
- hypertension
- heart failure
- post-myocardial infarction
- diabetic nephropathy
- progressive renal insufficiency (BUT NOT RENAL ARTERY STENOSIS!)
- patients at high risk of cardiovascular disease
ACE inhiitor names
end in -pril
How does ACEi work in HTN and HF
HTN: reduce vasoconstriction due to less AT1 activation (reduce TPR) and salt and water retnetion (reduce CO)
trying to reduce pressure in vasc.
HF: trying to reduce work for heart
reduce afterload due to vasodilation, reduce venous return (reduce congestion from right sided heart failure, and reduce stress on heart)
What is the effect of Angiotensin II binding to VSMC
ACTIVATES AT 1
activated receptor in turn couples to Gq/11 and thus activates phospholipase C. This increases IP3 which increases the cytosolic Ca2+ concentrations, which works with CaM to activate MLCK
Also links to Gi receptor, so inhibits AC, so there is less cAMP. cAMP inhibits MLCK so less of this will mean more contraction
ARB blocks this (indirectly reduces calcium concentration)
CCB directly reduce calcium entry
Effect of ARBs
name
Antagonists of type 1 (AT1) receptors for Ang II, preventing the renal and vascular actions of Ang II.
-artan
Use of ARB
hypertension, heart failure
2 actions of ACE
Breaks down bradykinin
Convert angiotensin 1 to angiotensin 2
Side effects of ACEi/ARB
Generally well tolerated (particularly ARB)
Cough (ACEI)
Both:
Hypotension
Hyperkalaemia (care with K supplements or K sparing diuretics)
Renal failure in patients with renal artery stenosis (both)
Why do ACEi cause cough
Increasing levels of bradykinin
What is the effect of Angiotensin II on VSMC
It inreases Ca2+ into the cell, so ARB blocks this
Angiotensin II is coupled to both a Gq protein, which acts via IP3 to increase intracellular [Ca2+], and also a Gi protein, which reduces cAMP mediated inhibition of MLCK. The increased [Ca2+] associated with calmodulin, as a Ca2+-CaM complex, to activate MLCK.
Why does do ARB/ACEi cuase hyperkalaemia.
Care mist be taken when prescribing ACEi or ARBs with which other drugs
They reduce aldosterone release….
Thus less secretion of insertion of Na+/K+ATPase into basolateral membrane AND Na+ channels for influx into apical membrane AND K+ channels for efflux across apical membrane….
thus fewer of these channels in these drugs
so less Na+ in the cell, so less movement of K+ into the cell too
and less mvoement of K+ out of the cell
Thus you can’t excrete potassium
TAKE CARE WITH POTASSIUM SPARING DIURECTICS
Why sholdn’t ARB/ACEi be used in renal artery stenosis
In renal artery stenosis, poor blood flow into the aferent arteriole so there is poor GFR.
In response, increases renin etc. which then causes Angiotensin II to come and constrict the efferent arteriole to increase pressure in teh glomerulus
Giving ARB/ACEi will then reduce this efferent arteriole vasoconstriction….. this will then lower the GFR and allow renal failure to continue
